Management of acute hemorrhage in patients with hemophilia or von Willebrand disease in the emergency department

Patients with hemophilia or von Willebrand disease may present to the emergency department (ED) with life-threatening bleeding, as severe hemorrhage can lead to hemodynamic instability and bleeding in the central nervous system, throat, and neck. Thus, inappropriate, or delayed management could lead to serious treatment-related complications or even death, and therefore, emergency medical staffs should be well-equipped with the latest knowledge to properly and timely treat these patients. The goal of treatment in emergency settings is to achieve hemostasis by replacing clotting factor levels, prevent hemodynamic instability, and prompt initiation of further specialized treatments. In this study, we searched Medline, PubMed, Embase and Google Scholar for papers addressing hemophilia- and Von Willebrand disease (VWD)-related bleeding and factors in emergency settings to determine evidence-based approaches for managing severe hemorrhage in these patients in the ED.

Hemophilia; von Willebrand disease; Hemorrhage; Bleeding; Emergency medicine

[1] Singleton T, Kruse-Jarres R, Leissinger C. Emergency department care for patients with hemophilia and von Willebrand disease. The Journal of Emergency Medicine. 2010; 39: 158–165.

[2] Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, et al. Guidelines for the management of hemophilia. Haemophilia. 2013; 19: e1–e47.

[3] Manco-Johnson MJ. Advances in the care and treatment of children with hemophilia. Advances in Pediatrics. 2010; 57: 287–294.

[4] Bolton-Maggs PHB. Optimal haemophilia care versus the reality. British Journal of Haematology. 2006; 132: 671–682.

[5] Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A. Definitions in hemophilia: communication from the SSC of the ISTH. Journal of Thrombosis and Haemostasis. 2014; 12: 1935–1939.

[6] Tebo C, Gibson C, Mazer-Amirshahi M. Hemophilia and von Willebrand disease: a review of emergency department management. The Journal of Emergency Medicine. 2020; 58: 756–766.

[7] Witmer CM, Raffini LJ, Manno CS. Utility of computed tomography of the head following head trauma in boys with haemophilia. Haemophilia. 2007; 13: 560–566.

[8] Khoshnaw N, Muhammad BA, Elmeshhedany A. Spontaneous life threatening massive retroperitoneal and iliopsoas hemorrhages in adult hemophilia—a patients with inhibitor—case series. Journal of Blood Disorders & Transfusion. 2015; 6: 1000261.

[9] Shander A, Walsh C, Bailey H, Cromwell C. Acquired hemophilia pre-senting as profound hematuria: evaluation, diagnosis, and management of elusive cause of bleeding in the emergency department setting. The Journal of Emergency Medicine. 2013; 45: e1–e6.

[10] Collins P, Baudo F, Huth-Kühne A, Ingerslev J, Kessler CM, Castellano ME, et al. Consensus recommendations for the diagnosis and treatment of acquired hemophilia A. BMC Research Notes. 2010; 3: 1–8.

[11] Tiede A, Werwitzke S, Scharf RE. Laboratory diagnosis of acquired hemophilia A: limitations, consequences, and challenges. Seminars in Thrombosis and Hemostasis. 2014; 40: 803–811.

[12] Valentino LA, Khair K. Prophylaxis for hemophilia A without inhibitors: treatment options and considerations. Expert Review of Hematology. 2020; 13: 731–743.

[13] Sørensen B, Benson GM, Bladen M, Classey S, Keeling DM, Mclaughlin P, et al. Management of muscle haematomas in patients with severe haemophilia in an evidence-poor world. Haemophilia. 2012; 18: 598–606.

[14] Khokhar R, Hussain A, Khan M, Hajnour M, Qureshi S, Aqil M. Anesthetic management of patient with hemophilia A undergoing emergency ventriculoperitoneal shunting: a case report and review of literature. Saudi Journal of Anaesthesia. 2016; 10: 474–476.

[15] Kageyama Y, Matsumoto T, Tawara I, Wada H, Katayama N. Life-threatening tongue and retropharyngeal hemorrhage in a patient with hemophilia A with inhibitors. The American Journal of Case Reports. 2019; 20: 1022–1026.

[16] Alansari M, Alotair H, Al Aseri Z, Elhoseny MA. Use of ultrasound guidance to improve the safety of percutaneous dilatational tracheostomy: a literature review. Critical Care. 2015; 19: 229.

[17] Aseri ZAA, Hussein RMA, Malabarey MA, Yahya BAA, Moaiqel FAA, Ansari MAA, et al. Use of ultrasound guidance in central venous catheter placement by emergency physicians in Saudi Arabia. Saudi Medical Journal. 2020; 41: 698–702.

[18] Auerswald G, Dolan G, Duffy A, Hermans C, Jiménez-Yuste V, Ljung R, et al. Pain and pain management in haemophilia. Blood Coagulation & Fibrinolysis. 2016; 27: 845–854.

[19] Holme PA, Tjønnfjord GE, Batorova A. Continuous infusion of coagulation factor concentrates during intensive treatment. Haemophilia. 2018; 24: 24–32.

[20] Droubatchevskaia N, Wong MP, Chipperfield KM, Wadsworth LD, Fer-guson DJ. Guidelines for cryoprecipitate transfusion. British Columbia Medical Journal. 2007; 49: 441–445.

[21] Franchini M, Zaffanello M, Lippi G. The use of desmopressin in mild hemophilia A. Blood Coagulation & Fibrinolysis. 2010; 21: 615–619.

[22] Revel-Vilk S, Blanchette VS, Sparling C, Stain AM, Carcao MD. DDAVP challenge tests in boys with mild/moderate haemophilia A. British Journal of Haematology. 2002; 117: 947–951.

[23] Gill JC, Ottum M, Schwartz B. Evaluation of high concentration intranasal and intravenous desmopressin in pediatric patients with mild hemophilia A or mild-to-moderate type 1 von Willebrand disease. The Journal of Pediatrics. 2002; 140: 595–599.

[24] Preijers T, Schütte LM, Kruip MJHA, Cnossen MH, Leebeek FWG, van Hest RM, et al. Strategies for Individualized Dosing of Clotting Factor Concentrates and Desmopressin in Hemophilia A and B. Therapeutic Drug Monitoring. 2019; 41: 192–212.

[25] Franchini M, Lippi G. Acquired factor VIII inhibitors. Blood. 2008; 112: 250–255.

[26] Huth-Kuhne A, Baudo F, Collins P, Ingerslev J, Kessler CM, Levesque H, et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica. 2009; 94: 566–575.

[27] Erkan D, Bateman H, Lockshin MD. Lupus anticoagulant-hypoprothrombinemia syndrome associated with systemic lupus erythematosus: report of 2 cases and review of literature. Lupus. 1999; 8: 560–564.

[28] Mathew P, Valentino L, Sumner M, Seremetis S, Hoots K, Pruthi R. Haemostatic efficacy and safety of bolus and continuous infusion of recombinant factor VIIa are comparable in haemophilia patients with inhibitors undergoing major surgery. Thrombosis and Haemostasis. 2007; 98: 726–732.

[29] Giangrande PLF. Treatment of patients with haemophilia and inhibitory antibodies. The Indian Journal of Pediatrics. 2003; 70: 655–659.

[30] Yank V, Tuohy CV, Logan AC, Bravata DM, Staudenmayer K, Eisenhut R, et al. Systematic review: benefits and harms of in-hospital use of recombinant factor VIIa for off-label indications. Annals of Internal Medicine. 2011; 154: 529–540.

[31] Tanaka KA, Kor DJ. Emerging haemostatic agents and patient blood management. Best Practice & Research Clinical Anaesthesiology. 2013; 27: 141–160.

[32] Hassan S, Cannavò A, Gouw SC, Rosendaal FR, van der Bom JG. Factor VIII products and inhibitor development in previously treated patients with severe or moderately severe hemophilia A: a systematic review. Journal of Thrombosis and Haemostasis. 2018; 16: 1055–1068.

[33] Berntorp E. Differential response to bypassing agents complicates treatment in patients with haemophilia and inhibitors. Haemophilia. 2009; 15: 3–10.

[34] Kruse‐Jarres R, St‐Louis J, Greist A, Shapiro A, Smith H, Chowdary P, et al. Efficacy and safety of OBI‐1, an antihaemophilic factor VIII (recombinant), porcine sequence, in subjects with acquired haemophilia A. Haemophilia. 2015; 21: 162–170.

[35] Huang L, Anand S, Hassan S, Onwuemene O. Bruised black and blue: acquired hypoprothrombinemia. The American Journal of Medicine. 2015; 128: e7–e11.

[36] Spada ARL, Skålhegg BS, Henderson R, Schmer G, Pierce R, Chandler W. Fatal hemorrhage in a patient with an acquired inhibitor of human thrombin. New England Journal of Medicine. 1995; 333: 494–497.

[37] Chediak J, Ashenhurst J, Garlick I, Desser R. Successful management of bleeding in a patient with factor V inhibitor by platelet transfusions. Blood. 1980; 56: 835–841.

[38] Bona RD, Pasquale DN, Kalish RI, Witter BA. Porcine factor VIII and plasmapheresis in the management of hemophiliac patients with inhibitors. American Journal of Hematology. 1986; 21: 201–207.

[39] Swami A, Kaur V. Von Willebrand disease: a concise review and update for the practicing physician. Clinical and Applied Thrombo-sis/Hemostasis. 2017; 23: 900–910.

[40] Kyrle PA, Minar E, Hirschl M, Bialonczyk C, Stain M, Schneider B, et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. New England Journal of Medicine. 2000; 343: 457–462.

[41] Sharma R, Flood VH. Advances in the diagnosis and treatment of Von Willebrand disease. Hematology. 2017; 2017: 379–384.

[42] Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL, et al. Von Willebrand disease (VWD): evidence‐based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA) 1. Haemophilia. 2008; 14: 171–232.

[43] Gill JC, Castaman G, Windyga J, Kouides P, Ragni M, Leebeek F, et al. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood. 2015; 126: 2038–2046.

[44] Brignardello-Petersen R, El Alayli A, Husainat N, Kalot M, Shahid S, Aljabirii Y, et al. Surgical management of patients with von Willebrand disease: summary of 2 systematic reviews of the literature. Blood Advances. 2022; 6: 121–128.

[45] El Alayli A, Brignardello Petersen R, Husainat NM, Kalot MA, Aljabiri Y, Turkmani H, et al. Outcomes of long‐term von Willebrand factor prophylaxis use in von Willebrand disease: a systematic literature review. Haemophilia. 2022; 28: 373–387.

[46] Siew D, Mangel J, Laudenbach L, Schembri S, Minuk L. Desmopressin responsiveness at a capped dose of 15 µg in type 1 von Willebrand disease and mild hemophilia A. Blood Coagulation & Fibrinolysis. 2014; 25: 820–823.

[47] Leissinger C, Carcao M, Gill JC, Journeycake J, Singleton T, Valentino L. Desmopressin (DDAVP) in the management of patients with congenital bleeding disorders. Haemophilia. 2014; 20: 158–167.

[48] Mannucci PM, And DB, Cattaneo M. Patterns of development of tachyphylaxis in patients with haemophilia and von Willebrand disease after repeated doses of desmopressin (DDAVP). British Journal of Haematology. 1992; 82: 87–93.

[49] Vicente V, Estellés A, Laso J, Moraleda JM, Rivera J, Aznar J. Repeated infusions of DDAVP induce low response of FVIII and vWF but not of plasminogen activators. Thrombosis Research. 1993; 70: 117–122.

[50] Stoof SCM, Cnossen MH, De Maat MPM, Leebeek FWG, Kruip MJHA. Side effects of desmopressin in patients with bleeding disorders. Haemophilia. 2016; 22: 39–45.

[51] Eghbali A, Melikof L, Taherahmadi H, Bagheri B. Efficacy of tranexamic acid for the prevention of bleeding in patients with von Willebrand disease and Glanzmann thrombasthenia: a controlled, before and after trial. Haemophilia. 2016; 22: e423–e426.

[52] Lavin M, O’Donnell JS. New treatment approaches to von Willebrand disease. Hematology. 2016; 2016: 683–689.

[53] Kouides PA, Byams VR, Philipp CS, Stein SF, Heit JA, Lukes AS, et al. Multisite management study of menorrhagia with abnormal laboratory haemostasis: a prospective crossover study of intranasal desmopressin and oral tranexamic acid. British Journal of Haematology. 2009; 145: 212–220.

[54] van Galen KPM, Engelen ET, Mauser‐Bunschoten EP, van Es RJJ, Schutgens REG. Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions. Cochrane Database of Systematic Reviews. 2019; 4: CD011385.

[55] Federici AB, Mazurier C, Berntorp E, Lee CA, Scharrer I, Goudemand J, 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: 2032–2038.