Pål Andre Holme

• Astermark, Jan; Ranta, Susanna; Myrin-Westesson, Linda; Hoffmann, Marianne; Quere, Sandrine & Sanchez, Amparo Yovanna Castro [Show all 10 contributors for this article] (2025). Health-Related Quality of Life, Physical Activity and Joint Health in People With Severe Haemophilia A Receiving Emicizumab: Results From the Phase IV HemiNorth 2 Study. Haemophilia. ISSN 1351-8216. 31(6), p. 1271–1282. doi: 10.1111/hae.70121. Full text in Research Archive
• Tsykunova, Galina; Holme, Pål Andre; Tran, Hoa Thi Tuyet; Frederiksen, Henrik; Tjønnfjord, Eirik & Munthe, Ludvig Andre [Show all 16 contributors for this article] (2025). Safety and Efficacy of Daratumumab in Immune Thrombocytopenia. Blood Advances. ISSN 2473-9529. 10(1), p. 143–154. doi: 10.1182/bloodadvances.2025017279. Full text in Research Archive Show summary

  Resistance to B-cell targeted therapies in immune thrombocytopenia (ITP) has been linked to persistence of autoantibody-producing CD38-positive long-lived plasma cells. CD38 antibody daratumumab has been proposed as a potential therapy for ITP. This multicenter, open-label, phase II study evaluated safety and efficacy of daratumumab in 21 previously treated ITP patients. Following a safety run-in, two dosing cohorts were included, receiving eight and ten subcutaneous injections of 1800 mg daratumumab weekly, respectively. Primary endpoints were safety and response (two consecutive platelet counts ≥50x109/L at week 12 for the safety run-in/Cohort 1, and at week 16 for Cohort 2). At baseline, median platelet count was 17x109/L, median number of prior therapies was four. Most treatment-emergent adverse events were transient grade 1-2, most commonly infections (38%).Two patients (4.7%) experienced grade 3 adverse events, one infusion-related reaction, and one SARS-CoV-2 infection with acute renal failure. Ten patients (48%) met the primary efficacy endpoint. Sustained response (two consecutive platelet counts ≥50x109/L at week 24) was achieved in eight patients (38%). Two patients relapsed after week 24. There was no difference in response or relapse rates between cohorts. Patient-reported quality of life measured by SF-36 improved in responding patients. Daratumumab decreased immunoglobulin levels in all patients, and substantially reduced CD38+ cells in peripheral blood and bone marrow. There was no significant difference in anti-platelet antibodies between responders and non-responders. This study confirms CD38 as an important target in ITP. NCT04703621; EudraCT 2019-004683-22.

• Atar, Dan; Vandenbriele, Christophe; Agewall, Stefan; Gigante, Bruna; Goette, Andreas & Gorog, Diana A. [Show all 13 contributors for this article] (2025). Management of patients with congenital bleeding disorders and cardiac indications for antithrombotic therapy. European Heart Journal (EHJ) - Cardiovascular Pharmacotherapy. ISSN 2055-6837. 11(3), p. 275–289. doi: 10.1093/ehjcvp/pvaf006. Full text in Research Archive Show summary

  Aims Cardiologists have only had rare exposure to haemophilia patients and patients with other congenital bleeding disorders during the last decades, as these patients had a reduced life expectancy and were partly protected against thrombosis due to the bleeding disorder. With the availability of effective and safe replacement therapies of clotting factors, the average life expectancy in these populations of patients has significantly increased, and thrombotic complications may occur. Methods and results The European Society of Cardiology Working Group on Thrombosis has taken the initiative to broaden the spectrum of these haematological conditions to include patients with a larger variety of congenital bleeding disorders with concomitant cardiac conditions as compared to a recent position paper by the European Haematology Association in collaboration with other societies (ISTH, European Association for Haemophilia and Allied Disorders, and ESO). Management of antithrombotic therapy or thromboprophylaxis in these individuals is challenging due to the wide phenotypes encompassed by congenital bleeding disorders. These include abnormalities in both primary haemostasis (involving von Willebrand factor and platelet function) and secondary haemostasis (related to coagulation factors and fibrinogen). Bleeding disorders range from mild to very severe. Based on existing literature, we provide clinical consensus statements on optimizing antithrombotic treatment strategies for patients with congenital bleeding disorders and highlight the current gaps in knowledge in these complex clinical settings. Conclusion Of importance, an individualized approach to antithrombotic therapy is warranted to properly balance the two risks of thrombosis and bleeding. Adoption of the safest interventional techniques, reduction of the intensity and/or duration of antithrombotic therapies, and attention to the safe levels of clotting factors is generally advised.

• Reding, Mark T.; Lalezari, Shadan; Kenet, Gili; Minno, Giovanni Di; Ducore, Jonathan & Solms, Alexander [Show all 12 contributors for this article] (2024). Damoctocog Alfa Pegol, a PEGylated B-domain Deleted Recombinant Extended Half-life Factor VIII for the Treatment of Hemophilia A: A Product Review. Drugs in R&D. ISSN 1174-5886. doi: 10.1007/s40268-024-00481-7. Full text in Research Archive Show summary

  Damoctocog alfa pegol (BAY 94-9027, Jivi®), is a site-specifically PEGylated, extended half-life recombinant factor VIII (FVIII) that is approved in several European and non-European countries for on-demand treatment and prophylaxis of bleeding in previously treated patients aged ≥ 12 years with hemophilia A. Reliable measurements can be obtained using most one-stage and chromogenic FVIII assays over a wide concentration range. The efficacy, safety and pharmacokinetics (PK) of damoctocog alfa pegol have been studied extensively in the PROTECT VIII clinical trials, and its long-term safety and effectiveness profile is continuing to build through observational and interventional real-world studies. The PK of damoctocog alfa pegol was shown to be improved as compared with that of sucrose-formulated rFVIII (rFVIII-FS, Kogenate®), and was also demonstrated to be non-inferior to and, for some variables, more favorable than rFVIII-Fc fusion protein, efmoroctocog alfa (Elocta®; NCT03364998), rurioctocog alfa pegol (BAX 855, Adynovate®/Adynovi®; NCT04015492), and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, Advate®; NCT02483208). Damoctocog alfa pegol was generally well tolerated and none of the patients in any of the clinical trials, including the PROTECT VIII clinical program, HEM-POWR, or ongoing single-center studies, developed FVIII inhibitors. Efficacy for perioperative hemostasis has been demonstrated. Low bleeding rates were achieved across the studies, with twice weekly, every 5-day and every 7-day prophylaxis offering patients ≥ 12 years and their clinicians the chance to tailor treatment to individual needs and lifestyles, while maintaining long-term protection from bleeds and their consequences.

• Holme, Pål Andre; Poulsen, Lone Hvitfeldt; Tueckmantel, Claudia; Enriquez, Monika Maas; Román, María Teresa Alvarez & Cristofaro, Raimondo De (2024). Safety and efficacy of damoctocog alfa pegol prophylaxis in patients with severe haemophilia A: Results of an interventional, post-marketing study. Haemophilia. ISSN 1351-8216. doi: 10.1111/hae.14930. Full text in Research Archive Show summary

  Introduction Damoctocog alfa pegol (BAY 94-9027, Jivi®) is an approved extended half-life factor VIII (FVIII) for treatment of previously treated patients with haemophilia A aged ≥12 years. We report the final results of an interventional, post-marketing study of damoctocog alfa pegol prophylaxis in patients with severe haemophilia A. Methods In this open-label, interventional, post-marketing, phase 4 trial (NCT04085458), previously FVIII-treated patients with severe haemophilia A aged ≥18 years received damoctocog alfa pegol for ≥100 exposure days (EDs). Patients initially received 45 IU/kg every 5 days (recommended) or 40 IU/kg twice-weekly. At Visit 3, patients’ doses could be increased, or treatment frequency adapted. The primary endpoint was FVIII inhibitor development (titre ≥.6 Bethesda units). Secondary endpoints included anti-polyethylene glycol (PEG) antibody development, treatment-emergent adverse events (AEs) and annualized bleeding rate (ABR). Results Overall, 36 patients were enrolled; 32 patients received treatment, of whom, 27 completed the study. No patients developed FVIII inhibitors; three tested transiently positive for low-titre anti-PEG antibodies without clinical relevance. Three patients reported study-drug-related AEs of mild or moderate intensity. Two patients discontinued the study due to AEs. No deaths occurred. Most patients (70%) were treated with E5D/E7D regimens. The median (Q1;Q3) total ABR (N = 30) was 3.0 (.0;9.0) pre-study and 1.8 (.7;5.9) during the study. Conclusion Damoctocog alfa pegol individualized prophylaxis regimens were well-tolerated with no immunogenicity concerns. ABRs improved following the switch from pre-study prophylaxis to damoctocog alfa pegol prophylaxis. These results support the favourable safety and efficacy profile of damoctocog alfa pegol prophylaxis.

• Reding, Mark T.; Simpson, Mindy; Ducore, Jonathan; Holme, Pål Andre; Enriquez, Monika Maas & Mancuso, Maria Elisa (2024). Long-Term Efficacy and Safety of Damoctocog Alfa Pegol Prophylaxis in Patients with Haemophilia A Aged 12-<18 Years at Enrolment into PROTECT VIII. Acta Haematologica. ISSN 0001-5792. doi: 10.1159/000538702. Full text in Research Archive Show summary

  Introduction: The phase 2/3 PROTECT VIII study demonstrated long-term efficacy and safety of damoctocog alfa pegol (BAY 94-9027; Jivi®), a B-domain-deleted recombinant factor VIII (FVIII), site-specifically PEGylated to improve its pharmacokinetic profile. We report a post hoc assessment of bleeding and safety outcomes in the subgroup of patients, aged 12–<18 years at enrolment. Method: PROTECT VIII was a multicentre, open-label study of previously treated males aged 12–65 years with severe haemophilia A (FVIII <1%). Twelve patients were included in this analysis. All received damoctocog alfa pegol prophylaxis for the total time in study (median [range] time in study 4.0 [1.3–6.2] years). Results: Overall median (Q1; Q3) total and joint annualised bleeding rates were 1.8 (0.4; 5.1) and 0.7 (0.2; 1.8), respectively, for the entire study. During the last 6 months of treatment, eight (66.7%) and ten (83.3%) out of 12 patients experienced zero total and joint bleeds, respectively. No patient developed FVIII inhibitors. No deaths or thrombotic events were reported. Conclusion: Efficacy and safety of damoctocog alfa pegol were confirmed in adolescent patients with haemophilia A, with data for up to 6 years supporting its use as a long-term treatment option in this group as they transition into adulthood.

• Oldenburg, Johannes; Hay, Charles; Peyvandi, Flora; Tagliaferri, Annarita; Holme, Pål Andre & Álvarez-Román, María Teresa [Show all 10 contributors for this article] (2024). Superior Prophylactic Effectiveness of a Recombinant FVIIIFc Over Standard Half-Life FVIII in Hemophilia A: A-SURE Study. European Journal of Haematology. ISSN 0902-4441. doi: 10.1111/ejh.14309. Full text in Research Archive Show summary

  Objectives The 24-month, prospective, non-interventional, European multicenter A-SURE study evaluated the real-world effectiveness of prophylaxis using an extended half-life recombinant factor VIII (FVIII) Fc fusion protein, efmoroctocog alfa (hereinafter rFVIIIFc), compared with prophylaxis using standard half-life (SHL) FVIII products in patients with hemophilia A. Methods Primary endpoints were annualized bleeding rate (ABR), annualized injection frequency, and annualized factor consumption. A comparative study design unique for an observational hemophilia study was implemented to reduce potential confounding in effectiveness estimates, wherein each patient prescribed rFVIIIFc was matched with one receiving SHL FVIII. Propensity scores were used for adjustment in statistical analyses. Results Outcomes for all primary endpoints were significantly better in the rFVIIIFc group (n = 184) compared with the SHL FVIII group (n = 170): mean ABR 1.5 versus 2.3 (difference of −0.8; p = 0.0147); mean annualized injection frequency 114.4 versus 169.2 (difference of −54.8; p < 0.0001); and mean annualized factor consumption 243 024.2 versus 288 718.6 International Units (difference of 45 694.5; p = 0.0003). rFVIIIFc was well tolerated, with no inhibitor development. Conclusions rFVIIIFc has superior prophylactic effectiveness versus SHL FVIII, providing higher bleed protection with fewer injections and lower factor consumption.

• Qvigstad, Christian; Sørensen, Lars A Q; Tjønnfjord, Geir Erland; Holme, Pål Andre; Pabinger, Ingrid & Hermans, Cedric [Show all 27 contributors for this article] (2024). The association between unemployment and treatment among adults with hemophilia. Research and Practice in Thrombosis and Haemostasis (RPTH). 8(5). doi: 10.1016/j.rpth.2024.102514. Full text in Research Archive Show summary

  Background People with hemophilia often experience pain and suffer from comorbidities related to their bleeding disorder. Consequently, unemployment due to disability is prevalent among people with hemophilia. Objectives To explore associations between unemployment due to disability and treatment while adjusting for known risk factors for unemployment. Methods Collecting data from 20 hemophilia centers from 15 European countries, the Age-related DeVelopments ANd ComorbiditiEs (ADVANCE) in hemophilia study recruited 785 participants aged 40 years and over with hemophilia A or B. A comprehensive electronic case report form included items related to patient characteristics, demographic information, past and current treatment regimens, and medical history, including a lifelong history of comorbidities. Baseline data from the ADVANCE study was analyzed using descriptive statistics and logistic regression models. Results Employment status was available for 756 of 785 participants aged 40 to 88 years (median, 53 years). We used regression analysis to compare people with hemophilia who were fully employed with those who were unemployed due to disability. This analysis included 424 participants. Using multivariable logistic regression, we found that age (odds ratio [OR], 1.07; P < .01), severe hemophilia (OR, 10.81; P < .01), current smoker (OR, 2.53; P < .01), and psychiatric disorder (OR, 4.18; P = .02) were associated with increased odds of unemployment due to disability. In contrast, prophylactic treatment (OR, 0.44; P = .01) was associated with decreased odds. Conclusion Our analysis suggests that by maintaining factor levels above a critical threshold (3%-5%), prophylactic treatment for people with hemophilia could help avoid unemployment due to disability. While prophylaxis is more costly and can be burdensome, the benefits to material well-being and quality of life could be substantial.

• Måseide, Ragnhild Johanne; Berntorp, Erik; Astermark, Jan; Olsson, Anna; Bruzelius, Maria & Frisk, Tony [Show all 11 contributors for this article] (2024). Nonneutralizing antibodies in Nordic persons with moderate hemophilia A and B (the MoHem study). Research and Practice in Thrombosis and Haemostasis (RPTH). 8(8). doi: 10.1016/j.rpth.2024.102611. Full text in Research Archive Show summary

  Background The impact of nonneutralizing antibodies (NNAs) in moderate hemophilia is elusive. Objectives To explore the presence of NNAs in Nordic persons with moderate hemophilia A (MHA) and B (MHB) in relation to treatment modality, clinical outcome, history of inhibitor, and the corresponding factor VIII (FVIII)/factor IX (FIX) gene mutation. Methods A cross-sectional multicenter study covering persons with MHA and MHB in Sweden, Finland, and Norway. Inhibitors were analyzed with the Bethesda assay, and NNAs were detected by enzyme-linked immunosorbent assay. Results Plasma samples from 137 MoHem study participants (median age 29 years; Q1-Q3, 15-54) were analyzed. NNAs were present in 11 of 82 (13%) of people with MHA and 7 of 55 (13%) of those with MHB irrespective of prophylactic or on-demand treatment, most frequently after 150 exposure days (EDs). Three NNA positive patients had a history of high-titer inhibitor, but current analyses were negative (<0.6 BU/mL). Baseline FVIII/FIX activity was similar among NNA positive and negative patients. Current bleeding rates were low, but patients with NNAs captured a higher Hemophilia Joint Health Score (7 [median]; Q1-Q3, 3-20 vs. 4; 1-9) (P = .02) and had more frequently undergone arthroplasty or arthrodesis (5 [33%] vs. 15 [13%]) (P = .03). Conclusion NNAs were detected in 13% of Nordic persons with MHA and MHB, most frequently after 150 EDs. Patients with NNAs had more severe hemophilic arthropathy than patients without NNAs. The relationship between NNAs and clinical outcome in hemophilia should be further explored in a large cohort including pharmacokinetics and longitudinal observations with repeated blood sampling.

• Holme, Pål Andre; Blatný, Jan; Chowdary, Pratima; Lassila, Riitta; O'Connell, Niamh & Hermans, Cédric [Show all 10 contributors for this article] (2024). Moving towards Normalization of haemostasis and health equity: Evolving treatment goals for haemophilia A. Haemophilia. ISSN 1351-8216. doi: 10.1111/hae.15031. Full text in Research Archive Show summary

  Background Treatment options for people with haemophilia are evolving at a rapid pace and a range of prophylactic treatment options using various technologies are currently available, each with their own distinct safety and efficacy profile. Treatment goals The access to replacement therapy and prophylaxis has driven a dramatic reduction in mortality and resultant increase in life expectancy. Beyond this, the abolition of bleeds and preservation of joint health represent the expected, but rarely attained, goals of haemophilia treatment and care. These outcomes also do not address the complexity of health-related quality of life impacted by haemophilia and its treatment. Conclusion Capitalizing on the major potential of therapeutic innovations, ‘Normalization’ of haemostasis, as a concept, should include the aspiration of enabling individuals to live as normal a life as possible, free from haemophilia-imposed limitations. To achieve this—being supported by the data reviewed in this manuscript—the concept of haemostatic and life Normalization needs to be explored and debated within the wider multidisciplinary teams and haemophilia community.

• Måseide, Ragnhild Johanne; Berntorp, Erik; Astermark, Jan; Olsson, Anna; Bruzelius, Maria & Frisk, Tony [Show all 10 contributors for this article] (2023). Health-related quality of life and physical activity in Nordic patients with moderate haemophilia A and B (the MoHem study). Haemophilia. ISSN 1351-8216. doi: 10.1111/hae.14899. Full text in Research Archive
• Arvanitakis, Alexandros; Holme, Pål Andre; Berntorp, Erik & Astermark, Jan (2023). Impact of timing of prophylaxis commencement, F8 genotype and age on factor consumption and health-related quality of life in patients with severe haemophilia A. Haemophilia. ISSN 1351-8216. doi: 10.1111/hae.14806. Full text in Research Archive Show summary

  Abstract Introduction The timing of prophylaxis and F8 genotype can impact treatment outcomes in adults with severe haemophilia A (HA). Aim To investigate how F8 genotype, timing, and type of prophylaxis influence arthropathy, bleeding rates, factor consumption and health‐related quality of life (HRQoL). Methods Thirty‐eight patients with severe HA were enrolled. Bleeding events were recorded retrospectively during median 12.5 months. F8 gene variants were classified as null or non‐null. Joint health and HRQoL were assessed with HJHS and EQ‐5D‐5L, respectively. Results The median age at prophylaxis start was 1.25 years in the primary prophylaxis group ( N  = 15, median age 26 years) and 31.5 years in the secondary group ( N  = 22, 45 years), respectively. There were significant differences in the medians of HJHS (4 vs. 20, p  &lt; .001), EQ‐5D‐5L index (0.9647 vs. 0.904, p  = .022), EQ VAS (87 vs. 75, p  = .01) and FVIII consumption (3883 vs. 2737 IU/kg/year, p  = .02), between the primary and secondary groups, respectively. Median annualized bleeding rate (ABR) was 0 for both groups. Twenty‐five null and thirteen non‐null F8 gene variants were identified. In the secondary prophylaxis group, lower median FVIII consumption (1926 vs. 3370 IU/kg/year) was shown for non‐null compared to null variants, respectively, with similar ABR and HJHS. Conclusion Delayed prophylaxis start with intermediate dose intensity prevents bleeds but at a cost of more arthropathy and reduced HRQoL, compared to higher intensity primary prophylaxis. Non‐null F8 genotype may allow lower factor consumption with similar HJHS and bleeding rates, compared to null genotype.

• Warlo, Ellen Mathea Kirsch; Kalstad, Are; Myhre, Peder Langeland; Solheim, Svein; Arnesen, Harald & Tveit, Arnljot [Show all 9 contributors for this article] (2023). von Willebrand factor, ADAMTS-13, and thrombospondin 1 in relation to clinical outcomes in elderly patients with a recent myocardial infarction. Research and Practice in Thrombosis and Haemostasis (RPTH). 7(4). doi: 10.1016/j.rpth.2023.100164. Full text in Research Archive Show summary

  Background von Willebrand factor (VWF) multimers are cleaved by A disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS-13) into less active fragments. Thrombospondin 1 (TSP-1) competes with VWF’s cleavage site, protecting it from degradation. Low ADAMTS-13 and high VWF have been associated with cardiovascular disease and atrial fibrillation (AF). Objectives We aimed to investigate whether VWF, ADAMTS-13, and TSP-1 are associated with clinical outcome. Methods Elderly patients with a recent myocardial infarction (MI) (n = 1027) were followed for 2 years. Blood was collected 2 to 8 weeks after the MI for ADAMTS-13, VWF, and TSP-1 measures. The primary endpoints (major adverse cardiovascular events; n = 210) included the first event of MI, stroke, heart failure hospitalization, coronary revascularization, and all-cause death. Total mortality was also registered (n = 56). The secondary endpoint was new-onset AF (n = 43). Results Concentrations of VWF, ADAMTS-13, and TSP-1 did not intercorrelate. The risk of major adverse cardiovascular events was altered in patients with VWF ≥ median (hazard ratio [HR], 1.4; 95% CI, 1.0-1.8; P = .03) and ADAMTS-13 ≥ median (HR, 0.7; 95% CI, 0.5-0.9; P = .02); however, it was not significant in adjusted models. VWF and ADAMTS-13 were significantly associated with total mortality, with a HR of 2.7 (95% CI, 1.6-4.6; P < .001) for VWF (Q4 vs. Q1-Q3) and HR of 0.3 (95% CI, 0.2-0.5; P < .001) for ADAMTS-13 (Q2-4 vs. Q1). The associations persisted in multivariable analysis, but the significance disappeared for VWF after correcting for high-sensitivity C-reactive protein. The risk of new-onset AF was lower in patients with VWF ≥ median (HR, 0.5; 95% CI, 0.3-1.0; P = .04]), and this was still significant after adjustments. Conclusion Although low ADAMTS-13 predicted death, the cardiovascular risk associated with VWF and ADAMTS-13 was weaker than previously reported. Low VWF is associated with new-onset AF and needs further research.

• Reding, Mark T.; Pabinger, Ingrid; Holme, Pål Andre; Enriquez, Monika Maas; Mancuso, Maria Elisa & Lalezari, Shadan [Show all 10 contributors for this article] (2023). Efficacy and safety of damoctocog alfa pegol prophylaxis in patients ⩾40 years with severe haemophilia A and comorbidities: post hoc analysis from the PROTECT VIII study. Therapeutic Advances in Hematology (TAH). ISSN 2040-6207. 14. doi: 10.1177/20406207231166779. Full text in Research Archive Show summary

  Background: Advances in treatment have enabled patients with haemophilia A to live longer and therefore may be subjected to comorbidities associated with ageing, in addition to disease-associated morbidities. There have been few reports to date on efficacy and safety of treatment specifically in patients with severe haemophilia A and comorbidities. Objective: To explore the efficacy and safety of damoctocog alfa pegol prophylaxis in patients with severe haemophilia A aged ⩾40 years with comorbidities of interest. Design: A post hoc analysis of data from the phase 2/3 PROTECT VIII study and its extension. Methods: Bleeding and safety outcomes were analysed in a subgroup of patients aged ⩾40 years with ⩾1 comorbidity receiving damoctocog alfa pegol (BAY 94-9027; Jivi ® ) prophylaxis. Results: Thirty-four patients with severe haemophilia A were included in this analysis, with a mean age of 49.4 years at time of enrolment. The most prevalent comorbidities were hepatitis C ( n = 33; chronic, n = 23), hepatitis B ( n = 8) and hypertension ( n = 11). Four patients had human immunodeficiency virus. All received damoctocog alfa pegol prophylaxis for the entire study [median (range) time in study = 3.9 (1.0–6.9) years]. During the main study and extension, median total annualised bleeding rates (ABRs) (Q1; Q3) were 2.1 (0.0; 5.8) and 2.2 (0.6; 6.0), respectively; median joint ABRs were 1.9 (0.0; 4.4) and 1.6 (0.0; 4.0), respectively. Mean adherence with prophylaxis schedule was greater than 95% throughout the study. No deaths or thrombotic events were reported. Conclusion: Efficacy, safety and adherence of damoctocog alfa pegol were confirmed in patients aged ⩾40 years with haemophilia A and one or more comorbidities, with data for up to 7 years supporting its use as a long-term treatment option in this group. Plain language summary Advances in treatment mean that people with haemophilia A are now living longer and, as a result, may have additional medical conditions that occur with ageing. We aimed to investigate the efficacy and safety of the long-acting replacement factor VIII damoctocog alfa pegol in people with severe haemophilia A who had additional medical conditions. To do this, we investigated the recorded information about patients aged 40 years of age or older who had been treated with damoctocog alfa pegol in a previously completed clinical trial. We found that the treatment was well-tolerated; no deaths or thrombotic events (undesirable clotting events) were reported. Treatment was efficacious in reducing bleeding in this group of patients. The findings support the use of damoctocog alfa pegol as a long-term treatment for older patients with haemophilia A and coexisting conditions.

• Kihlberg, Kristina; Baghaei, Fariba; Bruzelius, Maria; Funding, Eva; Holme, Pål Andre & Lassila, Riitta [Show all 11 contributors for this article] (2023). No difference in quality of life between persons with severe haemophilia A and B. Haemophilia. ISSN 1351-8216. doi: 10.1111/hae.14759. Full text in Research Archive Show summary

  Abstract Introduction Good health‐related quality of life (HRQoL) is an important goal in the treatment of persons with haemophilia B (PwHB). Studies focusing on this population are limited, however, and data are insufficient. Aim To assess the HRQoL in PwHB and to compare this to data on persons with haemophilia A (PwHA), as well as to evaluate the impact of joint health on HRQoL and to identify areas of insufficient care. Methods The B‐NORD study enrolled persons with severe haemophilia B and matched controls with haemophilia A. HRQoL was assessed using the EQ‐5D‐3L questionnaire and joint health using Haemophilia Joint Health Score 2.1 (HJHS). Results The EQ‐5D‐3L was completed by 63 PwHB and 63 PwHA. Mobility problems were reported by 46% of PwHB and 44% of PwHA, pain/discomfort by 62% and 56%, and anxiety/depression by 33% and 17%, respectively. No significant difference was observed between PwHA and PwHB in EQ‐5D profiles, level sum score, EQ‐5D index (PwHB mean .80, PwHA mean .83, p  = .24), or EQ VAS score (PwHB: mean 70, PwHA: mean 77, p  = .061). Linear regression adjusted for age demonstrated that an increase in HJHS score was associated with a significant decrease in both EQ‐5D index (B ‐.003, R 2 .22) and EQ VAS score (B ‐.37, R 2 .17). Conclusion Despite the majority of patients being treated with prophylaxis, impaired HRQoL was reported in both PwHB and PwHA. No differences in HRQoL were found between the two groups. Impaired joint health had a significant negative impact on HRQoL.

• Jørgensen, Ole Jakob; Steineger, Johan Edvard; Hillarp, Andreas; Wåland, Erik Pareli; Holme, Pål Andre & Heimdal, Ketil Riddervold [Show all 7 contributors for this article] (2023). Elevated FVIII levels in hereditary hemorrhagic telangiectasia: Implications for clinical management. Laryngoscope Investigative Otolaryngology (LIO). 9(1). doi: 10.1002/lio2.1196. Full text in Research Archive Show summary

  Objectives: The objective of this study was twofold: to determine the prevalence of arterial and venous thromboembolic events in the Norwegian Hereditary Hemor- rhagic Telangiectasia (HHT) population, and to explore potential factors linked to such events, with particular emphasis on FVIII. Methods: Patients with an HHT diagnosis attending the Otorhinolaryngology Department at Oslo University Hospital—Rikshospitalet were included consecutively between April 2021 and November 2022. We recorded the participants' medical his- tory with an emphasis on thromboembolic events. Measurements of blood constitu- ents, including FVIII, FIX, vWF, hemoglobin, iron, ferritin, and CRP were performed. Results: One hundred and thirty-four patients were included in the study. The total prevalence of thromboembolic events among the participants was 23.1%. FVIII levels were high (>150 IU/dL) in the majority of HHT patients (n = 84) (68.3%) and were significantly associated with thromboembolic events (p < .001), as was age. Of the patients with high FVIII levels, 28 (33%) had experienced a thromboembolic event. Furthermore, FVIII levels were measured consecutively in 51 patients and were found to fluctuate above or below 150 IU/dL in 25% of these cases. Conclusion: Thromboembolic events are highly prevalent in the Norwegian HHT popula- tion and are significantly associated with FVIII levels. FVIII levels can fluctuate, and measure- ments should be repeated in HHT patients to assess the risk of thromboembolic events. Level of Evidence: 4.

• Astermark, Jan; Baghaei, Fariba; Strandberg, Karin; Toplican, Petra Gabric; Birkedal, Maj Friberg & Grahn, Emma Engman [Show all 12 contributors for this article] (2023). Infrastructural considerations of implementing gene therapy for hemophilia in the Nordic context. Therapeutic Advances in Hematology (TAH). ISSN 2040-6207. 14. doi: 10.1177/20406207231202306. Full text in Research Archive Show summary

  Background: Despite improvements in hemophilia care, challenges remain, including treatment burden and impaired quality of life. Gene therapy may overcome these. However, its introduction presents a challenge. Objectives: To outline a function-based gene therapy working model describing critical milestones associated with gene therapy handling, administration, and follow-up to facilitate and implement an effective infrastructure for gene therapy introduction. Design: Literature review and consensus discussion among Hemophilia Comprehensive Care centers (HCCCs) in the Nordic region. Methods: Representatives from six HCCCs sought to pinpoint milestones and key stakeholders for site readiness at the pre-, peri-, and post-infusion stages, including authority and genetically modified organism (GMO) product requirements, awareness, medical eligibility, logistics and product handling for infusion, laboratory monitoring, and follow-up. Results: A gene therapy transit map was developed with key stakeholders identified. The approach to prepare the vector will differ between the Nordic centers, but the contracted pharmacy unit will be a key stakeholder. Therefore, a pharmacy checklist for the implementation of gene therapy was developed. For the future, Advanced Therapy Medicinal Product centers will also be implemented. Patients’ expectations, commitments, and concerns need to be addressed repeatedly and education of patients and the expanded health-care professionals team will be the key to successful and optimal clinical management. Eligibility testing according to the product’s summary of product characteristics and frequent follow-up and monitoring post-infusion according to the World Federation of Hemophilia chart will be crucial. Conclusion: The approach to deliver gene therapy in the Nordic region will differ partly between the hemophilia centers, but the defined road map with checklists for the implementation of this advanced therapy will be applicable to all. The map may also serve as a platform for the use of future GMO product options both within and outside the area of hemophilia.

• Matlary, Ruth Elise Dybvik; Grydeland, May; Glosli, Heidi; Rüegg, Corina Silvia & Holme, Pål Andre (2023). Factors associated with physical activity in young people with haemophilia A on prophylaxis. Haemophilia. ISSN 1351-8216. 29(3), p. 900–909. doi: 10.1111/hae.14776. Full text in Research Archive Show summary

  Introduction: Physical activity (PA) is influenced by numerous factors, and the literature describing why people with haemophilia (PWH) are physically active or not is inconclusive. Aims: To investigate factors associated with PA (mean min/day in light (LPA), moderate (MPA), vigorous (VPA) and total PA, and proportion meeting World Health Organization (WHO) weekly moderate-to-vigorous (MVPA) recommendations) among young PWH A. Methods: Forty PWH A on prophylaxis from the HemFitbit study were included. PA was measured using Fitbit devices and participant characteristics were collected. Potential factors associated with PA were investigated by univariable linear regression models for continuous PA outcomes, and descriptively for teenagers meeting/not meeting WHO MVPA recommendations only, because all except one adult met PA recommendations. Results: Mean age (n = 40) was 19.5 years (SD 5.7). Annual bleeding rate was nearly zero and joint scores were low. We found an increase of four min/day in LPA (95% confidence interval (CI) 1–7) per year increase in age. Participants with ‘Haemophilia Early Arthropathy Detection with Ultrasound’ (HEAD-US) score ≥1 engaged in mean 14 min/day less MPA (95% CI −23.2 to −3.8), and 8 min less VPA (95% CI −15.0 to −0.4) compared to participants with HEAD-US score 0. Teenagers who met PA recommendations had slightly better joint status compared to those who did not meet recommendations. Conclusion: These findings indicate that presence of mild arthropathy does not affect LPA but may have a negative impact on PA of higher intensities. Early start of prophylaxis may be an important determinant of PA.

• Ettingshausen, Carmen Escuriola; Hermans, Cedric; Holme, Pål Andre; Cid, Ana R; Khair, Kate & Oldenburg, Johannes [Show all 10 contributors for this article] (2023). Real-world data in patients with congenital hemophilia and inhibitors: final data from the FEIBA Global Outcome (FEIBA GO) study. Therapeutic Advances in Hematology (TAH). ISSN 2040-6207. doi: 10.1177/20406207231184323. Full text in Research Archive Show summary

  Background: The bypassing agent, activated prothrombin complex concentrate [aPCC, FEIBA (factor VIII inhibitor bypass activity); Baxalta US Inc, a Takeda company, Lexington, MA, USA], is indicated for the treatment of bleeding episodes, perioperative management, and routine prophylaxis in patients with hemophilia A or B with inhibitors. In certain countries, aPCC is also indicated for the treatment of bleeding episodes and perioperative management in patients with acquired hemophilia A. Objectives: To describe long-term, real-world effectiveness, safety, and quality-of-life outcomes for patients with congenital hemophilia A or B and high-responding inhibitors receiving aPCC treatment in routine clinical practice. Design: FEIBA Global Outcome (FEIBA GO; EUPAS6691) was a prospective, observational study. Methods: Investigators determined the treatment regimen and clinical monitoring frequency. The planned patient observation period was 4 years. Data are from the safety analysis set (patients who received ⩾1 aPCC infusion). Results: Overall, 50 patients received either aPCC prophylaxis (n = 37) or on-demand therapy (n = 13) at screening [hemophilia A, n = 49; hemophilia B, n = 1; median (range) age, 16.5 [2–71] years). Mean ± standard deviation overall annualized bleeding rate and annualized joint bleeding rate for patients receiving prophylaxis were 6.82 ± 11.52 and 3.77 ± 5.71, respectively, and for patients receiving on-demand therapy were 10.94 ± 11.27 and 6.94 ± 7.39, respectively. Overall, 177 and 31 adverse events (AEs) were reported in 28 of 40 and 10 of 13 patients receiving prophylaxis or on-demand therapy, respectively. Two serious AEs were considered possibly related to aPCC: acute myocardial infarction due to coronary artery embolism in one patient receiving prophylaxis. No thrombotic microangiopathy was reported. No AEs resulted in death. Conclusion: This study demonstrated the long-term, real-world effectiveness and consistent safety profile of aPCC as on-demand therapy and prophylactic treatment in patients with hemophilia and high-responding inhibitors. Trial registry: FEIBA Global Outcome Study; EUPAS6691 https://www.encepp.eu/encepp/viewResource.htm?id=32774

• Matlary, Ruth Elise Dybvik; Grydeland, May; Glosli, Heidi; Rüegg, Corina Silvia & Holme, Pål Andre (2023). Physical activity in Norwegian teenagers and young adults with haemophilia A compared to general population peers. Haemophilia. ISSN 1351-8216. 29(2). doi: 10.1111/hae.14752. Full text in Research Archive Show summary

  Introduction: Limited evidence exists on objectively measured habitual physical activity (PA) of young people with haemophilia (PWH). Aims: To compare different outcomes of objective PA between young PWH A and controls using a commercial activity tracker. Methods: We enrolled males aged 13–30 years with moderate and severe haemophilia A, without inhibitors on regular prophylaxis. PA was measured with the activity tracker Fitbit Charge 3 for 12 weeks. Control group data was obtained from ≈60,000 Fitbit users, matched on age, sex and measurement period. PA variables [steps, intensities, volume, activity types, exercise frequencies and proportion meeting the World Health Organization's moderate-to-vigorous PA (MVPA) recommendations] were compared between groups descriptively and using Welch's two-sample t-test and two-sample test of proportions. Results: Forty PWH A were enrolled (mean age 19.5 years, 50% teenagers, 50% adults, three (7.5%) with moderate and 37 (92.5%) with severe haemophilia). Mean daily steps and minutes MVPA were similar between PWH and controls. PWH spent more time in light PA (mean 227 vs. 192 min/day, P = .033) and exercised more frequently (mean 5.6 vs. 3.9 exercise sessions/week, P < .001). Among teenagers, 40% PWH and 8% controls reached MVPA recommendations, compared to 95% and 100% among adults. The most common type of PA was walking. Conclusion: This cohort of young PWH A on prophylactic treatment had PA levels comparable to controls. Still, a considerable proportion of teenagers did not meet the recommended weekly volume of MVPA, and we encourage clinicians to have a particular focus on promoting PA for this group.

• Hillarp, Andreas; Holme, Pål Andre; Wåland, Erik Pareli; Skogstad, Marie Jeanette; Henriksson, Carola Elisabeth & Tjønnfjord, Geir Erland [Show all 7 contributors for this article] (2023). Report on 4 cases with decreased recovery due to neutralizing antibodies specific for PEGylated recombinant factor VIII. Journal of Thrombosis and Haemostasis. ISSN 1538-7933. 21(10), p. 2771–2775. doi: 10.1016/j.jtha.2023.07.019. Full text in Research Archive Show summary

  Background The immunogenicity, safety, and efficacy of recombinant factor VIII (rFVIII) have gained increasing interest after the introduction of extended half-life products with various modifications of the rFVIII molecule, such as covalent attachment of polyethylene glycol (PEG). Anti-PEG antibodies may be associated with a temporary reduction of FVIII recovery, but according to previous studies, they usually disappear after continuous dosing. Anti-PEG antibodies with an inhibitory capacity have never been demonstrated in patients treated with PEGylated rFVIII products. Objectives To routinely switch from standard half-life to PEGylated extended half-life rFVIII products in patients with hemophilia A. Methods From December 2022 until May 2023, 83 adults with hemophilia A attending Oslo Haemophilia Comprehensive Care Centre received a test dose with a PEGylated rFVIII product to switch treatment. Four patients presented with decreased recovery without the presence of an FVIII inhibitor. Accordingly, we performed a variant inhibitor test utilizing different rFVIII concentrates as a source of FVIII and enzyme-linked immunosorbent assay to search for anti-PEG antibodies. Results We found inhibitory anti-PEG/anti-PEGylated rFVIII antibodies in 4 patients (5%), both persistent and transient, explaining the impaired recovery. The patients had neutralizing anti-PEG antibodies prior to the first dosing of PEGylated rFVIII. We demonstrated neutralizing antibodies (mainly immunoglobuline G) specific for PEG and all 3 commercially available PEGylated rFVIII products. Conclusion The number of patients with inhibitory anti-PEG antibodies was significant, and the presence of inhibitors against PEGylated rFVIII emphasizes the importance of individual monitoring when switching FVIII concentrates to ensure safety and efficacy of the treatment.

• Arvanitakis, Alexandros; Holme, Pål Andre; Berntorp, Erik & Astermark, Jan (2022). Clinical outcome and adherence rate in Scandinavian patients with intermediate-intensity prophylaxis before and after the switch of standard half-life FVIII products to BAY 81–8973. Haemophilia. ISSN 1351-8216. 28(2), p. 223–229. doi: 10.1111/hae.14489. Full text in Research Archive Show summary

  Introduction Treatment optimization in haemophilia A can be achieved by choice of FVIII product and knowledge of pharmacokinetics (PK), phenotype and adherence. A favourable PK profile of BAY 81–8973 (octocog alfa) (Kovaltry, Bayer AB) compared to other standard half-life (SHL) FVIII products has been suggested. Aim To evaluate whether the switch to BAY 81–8973, using the same dosing schedule, impact factor consumption and bleed rates, taking arthropathy and adherence into account Methods Forty patients on prophylaxis with SHL (median age 40.5 years) attending the haemophilia treatment centres in Malmö and Oslo were enrolled. The annualised bleeding rate (ABR) and joint bleeding rate (AJBR) before and after the switch to BAY 81–8973 was calculated. PK analyses were performed with WAPPS-Hemo. Joint health status and treatment adherence were assessed. Results The median ABR and AJBR was 0 before and after the switch, at both centres. The median yearly factor consumption was 3,345 IU/Kg/year in the entire study group corresponding to intermediate-intensity prophylaxis in most patients and with significantly more used in Malmö (3,862 IU/Kg/year), compared to Oslo (2,337 IU/Kg/year) (P .006). There was no correlation between arthropathy and bleeding. The median BAY 81–8973 t½ was 15.15 h (range 7.5–29 h), with significant correlation to VWF levels, and 13.4 h after exclusion of VWF outliers. Adherence to treatment was 97%. Conclusions Concentrate switch, using mainly intermediate-intensity regimens with high adherence rates, preserves excellent prophylaxis outcome using standard half-life FVIII products, indicating the value of individualized prophylaxis and close follow-up.

• Ueland, Thor; Sørvoll, Ingvild Hausberg; Mørtberg, Trude Victoria; Dahl, Tuva Børresdatter; Lerum, Tøri Vigeland & Michelsen, Annika Elisabet [Show all 16 contributors for this article] (2022). Anti-PF4/polyanion antibodies in COVID-19 patients are associated with disease severity and pulmonary pathology. Platelets. ISSN 0953-7104. 33(4), p. 640–644. doi: 10.1080/09537104.2022.2042238. Full text in Research Archive Show summary

  Thromboembolic events are frequent and associated with poor outcome in severe COVID-19 disease. Anti-PF4/polyanion antibodies are related to heparin-induced thrombocytopenia (HIT) and thrombus formation, but data on these antibodies in unselected COVID-19 populations are scarce. We assessed the presence of anti-PF4/polyanion antibodies in prospectively collected serum from an unselected cohort of hospitalized COVID-19 patients and evaluated if elevated levels could give prognostic information on ICU admission and respiratory failure (RF), were associated with markers of inflammation, endothelial activation, platelet activation, coagulation and fibrosis and were associated with long-term pulmonary CT changes. Five out of 65 patients had anti-PF4/polyanion reactivity with OD ≥0.200. These patients had more severe disease as reflected by ICU admission without any evidence of HIT. They also had signs of enhanced inflammation and fibrinogenesis as reflected by elevated ferritin and osteopontin, respectively, during the first 10 days of hospitalization. Increased ferritin and osteopontin persisted in these patients at 3 months follow-up, concomitant with pulmonary CT pathology. Our finding shows that the presence of anti-PF4/polyanion antibodies in unselected hospitalized COVID−19 patients was not related to HIT, but was associated with disease severity, inflammation, and pulmonary pathology after 3 months.

• Schultz, Nina Haagenrud; Søraas, Arne Vasli; Sørvoll, Ingvild Hausberg; Akkøk, Cigdem Ahaein; Vetlesen, Annette & Jagjit, Bhamra Singh [Show all 13 contributors for this article] (2022). Vaccine associated benign headache and cutaneous hemorrhage after ChAdOx1 nCoV-19 vaccine: A cohort study. Journal of Stroke & Cerebrovascular Diseases. ISSN 1052-3057. 32(1). doi: 10.1016/j.jstrokecerebrovasdis.2022.106860. Full text in Research Archive Show summary

  Objectives Fatal complications have occurred after vaccination with ChAdOx1 nCoV-19, a vaccine against Covid-19. Vaccine-induced immune thrombotic thrombocytopenia (VITT) with severe outcome is characterized by venous thrombosis, predominantly in cerebral veins, thrombocytopenia and anti-PF4/polyanion antibodies. Prolonged headaches and cutaneous hemorrhages, frequently observed after the ChAdOx1 nCoV-19 vaccine, have therefore caused anxiety among vaccinees. We investigated whether these symptoms represent a mild form of VITT, with a potential for aggravation, e.g. in case of a second vaccination dose, or a different entity of vaccine complications<p> <p>Materials and methods We included previously healthy individuals who had a combination of headache and spontaneous severe cutaneous hemorrhages emerging after the 1st dose of the ChAdOx1 nCoV-19 vaccine. Twelve individuals were found to meet the inclusion criteria, and a phone interview, cerebral MRI, assessment of platelet counts, anti PF4/polyanion antibodies and other laboratory tests were performed. <p>Results None of the symptomatic vaccinees had cerebral vein thrombosis, hemorrhage or other pathology on MRI. Platelet counts were within normal range and no anti-PF4/polyanion platelet activating antibodies were found. Moreover, vasculitis markers, platelet activation markers and thrombin generation were normal. Furthermore, almost all symptoms resolved, and none had recurrence of symptoms after further vaccination with mRNA vaccines against Covid-19. <p>Conclusions The combination of headaches and subcutaneous hemorrhage did not represent VITT and no other specific coagulation disorder or intracranial pathology was found. However, symptoms initially mimicking VITT demand vigilance and low threshold for a clinical evaluation combined with platelet counts and D–dimer.

• Kihlberg, Kristina; Baghaei, Fariba; Bruzelius, Maria; Funding, Eva; Holme, Pål Andre & Lassila, Riitta [Show all 13 contributors for this article] (2022). Factor IX antibodies and tolerance in hemophilia B in the Nordic countries – The impact of F9 variants and complications. Thrombosis Research. ISSN 0049-3848. 217, p. 22–32. doi: 10.1016/j.thromres.2022.06.015. Full text in Research Archive Show summary

  Introduction The development of inhibitory antibodies (inhibitors) in persons with hemophilia B (PwHB) causes significant morbidity. Data on the impact of the F9 variant and immune tolerance induction (ITI) outcome are limited. The aim of this study was to investigate the presence of neutralizing and non-neutralizing antibodies (NNA) in severe hemophilia B (HB) and to evaluate ITI outcome and complications in relation to the pathogenic F9 variant. Materials and methods Persons with severe HB in the Nordic countries were enrolled and information on F9 variants, inhibitors, ITI and complications were collected. Analyses of anti-FIX antibodies with a fluorescence-immunoassay (xFLI) and an ELISA method were conducted. Results Seventy-nine PwHB were enrolled. Null variants were seen in 33 (42 %) PwHB and 12 (15 %) had a current or former inhibitor. Eleven (92 %) of the inhibitor patients had experienced allergic manifestations and three (25 %) nephrotic syndrome. Of 10 PwHB with at least one ITI attempt, eight (80 %) were considered tolerant at enrolment. Immunosuppression was included in seven of eight successful or partially successful attempts. Five PwHB had at least one ITI failure before a successful or partially successful ITI. No NNA could be identified. Conclusion A high proportion of severe F9 gene defects among persons with severe HB in the Nordic countries may explain the observed relatively high prevalence of inhibitors. ITI success was independent of the F9 variant and attained despite allergic manifestations and previous ITI failures. Inclusion of immunosuppression tentatively enhances the chances of ITI success. No NNA were observed.

• Hetland, Geir; Fagerhol, Magne Kristoffer; Wiedmann, Markus; Søraas, Arne Vasli; Mirlashari, Mohammad Reza & Nissen-Meyer, Lise Sofie Haug [Show all 9 contributors for this article] (2022). Elevated NETs and Calprotectin Levels after ChAdOx1 nCoV-19 Vaccination Correlate with the Severity of Side Effects. Vaccines. 10(8). doi: 10.3390/vaccines10081267. Full text in Research Archive Show summary

  ChAdOx1 nCoV-19 vaccination has been associated with the rare side effect; vaccine-induced immune thrombotic thrombocytopenia (VITT). The mechanism of thrombosis in VITT is associated with high levels of neutrophil extracellular traps (NETs). The present study examines whether key markers for NETosis, such as H3-NETs and calprotectin, as well as syndecan-1 for endotheliopathy, can be used as prognostic factors to predict the severity of complications associated with ChAdOx1 vaccination. Five patients with VITT, 10 with prolonged symptoms and cutaneous hemorrhages but without VITT, and 15 with only brief and mild symptoms after the vaccination were examined. Levels of H3-NETs and calprotectin in the vaccinated individuals were markedly increased in VITT patients compared to vaccinees with milder vaccination-associated symptoms, and a strong correlation (r ≥ 0.745, p &lt; 0.001) was found with severity of vaccination side effects. Syndecan-1 levels were also positively correlated (r = 0.590, p &lt; 0.001) in vaccinees to side effects after ChAdOx1 nCoV-19 vaccination. We hypothesize that the inflammatory markers NETs and calprotectin may be used as confirmatory tests in diagnosing VITT.

• Warlo, Ellen Mathea Kirsch; Bratset, Vibeke; Pettersen, Alf Åge Reistad; Holme, Pål Andre; Arnesen, Harald & Seljeflot, Ingebjørg [Show all 7 contributors for this article] (2022). Genetic variation in ADAMTS13 is related to VWF levels, atrial fibrillation and cerebral ischemic events. Clinical and applied thrombosis/hemostasis. ISSN 1076-0296. 28, p. 1–8. doi: 10.1177/10760296221141893. Full text in Research Archive Show summary

  Introduction ADAMTS13 cleaves von Willebrand factor (VWF) multimers into less active fragments. Both markers have been related to cardiovascular disease (CVD). We aimed to investigate the influence of ADAMTS13 single nucleotide polymorphisms (SNPs) on levels of ADAMTS13 and VWF, and CVD. Methods The c.1342C&gt;G, g.41635A&gt;G and c.2699C&gt;T polymorphisms were determined in patients with chronic coronary syndrome (n = 1000). VWF and ADAMTS13 were analyzed. Clinical endpoints after 2 years (n = 106) were unstable angina pectoris, myocardial infarction, non-hemorrhagic stroke and death. Results The SNPs did not affect ADAMTS13 levels. The 41635A-allele associated with higher VWF levels ( P &lt; .001). Patients with the 1342G-allele had significantly higher frequency of previous atrial fibrillation (n = 26, P = .016) and cerebral ischemic events (n = 47, P = .030). Heterozygous of the 1342CG variant experienced more clinical endpoints compared to homozygous (CC and GG) ( P = .028). Conclusion The association between the 41635A-allele and VWF indicates a role for this polymorphism in VWF regulation. ADAMTS13 has previously been linked to atrial fibrillation and ischemic stroke, and our findings suggest that the 1342G-allele may be of significance. The association between the 1342CG genotype and endpoints needs further investigations. Clinicaltrials.gov, ASCET, NCT00222261. https://clinicaltrials.gov/ct2/show/NCT00222261?term=NCT00222261&amp;draw=2&amp;rank=1

• Matlary, Ruth Elise Dybvik; Holme, Pål Andre; Glosli, Heidi; Rueegg, Corina Silvia & Grydeland, May (2022). Comparison of free-living physical activity measurements between ActiGraph GT3X-BT and Fitbit Charge 3 in young people with haemophilia. Haemophilia. ISSN 1351-8216. p. 1–9. doi: 10.1111/hae.14624. Full text in Research Archive Show summary

  Introduction: Measurement of physical activity (PA) using commercial activity trackers such as Fitbit devices has become increasingly popular, also for people with haemophilia (PWH). The accuracy of the Fitbit model Charge 3 has not yet been examined. Aims: To compare the Fitbit Charge 3 against the research-grade accelerometer ActiGraph GT3X-BT in measuring average daily steps and minutes spent in different PA intensities. Methods: Twenty-four young PWH wore a wrist-worn Fitbit Charge 3 and hip-worn ActiGraph GT3X-BT simultaneously for seven consecutive days in free-living conditions. Correlation of and differences between the devices for daily averages of PA parameters were assessed using Pearson's correlation coefficient and paired t-test, respectively. Agreement between devices was assessed using Bland-Altman plots. Results: Twenty participants (mean age 21.8) were included in the analyses. We found moderate to high correlations between Fitbit and ActiGraph measured daily averages for all PA variables, but statistically significant differences between devices for all variables except daily minutes of moderate PA. Fitbit overestimated average daily steps, minutes of light, vigorous and moderate-to-vigorous PA. Bland-Altman plots showed a measurement bias between devices for all parameters with increasing overestimation by the Fitbit for higher volumes of PA. Conclusion: The Fitbit Charge 3 overestimated steps and minutes of light, moderate and moderate-to-vigorous PA as compared to the ActiGraph GT3X-BT, and this bias increased with PA volume. The Fitbit should therefore be used with caution in research, and we advise users of the device to be cognizant of this overestimation.

• Klintman, Jenny; Akesson, Kristina E; Holme, Pål Andre & Fischer, Kathelijn (2022). Bone mineral density in haemophilia – a multicentre study evaluating the impact of different replacement regimens. Haemophilia. ISSN 1351-8216. 28(2), p. 239–246. doi: 10.1111/hae.14487. Full text in Research Archive Show summary

  Aim The aim of this study was to investigate if prophylactic treatment in severe haemophilia impact on bone mineral densisty (BMD) in adults with haemophilia A/B. Methods Subjects with haemophilia (n = 120) underwent bone-density measurement and clinical data was collected. BMD in subjects with severe haemophilia on high-dose prophylaxis (n = 41) was compared to BMD in subjects with mild haemophilia (n = 33) and to severe haemophilia treated with intermediate-dose prophylaxis (n = 32) or on-demand replacement therapy (n = 14). Results Subjects with severe haemophilia on high-dose prophylaxis showed BMD at total hip comparable to subjects with mild haemophilia (median BMD 955.8 and 977.4 mg/cm2 (P = .17), respectively). No difference in BMD was found related to type of prophylactic regimen (median BMD 955.8 and 942.4 mg/cm2, in high-dose and intermediate dose groups, respectively; P = .70). Subjects with severe disease treated on-demand had significantly lower BMD compared to subjects on a high-dose prophylactic regimen (median BMD 771.8 and 955.8 mg/cm2 (P = .001), respectively). BMD decreased significantly with age, regardless of severity of haemophilia disease. In a multivariate analysis, adjusted for disease status and age, type of prophylactic regimen was not significantly associated with osteoporosis development. Conclusion We show that BMD differs in persons with severe haemophilia on propylaxis as compared to those treated on-demand, but that type of prophylactic regimen does not reflect on BMD. The difference between treatment groups was mainly explained by an age difference between groups. However, patients on prophylaxis displayed a high degree of normal BMD not far from mild haemophilia at comparative age.

• Lehtinen, Anna-Elina; Baghaei, Fariba; Astermark, Jan & Holme, Pål Andre (2022). Surgical outcomes in patients with haemophilia A or B receiving extended half-life recombinant factor VIII and IX Fc fusion proteins: Real-world experience in the Nordic countries. Haemophilia. ISSN 1351-8216. 28(5), p. 713–719. doi: 10.1111/hae.14585. Full text in Research Archive Show summary

  Introduction Perioperative dosing recommendations vary across Nordic haemophilia treatment centres (HTCs) for extended half-life (EHL) factor concentrates in haemophilia A/B (HA/HB) patients. Aim To summarise Nordic real-world surgical experiences with EHL recombinant factor VIII/IX Fc (rFVIIIFc/rFIXFc) fusion proteins using retrospective data from clinical records at four HTCs in Finland, Sweden and Norway. Methods Factor dosing and surgical outcomes were recorded from HA/HB patients who underwent surgery and were treated with rFVIIIFc/rFIXFc. Perioperative factor dosing regimens were clinician-determined based on local practises. Results Twenty five surgeries were performed on 20 patients, all covered by bolus injections except one minor HA surgery; eight minor surgeries were in paediatric patients. Median preoperative rFVIIIFc dose for major HA surgeries (n = 8) was 48 IU/kg (range: 35–57), with total consumption up to Day 14 of 427 IU/kg (196–568). For the two major HB surgeries (in one patient), preoperative rFIXFc doses were 50 IU/kg and 20 IU/kg; total consumption up to Day 14 was 130 IU/kg and 40 IU/kg. Median preoperative rFVIIIFc/rFIXFc bolus doses for minor HA (n = 10) and HB (n = 4) surgeries were 50 IU/kg (24–79) and 47 IU/kg (40–71), with total consumption up to Day 5 of 138 IU/kg (49–404) and 100 IU/kg (43–125), respectively. Intraoperative and postoperative haemostatic responses were rated as at least good/excellent for 24/25 surgeries, with bleeding episodes reported in only three surgeries. Conclusion Nordic real-world experiences suggest that EHL products can be used safely and effectively for peri-operative haemostasis. Further research is required to develop local dosing guidelines for optimised treatment schedules.

• Szanto, Timea; Zetterberg, Eva; Ramström, Sofia; Leinøe, Eva B.; Holme, Pål Andre & Antovic, Jovan P. [Show all 16 contributors for this article] (2022). Platelet function testing: Current practice among clinical centres in Northern Europe. Haemophilia. ISSN 1351-8216. 28(4), p. 642–648. doi: 10.1111/hae.14578. Full text in Research Archive Show summary

  Introduction Platelet function tests are used to screen and diagnose patients with possible inherited platelet function defects (IPFD). Some acquired platelet dysfunction may be caused by certain drugs or comorbidities, which need to be excluded before testing. Aims To identify current practice among centres performing platelet function tests in Northern Europe. Methods A total of 14 clinical centres from Sweden (six), Finland (two), Denmark (two), Norway (one), Estonia (two) and Iceland (one) completed the survey questionnaire, the population capture area of about 29.5 million. Results Six of the 14 (42.8%) centres providing platelet function assessment represent comprehensive treatment centres (EUHANET status). A Bleeding score (BS) or ISTH bleeding assessment tool (ISTH BAT score) is evaluated in 11/14 (78.6%) centres and family history in all. Five/14 centres (35.7%) use structured preanalytical patient instructions, and 10/14 (71.4%) recorded questionnaire on the preassessment of avoidance of any drugs or natural products affecting platelet functions. Preliminary investigations of screening tests of coagulation are performed in 10/14 (71.4%), while in 4/14 (28.6%), the diagnostic work-up of IPFD and von Willebrand disease (VWD) is performed simultaneously. The work-up of IPFD includes peripheral blood smear in 10/14 (71.4%), platelet aggregometry in all, flow cytometry in 10/14 (71.4%) and Platelet Function Analysis (PFA) in 3/11 (28.6%). Molecular genetic diagnosis is available in 7/14 (50%) centres. Conclusions The considerable variability in the current practice illustrates the need for harmonization between the Northern European centres according to the international registers (i.e. EUHASS) and IPFD guidelines (ISTH, EHA).

• Klamroth, Robert; Ay, Cihan; Moerloose, Philippe De; Fontana, Pierre; Windyga, Jerzy & Astermark, Jan [Show all 20 contributors for this article] (2022). Applicability of the European Society of Cardiology Guidelines on the management of acute coronary syndromes to older people with haemophilia A – A modified Delphi consensus by the ADVANCE Working Group. Haemophilia. ISSN 1351-8216. doi: 10.1111/hae.14674. Full text in Research Archive
• Schultz, Nina Haagenrud; Fareed, Jawed & Holme, Pål Andre (2021). Investigation of the Optimal Dose aPCC in Reversing the Effect of Factor Xa Inhibitors—An In Vitro Study. Clinical and applied thrombosis/hemostasis. ISSN 1076-0296. 27, p. 1–7. doi: 10.1177/10760296211021156. Full text in Research Archive Show summary

  Factor (F) Xa inhibitors are safe and effective alternatives to warfarin. There are concerns about the lack of a reversal strategy in case of serious bleeds or need for emergency surgery in situations when the antidote andexanet alfa is not available. Factor concentrates are widely used, but there are few clinical studies regarding the reversal effect of activated prothrombin complex concentrate (aPCC). Because of the feared thrombogenicity, administration of the lowest effective dose would be desirable. To determine the lowest concentration of aPCC sufficient to reverse the effect of rivaroxaban and apixaban. Blood from 18 healthy volunteers were supplemented with apixaban or rivaroxaban. aPCC was added to obtain 10 different concentrations ranging from 0.08-1.60 U/mL. Thromboelastometry and thrombin generation assay were used to assess the reversal effect. aPCC concentrations of 0.08 and 0.16 U/mL restored thromboelastometry clotting time to baseline in apixaban (P = 1.0) and rivaroxaban (P = 1.0)-containing samples, respectively. The concentrations 0.08 U/mL (P = 0.5) and 0.24 U/mL (P = 0.2) were sufficient to restore thrombin generation. Concentrations of 0.56 U/mL and higher, caused significantly higher ETP than baseline in apixaban-containing samples (P < 0.05). aPCC concentrations lower than previously reported were effective in reversing the effect of FXa inhibitors in vitro.

• Wiedmann, Markus; Skattør, Thor Håkon; Stray-Pedersen, Arne; Romundstad, Luis Georg; Antal, Ellen-Ann & Marthinsen, Pål Bache [Show all 16 contributors for this article] (2021). Vaccine Induced Immune Thrombotic Thrombocytopenia Causing a Severe Form of Cerebral Venous Thrombosis With High Fatality Rate: A Case Series. Frontiers in Neurology. 12:721146, p. 1–7. doi: 10.3389/fneur.2021.721146. Full text in Research Archive Show summary

  During a 2-week period, we have encountered five cases presenting with the combination of cerebral venous thrombosis (CVT), intracerebral hemorrhage and thrombocytopenia. A clinical hallmark was the rapid and severe progression of disease in spite of maximum treatment efforts, resulting in fatal outcome in for 4 out of 5 patients. All cases had received ChAdOx1 nCov-19 vaccine 1–2 weeks earlier and developed a characteristic syndrome thereafter. The rapid progressive clinical course and high fatality rate of CVT in combination with thrombocytopenia in such a cluster and in otherwise healthy adults is a recent phenomenon. Cerebral autopsy findings were those of venous hemorrhagic infarctions and thrombi in dural venous sinuses, including thrombus material apparently rich in thrombocytes, leukocytes and fibrin. Vessel walls were free of inflammation. Extra-cerebral manifestations included leech-like thrombi in large veins, fibrin clots in small venules and scattered hemorrhages on skin and membranes. CVT with thrombocytopenia after adenovirus vectored COVID-19 vaccination is a new clinical syndrome that needs to be recognized by clinicians, is challenging to treat and seems associated with a high mortality rate.

• Johansen, Silje; Lægreid, Ingvild Jenssen; Ernstsen, Siw Leiknes; Azrakhsh, Nessar Ahmad; Kittang, Astrid Marta Olsnes & Lindås, Roald [Show all 13 contributors for this article] (2021). Thrombosis and thrombocytopenia after HPV vaccination. Journal of Thrombosis and Haemostasis. ISSN 1538-7933. doi: 10.1111/jth.15604. Full text in Research Archive Show summary

  Background Vaccine-induced immune thrombotic thrombocytopenia (VITT) has so far only been reported after adenovirus vector severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. Objective We report findings in a 25-year-old woman who presented with thrombocytopenia, venous thrombosis, elevated D-dimer levels, and high levels of platelet-activating antibodies to platelet factor 4-polyanion complexes 10 days after Gardasil 9 vaccination for human papillomavirus (HPV). The patient exhibited clinical and laboratory features in line with the recently defined VITT syndrome, described after adenoviral vector vaccination to prevent coronavirus disease 2019. Conclusion We report a case of VITT following HPV vaccination. This should raise awareness of the possibility of VITT also occurring after other vaccines, not exclusively adenoviral vector-based SARS-CoV-2 vaccines.

• Holstein, Katharina; Quellec, Sandra Le; Klamroth, Robert; Batorova, A; Holme, Pål Andre & Jiménez-Yuste, Victor [Show all 7 contributors for this article] (2021). Immune tolerance induction in the era of emicizumab – still the first choice for patients with haemophilia A and inhibitors? Haemophilia. ISSN 1351-8216. doi: 10.1111/hae.14470. Full text in Research Archive Show summary

  Introduction The development of inhibitory antibodies is a severe complication of clotting factor replacement therapy in patients with severe haemophilia A (HA). Current World Federation of Hemophilia (WFH) guidelines for haemophilia care indicate that eradication of inhibitors is best achieved through immune tolerance induction (ITI) therapy. Aim The European Collaborative Haemophilia Network conducted a survey to determine whether ITI is still used in the routine management of patients with HA, and whether the availability of emicizumab prophylaxis has influenced treatment decisions. Methods The survey was conducted in late 2020/early 2021 in 18 centres representing 17 countries in the Europe/Middle East region treating a total of 4955 patients, and included sections specific to patient and centre demographics, treatment protocols (both ITI and prophylactic), inhibitor development and initiation of ITI, treatment success, and the incidence of adverse events. Results While our results indicate that ITI can still be considered a mainstay of treatment for patients with HA with inhibitors, less than daily dosing of ITI in combination with emicizumab prophylaxis is becoming commonplace across the spectrum of disease severity, with initiation being guided by bleeding patterns. The most frequently cited reasons for not initiating emicizumab prophylaxis were availability or reimbursement issues. Conclusion ITI remains a mainstay for haemophilia treatment of patients with HA with inhibitors, but emicizumab has become a preferred first-line approach to protect against bleeds and represents an alternative to burdensome ITI in certain patient groups.

• Astermark, Jan; Ay, Cihan; Carvalho, Manuela; D'Oiron, Roseline; Moerloose, Philippe De & Dolan, Gerard [Show all 18 contributors for this article] (2021). New Inhibitors in the Ageing Population: A Retrospective, Observational, Cohort Study of New Inhibitors in Older People with Hemophilia. Thrombosis and Haemostasis. ISSN 0340-6245. doi: 10.1055/a-1642-4067. Full text in Research Archive
• Jiménez-Yuste, Victor; Rodríguez-Merchán, E. Carlos; Matsushita, Tadashi & Holme, Pål Andre (2021). Concomitant use of bypassing agents with emicizumab for people with haemophilia A and inhibitors undergoing surgery. Haemophilia. ISSN 1351-8216. 27(4), p. 519–530. doi: 10.1111/hae.14322. Full text in Research Archive
• Kihlberg, Kristina; Baghaei, Fariba; Bruzelius, Maria; Funding, Eva; Holme, Pål Andre & Lassila, Riitta [Show all 11 contributors for this article] (2021). Treatment outcomes in persons with severe haemophilia B in the Nordic region: The B-NORD study. Haemophilia. ISSN 1351-8216. 27(3), p. 366–374. doi: 10.1111/hae.14299. Full text in Research Archive Show summary

  Introduction Data on outcome in persons with haemophilia B (PwHB) are limited and mainly extrapolated from studies of haemophilia A (HA). Aim To characterize treatment outcomes in persons with severe HB in the Nordic region, with a focus on joint health, compared with matched controls with HA. Methods PwHB attending haemophilia centres in Denmark, Finland, Norway and Sweden were enrolled and matched with controls with HA. Joint assessment using Haemophilia Joint Health Score (HJHS) and ultrasound according to Haemophilia Early Arthropathy Detection protocol (HEAD-US) was conducted. Adherence was evaluated using the Validated Haemophilia Regimen Treatment Adherence Scale (VERITAS). Results Seventy-nine males with HB, with median age of 30 years (range 1–75), were enrolled. Eleven patients (14%) had a history of or current inhibitor. Twenty-nine PwHB (37%) reported joint bleeds during the prior year, and 35% had previously undergone joint surgery. Ninety-five per cent were on prophylaxis, and 70% used recombinant concentrates, with a median factor consumption of 3,900 IU/kg/year for standard half-life products. Only two patients had a VERITAS score corresponding to ‘non-adherence'. Joint health, assessed with HJHS, showed a significant lower score among PwHB compared with HA controls, explained by a difference in the 18–49 age group, without observed differences in older or younger subgroups. The HEAD-US scores were overall low. Conclusion The Nordic cohort of PwHB is well treated by prophylaxis, but the goal of zero bleeds for all is not reached. Our findings suggest that patients with severe HB suffer from a milder arthropathy than patients with severe HA.

• Reding, Mark T.; Pabinger, Ingrid; Holme, Pål Andre; Poulsen, Lone; Negrier, Claude & Chalasani, Pavani [Show all 11 contributors for this article] (2021). Confirmed long-term safety and efficacy of prophylactic treatment with BAY 94–9027 in severe haemophilia A: final results of the PROTECT VIII extension study. Haemophilia. ISSN 1351-8216. 27(3), p. e347–e356. doi: 10.1111/hae.14297. Full text in Research Archive Show summary

  Introduction The phase 2/3 PROTECT VIII main study demonstrated efficacy and safety of BAY 94–9027 (damoctocog alfa pegol; Jivi®), a B-domain-deleted recombinant factor VIII (FVIII), site-specifically PEGylated to extend its half-life. Aim To report the final efficacy and safety data for BAY 94–9027 from the PROTECT VIII extension. Methods Previously treated males aged 12–65 years with severe haemophilia A (FVIII <1%) who completed the multicentre, open-label PROTECT VIII main study were eligible for the extension. Patients received either on demand or prophylaxis treatments (30‒40 IU/kg twice weekly [2 × W], 45‒60 IU/kg every 5 days [E5D], or 60 IU/kg every 7 days [E7D]) and could switch to any prophylaxis regimen (variable frequency) as needed. Annualised bleeding rates (ABR), zero bleeds and safety outcomes were included in this final analysis. Results At extension completion, patients (n = 121) received BAY 94–9027 for a median (range) total time of 3.9 (0.8–7.0) years. Median (Q1; Q3) total ABR was 1.49 (0.36; 4.80) for prophylaxis patients (n = 107), compared with 34.09 (20.3; 36.6) for on-demand patients (n = 14). Median total ABRs for 2 × W (n = 23), E5D (n = 33), E7D (n = 23) and variable frequency (n = 28) groups were 1.57, 1.17, 0.65 and 3.10, respectively. Of prophylaxis patients, 20.6% were bleed-free during the entire extension (median time, 3.2 years) and 50.0% were bleed-free during the last 6 months. No patient developed FVIII inhibitors. No deaths or thrombotic events were reported. Conclusions Efficacy and safety of BAY 94–9027 was confirmed, with extension data supporting its use as a long-term treatment option for patients with haemophilia A.

• Måseide, Ragnhild Johanne; Berntorp, Erik; Astermark, Jan; Hansen, Jessica; Olsson, Anna & Bruzelius, Maria [Show all 11 contributors for this article] (2021). Haemophilia early arthropathy detection with ultrasound and haemophilia joint health score in the moderate haemophilia (MoHem) study. Haemophilia. ISSN 1351-8216. 27(2), p. e253–e259. doi: 10.1111/hae.14245. Full text in Research Archive Show summary

  Introduction Detection of early arthropathy is crucial for the management of haemophilia, but data on moderate haemophilia are limited. Therefore, we evaluated joint health and treatment modalities in Nordic patients with moderate haemophilia A (MHA) and B (MHB). Aim To explore and compare the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) and Haemophilia Joint Health Score (HJHS) to detect early arthropathy in moderate haemophilia. Methods A cross-sectional, multicentre study covering Nordic patients with MHA and MHB. Arthropathy was evaluated by HEAD-US and HJHS 2.1. Results We assessed 693 joints in 118 patients. HEAD-US scores (medians [interquartile ranges]) were as follows: elbows 0 points (0–0), knees 0 (0–0) and ankles 0 (0–1). Respectively, by HJHS: elbows 0 (0–1), knees 0 (0–1) and ankles 0 (0–1). Cartilage (14%) and bone (13%) were most commonly affected by HEAD-US. Frequent HJHS findings were crepitus on motion in knees (39%), and loss of flexion (23%) and extension (13%) in ankles. HEAD-US correlated strongly with HJHS (elbows r = .70, knees r = .60 and ankles r = .65), but 24% had discordant scores. Joints with HJHS zero points, 5% captured HEAD-US ≥1 point. Moreover, 26% had HJHS findings without HEAD-US pathology. Notably, 31% of knees had crepitus on motion and normal HEAD-US. Conclusion Overall, the joints attained low scores implying good joint health. HEAD-US correlated strongly with HJHS. In 5%, HEAD-US detected subclinical pathology. Crepitus on motion was frequently reported despite normal HEAD-US, thus not necessarily reflecting arthropathy. HEAD-US therefore improves the joint assessment in moderate haemophilia.

• Schultz, Nina Haagenrud; Glosli, Heidi; Bjørnsen, Stine & Holme, Pål Andre (2021). The effect of emicizumab and bypassing agents in patients with hemophilia – An in vitro study. Research and Practice in Thrombosis and Haemostasis (RPTH). 5(5), p. 1–7. doi: 10.1002/rth2.12561. Full text in Research Archive Show summary

  Background Emicizumab is a nonfactor replacement therapy for hemophilia A (HA) and is a bispecific monoclonal antibody mimicking factor VIII by binding both factors IXa and X. Although it reduces the frequency of bleeding episodes, there is still need for bypassing agents in case of breakthrough bleeds or need for surgery. The HAVEN-1 study showed an increased risk of thrombotic events and episodes of thrombotic microangiopathic hemolytic anemia with simultaneous treatment with emicizumab and activated prothrombin complex concentrate (aPCC) in high doses (>100 U/kg daily) for more than 1 day, and it is suspected that these drugs have a synergistic hemostatic effect. Objectives To evaluate and compare the hemostatic effect of bypassing agents in vitro in people with HA before and after starting treatment with emicizumab to investigate if dosing should be adjusted to optimize treatment. Patients/Methods Blood collected before and after start of treatment with emicizumab was spiked with aPCC and recombinant factor VIIa (rFVIIa) at different concentrations. The effect of aPCC and rFVIIa was assessed by thrombin generation assay and thromboelastometry. Results Six people with HA were included. The response to aPCC in thrombin generation after starting emicizumab was significantly stronger than before. This synergistic effect was less pronounced for emicizumab and rFVIIa. Furthermore, aPCC shortened thromboelastometry clotting time more effectively after starting emicizumab than before starting this treatment. Conclusions We demonstrated a strong synergistic effect of emicizumab and aPCC and a similar but less pronounced effect of rFVIIa in people treated with emicizumab.

• Schultz, Nina Haagenrud; Sørvoll, Ingvild Hausberg; Michelsen, Annika; Munthe, Ludvig Andre; Lund-Johansen, Fridtjof & Ahlen, Maria Therese [Show all 11 contributors for this article] (2021). Thrombosis and thrombocytopenia after CHADOX1 NCoV-19 vaccination. New England Journal of Medicine. ISSN 0028-4793. 384(22), p. 2124–2130. doi: 10.1056/NEJMoa2104882. Full text in Research Archive Show summary

  We report findings in five patients who presented with venous thrombosis and thrombocytopenia 7 to 10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against coronavirus disease 2019 (Covid-19). The patients were health care workers who were 32 to 54 years of age. All the patients had high levels of antibodies to platelet factor 4–polyanion complexes; however, they had had no previous exposure to heparin. Because the five cases occurred in a population of more than 130,000 vaccinated persons, we propose that they represent a rare vaccine-related variant of spontaneous heparin-induced thrombocytopenia that we refer to as vaccine-induced immune thrombotic thrombocytopenia.

• Holm, Sverre; Kared, Hassen; Michelsen, Annika Elisabet; Kong, Xiang Yi; Dahl, Tuva Børresdatter & Schultz, Nina Haagenrud [Show all 21 contributors for this article] (2021). Immune complexes, innate immunity, and NETosis in ChAdOx1 vaccine-induced thrombocytopenia. European Heart Journal. ISSN 0195-668X. 42(39), p. 4064–4072. doi: 10.1093/eurheartj/ehab506. Full text in Research Archive Show summary

  Aims - We recently reported five cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) 7–10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against corona virus disease 2019 (COVID-19). We aimed to investigate the pathogenic immunological responses operating in these patients.<p> <p>Methods and results - We assessed circulating inflammatory markers by immune assays and immune cell phenotyping by flow cytometry analyses and performed immunoprecipitation with anti-platelet factor (PF)4 antibody in plasma samples followed by mass spectrometry from all five patients. A thrombus was retrieved from the sinus sagittal superior of one patient and analysed by immunohistochemistry and flow cytometry. Precipitated immune complexes revealed multiple innate immune pathway triggers for platelet and leucocyte activation. Plasma contained increased levels of innate immune response cytokines and markers of systemic inflammation, extensive degranulation of neutrophils, and tissue and endothelial damage. Blood analyses showed activation of neutrophils and increased levels of circulating H3Cit, dsDNA, and myeloperoxidase–DNA complex. The thrombus had extensive infiltration of neutrophils, formation of neutrophil extracellular traps (NETs), and IgG deposits.<p> <p>Conclusions - The results show that anti-PF4/polyanion IgG-mediated thrombus formation in VITT patients is accompanied by a massive innate immune activation and particularly the fulminant activation of neutrophils including NETosis. These results provide novel data on the immune response in this rare adenoviral vector-induced VITT.

• Måseide, Ragnhild Johanne; Berntorp, Erik; Nummi, Vuokko; Lassila, Riitta; Tjønnfjord, Geir E. & Holme, Pål A. (2021). Bleeding phenotype of patients with moderate haemophilia A and B assessed by thromboelastometry and thrombin generation. Haemophilia. ISSN 1351-8216. p. 1–10. doi: 10.1111/hae.14355. Full text in Research Archive Show summary

  Introduction Predicting the bleeding phenotype is crucial for the management of patients with moderate haemophilia. Global coagulation assays evaluate haemostasis more comprehensively than conventional methods. Aim To explore global coagulation assays and the bleeding phenotype of patients with moderate haemophilia A (MHA) and B (MHB). Methods The MoHem study is a cross-sectional, multicentre study covering Nordic patients with MHA and MHB. Thromboelastometry in whole blood and thrombin generation (TG) in platelet-poor plasma (1, 2.5 and 5 pM tissue factor (TF)) were compared with joint health (Haemophilia Joint Health Score (HJHS)) and treatment modality. Results We report on 61 patients from Oslo and Helsinki: 24 MHA and 37 MHB. By TG (2.5 pM TF), patients who had been without replacement therapy during the previous 12 months depicted higher endogenous thrombin potential (P = .03). In contrast, those who had low ETP (< median) captured higher HJHS (P = .02). Patients who had undergone orthopaedic surgery generated least thrombin (P = .02). By thromboelastometry, those without the need of factor consumption had short clotting times, and quick times to maximum velocity (< median values) (P = .03). Factor VIII/factor IX activity (FVIII/FIX:C) did not align with the bleeding phenotype, but FIX:C ≤ 3 IU/dL was associated with lower peak thrombin (P = .03). Conclusion TG differentiated patients with moderate haemophilia according to HJHS, annual factor consumption, and whether orthopaedic surgery had been performed. Thromboelastometry differentiated according to factor consumption only. Global coagulation assays may assist predicting the bleeding phenotype in moderate haemophilia.

• Kempton, Christine L.; Makris, Michael & Holme, Pål Andre (2020). Management of comorbidities in haemophilia. Haemophilia. ISSN 1351-8216. doi: 10.1111/hae.14013. Full text in Research Archive
• Gorkom, Britta; Holme, Pål Andre; Joch, Christine; Rogosch, Tobias; Feussner, Annette & McKeand, William [Show all 8 contributors for this article] (2020). Pharmacokinetics and pharmacodynamics of a recombinant fusion protein linking activated coagulation factor VII with human albumin (rVIIa-FP) in patients with congenital FVII deficiency. Hematology. ISSN 1024-5332. 25(1), p. 17–25. doi: 10.1080/16078454.2019.1700329. Full text in Research Archive Show summary

  Objectives: Recombinant fusion protein linking activated factor VIIa to human albumin (rVIIa-FP) is a therapeutic option designed to prevent and treat bleeding events in patients with congenital FVII deficiency with reduced infusion frequency compared to current FVII treatments. This study characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of rVIIa-FP. Methods: A phase I multicenter, randomized, open-label, parallel-arm, single-dose study (NCT02470871) was conducted in nine patients with severe congenital FVII deficiency. Patients received their routine FVII product (30 IU/kg plasma-derived FVII [pdFVII] or 25 μg/kg recombinant activated FVII (rFVIIa) [eptacog alfa]), and were then randomly assigned to receive 100 or 300 μg/kg of rVIIa-FP. Blood samples for PK and PD assessments were drawn up to 48 hr after administration. FVIIa activity was determined using a one-stage clotting assay. PD parameters were derived from thrombin generation testing, using the Nijmegen hemostasis assay. Results: rVIIa-FP showed improved PK compared to rFVIIa, with 2- to 3-fold longer t1/2 and 4- to 8-fold lower clearance. Analysis of PD data showed a sustained suppression of lag time below 4.5 min (upper limit of healthy people) for rVIIa-FP compared to rFVIIa. AUEC and ECmax were similar across the two dose groups of rVIIa-FP and rFVIIa. Discussion: rVIIa-FP was well tolerated in patients with congenital FVII deficiency, showed a longer half-life and lower clearance compared to rFVIIa, and lag time remaining within healthy ranges for ≥8 hr. Conclusion: These results warrant further investigation into the efficacy of rVIIa-FP to control and prevent bleeding in patients with FVII deficiency.

• Qvigstad, Christian; Sørensen, Lars A Q; Tait, R. Campbell; Moerloose, Philippe De & Holme, Pål Andre (2020). Macroscopic hematuria as a risk factor for hypertension in ageing people with hemophilia and a family history of hypertension. Medicine. ISSN 0025-7974. 99(9), p. 1–8. doi: 10.1097/MD.0000000000019339. Full text in Research Archive Show summary

  Ageing people with hemophilia (PWH) have a higher prevalence of hypertension than the general population. This study aimed to determine whether macroscopic hematuria was associated with hypertension in PWH in a post hoc analysis using data from a cross-sectional study conducted by the ADVANCE Working Group (the H3 study), which included PWH ≥ 40 years of age. Data from 16 contributing centers, located in 13 European countries and Israel, were analyzed using logistic regression models. Of 532 recruited PWH in the H3 study, 117 had hypertension and a positive family history of hypertension (hypertension FH+), 75 had hypertension and a negative family history of hypertension (hypertension FH−), 290 had no diagnosis of hypertension, and the remaining 50 had missing hypertension data. Logistic regressions showed that macroscopic hematuria was associated with hypertension FH+, both in the univariate (OR = 1.84 [1.17–2.90], P = .01) and in the multivariate model (OR = 1.80 [1.03–3.16], P = .04). Macroscopic hematuria was not associated with hypertension FH−. Moreover, in a multivariate logistic regression the odds of hypertension FH+ were increased with the number of macroscopic hematuria episodes. The association between macroscopic hematuria and hypertension was significant for PWH with a family history of hypertension.

• Måseide, Ragnhild Johanne; Berntorp, Erik; Astermark, Jan; Olsson, Anna; Bruzelius, Maria & Frisk, Tony [Show all 10 contributors for this article] (2020). Joint health and treatment modalities in Nordic patients with moderate haemophilia A and B – The MoHem study. Haemophilia. ISSN 1351-8216. 26(5), p. 891–897. doi: 10.1111/hae.14114. Full text in Research Archive Show summary

  Introduction The prevalence of arthropathy in moderate haemophilia A (MHA) and B (MHB) is not well known. Aim We evaluated joint health in Nordic patients in relation to their treatment modality. Methods A cross‐sectional, multicentre study covering MHA and MHB in Sweden, Finland and Norway. Arthropathy was evaluated by ultrasound (HEAD‐US) and Haemophilia Joint Health Score (HJHS). Results We report on 145 patients: median age 28 years (IQR 13‐52) and 61% MHA. Baseline factor VIII/factor IX activity (FVIII/FIX:C) was 2 IU/dL (median) (IQR 2‐4): lower for MHB (2 IU/dL, IQR 1‐2) than MHA (3 IU/dL, IQR 2‐4) (P < .01). Eighty‐five per cent of MHA and 73% MHB had a history of haemarthrosis (P = .07). Age at first joint bleed was lower for MHA (5 years [median], IQR 3‐7) than MHB (7 years, IQR 5‐12) (P = .01). Thirty‐eight per cent received prophylaxis, started at median 10 years of age (IQR 4‐24). Median joint bleeds and serious other bleeds during the last 12 months were both zero (IQR 0‐1). Total HEAD‐US captured 0/48 points (median) (IQR 0‐2) and HJHS 4/120 points (IQR 1‐10) with strong correlation between them (r = .72). FVIII/FIX:C ≤ 3 IU/dL was associated with higher HJHS (P = .04). Fifteen per cent had undergone orthopaedic surgery. Conclusion The current joint health in Nordic moderate haemophilia patients was rather good, but a subgroup had severe arthropathy. FVIII/FIX:C ≤ 3 IU/dL and MHA were associated with a more severe bleeding phenotype. We suggest primary prophylaxis to all patients with FVIII/FIX:C ≤ 3 IU/dL.

• Tjønnfjord, Eirik; Holme, Pål Andre; Darne, Bernadette; Khelif, Abderrahim; Waage, Anders & Michel, Marc [Show all 8 contributors for this article] (2020). Long-term outcomes of patients treated with rituximab as second-line treatment for adult immune thrombocytopenia – Follow-up of the RITP study. British Journal of Haematology. ISSN 0007-1048. 191(3), p. 460–465. doi: 10.1111/bjh.16672. Full text in Research Archive Show summary

  RITP was a double‐blind randomized, 78‐week follow‐up trial in which 109 adults with immune thrombocytopenias (ITP) who failed to achieve adequate response to steroids, were randomized to receive rituximab or placebo. Here, we provide the duration of response, splenectomy and mortality rates based on extended follow‐up after completion of the RITP study. Extended follow‐up data were retrospectively collected for 72 (83%) patients out of the 84 patients who were not splenectomized during the initial RITP study. For the present analysis, median [interquartile range] duration of follow‐up after randomization was 72 [62–82] months. Median duration of response among patients who achieved an initial response was significantly longer in patients who received rituximab (8·2 [5·5–16·7] months) as compared to placebo (1·8 [1·3–3·6] months), P = 0·036. Overall, 35 patients underwent splenectomy (13 in the rituximab, and 22 in the placebo arm, P = 0·12). Eleven patients (10%) died during the study: five in the rituximab and six in the placebo arms, including four deaths from severe bleeding. Although most rituximab‐treated patients eventually relapsed, a longer duration of response and a trend towards lower splenectomy rate were observed in rituximab‐treated patients.

• Qvigstad, Christian; Tait, R. Campbell; Moerloose, Philippe de & Holme, Pål Andre (2020). Hematuria in aging men with hemophilia: Association with factor prophylaxis. Research and Practice in Thrombosis and Haemostasis (RPTH). 4(2), p. 309–317. doi: 10.1002/rth2.12298. Full text in Research Archive Show summary

  Introduction Macroscopic hematuria is considered a significant risk factor for urologic disease, and it is highly prevalent in people with hemophilia. Aim To determine whether prophylactic factor replacement therapy is associated with reduced occurrence of macroscopic hematuria in people with hemophilia in a post hoc analysis using data from a cross‐sectional study conducted by the Age‐Related Developments and Comobordities in Hemophilia (ADVANCE) Working Group that included males with hemophilia ≥40 years of age. Methods Data from 16 contributing centers, in 13 European countries and Israel, were analyzed using logistic regression. Of 532 recruited individuals, this analysis included 370 patients with moderate or severe hemophilia who received on‐demand or prophylactic therapy. Results For patients with a history of macroscopic hematuria, we analyzed the association between prophylaxis and reoccurrence of macroscopic hematuria within the past 5 years (n = 235 patients). Frequent (≥3 times/wk) prophylaxis was negatively associated with a recent episode of macroscopic hematuria (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.18‐0.76). We also analyzed whether prophylaxis corresponded to a lower lifetime number of macroscopic hematuria episodes (n = 285 patients). Frequent prophylaxis for >15 years was associated with a lower number of episodes compared to on‐demand treatment (OR, 0.29; 95% CI, 0.16‐0.54), whereas nonsteroidal anti‐inflammatory drugs (NSAIDs) and severe hemophilia were associated with a higher number. There was no association of prophylaxis <3 times/wk with hematuria. Conclusion Frequent prophylaxis was negatively associated with the number of episodes of macroscopic hematuria in people with hemophilia. Prevalence of macroscopic hematuria was higher among individuals with severe hemophilia and those regularly using NSAIDs.

• Lalezari, Shadan; Reding, Mark T.; Pabinger, Ingrid; Holme, Pål Andre; Negrier, Claude & Chalasani, Pavani [Show all 10 contributors for this article] (2019). BAY 94-9027 prophylaxis is efficacious and well tolerated for up to &amp;gt;5 years with extended dosing intervals: PROTECT VIII extension interim results. Haemophilia. ISSN 1351-8216. 25(6), p. 1011–1019. doi: 10.1111/hae.13853. Full text in Research Archive Show summary

  Introduction BAY 94‐9027 is an extended‒half‐life, site‐specifically PEGylated, B‐domain‒deleted recombinant factor VIII (FVIII). The PROTECT VIII main study demonstrated efficacy of bleed control using extended‐interval prophylaxis with BAY 94‐9027 for 36 weeks. Aim To report long‐term efficacy and safety of prophylaxis with BAY 94‐9027 in a descriptive analysis of the ongoing PROTECT VIII extension with a total treatment time of up to >5 years. Methods Previously treated males aged 12‐65 years with severe haemophilia A who completed the PROTECT VIII main study were eligible for the open‐label extension. Patients received on‐demand treatment or prophylaxis (30‒40 IU/kg twice weekly, 45‒60 IU/kg every 5 days, or 60 IU/kg every 7 days) and could switch regimens as needed. Results Patients (N = 121; on demand, n = 14; prophylaxis, n = 107) accumulated a median (range) of 3.9 years (297‒1965 days) and 223 (23‒563) total exposure days by 31 January 2018. During the extension, median (quartile [Q]1; Q3) annualized bleeding rates (ABRs) for total bleeds were 1.6 (0.3; 4.6) for patients receiving prophylaxis and 34.1 (20.3; 36.6) for patients receiving on‐demand treatment. ABRs for twice‐weekly (n = 23), every‐5‐days (n = 33), every‐7‐days (n = 23) and variable frequency (n = 28) treatments were 1.7, 1.2, 0.7 and 3.1, respectively. Of prophylaxis patients, 20.6% were bleed‐free throughout the extension (median time, 3.2 years), and 51.0% were bleed‐free during the last 6 months. No patients developed FVIII inhibitors. Conclusions BAY 94‐9027 prophylaxis was efficacious and well tolerated with dosing intervals up to every 7 days for a median (range) of 3.9 years (0.8‐5.4 years).

• Ljungkvist, Marcus; Strandberg, Karin; Berntorp, Erik; Chaireti, Roza; Holme, Pål Andre & Larsen, Ole Halfdan [Show all 10 contributors for this article] (2019). Evaluation of a standardized protocol for thrombin generation using the calibrated automated thrombogram: A Nordic study. Haemophilia. ISSN 1351-8216. p. 1–9. doi: 10.1111/hae.13640. Full text in Research Archive Show summary

  Introduction The thrombin generation assay‐calibrated automated thrombogram (TGA‐CAT) method is used to measure the overall coagulation capacity in plasma. However, the method is still considered to be a research tool, mainly because of its’ lack of standardization. Aim Our study aimed to further raise the standardization level for the TGA‐CAT method by evaluating a detailed standardization protocol and three reference plasmas’ (RP)s ability to normalize results. Methods Six Nordic centres participated in the study, and with input from all centres a detailed laboratory standardization protocol based on the TGA‐CAT manual of the manufacturer was established. Three types of plasma, hypo‐, normal and hyper coagulable plasma were assessed. Three commercial lyophilized RPs were used for normalization of data. All samples were aliquoted at the Malmö centre and sent frozen at −20˚C to participating centres. Results Before normalization, all results under all testing conditions showed inter‐laboratory coefficient of variability of 10% or lower except for endogenous thrombin potential (12%) and peak (14%) in hypo‐ plasma with 1 pmol/L tissue factor as starting agent. Successful normalization, improving variability in results, was obtained with two of the three evaluated RPs (HemosIL RP and Affinity RP). Conclusion With our standardization concept, we were able to produce TGA‐CAT results as robust as standard coagulation assays used in the routine laboratories. Normalization with HemosIL RP may be considered in populations with low or unknown coagulability, while when analysing plasma samples from populations where hypercoagulability is known or suspected, normalization with Affinity RP may be preferred.

• Chowdary, Pratima; Carcao, Manuel; Holme, Pål Andre; Jiménez-Yuste, Victor; Lentz, Steven R. & Møss, Judi [Show all 11 contributors for this article] (2019). Fixed doses of N8-GP prophylaxis maintain moderate-to-mild factor VIII levels in the majority of patients with severe hemophilia A. Research and Practice in Thrombosis and Haemostasis (RPTH). 3(3), p. 542–554. doi: 10.1002/rth2.12220. Full text in Research Archive Show summary

  Background N8‐GP is an extended half‐life recombinant factor VIII developed for prophylaxis and treatment of bleeds in patients with hemophilia A. Objective To assess pharmacokinetic (PK ) characteristics of N8‐GP in previously treated patients with severe hemophilia A, model the time spent at hemophilia thresholds of ≥1 and ≤5 IU/dL (moderate) or >5 IU/dL (mild) FVIII levels during N8‐GP prophylaxis, and investigate the relationship between N8‐GP half‐life and von Willebrand factor (vWF ). Methods PK assessments were obtained from patients with severe hemophilia A (FVIII < 1 IU/dL) participating in 4 clinical trials: pathfinder 1 (20‐60 years); pathfinder 2 (12‐17 and ≥18 years); pathfinder 5 (0‐11 years), and pathfinder 7 (25‐71 years). All PK profiles were assessed after washout and considered single‐dose PK profiles. Pre‐ and postdose FVIII activity at steady state was measured at all visits. Results From 69 patients, 108 PK profiles of N8‐GP 50 IU/kg were assessed. Adults/adolescents received 50 IU/kg every 4 days, achieving mean trough levels of 3.0 IU/dL (95% confidence interval, 2.6‐3.5, adults) and 2.7 IU/dL (1.8‐4.0, adolescents). Children received 60 IU/kg twice weekly, leading to mean trough levels of 1.2 IU/dL (0.8‐1.6, 0‐ to 5‐year‐olds) and 2.0 IU/dL (1.5‐2.7, 6‐ to 11‐year‐olds). PK modeling predicted children dosed every 3 days and adults/adolescents dosed every 3 to 4 days would maintain FVIII levels >5 and >1 IU/dL for >80% and 100% of the time, respectively. N8‐GP half‐life correlated linearly with von Willebrand factor levels in adults/adolescents, less in children. Conclusions Prophylaxis with fixed intervals (Q4D/twice weekly) and fixed weight‐based dosing (50/60 IU/kg) ensured >1 IU/dL FVIII trough levels in both adults and children.

• Curry, Nicola; Albayrak, Canan; Escobar, Miguel; Holme, Pål Andre; Kearney, Susan & Klamroth, Robert [Show all 14 contributors for this article] (2019). Once-weekly prophylaxis with glycoPEGylated recombinant factor VIII (N8-GP) in severe haemophilia A: Safety and efficacy results from pathfinder 2 (randomized phase III trial). Haemophilia. ISSN 1351-8216. 25(3), p. 373–381. doi: 10.1111/hae.13712. Full text in Research Archive Show summary

  Introduction Turoctocog alfa pegol (N8‐GP) is a site‐specific, 40 kDa glycoPEGylated recombinant factor VIII (FVIII) product with an extended half‐life. The comprehensive main phase of the pivotal pathfinder 2 trial showed N8‐GP dosed every 4 days (Q4D) provided favourable safety and efficacy for preventing bleeds in 175 patients with haemophilia A. Aim and methods We investigated the safety and efficacy of N8‐GP prophylaxis when administered weekly (Q7D) for 24 weeks to patients with low bleeding rates in the pathfinder 2 extension trial. Patients (≥12 years) with ≤2 bleeds during the preceding 6 months of the pathfinder 2 main phase were eligible for randomization to receive N8‐GP 50 IU/kg Q4D or 75 IU/kg Q7D. Safety and efficacy endpoints were incidence of FVIII inhibitors and annualized bleeding rate (ABR), respectively. Results Fifty‐five of 143 (38.5%) patients on prophylaxis who continued into the extension phase were randomized to receive 50 IU/kg Q4D (n = 17) or 75 IU/kg Q7D (n = 38). Nine patients in the Q7D cohort reverted to 50 IU/kg Q4D. No inhibitors were detected. In both cohorts, >50% of patients experienced no bleeds. Median ABR for overall, joint, spontaneous, traumatic and muscle was 0.00 for both cohorts. Overall estimated success rate for treating bleeding episodes was 87.5%; 94.7% of bleeds were controlled with ≤2 injections. Conclusions Weekly N8‐GP was well tolerated and efficacious and may benefit selected “low bleeder” patients with haemophilia A.

• Andersen, May-Linn Fauske; Holme, Pål Andre & Tjønnfjord, Geir Erland (2019). Kirurgiske inngrep hos pasienter med alvorlig blødersykdom 1997–2014. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 139(8), p. 709–712. doi: 10.4045/tidsskr.18.0592. Full text in Research Archive Show summary

  BAKGRUNN Som følge av god medisinsk behandling er forventet levealder hos pasienter med alvorlig blødersykdom nå nærmest normal. Det medfører et økende behov for behandling av sykdom relatert til livsstil og økt levealder. Vi beskriver kirurgi hos pasienter med alvorlig blødersykdom i perioden 1997–2014. MATERIALE OG METODE Data ble hentet fra registeret knyttet til Nasjonal behandlingstjeneste for kirurgi, intervensjon og avansert diagnostikk ved blødersykdom. Pasientene ble kategorisert etter type blødersykdom og type inngrep i ortopediske og ikke-ortopediske kirurgiske inngrep. RESULTATER 825 kirurgiske inngrep ble utført hos 286 pasienter. Antall inngrep økte fra 21 i 1997 til 66 i 2014. Økningen var knyttet til ikke-ortopediske inngrep: Det ble utført 4 slike inngrep i 1997 og 45 i 2014. Antall ortopediske inngrep varierte en del fra år til år, men viste ingen tydelig trend. FORTOLKNING Med økende levealder sees et økende behov for behandling av sykdommer som ikke er kausalt relatert til blødersykdom. Leger med liten erfaring med pasienter med alvorlig blødersykdom vil måtte forholde seg til sykdom relatert til livsstil og alderdom hos denne pasientgruppen.

• Gamage, Thilini Hansamali Gamage Yaddehi; Gunnes, Gjermund; Lee, Robert Hugh; Louch, William Edward; Holmgren, Asbjørn & Bruton, Joseph D. [Show all 19 contributors for this article] (2018). STIM1 R304W causes muscle degeneration and impaired platelet activation in mice. Cell Calcium. ISSN 0143-4160. 76, p. 87–100. doi: 10.1016/j.ceca.2018.10.001. Full text in Research Archive Show summary

  STIM1 and ORAI1 regulate store-operated Ca2+ entry (SOCE) in most cell types, and mutations in these proteins have deleterious and diverse effects. We established a mouse line expressing the STIM1 R304 W gain-of-function mutation causing Stormorken syndrome to explore effects on organ and cell physiology. While STIM1 R304 W was lethal in the homozygous state, surviving mice presented with reduced growth, skeletal muscle degeneration, and reduced exercise endurance. Variable STIM1 expression levels between tissues directly impacted cellular SOCE capacity. In contrast to patients with Stormorken syndrome, STIM1 was downregulated in fibroblasts from Stim1R304W/R304W mice, which maintained SOCE despite constitutive protein activity. In studies using foetal liver chimeras, STIM1 protein was undetectable in homozygous megakaryocytes and platelets, resulting in impaired platelet activation and absent SOCE. These data indicate that downregulation of STIM1 R304 W effectively opposes the gain-of-function phenotype associated with this mutation, and highlight the importance of STIM1 in skeletal muscle development and integrity.

• Qvigstad, Christian; Tait, Robert Cambell; Rauchensteiner, Stephan; Berntorp, Erik; Moerloose, Philippe de & Schutgens, Roger E. [Show all 7 contributors for this article] (2018). The elevated prevalence of risk factors for chronic liver disease among ageing people with hemophilia and implications for treatment. Medicine. ISSN 0025-7974. 97:e12551(39), p. 1–7. doi: 10.1097/MD.0000000000012551. Full text in Research Archive Show summary

  Chronic liver disease (CLD) is frequently seen in the hemophilia population. The ADVANCE Working Group conducted a crosssectional study in which people with hemophilia (PWH) aged ≥40 years were included. This study aimed to assess the associations between CLD and its risk factors using data from the H3 study, and to suggest implications for optimal care. Data from 13 European countries were collected at a single time-point (2011–2013). Univariate and multivariate logistic regression (MLR) analyses were performed. A total of 532 PWH were included with either hemophilia A (n=467) or hemophilia B (n=65). A total of 127 (24%) were diagnosed with CLD. Hepatitis C virus (HCV), human immunodeficiency virus (HIV), total cholesterol, and severe hemophilia were significant risk factors in univariate logistic regressions. In MLR, HCV Ab+/PCR+ (OR=17.6, P<.001), diabetes (OR=3.0, P=.02), and HIV (OR= 1.9, P=.049) were positively associated with CLD. Total cholesterol (OR=0.6, P=.002) was negatively associated with CLD. We found no evidence of interaction effects among the explanatory variables. No significant associations with age and type of or severity of hemophilia were observed in MLR. The main risk factors for CLD in this European cohort also apply to the general population, but the prevalence of HCV and HIV is considerably larger in this cohort. With new and improved treatment options, intensified eradication therapy for HCV seems justified to prevent CLD. Similarly, intensified monitoring and treatment of diabetes seem warranted. Abbreviations: BMI = body mass index, CLD = chronic liver disease, CRF = case report form, DAA = direct-acting antiviral, ESLD = end-stage liver disease, HAART = highly active antiretroviral therapy, HBV = hepatitis B virus, HCC = hepatocellular carcinoma, HCV = hepatitis C virus, HIV = human immunodeficiency virus, IR = insulin resistance, MLR = multivariate logistic regression, NRTI = nucleotide reverse transcriptase inhibitor, PWH = people with hemophilia, SVR = sustained virologic response, T2D = type 2 diabetes.

• Schultz, Nina Haagenrud; Lundblad, Runar & Holme, Pål Andre (2018). Activated prothrombin complex concentrate to reverse the factor Xa inhibitor (apixaban) effect before emergency surgery: A case series. Journal of Medical Case Reports. 12(138). doi: 10.1186/s13256-018-1660-9. Full text in Research Archive Show summary

  Background The lack of an antidote against factor Xa inhibitors in case of major bleeding or need for urgent surgery is a concern to clinicians. Guidelines on managing major bleeding in patients under anticoagulation with a factor Xa inhibitor suggest several hemostatic agents to reverse the effect, but there is no consensus regarding the choice of drug or appropriate dose. The ability of prothrombin complex concentrate, activated prothrombin complex concentrate, and recombinant factor VIIa to reverse the effect of factor Xa inhibitors has been evaluated in animal studies, in vitro studies, and healthy volunteers, but not yet in randomized clinical studies. Case presentation We report a consecutive case series of patients under factor Xa inhibitor (apixaban) treatment who received activated prothrombin complex concentrate to reverse the anticoagulation effect before emergency cardiovascular surgery. Patient 1, a 63-year-old white man, was operated with replacement of the aortic valve; patient 2, a 65-year-old white man, underwent heart transplantation; patient 3, a 68-year-old white man, was operated for acute type A aortic dissection. They all received activated prothrombin complex concentrate 25 IU/kg immediately before surgery. In two of the cases, the global coagulation assay thromboelastometry (ROTEM™) was performed before and after administering activated prothrombin complex concentrate. The ROTEM™ clotting time was reduced from 1900 seconds to 740 seconds and from 1482 to 807 seconds, respectively, after administering a dose of 25 IU/kg activated prothrombin complex concentrate. The apixaban concentration before reversal was within the range considered to be the therapeutic level in all cases. No bleeding complications occurred during surgery, but one case was complicated with bleeding postoperatively. No thromboembolic complications were observed during or after surgery. Conclusions Activated prothrombin complex concentrate 25 IU/kg reversed the anticoagulation effect of apixaban effectively and safely before emergency cardiovascular surgery.

• Schultz, Nina Haagenrud; Holme, Pål Andre; Bjørnsen, Stine; Henriksson, Carola; Sandset, Per Morten & Jacobsen, Eva-Marie (2018). The impact of rivaroxaban on primary hemostasis in patients with venous thrombosis. Platelets. ISSN 0953-7104. doi: 10.1080/09537104.2018.1557618. Full text in Research Archive
• Holme, Pål Andre & Tjønnfjord, Geir Erland (2018). Continuous infusion of simoctocog alfa in haemophilia A patients undergoing surgeries. Haemophilia. ISSN 1351-8216. p. 1–6. doi: 10.1111/hae.13625. Full text in Research Archive Show summary

  Introduction There are two major principles for coagulation factor replacement in the clinical management of surgical procedures in patients with haemophilia, repetitive bolus injections every 6‐12 hours or administration of coagulation factor concentrates by continuous infusion. Aim The aim was to investigate the efficacy of simoctocog alfa (human‐cl rhFVIII) delivered by continuous infusion for bleeding prophylaxis during surgery in patients with haemophilia A. Methods We investigated the use of continuous infusion with simoctocog alfa in haemophilia A patients undergoing major surgical procedures at Oslo University Hospital from September 2015 to March 2018. The objectives were haemostatic outcome, in vivo recovery, stability over time at room temperature (3 days) and inhibitor development. Results Simoctocog alfa demonstrated treatment success in terms of haemostatic efficacy in 100% of major surgeries used as CI: 87% (n=21) excellent; 13% (n=3) good. No erythrocyte transfusions were required in any patient, no adverse events occurred and no inhibitors developed. The product was stable for 3 days at room temperature without loss of activity. Mean in vivo recovery was 1.8 (0.3) (IU/mL/IU/kg). Conclusion Continuous infusion with simoctocog alfa was found to achieve good/excellent haemostatic efficacy in all procedures. No adverse events occurred and no inhibitors developed.

• Holme, Pål Andre; Tjønnfjord, Geir Erland & Batorova, A (2017). Continuous infusion of coagulation factor concentrates during intensive treatment. Haemophilia. ISSN 1351-8216. 24(1), p. 24–32. doi: 10.1111/hae.13331. Full text in Research Archive
• Schultz, Nina Haagenrud; Tran, Hoa Thi Tuyet; Bjørnsen, Stine; Henriksson, Carola; Sandset, Per Morten & Holme, Pål Andre (2017). The reversal effect of prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor VII against anticoagulation of Xa inhibitor. Thrombosis Journal. 15(1). doi: 10.1186/s12959-017-0129-1. Full text in Research Archive Show summary

  Background An increasing number of patients are treated with direct-acting oral anticoagulants (DOACs), but the optimal way to reverse the anticoagulant effect is not known. Specific antidotes are not available and prothrombin complex concentrate (PCC), activated PCC (aPCC) and recombinant factor VIIa (rFVIIa) are variously used as reversal agents in case of a major bleeding. We aimed to determine the most effective haemostatic agent and dose to reverse the effect of rivaroxaban in blood samples from patients taking rivaroxaban for therapeutic reasons. Methods Blood samples from rivaroxaban-treated patients (n = 50) were spiked with PCC, aPCC and rFVIIa at concentrations imitating 80%, 100% and 125% of suggested therapeutic doses. The reversal effect was assessed by thromboelastometry in whole blood and a thrombin generation assay (TGA) in platelet-poor plasma. Samples from healthy subjects (n = 40) were included as controls. Results In thromboelastometry measurements, aPCC and rFVIIa had a superior effect to PCC in reversing the rivaroxaban-induced lenghtening of clotting time (CT). aPCC was the only haemostatic agent that shortened the CT down to below the control level. Compared to healthy controls, patients on rivaroxaban also had a prolonged lag time and decreased peak concentration, velocity index and endogenous thrombin potential (ETP) in platelet-poor plasma. aPCC reversed these parameters more effectively than rFVIIa and PCC. There were no differences in efficacy between 80%, 100% and 125% doses of aPCC. Conclusions aPCC seems to reverse the anticoagulant effect of rivaroxaban more effectively than rFVIIa and PCC by evaluation with thromboelastometry and TGA in vitro.

• Berntorp, Erik; Dargaud, Yesim; Hart, Daniel; Lobet, Sébastien; Mancuso, Maria Elisa & d'Oiron, Roseline [Show all 26 contributors for this article] (2017). The second Team Haemophilia Education Meeting, 2016, Frankfurt, Germany. European Journal of Haematology. ISSN 0902-4441. 98, p. 1–15. doi: 10.1111/ejh.12828. Full text in Research Archive
• Osooli, Mehdi; Carlsson, Katarina Steen; Baghaei, Fariba; Holmström, Margareta; Rauchensteiner, Stephan & Holme, Pål Andre [Show all 9 contributors for this article] (2017). The association between health utility and joint status among people with severe haemophilia A: findings from the KAPPA register. Haemophilia. ISSN 1351-8216. 23(3), p. e180–e187. doi: 10.1111/hae.13231. Full text in Research Archive
• Schultz, Nina Haagenrud; Tran, Hoa Thi Tuyet; Bjørnsen, Stine; Henriksson, Carola Elisabeth; Sandset, Per Morten & Holme, Pål Andre (2017). The reversal effect of prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor VII in apixaban-treated patients in vitro. Research and Practice in Thrombosis and Haemostasis (RPTH). 1(1), p. 49–56. doi: 10.1002/rth2.12015. Full text in Research Archive
• Barratt-Due, Andreas; Fløisand, Yngvar; Lang, Hilde Elisabeth; Kvam, Ann Kristin; Holme, Pål Andre & Bergseth, Grete [Show all 8 contributors for this article] (2016). Complement activation is a crucial pathogenic factor in catastrophic antiphospholipid syndrome. Rheumatology. ISSN 1462-0324. doi: 10.1093/rheumatology/kew040. Full text in Research Archive Show summary

  Catastrophic antiphospholipid syndrome is associated with excessive complement activation explaining the clinical efficacy of complement inhibitory treatment.

• HAIG, YLVA; Enden, Tone Rønnaug; Grøtta, Ole Jørgen; Kløw, Nils-Einar; Slagsvold, Carl Erik & Ghanima, Waleed Khalid [Show all 13 contributors for this article] (2016). Post-thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomised controlled trial. The Lancet Haematology. ISSN 2352-3026. 3(2), p. e64–e71. doi: 10.1016/S2352-3026(15)00248-3. Full text in Research Archive
• Holme, Pål Andre; Combescure, Christophe; Tait, Robert Cambell; Berntorp, Erik E.; Rauchensteiner, Stephan & Moerloose, Philippe R. de (2016). Hypertension, haematuria and renal functioning in haemophilia - a cross-sectional study in Europe. Haemophilia. ISSN 1351-8216. 22(2), p. 248–255. doi: 10.1111/hae.12847. Full text in Research Archive
• Holstein, K; Batorova, A; Carvalho, M.; Fijnvandraat, K.; Holme, Pål Andre & Kavakli, K [Show all 10 contributors for this article] (2016). Current view and outcome of ITI therapy - A change over time? Thrombosis Research. ISSN 0049-3848. 148, p. 38–44. doi: 10.1016/j.thromres.2016.10.015. Full text in Research Archive Show summary

  Introduction Inhibitor development in people with haemophilia is a serious complication that may require intensive and costly interventions. The goal of inhibitor management should be permanent inhibitor eradication through immune tolerance induction (ITI), but well-designed studies are lacking and the management of patients is therefore defined by the experience and views of the clinician. Objectives To explore the current clinical practice and outcome of ITI therapy in Europe and how this may have changed over the last decade, as well as to provide consensus recommendations to guide clinicians in their clinical practice. Methods A survey was conducted among 16 European haemophilia comprehensive care centres to evaluate current ITI treatment regimens and success rates in severe and mild/moderate haemophilia A and haemophilia B. In addition, an updated literature review was performed as guidance for providing recommendations. Results We demonstrated successful inhibitor treatment in 86% of severe haemophilia A patients with low responding (LR) and 59% of patients with high responding (HR) inhibitors. Some new trends in the management of patients with inhibitors were identified, including a tendency to use low-dose regimens (< 50 IU/kg/d) in both children and adults with HR inhibitors possibly based on similar success rates demonstrated in the I-ITI study compared to a high-dose protocol. Data on ITI therapy in mild and moderate haemophilia as well as haemophilia B were limited. Conclusions The outcome of ITI therapy seems to be stable over time, and treatment regimens remain heterogeneous. The use of low dose regimens however is considered more frequently.

• Berger, Karin B.; Schopohl, Dorothee; Lowe, Gordon; Holme, Pål Andre; Tait, Robert Cambell & Combescure, Christophe [Show all 8 contributors for this article] (2016). How to compare cardiovascular disease and risk factors in elderly patients with haemophilia with the general population. Haemophilia. ISSN 1351-8216. 22(5), p. e406–e416. doi: 10.1111/hae.13069. Full text in Research Archive
• James, PD; Mahlangu, J; Bidlingmaier, C; Mingot-Castellano, María Eva; Chitlur, M & Fogarty, PF [Show all 13 contributors for this article] (2016). Evaluation of the utility of the ISTH-BAT in haemophilia carriers: a multinational study. Haemophilia. ISSN 1351-8216. 22(6), p. 912–918. doi: 10.1111/hae.13089. Full text in Research Archive
• Tran, Hoa Thi Tuyet; Sørensen, B.; Bjørnsen, Stine; Pripp, Are Hugo; Tjønnfjord, Geir Erland & Holme, Pål Andre (2015). Monitoring bypassing agent therapy - a prospective crossover study comparing thromboelastometry and thrombin generation assay. Haemophilia. ISSN 1351-8216. 21(2), p. 275–283. doi: 10.1111/hae.12570. Full text in Research Archive
• Fogarty, Patrick F.; Mancuso, Maria Elisa; Kasthuri, Ram S.; Bidlingmaier, Christoph M.; Chitlur, Meera B. & Gomez, Keith [Show all 12 contributors for this article] (2015). Presentation and management of acute coronary syndromes among adult persons with haemophilia: Results of an international, retrospective, 10-year survey. Haemophilia. ISSN 1351-8216. 21(5), p. 589–597. doi: 10.1111/hae.12652. Full text in Research Archive
• Ghanima, Waleed Khalid; Khelif, Abderrahim; Waage, Anders; Michel, Marc; Tjønnfjord, Geir Erland & Romdhan, Neila Ben [Show all 9 contributors for this article] (2015). Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): A multicentre, randomised, double-blind, placebo-controlled trial. The Lancet. ISSN 0140-6736. 385(9978), p. 1653–1661. doi: 10.1016/S0140-6736(14)61495-1. Full text in Research Archive
• Valentino, Leonard A. & Holme, Pål Andre (2015). Should anti-inhibitor coagulant complex and tranexamic acid be used concomitantly? Haemophilia. ISSN 1351-8216. 21(6), p. 709–714. doi: 10.1111/hae.12723. Full text in Research Archive
• Tran, Hoa Thi Tuyet; Tjønnfjord, Geir Erland & Holme, Pål Andre (2014). Use of thromboelastography and thrombin generation assay to predict clinical phenotype in patients with severe FVII deficiency. Haemophilia. ISSN 1351-8216. 20(1), p. 141–146. doi: 10.1111/hae.12256. Full text in Research Archive
• Kristiansen, Annette; Brandt, Linn; Agoritsas, Thomas; Akl, Elie A.; Berge, Eivind & Bondi, Johan Fridtjof [Show all 19 contributors for this article] (2014). Adaptation of trustworthy guidelines developed using the GRADE methodology: a novel five-step process. Chest. ISSN 0012-3692. 146(3), p. 727–734. doi: 10.1378/chest.13-2828. Full text in Research Archive Show summary

  BACKGROUND: Adaptation of guidelines for use at the national or local level can facilitate their implementation. We developed and evaluated an adaptation process in adherence with standards for trustworthy guidelines and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, aiming for efficiency and transparency. This article is the first in a series describing our adaptation of Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for a Norwegian setting. METHODS: Informed by the ADAPTE framework, we developed a five-step adaptation process customized to guidelines developed using GRADE: (1) planning, (2) initial assessment of the recommendations, (3) modification, (4) publication, and (5) evaluation. We developed a taxonomy for describing how and why recommendations from the parent guideline were modified and applied a mixed-methods case study design for evaluation of the process. RESULTS: We published the adapted guideline in November 2013 in a novel multilayered format. The taxonomy for adaptation facilitated transparency of the modification process for both the guideline developers and the end users. We excluded 30 and modified 131 of the 333 original recommendations according to the taxonomy and developed eight new recommendations. Unforeseen obstacles related to acquiring a licensing agreement and procuring a publisher resulted in a 9-month delay. We propose modifications of the adaptation process to overcome these obstacles in the future. CONCLUSIONS: This case study demonstrates the feasibility of a novel guideline adaptation process. Replication is needed to further validate the usefulness of the process in increasing the organizational and methodologic efficiency of guideline adaptation.

• Misceo, Doriana; Holmgren, Asbjørn; Louch, William Edward; Holme, Pål Andre; Mizobuchi, Masahiro & Morales, Raul J. [Show all 14 contributors for this article] (2014). A Dominant STIM1 Mutation Causes Stormorken Syndrome. Human Mutation. ISSN 1059-7794. 35(5), p. 556–564. doi: 10.1002/humu.22544. Full text in Research Archive
• Tvedt, Tor Henrik Anderson; Holme, Pål Andre & Bruserud, Øystein (2014). En mann i 80-årene med muskelstivhet og hudblødninger 1058. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 134(10), p. 1058–1061. doi: 10.4045/tidsskr.13.0817. Full text in Research Archive
• Husøy, Magnus Andreas Rognlien; Brinch, Lorentz; Tjønnfjord, Geir Erland; Gedde-Dahl, Tobias Jr.; Heldal, Dag & Holme, Pål Andre [Show all 16 contributors for this article] (2014). Allogen stamcelletransplantasjon hos voksne 1985-2012. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 134(16), p. 1569–1575. doi: 10.4045/tidsskr.13.1415. Full text in Research Archive
• WESTBERG, MARIANNE; Paus, Albert Collett; Holme, Pål Andre & Tjønnfjord, Geir Erland (2014). Haemophilic arthropathy: Long-term outcomes in 107 primary total knee arthroplasties. Knee (Oxford). ISSN 0968-0160. 21(1), p. 147–150. doi: 10.1016/j.knee.2013.09.010. Full text in Research Archive
• Tran, Hoa Thi Tuyet; Sørensen, B.; Rea, C.J.; Bjørnsen, Stine; Ueland, Thor & Pripp, Are Hugo [Show all 8 contributors for this article] (2014). Tranexamic acid as adjunct therapy to bypassing agents in haemophilia A patients with inhibitors. Haemophilia. ISSN 1351-8216. 20(3), p. 369–375. doi: 10.1111/hae.12318. Full text in Research Archive
• Mathijssen, Natascha C.J.; Masereeuw, Roselinde; Holme, Pål Andre; Kraaij, Marian G.J. van; Gorkom, Britta A.P. Laros-van & Peyvandi, Flora [Show all 7 contributors for this article] (2013). Increased volume of distribution for recombinant activated factor VII and longer plasma-derived factor VII half-life may explain their long lasting prophylactic effect. Thrombosis Research. ISSN 0049-3848. 132(2), p. 256–262. doi: 10.1016/j.thromres.2013.05.027. Full text in Research Archive
• Geffen, Mark van; Mathijssen, Natascha C.J.; Holme, Pål Andre; Gorkom, Britta A.P. Laros-van; Kraaij, Marian G.J. van & Masereeuw, Roselinde [Show all 8 contributors for this article] (2013). Pharmacodynamics of recombinant activated factor VII and plasma-derived factor VII in a cohort of severe FVII deficient patients. Thrombosis Research. ISSN 0049-3848. 132(1), p. 116–122. doi: 10.1016/j.thromres.2013.04.021. Full text in Research Archive
• Holmström, M.; Tran, Hoa Thi Tuyet & Holme, Pål Andre (2012). Combined treatment with APCC (FEIBA (R)) and tranexamic acid in patients with haemophilia A with inhibitors and in patients with acquired haemophilia A - a two-centre experience. Haemophilia. ISSN 1351-8216. 18(4), p. 544–549. doi: 10.1111/j.1365-2516.2012.02748.x. Full text in Research Archive
• Vetlesen, Annette; Holme, Pål Andre; Lyberg, Torstein & Kjeldsen-Kragh, Jens (2012). Recovery, survival, and function of transfused platelets and detection of platelet engraftment after allogeneic stem cell transplantation. Transfusion. ISSN 0041-1132. 52(6), p. 1321–1332. doi: 10.1111/j.1537-2995.2011.03442.x. Full text in Research Archive
• Batorova, A; Holme, Pål Andre; Gringeri, A; Richards, M.; Hermans, C. & Altisent, C. [Show all 8 contributors for this article] (2012). Continuous infusion in haemophilia: current practice in Europe. Haemophilia. ISSN 1351-8216. 18(5), p. 753–759. doi: 10.1111/j.1365-2516.2012.02810.x. Full text in Research Archive
• Enden, Tone Rønnaug; HAIG, YLVA; Klow, Nils-Einar; Slagsvold, Carl Erik; Sandvik, Leiv & Ghanima, Waleed Khalid [Show all 12 contributors for this article] (2012). Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. The Lancet. ISSN 0140-6736. 379(9810), p. 31–38. doi: 10.1016/S0140-6736(11)61753-4. Full text in Research Archive
• Lassila, Riita; Holme, Pål Andre; Landorph, Andrea; Petrini, Pia; Onundarson, Páll T. & Hillarp, Andreas (2011). Nordic Haemophilia Council's Practical Guidelines on Diagnosis and Management of von Willebrand Disease. Seminars in Thrombosis and Hemostasis. ISSN 0094-6176. 37(5), p. 495–502. doi: 10.1055/s-0031-1281034. Full text in Research Archive
• Lassila, R; Antovic, Jovan P; Armstrong, Elina; Baghaei, Fariba; Dalsgaard-Nielsen, Jørn & Hilllarp, Andreas [Show all 11 contributors for this article] (2011). Practical viewpoints on the diagnosis and management of heparin induced thrombocytopenia. Seminars in Thrombosis and Hemostasis. ISSN 0094-6176. 37(3), p. 328–335. doi: 10.1055/s-0031-1274516. Full text in Research Archive Show summary

  Heparin-induced thrombocytopenia (HIT, type II) is an immune-mediated disorder due to antibodies formed against heparin-platelet factor 4 complexes, usually appearing at days 5 to 14 after initiation of heparin. It is important to recognize HIT because heparin prophylaxis or treatment paradoxically associates with new venous and/or arterial thrombosis. Early clinical suspicion and diagnosis together with proper pharmacotherapy and close laboratory monitoring are the cornerstones for successful management. This includes monitoring of Thrombocytopenia, its Timing to heparin administration, appearance of new Thrombosis or resistance to treatment, and differential diagnosis by exclusion of o Ther causes (the 4T's). Specific attention should be paid to the absence or presence of thrombosis and to tailoring thromboprophylaxis or anticoagulant therapy with a nonheparin alternative. Even in the absence of HIT-associated thrombosis, an active policy for prolonged thromboprophylaxis is demanded. Rapid and reliable assays should be developed for diagnosis and anticoagulation monitoring to secure safe management with nonheparins. Semiquantitative testing for on-call hours should be available and later confirmed as clinically needed. Alternative therapeutic options are available, but because their use is infrequent, experienced coagulation treatment centers should provide guidance in the treatment and in laboratory monitoring. Most of the evidence in HIT is grade IC, and thus the best evidence is provided by clinical experience. New anticoagulants and platelet inhibitors may offer future alternatives in the management of HIT, but the current treatment options provide the best experience and benefit. The joint clinical and laboratory guidelines provided in this article along with two practical case scenarios were prepared by a Nordic expert panel. They will be valuable for hematologists and colleagues who do not routinely encounter HIT.

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• Drivet, Elsa Maria Caroline; Tsykunova, Galina; Egner, Ingrid Marie; Lund, Katrine Persgård; Goll, Guro Løvik & Tran, Hoa Thi Thyuet [Show all 11 contributors for this article] (2026). Interleukin-17-associated inflammation in non-responders and B-cell remodeling after daratumumab in refractory immune thrombocytopenia. Haematologica. ISSN 0390-6078. doi: 10.3324/haematol.2026.301032. Full text in Research Archive Show summary

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• Dugarte, Maria Eugenia Chollet; Bhattacharya, Anindita; Roman, Giacomo; Harrison, Sean Philip; Baumgarten, Saphira Felicitas & Andersen, Elisabeth [Show all 12 contributors for this article] (2025). Autologous gene-corrected hepatic organoids for the treatment of FVII deficiency. Research and Practice in Thrombosis and Haemostasis (RPTH). 9(S2), p. 265–266. doi: 10.1016/j.rpth.2025.102925. Full text in Research Archive
• Reding, Mark T.; Lalezari, Shadan; Kenet, Gili; Minno, Giovanni Di; Ducore, Jonathan & Solms, Alexander [Show all 12 contributors for this article] (2024). Correction to: Damoctocog Alfa Pegol, a PEGylated B-domain Deleted Recombinant Extended Half-life Factor VIII for the Treatment of Hemophilia A: A Product Review (Drugs in R&D, (2024), 24, 3, (359-381), 10.1007/s40268-024-00481-7). Drugs in R&D. ISSN 1174-5886. doi: 10.1007/s40268-024-00494-2. Full text in Research Archive
• Holm, Sverre; Michelsen, Annika Elisabet; Schultz, Nina Haagenrud; Ueland, Thor; Reikvam, Håkon & Holme, Pål Andre [Show all 8 contributors for this article] (2024). Human papilloma virus vaccine induced thrombocytopenia accompanied by a wide spectrum of reversible inflammatory responses – a case report. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 84(6). doi: 10.1080/00365513.2024.2400663. Full text in Research Archive
• Dugarte, Maria Eugenia Chollet; Bhattacharya, Anindita; Roman, Giacomo; Harrison, Sean; Baumgarten, Saphira Felicitas & Andersen, Elisabeth [Show all 12 contributors for this article] (2024). Autologous gene-corrected stem cell-derived hepatic organoids for the treatment of FVII deficiency. HemaSphere. doi: 10.1002/hem3.104. Full text in Research Archive
• Hermans, Cedric; Astermark, Jan; Carvalho, Manuela; Dolan, Gerry; d'Oiron, Roseline & Fontana, Pierre [Show all 20 contributors for this article] (2023). Prevalence of COVID-19 related hospitalizations and mortality in adults aged ≥40 years with haemophilia: A survey from Europe. Haemophilia. ISSN 1351-8216. 29(3), p. 913–916. doi: 10.1111/hae.14761. Full text in Research Archive
• Holme, Pål Andre; Ghanima, Waleed; Wik, Hilde Skuterud; Jacobsen, Eva-Marie & Fløisand, Yngvar (2022). Koagulasjonsforstyrrelser. In Birkeland, Kåre Inge; Gullestad, Lars & Aabakken, Lars (Ed.), Indremedisin I. Fagbokforlaget. ISSN 9788245043365. p. 447–458. Full text in Research Archive
• Schultz, Nina Haagenrud; Holme, Pål Andre; Henriksson, Carola; Mowinckel, Marie-Christine; Sandset, Per Morten & Bratseth, Vibeke [Show all 7 contributors for this article] (2019). The influence of rivaroxaban on markers of fibrinolysis and endothelial cell activation/injury in patients with venous thrombosis. Thrombosis Research. ISSN 0049-3848. 177, p. 154–156. doi: 10.1016/j.thromres.2019.03.010. Full text in Research Archive
• Holme, Pål Andre; Berntorp, E; Moerloose, P De & Tait, R.C. (2011). Haematuria and hypertension in haemophilia - the H3 study. Haemophilia. ISSN 1351-8216. 17(2), p. 377–377. Full text in Research Archive

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