Thrombotic complications in patients with hereditary bleeding disorders

Summary

Thromboses in patients with hereditary bleeding disorders are uncommon. However, in some cases, the co-existence of prothrombotic risk factors may increase the likelihood of developing thrombotic complications in such patients. This review summarizes the cases of thrombosis reported in the literature and analyzes the most important risk factors for thrombosis in patients with a congenital bleeding tendency. In particular we focus on central venous catheter (CVC)-associated thrombosis, on the thrombotic complications of coagulation factor concentrate therapy and on the presence of prothrom-botic gene mutations. Data were identified by searches of the published literature, including PubMed, references from reviews and abstracts from the most important meetings on this topic. In conclusion, there is increasing evidence that thrombotic complications in patients with hereditary bleeding disorders have a multifactorial pathogenesis, depending on exogenous (coagulation factor replacement therapy, CVC, HIV infection) and/or endogenous (prothrombotic gene mutations) risk factors.

Keywords

Bleeding disorders - hemophilia - thrombosis

• References

• 1 Ritchie B, Woodman RC, Poon MC. Deep venous thrombosis in hemophilia A. Am J Med 1992; 93: 699-700.
• 2 Djulbegovic B. Lack of prophylactic anticoagulant therapy is not associated with clinical thrombotic complications in patients with hemophilia who undergo orthopedic surgical procedures. Am J Hematol 1995; 50: 229-230.
• 3 Franchini M, Tagliaferri A, Rossetti G. et al. Absence of thromboembolic complications in patients with hereditary bleeding disorders undergoing major orthopedic surgery without antithrombotic prophylaxis. Thromb Haemost 2004; 91: 1053-1055.
• 4 Goodnough LT, Saito H, Ratnoff OD. Thrombosis or myocardial infarction in congenital clotting factor abnormalities and chronic thrombocytopenias: a report of 21 patients and a review of 50 previously reported cases. Medicine (Baltimore) 1983; 62: 248-255.
• 5 Small M, Jack AS, Lowe GDO. et al. Coronary artery disease in severe hemophilia. Br Heart J 1983; 49: 604-607.
• 6 Stewart AJ, Manson LM, Dennis R. et al. Thrombosis in a duplicated superficial femoral vein in a patient with hemophilia A. Haemophilia 2000; 06: 47-49.
• 7 Dargaud Y, Chruchaudet BB, Lienhart A. et al. Spontaneous proximal deep vein thrombosis in a patient with severe haemophilia A. Blood Coagul Fibrinol 2003; 14: 407-409.
• 8 Kasper CK. Postoperative thrombosis in hemophilia B. N Engl J Med 1973; 289: 160.
• 9 Franchini M, Krampera M, Veneri D. Deep vein thrombosis after orthopedic surgery in a patient with type 1 von Willebrand disease and mutations in the MTHFR and beta-fibrinogen genes. Thromb Haemost 2003; 90: 963-964.
• 10 Mannucci PM. Venous thromboembolism in von Willebrand disease. Thromb Haemost 2002; 88: 378-379.
• 11 Sˇrámek A, Bucciarelli P, Federici AB. et al. Patients with type 3 severe von Willebrand disease are not protected against atherosclerosis. Results from a multicenter study in 47 patients. Circulation 2004; 109: 740-744.
• 12 Ljung R. Central venous lines in haemophilia. Haemophilia 2003; 09: 88-93.
• 13 Liesner RJ, Vora AJ, Hann IM. et al. Use of central venous catheters in children with severe congenital coagulopathy. Br J Haematol 1995; 91: 203-207.
• 14 Van Den Berg HM, Fischer K, Rosendaal G. et al. The use of the Port-A-Cath in children with haemophilia – a review. Haemophilia 1998; 04: 418-420.
• 15 Blanchette VS, Al-Musa A, Stain AM. et al. Central venous access catheters in children with haemophilia. Blood Coagul Fibrinol 1996; 07: S39-44.
• 16 Warrier I, Baird-Cox K, Luscher JM. Use of central venous catheters in children with haemophilia: one haemophilia treatment centre experience. Haemophilia 1997; 03: 194-198.
• 17 Santagostino E, Gringeri A, Muca-Perja M. et al. A prospective clinical trial of implantable central venous access in children with haemophilia. Br J Haematol 1998; 102: 1224-1228.
• 18 Ljung R, Petrini P, Lindgren AC. et al. The long-term feasibility of venous access in children with haemophilia. Sem Hematol 1994; 31 (Suppl. 02) 16-18.
• 19 Medeiros D, Miller KL, Rollins NK. et al. Contrast venography in young hemophiliacs with implantable central venous access devices. Haemophilia 1998; 04: 10-15.
• 20 Ljung R, van den Berg M, Petrini P. et al. Port-a-cath usage in children with haemophilia: experience of 53 cases. Acta Paediatr 1998; 87: 1051-1054.
• 21 Blanchette VS, Al-Trabolsi H, Stain AM. High risk of central venous line-associated thrombosis in boys with hemophilia. Blood. 1999 94. 1035 Abstract.
• 22 Bollard CM, Teague LR, Berry EW. et al. The use of central venous catheter (portacaths) in children with haemophilia. Haemophilia 2000; 06: 66-70.
• 23 McMahon C, Smith J, Khair K. et al. Central venous access devices in children with congenital coagulation disorders; complications and long-term outcome. Br J Haematol 2000; 110: 461-468.
• 24 Journeycake JM, Qiunn CT, Miller KL. et al. Catheter-related deep venous thrombosis in children with hemophilia. Blood 2001; 98: 1727-1731.
• 25 Morado M, Jimenez-Yuste V, Villar M. et al. Complications of central venous catheters in patients with haemophilia and inhibitors. Haemophilia 2001; 07: 551-556.
• 26 Ettingshausen CE, Kurnik K, Schobess R. et al. Catheter-related thrombosis in children with hemophilia A: evidence of a multifactorial disease. Blood 2002; 99: 1499-1500.
• 27 Van Dijk K, Van den Berg HM, Van der Bom JG. Complications of port-a-cath (PAC) in children with severe hemophilia. Haemophilia. 2002 08. 488 abstract.
• 28 Domm JA, Hudson MG, Janco RL. Complications of central venous access devi-ces in paediatric haemophilia patients. Haemophilia 2003; 03: 50-56.
• 29 Massicotte MP, Dix D, Monagle P. et al. Central venous catheter related thrombosis in children: analysis of the Canadian Registry of Venous Thromboembolic Complications. J Pediatr 1998; 133: 770-775.
• 30 Giangrande PLF. Adverse events in the prophylaxis of haemophilia. Haemophilia 2003; 09 (Suppl. 01) 50-56.
• 31 Collins PW, Khair KS, Liesner R. et al. Complications experienced with central venous catheters in children with congenital bleeding disorders. Br J Haematol 1997; 99: 206-208.
• 32 Carcao MD, Connolly BL, Chait P. et al. Central venous catheter-related thrombosis presenting as superior vena cava syndrome in a haemophilic patient with inhibitors. Haemophilia 2003; 09: 578-583.
• 33 Vidler V, Richards M, Vora A. Central venous catheter-associated thrombosis in severe haemophilia. Br J Haematol 1999; 104: 461-464.
• 34 Makris M, Colvin B, Gupta V. et al. Venous thrombosis following the use of intermediate purity FVIII concentrate to treat patients with von Willebrand’s disease. Thromb Haemost 2002; 88: 387-388.
• 35 Sullivan DW, Purdy LJ, Billingham M. et al. Fatal myocardial infarction following therapy with prothrombin complex concentrates in a young man with hemophilia. Pediatrics 1984; 74: 279-281.
• 36 Karayalcin G, Goldberg B, Cherrick I. et al. Acute myocardial infarction complicating prothrombin complex concentrate therapy in an 8-year-old boy with hemophilia A and factor VIII inhibitor. Am J Pediatr Hematol Oncol 1993; 15: 416-419.
• 37 Peerlink K, Vermylen J. Acute myocardial infarction following administration of recombinant activated factor VII (Novo Seven) in a patient with haemophilia A and inhibitor. Thromb Haemost 1999; 82: 1775-1776.
• 38 Schimpf KL, Zeltsch C, Zeltsch P. Myocardial infarction complicating activated prothrombin complex concentrate substitution in a patient with hemophilia A. Lancet 1982; 02: 1043.
• 39 Chavin SI, Siegel DM, Rocco TA. et al. Acute myocardial infarction during treatment with an activated prothrombin complex concentrate in a patient with factor VIII deficiency and a factor VIII inhibitor. Am J Med 1988; 85: 245-249.
• 40 Kopitsky RG, Geltman EM. Unstable angina associated with factor VIII concentrate therapy for hemophilia A. Ann Intern Med 1986; 105: 215-216.
• 41 Mizon P, Goudemand J, Jude B. et al. Myocardial infarction after FEIBA therapy in a hemophilia-B patient with a factor IX inhibitor. Ann Hematol 1992; 64: 309-311.
• 42 Agrawal BL, Zelkowitz L, Hletko P. Acute myocardial infarction in a young hemophiliac patient during therapy with factor IX concentrate and epsilon aminocaproic acid. J Ped 1981; 98: 931-933.
• 43 Bolton-Maggs PHB, Colvin BT, Satchi G. et al. Thrombogenic potential of factor XI concentrate. Lancet 1994; 344: 748-749.
• 44 Mannucci PM, Chediak J, Hanna W. et al. Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study. Blood 2002; 99: 450-456.
• 45 Franchini M, Rossetti G, Tagliaferri A. et al. Efficacy and safety of factor VIII/ von Willebrand factor concentrate (Haemate-P) in preventing bleeding during surgery or invasive procedures in patients with von Willebrand’s disease. Haematologica 2003; 88: 1279-1283.
• 46 Ehlrich HJ, Henzl MJ, Gomperts ED. Safety of factor VIII inhibitor bypass activity (FEIBA): 10-year compilation of thrombotic adverse events. Haemophilia 2002; 08: 83-90.
• 47 Limentani SA, Gowell KP, Deitcher SR. High-purity factor IX concentrates for treatment of hemophilia B: relative purity and thrombogenic potential. Acta Haematol 1995; 94: S12-7.
• 48 Koster T, Blann AD, Briet E. et al. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-155.
• 49 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-1173.
• 50 Kyrle PA, Minar E, Hirschl M. et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000; 343: 457-462.
• 51 Kraaijenhagen RA, Anker PS, Koopman MMW. et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000; 83: 5-9.
• 52 Lowe GDO. Factor IX and thrombosis. Br J Haematol 2001; 115: 507-513.
• 53 Cederbaum AI, Blatt PM, Roberts HR. Intravascular coagulation with the use of human prothrombin complex concentrates. Ann Intern Med 1976; 84: 683-687.
• 54 Lusher JM. Thrombogenicity associated with factor IX complex concentrates. Sem Hematol 1991; 28: 3-5.
• 55 Kohler M, Hellstern P, Lechler E. et al. Thromboembolic complications associated with the use of prothrombin complex and factor IX concentrates. Thromb Haemost 1998; 80: 399-402.
• 56 Gruppo RA, Bove KE, Donaldson VH. Fatal myocardial necrosis associated with prothrombin complex concentrate therapy in hemophilia A. N Engl J Med 1983; 309: 242-243.
• 57 Hultin MB. Activated clotting factors in factor IX concentrates. Blood 1979; 54: 1028-1038.
• 58 MacGregor I, McLaughlin L, Drummond O. et al. In vivo models of thrombogenic potential: usefulness and limitations. Acta Haematol 1995; 94: S18-24.
• 59 Gray E, Tubbs J, Thomas S. et al. Measurement of activated factor IX in factor IX concentrates: correlation with in vivo thrombogenicity. Thromb Haemost 1995; 73: 675-679.
• 60 Santagostino E, Mannucci PM, Gringeri A. et al. Markers of hypercoagulability in patients with hemophilia B given repeated, large doses of factor IX concentrates during and after surgery. Thromb Haemost 1994; 71: 737-740.
• 61 Gitel SN, Varon D, Schulman S. et al. Clinical experience of a F XI-concentrate: possible side effects. Thromb Haemost 1991; 65: 1157.
• 62 Mannucci PM, Bauer KA, Santagostino E. et al. Activation of the coagulation cascade after infusion of a factor XI concentrate in congenitally deficient patients. Blood 1994; 84: 1314-1319.
• 63 Bolton-Maggs PHB, Colvin BT, Satchi G. et al. Thrombogenic potential of factor XI concentrate. Lancet 1994; 344: 748-9.
• 64 Richards EM, Makris MM, Cooper P. et al. In vivo coagulation activation following infusion of highly purified factor XI concentrate. Br J Haematol 1997; 96: 293-297.
• 65 Green D. Complications associated with the treatment of hemophiliacs with inhibitors. Haemophilia 1999; 05: 11-17.
• 66 Lozier JN, Santagostino E, Kasper CK. et al. Use of porcine factor VIII for surgical procedures in hemophilia A patients with inhibitors. Sem Hematol 1993; 30 (Suppl. 01) 10-21.
• 67 Fuerth JH, Mahrer P. Myocardial infarction after factor IX therapy. JAMA 1981; 245: 1455-1456.
• 68 Hough RE, Hampton KK, Preston FE. et al. Recombinant VIIa concentrate in the management of bleeding following prothrombin complex concentrate-related myocardial infarction in patients with haemophilia and inhibitors. Br J Haematol 2000; 111: 974-979.
• 69 Fukui H, Fyjimura Y, Takahasshi Y. et al. Laboratory evidence of DIC under FEIBA treatment of a hemophilic patient with intracranial bleeding and high titre factor VIII inhibitor. Thromb Res 1981; 22: 177-184.
• 70 Stenbjerg S, Jørgensen J. Disseminated intravascular coagulation and infusion of factor-VIII-inhibitor bypassing activity. Lancet 1977; 01: 360.
• 71 Negrier C, Goudemand J, Sultan Y. et al. and the members of the French FEIBA study group. Multicenter retrospective study on the utilization of FEIBA in France patients with factor VIII and factor IX inhibitors. Thromb Haemost 1997; 77: 1113-1119.
• 72 Leissinger CA. Use of prothrombin complex concentrates and activated prothrombin complex concentrates as prophylactic therapy in haemophilia patients with inhibitors. Haemophilia 1999; 05: 25-32.
• 73 Lusher J, Ingerslev J, Roberts H. et al. Clinical experience with recombinant factor VIIa. Blood Coagul Fibrinol 1998; 09: 119-128.
• 74 Schulman S. Safety, efficacy and lessons from continuous infusion with rFVIIa. Haemophilia 1998; 04: 564-567.
• 75 Aledort LM. RVIIa – its thrombogenicity. Thromb Haemost 2000; 84: 522-523.
• 76 Rosenfeld SB, Watkinson KK, Thompson BH. et al. Pulmonary embolism after sequential use of recombinant factor VIIa and activated prothrombin complex concentrate in a factor VIII inhibitor patient. Thromb Haemost 2002; 87: 925-926.
• 77 Stein SF, Duncar A, Cutter D. Disseminated intravascular coagulation (DIC) in a hemophilic treated with recombinant factor VIIa. Blood 1990; 76 (Suppl. 01) S1743.
• 78 Gallistl S, Cvrin G, Muntean W. Recombinant factor VIIa does not induce hypercoagulability in vitro. Thromb Haemost 1999; 81: 245-9.
• 79 Van der Planken MG, Schroyens W, Vertessen F. et al. Distal deep venous thrombosis in a hemophilia A patient with inhibitor and severe infectious disease, 18 days after recombinant activated factor VII transfusion. Blood Coagul Fibrinol 2002; 13: 367-36370.
• 80 Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222-1231.
• 81 Lane DA, Grant PJ. Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood 2000; 95: 1517-1532.
• 82 Oldenburg J, Scröder J, Schnitt C. et al. Small deletion/insertion mutations within poly-A runs of the factor VIII gene mitigate the sever hemophilia A phenotype. Thromb Haemost 1998; 79: 452-453.
• 83 Young M, Inaba H, Hoyer LW. et al. Partial correction of a severe molecular defect in hemophilia A because of errors during expression of the factor VIII gene. Am J Hum Gen 1997; 60: 565-573.
• 84 Escuriola CEttingshausen, Halimeh S, Kurnik K. et al. Symptomatic onset of severe hemophilia A in childhood is dependent on the presence of prothrombotic risk factors. Thromb Haemost 2001; 85: 218-220.
• 85 Arbini AA, Mannucci PM, Bauer KA. Low prevalence of the factor V Leiden mutation among “severe” hemophiliacs with a “milder” bleeding diathesis. Thromb Haemost 1995; 74: 1255-1258.
• 86 Nichols WC, Amano K, Cacheris PM. et al. Moderation of hemophilia A phenotype by the factor V R506Q mutation. Blood 1996; 88: 1183-1187.
• 87 Lee DH, Walker IR, Teitel J. et al. Effect of the factor V Leiden mutation on the clinical expression of severe hemophilia A. Thromb Haemost 2000; 83: 387-389.
• 88 Araújo F, Fraga M, Henriques I. et al. The clinical phenotype modulation of haemophilia by prothrombotic gene mutations. Haemophilia 2003; 09: 235-236.
• 89 Arruda VR, Annichino-Bizzacchi JM, Antunes SV. et al. Association of severe hemophilia A and factor V Leiden: report of three cases. Haemophilia 1996; 02: 51-53.
• 90 Vianello F, Belvini D, Dal Bello F. et al. Mild bleeding diathesis in a boy with combined severe haemophilia B (C10400→T) and heterozygous factor V Leiden. Haemophilia 2001; 07: 511-514.
• 91 Lindqvist PG, Svensson PJ, Dahlbäck B. et al. Factor V Q506 mutation (activated protein C resistance) associated with reduced intrapartum blood loss – a possible evolutionary selection mechanism. Thromb Haemost 1998; 79: 69-73.
• 92 Ten Cate DPBrandjes, Smits PH. et al. The role of platelets in venous thrombosis: a patient with Glanzmann’s thromboasthenia and factor V Leiden mutation suffering from deep venous thrombosis. J Thromb Haemost 2003; 01: 394-395.
• 93 Ettinghausen CE, Saguer MI, Kreuz W. Portal vein thrombosis in a patient with severe hemophilia A and F V G1691A mutation during continuous infusion of factor VIII after intramural jejunal bleeding – successful thrombolysis under heparin therapy. Eur J Pediatr 1999; 158: 180-182.
• 94 Bowen D, Dasani H, Yung B. et al. Deep venous thrombosis and pulmonary embolism in a patient with type III von Willebrand’s disease, protein C and antithrombin III deficiency. Br J Haematol 1992; 81: 446-447.
• 95 Olcay L, Gurgey A, Toplaoglu H. et al. Cerebral infarction associated with factor V Leiden mutation in a boy with hemophilia A. Am J Hematol 1997; 56: 189-190.
• 96 Evans G, Pasi KJ, Mehta A. et al. Recurrent venous thromboembolic disease and factor XI concentrate in a patient with severe factor XI deficiency, chronic myelomonocytic leukaemia, factor V Leiden and heterozygous plasminogen deficiency. Blood Coagul Fibrinol 1997; 08: 437-440.
• 97 Pruthi RK, Heit JA, Green MM. et al. Venous thromboembolism after hip fracture surgery in a patient with hemophilia B and factor V Arg506Gln (factor V Leiden). Haemophilia 2000; 06: 631-634.
• 98 Saif MW, Bona R, Greenberg B. AIDS and thrombosis: retrospective study of 131 HIVinfected patients. AIDS Patient Care STDS 2001; 15: 311-320.
• 99 Majluf-Cruz A, Silva-Estrada M, SanchezBarboza R. et al. Venous thrombosis among patients with AIDS. Clin Appl Thromb Haemost 2004; 10: 19-25.
• 100 Saber AA, Aboolian A, LaRaja RD. et al. HIV/AIDS and the risk of deep vein thrombosis: a study of 45 patients with lower extremity involvement. Am Surg 2001; 67: 645-647.
• 101 Saif MW, Greenberg B. HIV and thrombosis: a review. AIDS Patient Care STDS 2001; 15: 15-24.
• 102 Leder AN, Flansbaum B, Zandman-Goddard G. et al. Antiphospholipid syndrome induced by HIV. Lupus 2001; 10: 370-374.
• 103 Stahl CP, Wideman CS, Spira TJ. et al. Protein S deficiency in men with long term human immunodeficiency virus. Blood 1993; 81: 1801-1807.
• 104 Lafeuillade A, Alessi MC, Poizot-Martin I. et al. Endothelial cell dysfunction in HIV infection. J Acquir Immune Defic Syndr 1992; 05: 127-131.
• 105 De Gaetano KDonati, Tacconelli E, Scoppettuolo G. et al. Recurrent venous thrombosis in a patient with hemophilia A and human immunodeficiency virus infection. Haematologica 2002; 87: ECR04.