University of Wisconsin Hematology

Congenital bleeding disorders

General

  1. Rick et al. Congenital Bleeding Disorders. Hematology 2003:559-574
  2. Mezzano and Quiroga. Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research. J Thromb Haemost 2019;17:257(An in-depth discussion of the difficulties encountered in diagnosing VWD and other mild bleeding disorders)
  3. Adams et al. Next-Generation Sequencing to Diagnose Suspected Genetic Disorders. NEJM 2018;379:1353
  4. Peyvandi et al. Genetic sequence analysis of inherited bleeding disorders. Blood 2013;122:3423
  5. Freson and Turro. High-throughput sequencing approaches for diagnosing hereditary bleeding and platelet disorders. J Thromb Haemost 2017;15:1262
  6. Martin and Key. How I treat patients with inherited bleeding disorders who need anticoagulant therapy. Blood 2016;128:178

Hemophilia

Pathophysiology, complications

  1. Samelson-Jones et al. Coagulation factor VIII: biological basis of emerging hemophilia A therapies. Blood 2024;144:2185
  2. Bos et al. Blood coagulation factor IX: structural insights impacting hemophilia B therapy. Blood 22024;144:2198
  3. Josephson N. The hemophilias and their clinical management. Hematology 2013:261
  4. Johnsen et al. Results of genetic analysis of 11 341 participants enrolled in the My Life, Our Future hemophilia genotyping initiative in the United States. J Thromb Haemost 2022;20:2022
  5. Iorio et al. Establishing the Prevalence and Prevalence at Birth of Hemophilia in Males: A Meta-analytic Approach Using National Registries. Ann Intern Med 2019;171:540
  6. Mancuso et al. The predictive value of factor VIII/factor IX levels to define the severity of hemophilia: communication from the SSC of ISTH. J Thromb Haemost 2018;16:2106
  7. Makris et al. The definition, diagnosis and management of mild hemophilia A: communication from the SSC of the ISTH. J Thromb Haemost 2018;16:2530
  8. Everett et al. Murine factor VIII is synthesized in endothelial cells. Blood 2014;123:3697
  9. Fahs et al. A conditional knockout mouse model reveals endothelial cells as the principal and possibly exclusive source of plasma factor VIII. Blood 2014;123:3706
  10. Escobar and Sallah. Hemophilia A and hemophilia B: focus on arthropathy and variables affecting bleeding severity and prophylaxis. J Thromb Haemost 2013;11:1449
  11. Peyvandi et al. A critical appraisal of one-stage and chromogenic assays of factor VIII activity. J Thromb Haemost 2016;14:248(Conventional factor VIII assays may underestimate factor activity after treatment with some clotting factor products)
  12. Boylan et al. Evaluation of von Willebrand factor phenotypes and genotypes in Hemophilia A patients with and without identified F8 mutations. J Thromb Haemost 2015;13:1036(Patients with hemophilia A phenotype should have VWF evaluation)
  13. Gualtierotti et al. Hemophilic arthropathy: Current knowledge and future perspectives. J Thromb Haemost 2021;19:2112
  14. Soucie et al.  Joint range-of-motion limitations among young males with hemophilia: prevalence and risk factors.  Blood 2004;103:2467
  15. Tagariello et al. Comparison of the rates of joint arthroplasty in patients with severe factor VIII and IX deficiency: an index of different clinical severity of the 2 coagulation disorders. Blood 2009;114:779(3-fold higher rate of arthroplasty in hemophilia A vs B)
  16. Manco-Johnson et al. Prophylaxis usage, bleeding rates, and joint outcomes of hemophilia, 1999 to 2010: a surveillance project. Blood 2017;129:2368(Prophylaxis markedly decreases bleeding rates; if started before age 4 it preserves joint function)
  17. Zwagemaker et al. Incidence and mortality rates of intracranial hemorrhage in hemophilia: a systematic review and meta-analysis. Blood 2021;138:2853
  18. Darby et al. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood 2007;110:815
  19. Hassan et al. Health and treatment outcomes of patients with hemophilia in the Netherlands, 1972–2019. J Thromb Haemost 2021;19:2394
  20. La Mura et al. The management of liver disease in people with congenital bleeding disorders: guidance from European Association for Haemophilia and Allied Disorders, European Haemophilia Consortium, ISTH, and World Federation of Hemophilia. J Thromb Haemost 2024;22:3629
  21. Posthouwer et al. Progression to end-stage liver disease in patients with inherited bleeding disorders and hepatitis C: an international, multicenter cohort study. Blood 2007; 109:3667
  22. Kamphuisen and ten Cate. Cardiovascular risk in patients with hemophilia. Blood 2014;123:1297
  23. Dix et al. Reducing the risk of atherosclerotic cardiovascular disease in people with hemophilia: the importance of primary prevention. J Thromb Haemost 2024;22:1304
  24. de Koning et al. Comparing thrombin generation in patients with hemophilia A and patients on vitamin K antagonists. J Thromb Haemost 2017;15:868(Thrombin generation in severe hemophilia comparable to that found with therapeutic INR, suggests that severe hemophiliacs with AF would not require anticoagulation)
  25. Mannucci et al. How I treat age-related morbidities in elderly persons with hemophilia. Blood 2009;114:5256
  26. Plug et al. Bleeding in carriers of hemophilia.  Blood 2006;108:52
  27. Kurian et al. Successful liver transplant from a hemophilia A donor with no development of hemophilia A in recipient. J Thromb Haemost 2020;18:853(Normal factor VIII levels in recipient post-transplant, confirrming extra-hepatic source of factor VIII)
  28. Kumar et al. Moderate-intensity aerobic exercise vs desmopressin in adolescent males with mild hemophilia A: a randomized trial. Blood 2022;140:1156 (Transient 1.7 fold increase in FVIII after moderate exercise in adolescents with mild HA)
  29. Kitchen et al. Both one-stage and chromogenic factor VIII assays are required for the diagnosis of mild hemophilia A. J Thromb Haemost 2023;21:773
  30. Zwagemaker et al. Little discrepancy between one-stage and chromogenic factor VIII (FVIII)/IX assays in a large international cohort of persons with nonsevere hemophilia A and B. J Thromb Haemost 2023;21:850

Treatment: clotting factor concentrate

  1. Rezende et al. International Society on Thrombosis and Haemostasis clinical practice guideline for treatment of congenital hemophilia A and B based on the Grading of Recommendations Assessment, Development, and Evaluation methodology. J Thromb Haemost 2024;22:2629
  2. Manco-Johnson et al. Prophylaxis versis episodic treatment to prevent joint disease in boys with severe hemophilia. NEJM 2007;357:535
  3. Manco-Johnson et al. Effect of late prophylaxis in hemophilia on joint status: a randomized trial. J Thromb Haemost 2017;15:2115(Prophylaxis in adults was beneficial, but did not reverse pre-existing joint disease)
  4. Fischer et al. Intermediate-dose versus high-dose prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s. Blood 2013;122:1129 (“the incremental benefits of high-dose prophylaxis appear limited”)
  5. Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. Blood 2015;125:2038
  6. DeBiasi et al. The impact of a very high purity factor VIII concentrate on the immune system of human immunodeficiency virus-infected hemophiliacs. Blood 1991; 78:1919
  7. Hazendonk et al. Perioperative treatment of hemophilia A patients: blood group O patients are at risk of bleeding complications. J Thromb Haemost 2016;14:468
  8. Inwood et al. The use and safety of ibuprofen in the hemophiliac. Blood 1983; 61:709
  9. Pipe et al. Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A. Blood 2016;128:2007(Half-life of VWF is limiting factor for half life of extended half-life FVIII products)
  10. Tsoukaset al. Evaluation of the efficacy and safety of etoricoxib in the treatment of hemophilic arthropathy. Blood 2006;107:1785
  11. Leebeek et al. How I manage pregnancy in carriers of hemophilia and patients with von Willebrand disease. Blood 2020;136:2143
  12. Santagata et al. Rates of venous thromboembolism and use of thromboprophylaxis after major orthopedic surgery in patients with congenital hemophilia A or B: a systematic review. J Thromb Haemost 2024;22:1117 (Low incidence of VTE despite lack of thromboprophylaxis)
  13. Escobar et al. Use of antithrombotic therapy in patients with hemophilia: a selected synopsis of the European Hematology Association – International Society on Thrombosis and Haemostasis – European Association for Hemophilia and Allied Disorders – European Stroke Organization Clinical Practice Guidance document. J Thromb Haemost 2025;23:745

New treatments

  1. Ragni and Chan. Innovations in RNA therapy for hemophilia. Blood 2023;142:1613
  2. Weyand and Pipe. New therapies for hemophilia. Blood 2019;133:389
  3. Callaghan et al. Novel therapeutics for hemophilia and other bleeding disorders. Blood 2018;132:23
  4. Arruda et al. Novel approaches to hemophilia therapy: successes and challenges. Blood 2017;130:2251
  5. Young et al. Laboratory assay measurement of modified clotting factor concentrates: a review of the literature and recommendations for practice. J Thromb Haemost 2019;17:567
  6. Peyvandi et al. Laboratory testing in hemophilia: Impact of factor and non‐factor replacement therapy on coagulation assays. J Thromb Haemost 2020;18:1242
  7. Powell et al. Phase 3 Study of Recombinant Factor IX Fc Fusion Protein in Hemophilia B. NEJM 2013;369:2313(Prophylaxis with this long-acting derivative of Factor IX substantially reduced bleeding rates)
  8. Collins et al. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood 2014;124:3880(Weekly prophylaxis lowered bleeding rates, improved QOL)
  9. Santogostino et al. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood 2016;127:1761(Weekly and q14 day prophylaxis schedules effective; mean trough levels 20% and 12% respectively)
  10. Mahlangu et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood 2014;123:317
  11. Young et al. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. J Thromb Haemost 2015;13:967 (Twice weekly prophylaxis; 46% had no bleeding episodes while on treatment)
  12. Shapiro et al. Recombinant factor VIII Fc fusion protein: extended-interval dosing maintains low bleeding rates and correlates with von Willebrand factor levels. J Thromb Haemost 2014;12:1788(Higher VWF levels allow less frequent dosing; 5-day interval effective in many cases)
  13. Konkle et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood 2015;126:1078(1.5x extended half-life. Twice-weekly prophylaxis reduced bleed rate vs standard Rx, no inhibitors found)
  14. Klamroth et al. Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study. Blood 2021;137:1818(8-12% trough levels better than 1-3%)
  15. Mahlangu et al. Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A. Blood 2016;128:630
  16. Konkle et al. BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A. NEJM 2020;383:1018(Half-life 3-4x that of recombinant FVIII; with editorial)
  17. Königs et al. First study of extended half-life rFVIIIFc in previously untreated patients with hemophilia A: PUPs A-LONG final results. Blood 2022; 139:3699
  18. von Drygalski et al. Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A. NEJM 2023;388:310 (Once-weekly treatment with modified FVIII molecule maintains mean trough FVIII level of 15%; superior to standard prophylaxis; with editorial)
  19. Uchida et al. A first-in-human phase 1 study of ACE910, a novel factor VIII–mimetic bispecific antibody, in healthy subjects. Blood 2016;127:1633(Antibody binds to both factor IXa and factor X, shortens clotting times and enhances thrombin generation with half-life > 4 weeks)
  20. Shima et al. Factor VIII–Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. NEJM 2016;374:2044(With editorial)
  21. Mahlangu et al. Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. NEJM 2018;379:811(>95% reduction in bleeding rate with every 2 week prophylaxis; with editorial)
  22. Pipe et al. Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. Lancet Haematol 2019;6:e295
  23. Ragni MV. The effect of emicizumab regimen on haemophilia outcomes. Lancet Haem 2019;6:e286(Summarizes results from the HAVEN trials)
  24. Callaghan et al. Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. Blood 2021;137:2231
  25. Abbattista et al. Hemorrhagic and thrombotic adverse events associated with emicizumab and extended half-life factor VIII replacement drugs: EudraVigilance data of 2021. J Thromb Haemost 2023;21:546 (Less bleeding, more thrombotic events with emicizumab)
  26. Cho et al. Comparison of thrombotic adverse events in patients treated with factor VIII products and emicizumab using the 2018-2022 US Food and Drug Administration Adverse Event Reporting System data. J Thromb Haemost 2024;22:1640 (Thrombotic events more common with emicizumab)
  27. Druzgal et al. Neutralizing antidrug antibody to emicizumab in a patient with severe hemophilia A with inhibitors: New case with detailed laboratory evaluation. J Thromb Haemost 2020;18:2205
  28. Pezeshkpoor et al. Comprehensive evaluation of anti-emicizumab antibodies in acquired hemophilia A: a detailed case study and methodological evaluation. J Thromb Haemost 2025;23:85
  29. Pasi et al. Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy. NEJM 2017;377:819
  30. Young et al. Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial. Lancet 2023;401:1427 (Once monthly fitusiran prophylaxis markedly superior to on-demand bypassing agents)
  31. Srivastava et al. Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial. Lancet Haematol 2023;10:E322
  32. Kenet et al. Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA/CFC prophylaxis: the ATLAS-PPX trial. Blood 2024;143:2256
  33. Fogarty PF. Biologic rationale for new drugs in the bleeding disorder pipeline. Hematology 2011:397
  34. Ragni MV. The old and new: PCCs, VIIa, and long-lasting clotting factors for hemophilia and other bleeding disorders. Hematology 2013:44
  35. Prince et al. Targeting anticoagulant protein S to improve hemostasis in hemophilia. Blood 2018;131:1360(“Rebalancing” coagulation with PS silencing RNA- mouse model)
  36. Eichler et al. A randomized trial of safety, pharmacokinetics and pharmacodynamics of concizumab in people with hemophilia A. J Thromb Haemost 2018;16:2184(Anti-TFPI monoclonal Ab)
  37. Ay et al. The von Willebrand factor–binding aptamer rondaptivon pegol as a treatment for severe and nonsevere hemophilia A. Blood 2023;141:1147
  38. Abbattista et al. Hemorrhagic and thrombotic adverse events associated with emicizumab and extended half-life factor VIII replacement drugs: EudraVigilance data of 2021. J Thromb Haemost 2023;21:546 (Emicizumab associated with less bleeding but more thrombotic events than extended half-life products)

Gene therapy

  1. Leebeek and Miesbach. Gene therapy for hemophilia: a review on clinical benefit, limitations, and remaining issues. Blood 2021;138:923
  2. Baas et al. The ethics of gene therapy for hemophilia: a narrative review. J Thromb Haemost 2023;21:413
  3. Perrin et al. Update on clinical gene therapy for hemophilia. Blood 2019;133:407
  4. Nathwani et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. NEJM 2011;365:2357
  5. Nathwani et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. NEJM 2014;371:1994
  6. George et al. Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant. NEJM 2017;377:2215
  7. Sehgal et al. An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia. Nat Med 2015;21:492(In animal models)
  8. Rangarajan et al. AAV5–Factor VIII Gene Transfer in Severe Hemophilia A. NEJM 2017; 377:2519 (With editorial)
  9. Pasi et al. Multiyear followup of AAV5-hFVIII-SQ gene therapy for hemophilia A. NEJM 2020;382:29
  10. Miesbach et al. Gene therapy with adeno-associated virus vector 5–human factor IX in adults with hemophilia B. Blood 2018;131:1022
  11. Chowdary et al. Phase 1–2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B. NEJM 2022;387:237 (Normal or supranormal factor levels achievable, requires immunosuppression)
  12. Srivastava et al. Lentiviral Gene Therapy with CD34+ Hematopoietic Cells for Hemophilia A. NEJM 2025;392:450
  13. Cuker et al. Gene Therapy with Fidanacogene Elaparvovec in Adults with Hemophilia B. NEJM 2024;391:1108
  14. Rasko et al. : Fidanacogene Elaparvovec for Hemophilia B — A Multiyear Follow-up Study. NEJM 2025;392:1508
  15. O’Connell et al. Invasive procedures and surgery following etranacogene dezaparvovec gene therapy in people with hemophilia B. J Thromb Haemost 2025;73
  16. George et al. Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A. NEJM 2021;385:1961
  17. Mahlangu et al. Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A.  NEJM 2023;388:694 (85% reduction in bleed rate; gradual decline in F VIII activity although benefit expected to last several years. With editorial)
  18. Pipe et al. Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B. NEJM 2023;388:706 (74% reduction in bleed rate)
  19. Leavitt et al. Giroctocogene fitelparvovec gene therapy for severe hemophilia A: 104-week analysis of the phase 1/2 Alta study. Blood 2024;143:796
  20. Kumar et al. Platelet-targeted gene therapy induces immune tolerance in hemophilia and beyond. J Thromb Haemost 2024:22:23

Inhibitors in Hemophilia

  1. Arruda et al. Immune complications and their management in inherited and acquired bleeding disorders. Blood 2022;140:1075
  2. Astermark J. FVIII inhibitors: pathogenesis and avoidance. Blood 2015;125:2045
  3. Lai et al. Biological considerations of plasma-derived and recombinant factor VIII immunogenicity. Blood 2017;129:3147
  4. Batsuli et al. High-affinity, noninhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors. Blood 2016;128:2055(Inhibitors that are weakly inhibitory in a Bethesda assay but can accelerate FVIII clearance)
  5. Cannavò et al. Nonneutralizing antibodies against factor VIII and risk of inhibitor development in severe hemophilia A. Blood 2017;129:1245(Antibodies present in untreated hemophilia patients predict subsequent inhibitor development)
  6. Leissinger et al. How I use bypassing therapy for prophylaxis in patients with hemophilia A and inhibitors. Blood 2015;126:153
  7. Shapiro et al. The future of bypassing agents for hemophilia with inhibitors in the era of novel agents. J Thromb Haemost 2018;16:2362
  8. Nogami and Shima. New therapies using nonfactor products for patients with hemophilia and inhibitors. Blood 2019;133:399
  9. Oldenburg et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. NEJM 2017;377:809(This bispecific antibody lowered bleeding rates substantially in patients with inhibitors; with editorial; see also lettersregarding complications)
  10. Kempton and Meeks. Toward optimal therapy for inhibitors in hemophilia. Blood 2014;124:3365
  11. Blumberg et al. Tolerogenic properties of the Fc portion of IgG and its relevance to the treatment and management of hemophilia. Blood 2018;131:2205
  12. Malec et al. Recombinant factor VIII Fc fusion protein for first-time immune tolerance induction: final results of the verITI-8 study. Blood 2023;141:1982
  13. Young et al. Thrombin generation and whole blood viscoelastic assays in the management of hemophilia: current state of art and future perspectives. Blood 2013;121:1944(Use of TEG in assessing response to bypass agents in hemophiliacs with inhibitors)
  14. Gouw et al. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood 2012;119:2922
  15. Eckhardt et al. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. Blood 2013;122:1954
  16. Gouw et al. Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study. Blood 2013;121:4046(High dose factor replacement increases risk, prophylactic treatment decreases it)
  17. Castaman and Fijnvandraat. Molecular and clinical predictors of inhibitor risk and its prevention and treatment in mild hemophilia A. Blood 2014;124:2333(Lifelong risk of inhibitor development in mild HA, increasing in parallel with factor exposure; risk also dependent on type of mutation)
  18. Hassan et al. Factor VIII products and inhibitor development in previously treated patients with severe or moderately severe hemophilia A: a systematic review. J Thromb Haemost 2018;16:1055
  19. Callaghan and Fogarty. What is the Evidence for the Use of Immunomodulatory Agents to Eradicate Inhibitory Antibodies in Patients with Severe Hemophilia A Who Have Previously Failed to Respond to Immune Tolerance Induction? Hematology 2011:405
  20. Kruse-Jarres R. Current Controversies in the Formation and Treatment of Alloantibodies to Factor VIII in Congenital Hemophilia A. Hematology 2011:407
  21. Scott et al. Progress toward inducing immunologic tolerance to factor VIII. Blood 2013;121:4449
  22. Lim et al. Rituximab as first-line treatment for the management of adult patients with non-severe hemophilia A and inhibitors. J Thromb Haemost 2014;12:897(9/9 patients had eradication of inhibitors with mean response time of 95 days)
  23. Franchini and Lippi. How I treat acquired factor VIII inhibitors. Blood 2008;112:250
  24. McMillan C et al. The natural history of factor VIII:c inhibitors in patients with hemophilia A. Blood 1988; 71:344
  25. Goudemand et al. Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A. Blood 2006;107:46 (2 to 3-fold higher risk of inhibitor development with use of recombinant factor VIII vs plasma-derived factor)
  26. Collins et al. Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe hemophilia A, 2000-2011. Blood 2014;124:3389(Risk factors for inhibitor development: brand of factor, FVIII genotype, ethnicity, intensive treatment episodes)
  27. Calvez et al. Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A. Blood 2014;124:3398
  28. Peyvandi et al. Timing and severity of inhibitor development in recombinant versus plasma-derived factor VIII concentrates: a SIPPET analysis. J Thromb Haemost 2018;16:39(Recombinant concentrates more likely to cause inhibitor formation, inhibitors tend to be higher titer)
  29. Peyvandi et al. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. NEJM 2016;374:2054(VWF-containing plasma-derived concentrate caused less inhibitor development than recombinant VIII; with editorial)
  30. Shima et al. Factor VIII–Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. NEJM 2016;374:2044(Antibody effective in patients with and without inhibitors. With editorial)
  31. Lenting et al. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII? Blood 2017;130:2463
  32. Ragni MV. The effect of emicizumab regimen on haemophilia outcomes. Lancet Haem 2019;6:e286(Summarizes results from the HAVEN trials)
  33. Levy et al. Safety analysis of rFVIIa with emicizumab dosing in congenital hemophilia A with inhibitors: Experience from the HAVEN clinical program. J Thromb Haemost 2019;17:1470(rFVIIa appears safe to use in conjunction with emicizumab)
  34. Young et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood 2019;134:2127
  35. Makris et al. Emicizumab and thrombosis: The story so far. J Thromb Haemost 2019;17:1269 (Most events associated with concurrent FEIBA administration)
  36. Shapiro et al. Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Blood 2019;134:1973
  37. Matsushita et al. Phase 3 Trial of Concizumab in Hemophilia with Inhibitors. NEJM 2023;389:783 (anti-TFPI; with editorial)
  38. Roberts et al. The use of recombinant factor VIIa in the treatment of bleeding disorders. Blood 2004;104:3858
  39. Lentz et al. Recombinant factor VIIa analog in the management of hemophilia with inhibitors: results from a multicenter, randomized, controlled trial of vatreptacog alfa. J Thromb Haemost 2014;12:1244
  40. Leissinger et al. Anti-Inhibitor Coagulant Complex Prophylaxis in Hemophilia with Inhibitors. NEJM 2011;365:1684
  41. Rota et al. Thromboembolic event rate in patients exposed to anti-inhibitor coagulant complex: a meta-analysis of 40-year published data. Blood Adv 2017;1:2637(FEIBA)
  42. Lillicrap D. The Role of Immunomodulation in the Management of Factor VIII Inhibitors. Hematology 2006;421
  43. Antun et al. Inhibitor recurrence after immune tolerance induction: a multicenter retrospective cohort study. J Thromb Haemost 2015;13:1980(Treatment with immunosuppressive drugs associated with higher rate of inhibitor recurrence)

von Willebrand Disease

Biology and Diagnosis

  1. Lenting et al. How unique structural adaptations support and coordinate the complex function of von Willebrand factor. Blood 2024;144:2174
  2. James et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv 2021;5:280
  3. Sharma and Flood. Advances in the diagnosis and treatment of von Willebrand disease. Blood 2017;130:2386
  4. Laffan et al. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol 2014;167:453
  5. Leebeek and Eikenboom. Von Willebrand’s disease. NEJM 2016;375:2067
  6. Seidizadeh et al. Application of genetic testing for the diagnosis of von Willebrand disease. J Thromb Haemost 2024;22:2115
  7. Mezzano and Quiroga. Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research. J Thromb Haemost 2019;17:257(An in-depth discussion of the difficulties encountered in diagnosing VWD and other mild bleeding disorders)
  8. Mehic et al. The necessity of repeat testing for von Willebrand disease in adult patients with mild to moderate bleeding disorders. J Thromb Haemost 2024;22:101 (Consider repeat testing in patients with baseline VWF activity 50-80%)
  9. Biguzzi et al .Increasing levels of von Willebrand factor and factor VIII with age in patients affected by von Willebrand disease. J Thromb Haemost 2021;19:96
  10. Lavin et al. Novel insights into the clinical phenotype and pathophysiology underlying low VWF levels. Blood 2017;130:2344
  11. Lenting et al. von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends. Blood 2015;125:2019
  12. Ishihara et al. The heparin binding domain of von Willebrand factor binds to growth factors and promotes angiogenesis in wound healing. Blood 2019;133:2559
  13. Lippok et al. von Willebrand factor is dimerized by protein disulfide isomerase. Blood 2016;127:1183
  14. Ward et al. von Willebrand factor sialylation—A critical regulator of biological function. J Thromb Haemost 2019;17:1018
  15. Lillicrap D. von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy. Hematology 2013:254
  16. Sadler E. Low von Willebrand factor: sometimes a risk factor and sometimes a disease. Hematology 2009: 106
  17. Roberts et al. Rapid discrimination of the phenotypic variants of von Willebrand disease. Blood 2016;127:2472
  18. Boender et al. Clinically relevant differences between assays for von Willebrand factor activity. J Thromb Haemost 2018;16:2413
  19. Tosetto et al. Impact of plasma von Willebrand factor levels in the diagnosis of type 1 von Willebrand disease: results from a multicenter European study (MCMDM‐1VWD). J Thromb Haemost 2007;5:715 (VWF levels <40% associated with high likelihood of VWD)
  20. Flood et al. Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States. Blood 2016;127:2481 (Poor correlation between VWF level and bleeding score; most patients with mild VWF deficiency did not have VWF sequence variants)
  21. DiGiandomenico et al. Laboratory variability in the diagnosis of type 2 VWD variants. J Thromb Haemost 2021;19:131
  22. Doshi et al. Utility of repeat testing in the evaluation for von Willebrand disease in pediatric patients. J Thromb Haemost 2019;17:1838 (Repeat testing not needed if VWF > 100%)
  23. Valentijn and Eikenboom. Weibel-Palade bodies: a window to von Willebrand disease. J Thromb Haemst 2013;11:581
  24. Kanaji et al. Contribution of platelet vs. endothelial VWF to platelet adhesion and hemostasis. J Thromb Haemost 2012;1646 (Endothelial cell VWF sufficient for normal hemostasis in mice)
  25. De Jong and Eikenboom. Developments in the diagnostic procedures for von Willebrand disease. J Thromb Haemost 2016;14:449
  26. Quiroga et al. Quantitative impact of using different criteria for the laboratory diagnosis of type 1 von Willebrand disease. J Thromb Haemost 2014;12:1238(3-fold increase in rate of VWD diagnosis when VWF blood level cutoff raised from 30 to 40%; commentaryemphasizes role of bleeding score in making treatment decisions)
  27. Kalot et al. von Willebrand factor levels in the diagnosis of von Willebrand disease: a systematic review and meta-analysis. Blood Adv 2022;6:62 (Normalization of VWF levels with age does not protecct against bleeding; activity:antigen ratio <0.7 predicts type 2 VWD)
  28. Federici et al. The bleeding score predicts clinical outcomes and replacement therapy in adults with von Willebrand disease. Blood 2014;123:4037
  29. Sanders et al. von Willebrand disease and aging: an evolving phenotype. J Thromb Haemost 2014;12:1066(VWF levels increase with aging in type I VWD but not in type 2 VWD; bleeding risk increases with age more in type 2 than type 1)
  30. Tosetto et al. Evidence-based diagnosis of type 1 von Willebrand disease: a Bayes theorem approach. Blood 2008;111:3998
  31. Ng et al. Diagnostic approach to von Willebrand disease. Blood 2015;125:2029
  32. Sadler E. Von Willebrand disease type 1: a diagnosis in search of a disease.  Blood 2003;101:2089
  33. Haberichter et al. Assay of the von Willebrand factor (VWF) propeptide to identify patients with type 1 von Willebrand disease with decreased VWF survival.  Blood 2006;108:3344.
  34. Haberichter et al. Identification of type 1 von Willebrand disease patients with reduced von Willebrand factor survival by assay of the VWF propeptide in the European study: Molecular and Clinical Markers for the Diagnosis and Management of Type 1 VWD (MCMDM-1VWD). Blood 2008;111:4979
  35. Sanders et al. von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease. Blood 2015;125:3006(41% of individuals thought to have type 3 VWD had circulating VWF propeptide, indicating that they actually have severe type 1 disease)
  36. Kalot et al. Laboratory assays of VWF activity and use of desmopressin trials in the diagnosis of VWD: a systematic review and meta-analysis. Blood Adv 2022;6:3735 (DDAVP trial for confirming rapid VWF clearance)
  37. Doruelo et al. Clinical and laboratory phenotype variability in type 2M von Willebrand disease. J Thromb Haemost 2017;15:1559(Much clinical and laboratory variability among variants; overlaps with type 2A)
  38. Gallinaro et al. A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. Blood 2008;111:3570
  39. Dunne et al. Blood group alters platelet binding kinetics to von Willebrand factor and consequently platelet function. Blood 2019;133:1371(VWF in type O individuals is less sticky)
  40. Ward et al. The relationship between ABO blood group, von Willebrand factor, and primary hemostasis. Blood 2020;136:2864
  41. Aguila et al. Increased galactose expression and enhanced clearance in patients with low von Willebrand factor. Blood 2019;133:1585
  42. James et al. Alloantibodies in von Willebrand disease. Blood 2013;122:636 (Acquired inhibitors develop in 5-10% of patients with type 3 VWD)
  43. Pagliari et al. von Willebrand factor neutralizing and non-neutralizing alloantibodies in 213 subjects with type 3 von Willebrand disease enrolled in 3WINTERS-IPS. J Thromb Haemost 2023;21:787
  44. Sanders et al. Reduced prevalence of arterial thrombosis in von Willebrand disease. J Thromb Haemost 2013;11:845
  45. Seaman et al. Does deficiency of von Willebrand factor protect against cardiovascular disease? Analysis of a national discharge register. J Thromb Haemost 2015;13:1999(Yes)
  46. Othman et al. Platelet type von Willebrand disease and registry report: communication from the SSC of the ISTH. J Thromb Haemost 2016;14:411
  47. Gil et al. Low VWF levels in children and lack of association with bleeding in children undergoing tonsillectomy. Blood Adv 2020;4:100
  48. Atiq et al. Criteria for low von Willebrand factor diagnosis and risk score to predict future bleeding. J Thromb Haemost 2021; 19:719 (Suggests cutoff for “low VWF” diagnosis should be set at 60%; no difference in bleeding risk between those with levels 30-50% and 50-60%)
  49. O’Donnell et al. Low von Willebrand factor—unraveling an enigma wrapped in a conundrum. J Thromb Haemost 2024;22:3383
  50. Atiq et al. Type 1 VWD classification revisited: novel insights from combined analysis of the LoVIC and WiN studies. Blood 2024;143:1414 (Patients with “Low VWF” are not genetically different from a subset of those with type I VWD in whom VWF levels rise with age)
  51. Atiq et al. Clinical phenotype and pathophysiological mechanisms underlying qualitative low VWF. Blood 2025;146:369 (Mild functional deficiency of VWF with activity 30-50% and antigen > 50% distinct from type 2 variants, often with bleeding phenotype)
  52. Othman and Gresele. Guidance on the diagnosis and management of platelet‐type von Willebrand disease: A communication from the Platelet Physiology Subcommittee of the ISTH. J Thromb Haemost 2020;18:1855
  53. Seidizadeh et al. Von Willebrand disease type 2N: An update. J Thromb Haemost 2021;19:909
  54. Daniel et al. Type 2N von Willebrand disease: genotype drives different bleeding phenotypes and treatment needs. J Thromb Haemost 2024;22:2702
  55. Tosetto et al. Bleeding symptoms in patients diagnosed as type 3 von Willebrand disease: Results from 3WINTERS‐IPS, an international and collaborative cross‐sectional study. J Thromb Haemost 2020;18:2145(Intracranial bleeding, oral cavity bleeding, hemarthroses, deep hematomas)
  56. Chornenki et al. Vascular abnormalities in patients with von Willebrand disease: A scoping review. J Thromb Haemost 2021;19:2151(AVMs associated with type 2A and type 3 VWD, most in GI tract)

Genetics and genetic testing

  1. Swystun and Lillicrap. Genetic regulation of plasma von Willebrand factor levels in health and disease. J Thromb Haemost 2018;16:2375
  2. James et al. The mutational spectrum of type 1 von Willebrand disease: results from a Canadian cohort study. Blood 2007;109:145
  3. Sadler et al. von Willebrand factor antigen levels are associated with burden of rare nonsynonymous variants in the VWF gene. Blood 2021;137:3277(Higher number of variants associated with lower VWF antigen levels)
  4. Christopherson  et al. Molecular pathogenesis and heterogeneity in type 3 VWD families in U.S. Zimmerman program. J  Thromb Haemost 2022;20:1576 (It’s complicated…)
  5. van Kwawegen et al. Genetic variants, thrombocytopenia, and clinical phenotype of type 2B von Willebrand disease: a median 16-year follow-up study. J Thromb Haemost 2024;22:3460
  6. Krahforst et al. Unravelling the spectrum of von Willebrand factor variants in quantitative von Willebrand disease: results from a German cohort study. J Thromb Haemost 2024;22:3010

von Willebrand Disease & Women’s Health

  1. Leebeek et al. How I manage pregnancy in carriers of hemophilia and patients with von Willebrand disease. Blood 2020;136:2143
  2. Johnsen and MacKinnon. Obstetric bleeding: VWD and other inherited bleeding disorders. J Thromb Haemost 2022;20:1568
  3. James and Jamison. Bleeding events and other complications during pregnancy and childbirth in women with von Willebrand disease. J Thromb Haemost 2007;5:1165
  4. Lavin et al. Significant gynecological bleeding in women with low von Willebrand factor levels. Blood Adv 2018;2:1784
  5. Iorio et al. Hemostatic management of von Willebrand disease during childbirth with a plasma-derived von Willebrand factor/factor VIII concentrate. J Thromb Haemost 2024;22:2739

Treatment

  1. Connell et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease.Blood Adv 2021;5:301
  2. Sharma and Flood. Advances in the diagnosis and treatment of von Willebrand disease. Blood 2017;130:2386
  3. Rodeghiero et al. Optimizing treatment of von Willebrand disease by using phenotypic and molecular data. Hematology 2009: 113
  4. Tosetto and Castaman. How I treat type 2 variant forms of von Willebrand disease. Blood 2015;125:907
  5. Kruse-Jarres and Johnsen. How I treat type 2B von Willebrand disease. Blood 2018;131:1292
  6. Lavin and O’Donnell. How I treat low von Willebrand factor levels. Blood 2019;133:795
  7. Poston and Kruse-Jarres. How I treat von Willebrand disorders in older adults. Blood 2024;143:197
  8. Ruggeri et al. Multimeric composition of factor VIII/von Willebrand factor following administration of DDAVP. Blood 1982; 59:1272
  9. Federici et al.  Biologic response to desmopressin in patients with severe type 1 and type 2 von Willebrand disease: results of a multicenter European study.  Blood 2004;103:2032
  10. Castaman et al. Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD. Blood 2008;111:3531
  11. Peyvandi et al. Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery. J Thromb Haemost 2019;17:52
  12. Leebeek et al. Recombinant von Willebrand factor prophylaxis in patients with severe von Willebrand disease: phase 3 study results. Blood 2022;140:89
  13. Buguzzi et al. How I treat gastrointestinal bleeding in congenital and acquired von Willebrand disease. Blood 2020;136:1125
  14. Doherty et al. Management of elective procedures in low von Willebrand factor patients in the LoVIC study. J Thromb Haemost 2021;19:701(DDAVP, TXA efficacious; age-related increases in VWF not necessarily protective)
  15. Brignardello-Petersen et al. Surgical management of patients with von Willebrand disease: summary of 2 systematic reviews of the literature. Blood Adv 2022;6:121

Inherited platelet function disorders

  1. Botero and Di Paola. Diagnostic approach to the patient with a suspected inherited platelet disorder: Who and how to test. J Thromb Haemost 2021;19:2127
  2. Gomez et al. Clinical and laboratory diagnosis of heritable platelet disorders in adults and children: a British Society for Haematology Guideline. Br J Haematol 2021;195:46
  3. Bianchi et al. Genomic landscape of megakaryopoiesis and platelet function defects. Blood 2016;127:1249
  4. Yao and Kahr. Molecular basis of platelet granule defects. J Thromb Haemost 2025;23:381
  5. Lentaigne et al. Inherited platelet disorders: toward DNA-based diagnosis. Blood 2016;127:2814
  6. Oved et al. Population based frequency of naturally occurring loss‐of‐function variants in genes associated with platelet disorders. J Thromb Haemost 2021;19:248
  7. Greinacher and Eekels. Simplifying the diagnosis of inherited platelet disorders? The new tools do not make it any easier. Blood 2019;133:2478
  8. Diz-Küçükkaya R. Inherited platelet disorders including Glanzmann thrombasthenia and Bernard-Soulier syndrome. Hematology 2013:268
  9. Dovlatova N. Current status and future prospects for platelet function testing in the diagnosis of inherited bleeding disorders. Br J Haematol 2015;170:150
  10. Lambert MP. What to do when you suspect an inherited platelet disorder. Hematology 2011:377
  11. Gresele et al. The ISTH bleeding assessment tool as predictor of bleeding events in inherited platelet disorders: Communication from the ISTH SSC Subcommittee on Platelet Physiology. J Thromb Haemost 2021;19:1364
  12. Greinacher et al. Diagnosis of inherited platelet disorders on a blood smear: a tool to facilitate worldwide diagnosis of platelet disorders. J Thromb Haemost 2017;15:1511
  13. van Asten et al. Validation of flow cytometric analysis of platelet function in patients with a suspected platelet function defect. J Thromb Haemost 2018;16:689
  14. Kunicki and Nugent. The genetics of normal platelet reactivity. Blood 2010;116:2627
  15. Dawood et al. Evaluation of participants with suspected heritable platelet function disorders including recommendation and validation of a streamlined agonist panel. Blood 2012:120:5041
  16. Lopez et al. Bernard-Soulier syndrome. Blood 1998;91:4397
  17. Xu et al. GPIbα is required for platelet-mediated hepatic thrombopoietin generation. Blood 2018;132:622(Low TPO levels in BSS)
  18. Sandrock-Lang et al. Characterisation of patients with Glanzmann thrombasthenia and identification of 17 novel mutations. Thromb Haemost 2015;113:782
  19. Kuijpers et al. Natural history and early diagnosis of LAD-1/variant syndrome. Blood 2007;109:3529 (Defect in integrin signaling leading to platelet dysfunction and severe bleeding, as well as neutrophil dysfunction)
  20. Gunay-Aygun et al. Gray platelet syndrome: natural history of a large patient cohort and locus assignment to chromosome 3p. Blood 2010;116:4990
  21. Collins et al. Immune dysregulation, autoimmunity, and granule defects in gray platelet syndrome. J Thromb Haemost 2023;21:1409
  22. Sims et al. Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome. Blood 2020;136:1956 (Multiple cell types deficient in granule proteins causing pro-inflammatory state)
  23. Rensing-Ehl et al. Gray platelet syndrome can mimic autoimmune lymphoproliferative syndrome. Blood 2015;126:1967
  24. Monteferrario et al. A dominant-negative GFI1B mutation in the gray platelet syndrome. NEJM 2014;370:245
  25. Noris et al. Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Haematologica 2014;99:1387
  26. Civaschi et al. Analysis of 65 pregnancies in 34 women with five different forms of inherited platelet function disorders. Br J Haematol 2015;170:559 (Severe bleeding occurred in Glanzmann’s but not storage pool defects or aspirin-like defects)
  27. Fiore et al. How I manage pregnancy in women with Glanzmann thrombasthenia. Blood 2022; 139:2632
  28. Van Bergen et al. Specific proteome changes in platelets from individuals with GATA1-, GFI1B-, and RUNX1-linked bleeding disorders. Blood 2021;138:80 (Downregulation of platelet coagulation proteins, considerable case-to-case variation)
  29. Lee et al. RUNX1-deficient human megakaryocytes demonstrate thrombopoietic and platelet half-life and functional defects. Blood 2023;141:260

Factor XI deficiency

  1. Moellmer et al. Biology of factor XI. Blood 2024:143:1445
  2. Barg et al. Factor XI deficiency: phenotypic age-related considerations and clinical approach towards bleeding risk assessment. Blood 2024;143:1455
  3. Bolton-Maggs P. Factor XI deficiency—resolving the enigma? Hematology 2009: 97
  4. Asakai et al. Factor XI deficiency in Ashkenazi Jews in Israel. NEJM 1991; 325:153
  5. Asselta et al. Exploring the global landscape of genetic variation in coagulation factor XI deficiency. Blood 2017;130:e1(Deficiency is much more common than expected in many populations)
  6. Pike et al. Sample conditions determine the ability of thrombin generation parameters to identify bleeding phenotype in FXI deficiency. Blood2015;126:397(An assay that predicts bleeding tendency in F XI deficient patients)
  7. Preis et al. Factor XI deficiency is associated with lower risk for cardiovascular and venous thromboembolism events. Blood 2017;129:1210
  8. Gidley et al. Abnormal plasma clot formation and fibrinolysis reveal bleeding tendency in patients with partial factor XI deficiency. Blood Adv 2018;2:1076(Excessive in vitro fibrinolysis associated with bleeding phenotype in F XI deficiency)
  9. Minami et al. Emicizumab, the bispecific antibody to factors IX/IXa and X/Xa, potentiates coagulation function in factor XI‐deficient plasma in vitro. J Thromb Haemost 2019;17:126

Hereditary hemorrhagic telangiectasia

  1. Faughnan et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med 2020;173:989
  2. A-Samkari H. How I treat bleeding in hereditary hemorrhagic telangiectasia. Blood 2024;144:940
  3. Al-Samkari H. Hereditary hemorrhagic telangiectasia: systemic therapies, guidelines, and an evolving standard of care. Blood 2021;137:888
  4. Al-Samkari and Eng. A precision medicine approach to hereditary hemorrhagic telangiectasia and complex vascular anomalies. J Thromb Haemost 2022;20:1077
  5. Geisthoff et al. How to manage patients with hereditatry haemorrhagic telangiectasia. Br J Haematol 2015;171:443
  6. Shovlin et al. Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia. Blood 2020;136:1907
  7. Sabbà et al. Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers. J Thromb Haemost 2007;5:1149
  8. Iyer et al. Effect of Center Volume on Outcomes in Hospitalized Patients With Hereditary Hemorrhagic Telangiectasia. Mayo Clin Proc 2016;91:1753(Includes data on complication rates in over 9000 hospitalizations for HHT)
  9. Bose et al. Bevacizumab in Hereditary Hemorrhagic Telangiectasia (letter). NEJM 2009; 360:2143
  10. Dupuis-Girod et al. Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatiic vascular malformations and high cardiac output. JAMA 2012;307:948
  11. Dupuis-Gerod et al. Effect of Bevacizumab Nasal Spray on Epistaxis Duration in Hereditary Hemorrhagic Telangectasia.A Randomized Clinical Trial. JAMA 2016;316:934(No apparent benefit from this treatment)
  12. Whitehead et al. Effect of Topical Intranasal Therapy on Epistaxis Frequency in Patients With Hereditary Hemorrhagic Telangiectasia A Randomized Clinical Trial. JAMA 2016;316:943 (Neither bevacizumab or tranexamic acid reduced bleeding vs placebo)
  13. Lebrin et al. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med 2010; 16:420
  14. Al-Samkari et al. Pomalidomide for Epistaxis in Hereditary Hemorrhagic Telangiectasia. NEJM 2024;391:1015
  15. Lewandowska et al. Pazopanib in treatment of hereditary hemorrhagic telangiectasia-related epistaxis and gastrointestinal bleeding. J Thromb Haemost 2025;23:525 (VEGF receptor blocker)
  16. Lyle et al. Pulmonary hypertension in hereditary hemorrhagic telangiectasia. Chest 2016;149:362
  17. Virk et al. Safety, tolerability, and effectiveness of anticoagulation and antiplatelet therapy in hereditary hemorrhagic telangiectasia. J Thromb Haemost 2023;21:26 (High rates of both bleeding and thrombosis)

Inherited Bleeding Disorders

  1. Menegatti and Peyvandi. Treatment of rare factor deficiencies other than hemophilia. Blood 2019;133:415
  2. Palla et al. Rare bleeding disorders: diagnosis and treatment. Blood 2015;125:2052
  3. Peyvandi et al. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost 2012;10:615
  4. Mumford et al. Guideline for the diagnosis and management of the rare coagulation disorders. A United Kingdom Haemophilia Centre Doctors’ Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol 2014;167:304
  5. Maas et al. High prevalence of postpartum hemorrhage in women with rare bleeding disorders in the Netherlands: retrospective data from the RBiN study. J Thromb Haemost 2023;21:499
  6. Mannucci et al.  Recessively inherited coagulation disorders.  Blood 2004; 104:1243
  7. Tie et al. Characterization of vitamin K–dependent carboxylase mutations that cause bleeding and nonbleeding disorders. Blood 2016;127:1847(High dose vit K corrected coag defect, but not associated skeletal and vascular defects caused by lack of matrix Gla protein)
  8. Bouchard et al. Platelets and platelet-derived factor Va confer hemostatic competence in complete factor V deficiency. Blood 2015;125:3647
  9. Shao et al. Low factor V level ameliorates bleeding diathesis in patients with combined deficiency of factor V and factor VIII. Blood 2019;134:1745(Low TFPI activity and residual platelet FV support thrombin formation, DDAVP normalized thrombin generation)
  10. Casini et al. Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH. J Thromb Haemost 2018;16:1887
  11. Casini A. How I treat quantitative fibrinogen disorders. Blood 2025;145:801
  12. Nagler et al. Thromboembolism in patients with congenital afibrinogenaemia. Long-term observational data and systematic review. Thromb Haemost 2016;116:722(Increased VTE risk due to decreased thrombin scavenging? Replacement therapy may decrease risk)
  13. Casini and de Moerloose. How I treat dysfibrinogenemia. Blood 2021;138:2021
  14. Casini et al. Natural history of patients with congenital dysfibrinogenemia. Blood 2015;125:553(By age 50, 19% had major bleeding and 30% had a thrombotic event)
  15. Casini et al. Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management. J Thromb Haemost 2015;13:909
  16. Casini et al. Genetics, diagnosis and clinical features of congenital hypodysfibrinogenemia: a systematic literature review and report of a novel mutation. J Thromb Haemost 2017;15:876 (Fibrinogen act/ag ratio < 0.7 86% sensitive for Dx. 45% had bleeding, 43% thrombosis)
  17. Casini et al. Clinical phenotype, fibrinogen supplementation, and health-related quality of life in patients with afibrinogenemia. Blood 2021;137:3127 (Both bleeding and thrombotic complications common, phenotype-dependent)
  18. Khayat et al. Clinical pharmacology, efficacy and safety study of a triple‐secured fibrinogen concentrate in adults and adolescent patients with congenital fibrinogen deficiency. J Thromb Haemost 2019;17:635
  19. Hugon-Rodin et al. Obstetrical complications in hereditary fibrinogen disorders: the Fibrinogest study. J  Thromb Haemost 2023;21:2126
  20. Cassini et al. Management of pregnancy and delivery in congenital fibrinogen disorders: communication from the ISTH SSC Subcommittee on Factor XIII and Fibrinogen. J Thromb Haemost 2024;22:1516
  21. Benlakhal et al. A retrospective analysis of 157 surgical procedures performed without replacement therapy in 83 unrelated factor VII-deficient patients. J Thromb Haemost 2011;9:1149 (Individuals with f VII levels >10% do not routinely need prophylactic replacement therapy for major surgery)
  22. Abdul-Kadir and Gomez. Reproductive health and hemostatic issues in women and girls with congenital factor VII deficiency: A systematic review. J Thromb Haemost 2022;20:2758
  23. Barco et l. Severe plasma prekallikrein deficiency: Clinical characteristics, novel KLKB1 mutations, and estimated prevalence. J Thromb Haemost 2020;18:1598
  24. Adenaeuer et al. Severe high-molecular-weight kininogen deficiency: clinical characteristics, deficiency–causing KNG1 variants, and estimated prevalence. J Thromb Haemost 2023;21:237 (May be misdiagnosed as F XI deficiency)
  25. Singh et al. Cryo-EM structure of the human native plasma coagulation factor XIII complex. Blood 2025;145:438 (Discusses the genetics and mechanisms of inherited XIII deficiency)
  26. Lovejoy et al. Safety and pharmacokinetics of recombinant factor XIII-A2 administration in patients with congenital factor XIII deficiency. Blood 2006;108:57
  27. Inbal et al. Recombinant factor XIII: a safe and novel treatment for congenital factor XIII deficiency. Blood 2012;119:5111
  28. Kerlin et al. Recombinant factor XIII prophylaxis is safe and effective in young children with congenital factor XIII-A deficiency: international phase 3b trial results. J Thromb Haemost 2017;15:1601(Once-monthly prophylaxis)
  29. Memegatti et al. Minimal factor XIII activity to prevent major spontaneous bleeds. J Thromb Haemost 2017;15:1728(Bleeding rate high if FXIII activity < 15%)
  30. Kulkarni et al. Efficacy, safety and pharmacokinetics of a new high‐purity factor X concentrate in women and girls with hereditary factor X deficiency. J Thromb Haemost 2018;16:849
  31. Saes et al. Hemorrhagic disorders of fibrinolysis: a clinical review. J Thromb Haemost 2018;16:1498
  32. Iwaki et al. Life-threatening hemorrhage and prolonged wound healing are remarkable phenotypes manifested by complete plasminogen activator inhibitor-1 deficiency in humans. J Thromb Haemost 2011;9:1200
  33. Dargaud et al. Characterization of an autosomal dominant bleeding disorder caused by a thrombomodulin mutation. Blood 2015;125:1497
  34. Van Laer et al. Functional assessment of genetic variants in thrombomodulin detected in patients with bleeding and thrombosis. Blood 2025;145:1929
  35. Burley et al. Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy. Blood 2016;128:1879
  36. Rehill et al. A new thrombomodulin-related coagulopathy. J Thromb Haemost 2020;18:2123(Autosomal dominant; very high levels of soluble TM divert thrombin to its anticoagulant function)
  37. Schulman et al. A coagulation defect arising from heterozygous premature termination of tissue factor. J Clin Invest 2020;130:5302(See also this editorial)
  38. Peterson et al. Factor V east Texas variant causes bleeding in a three-generation family. J Thromb Haemost 2022;20:565
  39. Dahlbäck B. Natural anticoagulant discovery, the gift that keeps on giving: finding FV-Short. J Thromb Haemost 2023;21:716 (“East Texas” bleeding disorder)
  40. Ong et al. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet 2010;376:1476
  41. Artoni et al. Hemostatic abnormalities in patients with Ehlers–Danlos syndrome. J Thromb Haemost 2016;16:2425(Platelet function abnormalities found in most patients, associated with higher bleed risk)
  42. Kumskova et al. Characterization of bleeding symptoms in Ehlers–Danlos syndrome. J Thromb Haemost 2023;21:1824
  43. Lopez-Ramirez et al. Cerebral cavernous malformations form an anticoagulant vascular domain in humans and mice. Blood 2019;133:193(Bleeding due to increased protein C activation?)
  44. Pascreau et al. Hemostatic defects in congenital disorders of glycosylation. Res Pract Thromb Haemost 2023;7:e100142 (Combined antithrombin, factor XI deficiency in a majority)