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  • Print publication year: 2006
  • Online publication date: February 2010

3 - Von Willebrand disease and other bleeding disorders in obstetrics



Bleeding disorders in the female population often present unique challenges to an obstetrician. The hormonal and physical changes that occur during the menstrual cycle, pregnancy, childbirth, and the post-partum period continually place strain upon the hemostatic system. Although severe bleeding disorders are usually easily recognized, mild bleeding disorders often go undiagnosed due to the “mild degree” of signs and symptoms (e.g. slightly abnormal menstruation). Unfortunately, even these mild bleeding disorders often lead to a decrease in the quality of life, variable degrees of morbidity, and even life-threatening hemorrhage. Therefore, it is essential that the obstetrician be aware of the clinical clues, appropriate diagnostic tests, and treatment regimens for such disorders. This is particularly important for pregnant women, whose hemostatic system undergoes marked alterations in preparation for the unique challenge of delivery.

The hemostatic system

Basic knowledge of the hemostatic system assists in making clinical decisions regarding bleeding conditions in the obstetric population. Normal hemostasis is a highly regulated, physiologic process of clot formation and clot management that occurs in response to vascular injury. It involves 2 major systems: (i) primary hemostasis and (ii) secondary hemostasis. Although both systems are initiated at the same time and work together intricately to form stable platelet-fibrin clots, the influence that each system has upon clot formation in the arterial versus the venous systems is different.

Kadir, R. A., Sabin, C. A., Pollard, D., et al. Quality of life during menstruation in patients with inherited bleeding disorders. Haemophilia, 1998; 4(6): 836–41.
Kouides, P. A., Phatak, P. D., Burkart, P., et al. Gynaecological and obstetrical morbidity in women with type I von Willebrand disease: results of a patient survey. Haemophilia, 2000; 6(6): 643–8.
Rozeik, C. H.Gynecological disorders and psychological problems in 184 women with von Willebrand disease (vWD). Haemophilia, 1998; 4(3): 293.
Kulkarni, S., Dopheide, S. M., Yap, C. L., et al. A revised model of platelet aggregation. J. Clin. Invest., 2000; 105(6): 783–91.
Shattil, S. J., Kashiwagi, H. and Pampori, N.Integrin signaling: the platelet paradigm. Blood, 1998; 91(8): 2645–57.
Watson, S. P. and Gibbins, J.Collagen receptor signalling in platelets: extending the role of the ITAM. Immunol. Today, 1998; 19(6): 260–4.
Wickstrom, K., Edelstam, G., Lowbeer, C. H., et al. Reference intervals for plasma levels of fibronectin, von Willebrand factor, free protein S and antithrombin during third-trimester pregnancy. Scand. J. Clin. Lab. Invest., 2004; 64(1): 31–40.
Kadir, R. A., Lee, C. A., Sabin, C. A., et al. Pregnancy in women with von Willebrand's disease or factor XI deficiency. Br. J. Obstet. Gynaecol., 1998; 105(3): 314–21.
Conti, M., Mari, D., Conti, E., et al. Pregnancy in women with different types of von Willebrand disease. Obstet. Gynecol., 1986; 68(2): 282–5.
Stirling, Y., Woolf, L., North, W. R., et al. Haemostasis in normal pregnancy. Thromb. Haemost., 1984; 52(2): 176–82.
Economides, D. L., Kadir, R. A. and Lee, C. A.Inherited bleeding disorders in obstetrics and gynaecology. Br. J. Obstet. Gynaecol., 1999; 106(1): 5–13.
Cerneca, F., Ricci, G., Simeone, R., et al. Coagulation and fibrinolysis changes in normal pregnancy. Increased levels of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive fibrinolysis. Eur. J. Obstet. Gynecol. Reprod. Biol., 1997; 73(1): 31–6.
Dobrkovska, A., Krzensk, U. and Chediak, J. R.Pharmacokinetics, efficacy and safety of Humate-P in von Willebrand disease. Haemophilia, 1998; 4(Suppl 3): 33–9.
Condie, R. G.A serial study of coagulation factors XII, XI and X in plasma in normal pregnancy and in pregnancy complicated by pre-eclampsia. Br. J. Obstet. Gynaecol., 1976; 83(8): 636–9.
Phillips, L. L., Rosano, L. and Skrodelis, V.Changes in factor XI (plasma thromboplastin antecedent) levels during pregnancy. Am. J. Obstet. Gynecol., 1973; 116(8): 1114–6.
Beller, F. K. and Ebert, C.The coagulation and fibrinolytic enzyme system in pregnancy and in the puerperium. Eur. J. Obstet. Gynecol. Reprod. Biol., 1982; 13(3): 177–97.
Hilgartner, M. W. and Smith, C. H.Plasma thromboplastin antecedent (Factor Xi) in the neonate. J. Pediatr., 1965; 66: 747–52.
Fernandez, J. A., Estelles, A., Gilabert, J., et al. Functional and immunologic protein S in normal pregnant women and in full-term newborns. Thromb. Haemost., 1989; 61(3): 474–8.
Clark, P., Brennand, J., Conkie, J. A., et al. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Thromb. Haemost., 1998; 79(6): 1166–70.
Edelstam, G., Lowbeer, C., Kral, G., et al. New reference values for routine blood samples and human neutrophilic lipocalin during third-trimester pregnancy. Scand. J. Clin. Lab. Invest., 2001; 61(8): 583–92.
Kjellberg, U., Andersson, N. E., Rosen, S., et al. APC resistance and other haemostatic variables during pregnancy and puerperium. Thromb. Haemost., 1999; 81(4): 527–31.
Chabloz, P., Reber, G., Boehlen, F., et al. TAFI antigen and D-dimer levels during normal pregnancy and at delivery. Br. J. Haematol., 2001; 115(1): 150–2.
Cadroy, Y., Grandjean, H., Pichon, J., et al. Evaluation of six markers of haemostatic systems in normal pregnancy and pregnancy complicated by hypertension or pre-eclampsia. Br. J. Obstet. Gynaecol., 1993; 100(5): 416–20.
Koh, C. L., Viegas, O. A., Yuen, R., et al. Plasminogen activators and inhibitors in normal late pregnancy, postpartum and in the postnatal period. Int. J. Gynaecol. Obstet., 1992; 38(1): 9–18.
Wahlberg, T., Blomback, M., Hall, P., et al. Application of indicators, predictors and diagnostic indices in coagulation disorders. I. Evaluation of a self-administered questionnaire with binary questions. Methods Inf. Med., 1980; 19(4): 194–200.
Kouides, P. A.Menorrhagia from a haematologist's point of view. Part I: initial evaluation. Haemophilia, 2002; 8(3): 330–8.
Siegel, J. E. and Kouides, P. A.Menorrhagia from a haematologist's point of view. Part II: management. Haemophilia 2002; 8(3): 339–47.
Peterson, P., Hayes, T. E., Arkin, C. F., et al. The preoperative bleeding time test lacks clinical benefit: College of American Pathologists' and American Society of Clinical Pathologists' position article. Arch. Surg., 1998; 133(2): 134–9.
Favaloro, E. J.Utility of the PFA-100™ for assessing bleeding disorders and monitoring therapy: a review of analytical variables, benefits and limitations. Haemophilia, 2001; 7(2): 170–9.
Wuillemin, W., Gasser, K., Zeerleder, S., et al. Evaluation of a Platelet Function Analyser (PFA-100™) in patients with a bleeding tendency. Swiss Med. Wkly., 2002(132): 443–8.
Roa, A. Disorders of platelet function. In Kitchens, C. S. A. B., and Kessler, C. M., eds. Consultative Hemostasis and Thrombosis. 1st edn. Philadelphia: W. B. Saunders; 2002. pp. 133–48.
Wilner, K. D., Rushing, M., Walden, C., et al. Celecoxib does not affect the antiplatelet activity of aspirin in healthy volunteers. J. Clin. Pharmacol., 2002; 42(9): 1027–30.
Silverman, D. G., Halaszynski, T., Sinatra, R., et al. Rofecoxib does not compromise platelet aggregation during anesthesia and surgery. Can. J. Anaesth., 2003; 50(10): 1004–8.
Homoncik, M., Malec, M., Marsik, C., et al. Rofecoxib exerts no effect on platelet plug formation in healthy volunteers. Clin. Exp. Rheumatol., 2003; 21(2): 229–31.
Coukell, A. J. and Markham, A.Clopidogrel. Drugs, 1997; 54(5): 745–50; discussion p. 751.
Pritchard, J. A., Weisman, R. Jr., Ratnoff, O. D., et al. Intravascular hemolysis, thrombocytopenia and other hematologic abnormalities associated with severe toxemia of pregnancy. N. Engl. J. Med., 1954; 250(3): 89–98.
Pitkin, R. M. and Witte, D. L.Platelet and leukocyte counts in pregnancy. JAMA, 1979; 242(24): 2696–8.
Dilley, A., Drews, C., Miller, C., et al. Von Willebrand disease and other inherited bleeding disorders in women with diagnosed menorrhagia. Obstet. Gynecol., 2001; 97(4): 630–6.
Rodeghiero, F., Castaman, G. and Dini, E.Epidemiological investigation of the prevalence of von Willebrand's disease. Blood, 1987; 69(2): 454–9.
Edlund, M., Blomback, M., Schoultz, B., et al. On the value of menorrhagia as a predictor for coagulation disorders. Am. J. Hematol., 1996; 53(4): 234–8.
Ruggeri, Z. M.Structure of von Willebrand factor and its function in platelet adhesion and thrombus formation. Best Pract. Res. Clin. Haematol., 2001; 14(2): 257–79.
Siediecki, C.Shear-dependant changes in the three-dimensional structure of human von Willebrand factor. Blood, 1996; 88: 2939–50.
Ruggeri, Z. M., Dent, J. A. and Saldivar, E.Contribution of distinct adhesive interactions to platelet aggregation in flowing blood. Blood, 1999; 94(1): 172–8.
Fujimoto, T. and Hawiger, J.Adenosine diphosphate induces binding of von Willebrand factor to human platelets. Nature, 1982; 297(5862): 154–6.
Ni, H., Denis, C. V., Subbarao, S., et al. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J. Clin. Invest., 2000; 106(3): 385–92.
Goto, S., Ikeda, Y., Saldivar, E., et al. Distinct mechanisms of platelet aggregation as a consequence of different shearing flow conditions. J. Clin. Invest., 1998; 101(2): 479–86.
Seremetis S. and Afshani, V. Management of bleeding disorders in pregnancy. In Kitchens, C. S. A. B., and Kessler, C. M., eds. Consultative Hemostasis and Thrombosis. 1st edn. Philadelphia: W. B. Saunders; 2002. pp. 437–48.
Hennessy, B. J., White, B., Byrne, M., et al. Acquired von Willebrand's disease. Ir. J. Med. Sci., 1998; 167(2): 81–5.
Nitu-Whalley, I. C. and Lee, C. A.Acquired von Willebrand syndrome – report of 10 cases and review of the literature. Haemophilia, 1999; 5(5): 318–26.
Attivissimo, L. A., Lichtman, S. M. and Klein, I.Acquired von Willebrand's syndrome causing a hemorrhagic diathesis in a patient with hypothyroidism. Thyroid, 1995; 5(5): 399–401.
Lak, M., Peyvandi, F. and Mannucci, P. M.Clinical manifestations and complications of childbirth and replacement therapy in 385 Iranian patients with type 3 von Willebrand disease. Br. J. Haematol., 2000; 111(4): 1236–9.
Kroll, M.Manual of Coagulation Disorders. 1st edn. Malden, MA: Blackwell Science; 2001.
Castaman, G., Eikenboom, J. C., Contri, A., et al. Pregnancy in women with type 1 von Willebrand disease caused by heterozygosity for von Willebrand factor mutation C1130F. Thromb. Haemost., 2000; 84(2): 351–2.
Kouides, P. A.Obstetric and gynaecological aspects of von Willebrand disease. Best Pract. Res. Clin. Haematol., 2001; 14(2): 381–99.
Sorosky, J., Klatsky, A., Nobert, G. F.Von Willebrand's disease complicating second-trimester abortion. Obstet. Gynecol., 1980; 55(2): 253–4.
Meyer, D., Fressinaud, E., Hilbert, L., et al. Type 2 von Willebrand disease causing defective von Willebrand factor-dependent platelet function. Best. Pract. Res. Clin. Haematol., 2001; 14(2): 349–64.
Ginsburg, D. and Sadler, J. E.Von Willebrand disease: a database of point mutations, insertions, and deletions. For the Consortium on von Willebrand Factor Mutations and Polymorphisms, and the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb. Haemost., 1993; 69(2): 177–84.
Ruggeri, Z. M. and Zimmerman, T. S.Classification of variant von Willebrand's disease subtypes by analysis of functional characteristics and multimeric composition of factor VIII/von Willebrand factor. Ann. NY. Acad. Sci., 1981; 370: 205–9.
Weiss, H. J., Ball, A. P. and Mannucci, P. M.Incidence of severe von Willebrand's disease. N. Engl. J. Med., 1982; 307(2): 127.
Mannucci, P. M., Bloom, A. L., Larrieu, M. J., et al. Atherosclerosis and von Willebrand factor. I. Prevalence of severe von Willebrand's disease in western Europe and Israel. Br. J. Haematol., 1984; 57(1): 163–9.
Kadir, R. A., Economides, D. L., Sabin, C. A., et al. Variations in coagulation factors in women: effects of age, ethnicity, menstrual cycle and combined oral contraceptive. Thromb. Haemost., 1999; 82(5): 1456–61.
Miller, C., Dilley, A. B., Drews, C., et al. Changes in von Willebrand factor and Factor VIII during the menstrual cycle. Thromb. Haemost., 2002; 87(6): 1082–3.
Mandalaki, T., Louizou, C., Dimitriadou, C., et al. Variations in factor VIII during the menstrual cycle in normal women. N. Engl. J. Med., 1980; 302(19): 1093–4.
Blomback, M., Eneroth, P., Andersson, O., et al. On laboratory problems in diagnosing mild von Willebrand's disease. Am. J. Hematol., 1992; 40(2): 117–20.
Budde, U., Drewke, E., Mainusch, K., et al. Laboratory diagnosis of congenital von Willebrand disease. Semin. Thromb. Hemost., 2002; 28(2): 173–90.
Enayat, M. S. and Hill, F. G.Analysis of the complexity of the multimeric structure of factor VIII related antigen/von Willebrand protein using a modified electrophoretic technique. J. Clin. Pathol., 1983; 36(8): 915–9.
Walker, I. D., Walker, J. J., Colvin, B. T., et al. Investigation and management of haemorrhagic disorders in pregnancy. Haemostasis and Thrombosis Task Force. J. Clin. Pathol., 1994; 47(2): 100–8.
Eikenboom, J. C.Congenital von Willebrand disease type 3: clinical manifestations, pathophysiology and molecular biology. Best Pract. Res. Clin. Haematol., 2001; 14(2): 365–79.
Batlle, J., Noya, M. S., Giangrande, P., et al. Advances in the therapy of von Willebrand disease. Haemophilia, 2002; 8(3): 301–7.
Mannucci, P. M.How I treat patients with von Willebrand disease. Blood, 2001; 97(7): 1915–19.
Chediak, J. R., Alban, G. M. and Maxey, B.Von Willebrand's disease and pregnancy: management during delivery and outcome of offspring. Am. J. Obstet. Gynecol., 1986; 155(3): 618–24.
Mannucci, P. M.Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood, 1997; 90(7): 2515–21.
Mannucci, P. M.Hemostatic drugs. N. Engl. J. Med., 1998; 339(4): 245–53.
Charles, K., Preston, F. and Makris, M.Successful use of desmopression (DDAVP) in pregnant women with inherited storage pool disease. Haemophilia, 2000; 6: 241.
Burrow, G., Wassenaar, W. and Robertson, G.DDAVP treatment of diabetes insipidus during pregnancy and the post-partum period. Acta Endocrinol., 1981; 97: 23–5.
Rochelson, B., Caruso, R., Davenport, D., et al. The use of prophylactic desmopressin (DDAVP) in labor to prevent hemorrhage in a patient with Ehlers-Danlos syndrome. NY State J. Med., 1991; 91(6): 268–9.
Weinbaum, P. J., Cassidy, S. B., Campbell, W. A., et al. Pregnancy management and successful outcome of Ehlers-Danlos syndrome type IV. Am. J. Perinatol., 1987; 4(2): 134–7.
Ray, J. G.DDAVP use during pregnancy: an analysis of its safety for mother and child. Obstet. Gynecol. Surv., 1998; 53(7): 450–5.
Mannucci, P. M., Lombardi, R., Bader, R., et al. Heterogeneity of type I von Willebrand disease: evidence for a subgroup with an abnormal von Willebrand factor. Blood, 1985; 66(4): 796–802.
Sadler, J. E., Mannucci, P. M., Berntorp, E., et al. Impact, diagnosis and treatment of von Willebrand disease. Thromb. Haemost., 2000; 84(2): 160–74.
Mazurier, C., Gaucher, C., Jorieux, S., et al. Biological effect of desmopressin in eight patients with type 2N (‘Normandy’) von Willebrand disease. Collaborative Group. Br. J. Haematol., 1994; 88(4): 849–54.
Holmberg, L., Nilsson, I. M., Borge, L., et al. Platelet aggregation induced by 1-desamino-8-D-arginine vasopressin (DDAVP) in Type II B von Willebrand's disease. N. Engl. J. Med., 1983; 309(14): 816–21.
Fausett, B. and Silver, R. M.Congenital disorders of platelet function. Clin. Obstet. Gynecol. 1999; 42(2): 390–405.
Sage, D. J.Epidurals, spinals and bleeding disorders in pregnancy: a review. Anaesth. Intensive Care, 1990; 18(3): 319–26.
Phillips, M. D. and Santhouse, A.von Willebrand disease: recent advances in pathophysiology and treatment. Am. J. Med. Sci., 1998; 316(2): 77–86.
Pales, J. L., Lopez, A., Asensio, A., et al. Inhibitory effect of peak 2–4 of uremic middle molecules on platelet aggregation. Eur. J. Haematol., 1987; 39(3): 197–202.
Bazilinski, N., Shaykh, M., Dunea, G., et al. Inhibition of platelet function by uremic middle molecules. Nephron, 1985; 40(4): 423–8.
Moal, V., Brunet, P., Dou, L., et al. Impaired expression of glycoproteins on resting and stimulated platelets in uraemic patients. Nephrol. Dial. Transplant, 2003; 18(9): 1834–41.
Kunicki T. J. Platelet immunology. In Colman, R. W., Hirsh, J., Marder, V. J., et al., eds. Hemostasis and Thrombosis: Basic Principles & Clinical Practice. 4th edn. Philadelphia: Lippincott Williams & Wilkins; 2001, pp. 461–77.
Ramasamy, I.Inherited bleeding disorders: disorders of platelet adhesion and aggregation. Crit. Rev. Oncol. Hematol., 2004; 49(1): 1–35.
Khalil, A., Seoud, M., Tannous, R., et al. Bernard-Soulier syndrome in pregnancy: case report and review of the literature. Clin. Lab. Haematol., 1998; 20(2): 125–8.
Laurian, Y.Treatment of bleeding in patients with platelet disorders: is there a place for recombinant factor VIIa?Pathophysiol. Haemost. Thromb., 2002; 32(Suppl. 1): 37–40.
Caglar, K., Cetinkaya, A., Aytac, S., et al. Use of recombinant factor VIIa for bleeding in children with Glanzmann thrombasthenia. Pediatr. Hematol. Oncol., 2003; 20(6): 435–8.
Poon, M. C., d'Oiron, R., Hann, I., et al. Use of recombinant factor VIIa (NovoSeven) in patients with Glanzmann thrombasthenia. Semin. Hematol., 2001; 38(4 Suppl. 12): 21–5.
Almeida, A. M., Khair, K., Hann, I.The use of recombinant factor VIIa in children with inherited platelet function disorders. Br. J. Haematol., 2003; 121(3): 477–81.
Lusher, J. M. and McMillan, C. W.Severe factor VIII and factor IX deficiency in females. Am. J. Med., 1978; 65(4): 637–48.
Seligsohn, U.High gene frequency of factor XI (PTA) deficiency in Ashkenazi Jews. Blood, 1978; 51(6): 1223–8.
Bauduer, F., Dupreuilh, F., Ducout, L., et al. Factor XI deficiency in the French Basque Country. Haemophilia, 1999; 5(3): 187–90.
Kadir, R. A., Economides, D. L. and Lee, C. A.Factor XI deficiency in women. Am. J. Hematol., 1999; 60(1): 48–54.
Bolton-Maggs, P. H., Wan-Yin, Young B., McCraw, A. H., et al. Inheritance and bleeding in factor XI deficiency. Br. J. Haematol., 1988; 69(4): 521–8.
Bolton-Maggs, P. H., Colvin, B. T., Satchi, B. T., et al. Thrombogenic potential of factor XI concentrate. Lancet, 1994; 344(8924): 748–9.
Roberts, H. and Escobar, M. Less common congenital disorders of hemostasis. In Kitchens, C. S. A. B., and Kessler, C. M., eds. Consultative Hemostasis and Thrombosis. Philadelphia: W. B. Saunders; 2002, pp. 57–73.
Green, D. and Lechner, K.A survey of 215 non-hemophilic patients with inhibitors to Factor VIII. Thromb. Haemost., 1981; 45(3): 200–3.
Hauser, I., Schneider, B. and Lechner, K.Post-partum factor VIII inhibitors. A review of the literature with special reference to the value of steroid and immunosuppressive treatment. Thromb. Haemost., 1995; 73(1): 1–5.
Delgado, J., Jimenez-Yuste, V., Hernandez-Navarro, F., Villar, al. Acquired haemophilia: review and meta-analysis focused on therapy and prognostic factors. Br. J. Haematol., 2003; 121(1): 21–35.
Rubinger, M., Rivard, G. E., Teitel, J., et al. Suggestions for the management of factor VIII inhibitors. Haemophilia, 2000; 6(Suppl. 1): 52–9.
Ewenstein B., Putnam K. and Bohn R. Nonhemophilic inhibitors of coagulation. In Kitchens, C. S., Alving, B. M. and Kessler, C. M., eds. Consultative Hemostasis and Thrombosis. Philadelphia: W. B. Saunders; 2002, pp. 75–90.
Rubinger, M., Houston, D. S., Schwetz, N., et al. Continuous infusion of porcine factor VIII in the management of patients with factor VIII inhibitors. Am. J. Hematol., 1997; 56(2): 112–8.
Shulman, N. R. and Hirschman, R. J.Acquired hemophilia. Trans. Assoc. Am. Physicians, 1969; 82: 388–97.
Green, D.Suppression of an antibody to factor VIII by a combination of factor VIII and cyclophosphamide. Blood, 1971; 37(4): 381–7.
Spero, J. A., Lewis, J. H. and Hasiba, U.Corticosteroid therapy for acquired F VIII: C inhibitors. Br. J. Haematol., 1981; 48(4): 635–42.
Schwartz, R. S., Gabriel, D. A., Aledort, L. M., et al. A prospective study of treatment of acquired (autoimmune) factor VIII inhibitors with high-dose intravenous gammaglobulin. Blood, 1995; 86(2): 797–804.
Sultan, Y., Kazatchkine, M. D., Nydegger, U., et al. Intravenous immunoglobulin in the treatment of spontaneously acquired factor VIII: C inhibitors. Am. J. Med., 1991; 91(5A): 35–9(S).