Semin Thromb Hemost 2006; 32(5): 480-484
DOI: 10.1055/s-2006-947861
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Aspects of the Laboratory Identification of von Willebrand Disease in Women

Peter A. Kouides1
  • 1Mary M. Gooley Hemophilia Center, Rochester, New York
Further Information

Publication History

Publication Date:
24 July 2006 (online)

ABSTRACT

The increased prevalence of the laboratory diagnosis of von Willebrand disease (vWD) in women presenting with menorrhagia has raised concerns regarding certain specifics in vWD testing in women, including when vWD testing should be done in relation to menses and whether testing should be done while the patient is not taking an oral contraceptive (OC). These concerns have been based on historical reports that vWF and factor (F) VIII:coagulant activity levels can decrease during menses and conceivably increase the probability of diagnosing vWD when the patient is menstruating, whereas hormone therapy can increase the vWF levels and conceivably mask the diagnosis of vWD. Historically, the reports of a decrease in vWF levels during menstruation have been in a relatively small total number of patients; this has not been confirmed in two recent studies. In one study of 95 normal menstruating females sampled serially at days 4 to 7, 11 to 15, and 21 to 28, there was no variation. In another study of 40 volunteers, by cross-sectional analysis there was no difference. However, interestingly in that study, longitudinal analysis of samples showed a decrease in vWF antigen during menstruation. In another recently published study, using cross-sectional analysis, the lowest levels of vWF were found on days 1 through 4, whereas the highest were identified on days 9 through 10. Conceivably, these groups were more finely divided than were those in the other studies. In summary, in light of these conflicting results, recommendations for testing exclusively during menses cannot be made. At this point, it is not unreasonable to suggest that hematologists and gynecologists sample at least once at the time of menstrual bleeding when the diagnosis of vWD in a menstruating female is suspected. Consequently, sampling during the menstrual cycle may likely capture the lowest levels of FVIIIC and vWF antigen. Regarding testing while the patient is taking an OC, present preparations do not contain supraphysiological doses of estrogen and are unlikely to affect the laboratory diagnosis of vWD. These studies primarily have been in controls. Therefore, prospective studies in vWD women of menstrual variation of the vWF levels and the impact of OCs on vWF levels are in order before specific recommendations can be made regarding the timing of testing and whether patients should be tested while the patient is not taking an OC. Other aspects regarding race, age, preanalytical variables, and pregnancy potentially affecting the laboratory diagnosis of vWD are also discussed in this review.

REFERENCES

  • 1 Vessey M P, Villard-Mackintosh L, McPherson K, Coulter A, Yeates D. The epidemiology of hysterectomy: findings in a large cohort study.  Br J Obstet Gynaecol. 1992;  99 402-407
  • 2 Prentice A. Fortnightly review. Medical management of menorrhagia.  BMJ. 1999;  319 1343-1345
  • 3 Werner E J, Broxson E H, Tucker E L et al.. Prevalence of von Willebrand disease in children: a multiethnic study.  J Pediatr. 1993;  123 893-898
  • 4 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease.  Blood. 1987;  69 454-459
  • 5 Edlund M, Blombäck M, von Schoultz B, Andersson O. On the value of menorrhagia as a predictor for coagulation disorders.  Am J Hematol. 1996;  53 234-238
  • 6 Kadir R A, Economides D L, Sabin C A, Owens D, Lee C A. Frequency of inherited bleeding disorders in women with menorrhagia.  Lancet. 1998;  351 485-489
  • 7 Dilley A, Drews C, Miller C et al.. von Willebrand disease and other inherited bleeding disorders in women with diagnosed menorrhagia.  Obstet Gynecol. 2001;  97 630-636
  • 8 Woo Y L, White B, Corbally R et al.. von Willebrand's disease: an important cause of dysfunctional uterine bleeding.  Blood Coagul Fibrinolysis. 2002;  13 89-93
  • 9 Philipp C S, Dilley A, Miller C H et al.. Platelet functional defects in women with unexplained menorrhagia.  J Thromb Haemost. 2003;  1 477-484
  • 10 Shankar M, Lee C A, Sabin C A, Economides D L, Kadir R A. von Willebrand disease in women with menorrhagia: a systematic review.  BJOG. 2004;  111 734-740
  • 11 ACOG Committee on Gynecologic Practice . Committee Opinion: number 263, December 20001. von Willebrand's disease in gynecologic practice.  Obstet Gynecol. 2001;  98 1185-1186
  • 12 Dilley A, von Crudder S. Willebrand disease in women: the need for recognition and understanding.  J Womens Health Gend Based Med. 1999;  8 443-445
  • 13 Siegbahn A, Odlind V, Hedner U, Venge P. Coagulation and fibrinolysis during the normal menstrual cycle.  Upsala J Med Sci. 1989;  94 137-152
  • 14 Mandalaki T, Louizou C, Dimitriadou C, Symeonidis P. Variations in factor VIII during the menstrual cycle in normal women.  N Engl J Med. 1980;  302 1093-1094
  • 15 Blombäck M, Eneroth P, Andersson O, Anvret M. On laboratory problems in diagnosing mild von Willebrand's disease.  Am J Hematol. 1992;  40 117-120
  • 16 Blombäck M, Eneroth P, Landgren B M, Lagerstrom M, Anderson O. On the intraindividual and gender variability of haemostatic components.  Thromb Haemost. 1992;  67 70-75
  • 17 Jern C, Eriksson E, Tengborn L et al.. Changes in plasma coagulation and fibrinolysis in response to mental stress.  Thromb Haemost. 1989;  62 767-771
  • 18 Prentice C RM, Forbes D, Smith S M. Rise of factor VIII after exercise and adrenaline infusion, measured by immunological and biological techniques.  Thromb Res. 1972;  1 493
  • 19 Kadir R A, Economides D L, Sabin C A, Owens D, Lee C A. Variations in coagulation factors in women: effects of age, ethnicity, menstrual cycle and combined oral contraceptive.  Thromb Haemost. 1999;  82 1456-1461
  • 20 Onundarson P T, Gumundsdottir B R, Arnfinnsdottir A V, Kjeld M, Olafsson O. Von Willebrand factor does not vary during the normal menstrual cycle.  , [letter] Thromb Haemost. 2001;  85 183-184
  • 21 Miller C H, Dilley A, Drews C, Richardson L, Evatt B. Changes in von Willebrand factor and factor VIII levels during the menstrual cycle.  Thromb Haemost. 2002;  87 1082-1083
  • 22 Leissinger C, Becton D, Cornell C, Gill J C. High-dose DDAVP intranasal spray (Stimate) for the prevention and treatment of bleeding in patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease and symptomatic carriers of haemophilia A.  Haemophilia. 2001;  7 258-266
  • 23 Lethagen S. Desmopressin in the treatment of women's bleeding disorders.  Haemophilia. 1999;  5 233-237
  • 24 Abildgaard C F, Suzuki Z, Harrison J, Jefcoat K, Zimmerman T S. Serial studies in von Willebrand's disease: variability versus “variants.”  Blood. 1980;  56 712-716
  • 25 Alperin J B. Estrogens and surgery in women with von Willebrand's disease.  Am J Med. 1982;  73 367-371
  • 26 Mangal A K, Naiman S C. Oral contraceptives and von Willebrand's disease.  , [letter] Can Med Assoc J. 1983;  128 1274
  • 27 Bremme K, Wramsby H, Andersson O, Wallin M, Blombäck M. Do lowered factor VII levels at extremely high endogenous oestradiol levels protect against thrombin formation?.  Blood Coagul Fibrinolysis. 1994;  5 205-210
  • 28 He S, Bremme K, Silveira A. van RM, Blombäck M. Hypercoagulation in surgical postmenopausal women having hormone replacement with overdose estradiol.  Blood Coagul Fibrinolysis. 2001;  12 677-681
  • 29 Kadir R A, Lee C A, Sabin C A, Pollard D, Economides D L. Pregnancy in women with von Willebrand's disease or factor XI deficiency.  Br J Obstet Gynaecol. 1998;  105 314-321
  • 30 Ramsahoye B H, Davies S V, Dasani H, Pearson J F. Pregnancy in von Willebrand's disease.  J Clin Pathol. 1994;  47 569-570
  • 31 Prasad R N, Koh S C, Viegas O A, Ratnam S S. Effects on hemostasis after two-year use of low dose combined oral contraceptives with gestodene or levonorgestrel.  Clin Appl Thromb Hemost. 1999;  5 60-70
  • 32 Solerte S B, Fioravanti M, Spinillo A, Ferrari E, Guaschino S. Influence of triphasic oral contraceptives on blood rheology and hemostatic and metabolic patterns in young women. Results of a three-year study.  J Reprod Med. 1992;  37 725-732
  • 33 Gevers Leuven J A, Kluft C, Bertina R M, Hessel L W. Effects of two low-dose oral contraceptives on circulating components of the coagulation and fibrinolytic systems.  J Lab Clin Med. 1987;  109 631-636
  • 34 Hall G, Blombäck M, Landgren B M, Bremme K. Effects of vaginally administered high estradiol doses on hormonal pharmacokinetics and hemostasis in postmenopausal women.  Fertil Steril. 2002;  78 1172-1177
  • 35 David J L, Gaspard U J, Gillain D, Raskinet R, Lepot M R. Hemostasis profile in women taking low-dose oral contraceptives.  Am J Obstet Gynecol. 1990;  163 420-423
  • 36 Foster P A. The reproductive health of women with von Willebrand disease unresponsive to DDAVP: results of an international survey. On behalf of the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the ISTH.  Thromb Haemost. 1995;  74 784-790
  • 37 Lak M, Peyvandi F, 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 1236-1239
  • 38 Miller C H, Dilley A, Richardson L, Hooper W C, Evatt B L. Population differences in von Willebrand factor levels affect the diagnosis of von Willebrand disease in African-American women.  Am J Hematol. 2001;  67 125-129
  • 39 Miller C H, Haff E, Platt S J et al.. Measurement of von Willebrand factor activity: relative effects of ABO blood type and race.  J Thromb Haemost. 2003;  1 2191-2197
  • 40 Sanchez-Luceros A, Meschengieser S S, Marchese C et al.. Factor VIII and von Willebrand factor changes during normal pregnancy and puerperium.  Blood Coagul Fibrinolysis. 2003;  14 647-651
  • 41 Hanna W, McCarroll D, McDonald T et al.. Variant von Willebrand's disease and pregnancy.  Blood. 1981;  58 873-879
  • 42 Castaman G, Eikenboom J CJ, Contri A, Rodeghiero F. Pregnancy in women with type 1 von Willebrand disease caused by heterozygosity for von Willebrand factor mutation C1130F.  Thromb Haemost. 2000;  84 351-352
  • 43 Sorosky J, Klatsky A, Norbert G F, Burchill R C. von Willebrand's disease complicating second trimester abortion.  Obstet Gynecol. 1980;  55 253-254
  • 44 Lipton R A. Misdiagnosis by milk box.  Haemophilia. 2003;  9 235
  • 45 Bohm M, Taschner S, Kretzschmar E, Gerlach R, Favaloro E J, Scharrer I. Cold storage of citrated whole blood induces drastic time dependent losses in factor VIII and von Willebrand factor: potential for misdiagnosis of haemophilia and von Willebrand disease.  Blood Coagul Fibrinolysis. 2006;  17 39-46

Peter A KouidesM.D. 

Rochester General Hospital

1425 Portland Avenue, Rochester, NY 14621

Email: peter.kouides@viahealth.org