Case presentation

A 24-year-old woman pregnant with her first child presents for her first prenatal obstetric visit at 16 weeks’ gestation. She reports a history of von Willebrand disease (VWD) that she believes was diagnosed after she experienced excessive bleeding after a tonsillectomy as a child, but is unable to provide further details. She is otherwise healthy and has had no other significant hemostatic challenges in life. Her pregnancy has been unremarkable thus far, and she has a normal obstetric examination. She is subsequently referred to a hematologist for clarification of the nature of her bleeding disorder and for recommendations for hemostasis support during labor and delivery. Laboratory testing for VWD, however, identifies no abnormalities. Cases like these, commonly seen in hematology practice, pose several challenges for the hematologist, including ruling in or ruling out a diagnosis of VWD during pregnancy, management of the labor and delivery, and extending optimum postpartum care when uncertainty about what, if any, bleeding disorder exists. In this article the authors review VWD in pregnancy with special attention to current evidence-based guidelines as they pertain to the pregnant patient with suspected or confirmed VWD, as well as areas of uncertainty and controversy in the diagnosis and management in this frequently encountered condition are highlighted.

VWD results from a deficiency of or qualitative abnormality in the large plasma glycoprotein, von Willebrand factor (VWF). VWF serves two critical functions in hemostasis: (1) it mediates initial adhesion of platelets to sites of vascular endothelial damage, and (2) it binds and chaperones coagulation factor VIII, thus stabilizing and prolonging its circulating half-life as well as localizing factor VIII activity to the site of vascular injury. Estimates of the prevalence of VWD vary widely and depend on case definitions used in the various studies that have investigated this subject. Surveys of symptomatic patients followed at hemostasis centers arrive at a prevalence of symptomatic VWD of around 0.01%, while a recent study of the pediatric primary care population estimated a 10-fold higher prevalence of 0.1%. Older population-based studies, on the other hand, have yielded even higher prevalence estimates of up to 1.3%. While prevalence estimates differ, there is general agreement that VWD is likely the most common hereditary bleeding disorder, affecting both sexes and all ethnic groups. Women are at increased risk for bleeding complications with the hemostatic challenges of menstruation and childbirth, thus VWD can be expected to affect women disproportionately. Over 4 million births were recorded in the United States in 2009, of which as many as 50,000 may be expected to have occurred in women with VWD according to disease prevalence estimates. Given the scope of the disease, therefore, the public health implications are obvious, and the consequences of missing or ignoring the diagnosis may be catastrophic.

Diagnosis and classification of von Willebrand disease

VWD is a hereditary disorder, and the spectrum of VWF gene mutations leading to the condition is broad. Genetic testing is costly, not widely available, and impractical for the initial diagnosis of VWD. Routine screening coagulation laboratory tests such as the prothrombin time, activated partial thromboplastin time, bleeding time, and PFA-100 lack sensitivity for VWD. The diagnostic evaluation for VWD in a person with a personal and/or a family history of abnormal bleeding, therefore, is best accomplished with laboratory testing aimed at measuring the quantity and functionality of the VWF protein. Moreover, such testing characterizes the nature of the defect in VWF and allows rational classification of VWD. A typical initial VWD screening test panel includes assays for VWF antigen (VWF:Ag), VWF activity (ristocetin cofactor activity; VWF:RCo), and factor VIII coagulant activity (FVIII:C). The VWF:Ag test is a quantitative immunoassay that measures the concentration of VWF protein in plasma, whereas the VWF:RCo is a functional test that assays the ability of VWF to interact with platelets and mediate platelet agglutination via the antibiotic, ristocetin. Abnormalities in these tests should prompt a multimer analysis, a gel electrophoresis study that assesses the quantity and composition of the various VWF multimers. The ristocetin-induced platelet aggregation (RIPA) test provides additional diagnostic information, as the ability of ristocetin to mediate platelet aggregation in vitro is proportional to the level of VWF in plasma. At a high dose of ristocetin, platelet aggregation will be decreased in types 1 and 3 VWD and in most type 2 variants (see later discussion). Low-dose ristocetin is ineffective at causing platelet aggregation in vitro in normal subjects and in most VWD variants, but will mediate platelet aggregation in type 2B VWD. The VWF collagen-binding (VWF:CB) measures the ability of VWF to bind to collagen, and is abnormal in individuals with defects in the VWF collagen binding sites. This test is not routinely performed for the evaluation of VWD but may identify the occasional patient with VWD when the other tests are normal. In-depth discussion of diagnostic testing is beyond the scope of this article, but a summary of useful initial diagnostic tests for evaluating patients with suspected VWD is provided in Box 1 , and readers are directed to excellent reviews on the topic for more information.

At present, 3 major categories of VWD are recognized and are summarized in Table 1 . Each type of VWD exhibits autosomal inheritance, thus affecting both men and women. Types 1 and 3 result from quantitative deficiencies in the VWF protein, whereas type 2 VWD results from qualitative and functional abnormalities in VWF protein. Type 1 VWD accounts for 70% to 80% of symptomatic cases, and is a consequence of a partial deficiency of structurally and functionally normal VWF. The abnormality in type 1 VWD confers a generally mild to moderate bleeding risk. Type 2 VWD accounts for the majority of the remainder of symptomatic cases and imparts a moderate to moderately severe bleeding phenotype. Type 2 VWD is further divided into 4 subtypes depending on the nature of the qualitative defect in VWF. Type 2A is the most common of the qualitative VWF disorders and arises as a result of a reduction in the larger, more active VWF multimers. Types 2B and 2M are due to missense mutations in VWF that lead either to increased (2B) or decreased (2M) platelet binding via the GPIb binding site. Type 2B VWD is caused by a gain-of-function mutation in VWF such that there is enhanced binding between VWF and platelet receptor GPIb, leading to thrombocytopenia as platelet-VWF aggregates are sequestered by the microcirculation. Type 2N is caused by a mutation that leads to impaired binding of factor VIII to VWF, resulting in increased proteolysis of factor VIII and decreased circulating factor VIII levels on the order of those seen with mild hemophilia A. Type 2N VWD should be suspected in a woman presenting with a low factor VIII level with normal levels of VWF, and can be distinguished from hemophilia A carriership by the VWF-factor VIII binding assay. Type 3 disease is rare, is caused by a complete absence of VWF, and results in a severe bleeding disorder.

Genetic transmission of VWD types 1 and 2A, 2B, and 2M is characterized by an autosomal dominant inheritance pattern with variable penetration. VWD type 2N has an autosomal recessive inheritance pattern, as do rare cases of types 2A and 2M. VWD type 3 is also an autosomal recessive disease, resulting from either compound heterozygosity of 2 VWF gene mutations or homozygosity for a single gene defect.

In the recently updated VWD classification scheme, a distinction is made between genetic type 1 VWD and low levels of VWF that may occur as a result of population variation. For example, ABO blood group influences VWF levels, with type O individuals having mean levels that are roughly 25% lower than individuals with other ABO types. Racial differences have also been reported, with African Americans having higher levels than other groups. The accepted normal range for VWF:Ag is 50 to 200 IU/dL. In general, very low levels of VWF (ie, <20–30 IU/dL) correlate well with VWF gene mutations, bleeding symptoms, and a family history of bleeding (reviewed in Ref. ); however, levels of 30 to 50 IU/dL, while below the “normal range,” do not reliably correlate with genetic VWD and often occur in healthy individuals with type O blood. Levels of VWF between 30 and 50 IU/dL, while not diagnostic of the disease per se, nevertheless constitute a mild risk factor for bleeding. Many clinicians, therefore, elect to refer to these otherwise healthy patients as having “low VWF” rather than labeling them with a disease, which potentially carries adverse psychological, social, and insurance ramifications. The laboratory characteristics of the subtypes of VWD are summarized in Table 1 .

Diagnosis and classification of von Willebrand disease

VWD is a hereditary disorder, and the spectrum of VWF gene mutations leading to the condition is broad. Genetic testing is costly, not widely available, and impractical for the initial diagnosis of VWD. Routine screening coagulation laboratory tests such as the prothrombin time, activated partial thromboplastin time, bleeding time, and PFA-100 lack sensitivity for VWD. The diagnostic evaluation for VWD in a person with a personal and/or a family history of abnormal bleeding, therefore, is best accomplished with laboratory testing aimed at measuring the quantity and functionality of the VWF protein. Moreover, such testing characterizes the nature of the defect in VWF and allows rational classification of VWD. A typical initial VWD screening test panel includes assays for VWF antigen (VWF:Ag), VWF activity (ristocetin cofactor activity; VWF:RCo), and factor VIII coagulant activity (FVIII:C). The VWF:Ag test is a quantitative immunoassay that measures the concentration of VWF protein in plasma, whereas the VWF:RCo is a functional test that assays the ability of VWF to interact with platelets and mediate platelet agglutination via the antibiotic, ristocetin. Abnormalities in these tests should prompt a multimer analysis, a gel electrophoresis study that assesses the quantity and composition of the various VWF multimers. The ristocetin-induced platelet aggregation (RIPA) test provides additional diagnostic information, as the ability of ristocetin to mediate platelet aggregation in vitro is proportional to the level of VWF in plasma. At a high dose of ristocetin, platelet aggregation will be decreased in types 1 and 3 VWD and in most type 2 variants (see later discussion). Low-dose ristocetin is ineffective at causing platelet aggregation in vitro in normal subjects and in most VWD variants, but will mediate platelet aggregation in type 2B VWD. The VWF collagen-binding (VWF:CB) measures the ability of VWF to bind to collagen, and is abnormal in individuals with defects in the VWF collagen binding sites. This test is not routinely performed for the evaluation of VWD but may identify the occasional patient with VWD when the other tests are normal. In-depth discussion of diagnostic testing is beyond the scope of this article, but a summary of useful initial diagnostic tests for evaluating patients with suspected VWD is provided in Box 1 , and readers are directed to excellent reviews on the topic for more information.

At present, 3 major categories of VWD are recognized and are summarized in Table 1 . Each type of VWD exhibits autosomal inheritance, thus affecting both men and women. Types 1 and 3 result from quantitative deficiencies in the VWF protein, whereas type 2 VWD results from qualitative and functional abnormalities in VWF protein. Type 1 VWD accounts for 70% to 80% of symptomatic cases, and is a consequence of a partial deficiency of structurally and functionally normal VWF. The abnormality in type 1 VWD confers a generally mild to moderate bleeding risk. Type 2 VWD accounts for the majority of the remainder of symptomatic cases and imparts a moderate to moderately severe bleeding phenotype. Type 2 VWD is further divided into 4 subtypes depending on the nature of the qualitative defect in VWF. Type 2A is the most common of the qualitative VWF disorders and arises as a result of a reduction in the larger, more active VWF multimers. Types 2B and 2M are due to missense mutations in VWF that lead either to increased (2B) or decreased (2M) platelet binding via the GPIb binding site. Type 2B VWD is caused by a gain-of-function mutation in VWF such that there is enhanced binding between VWF and platelet receptor GPIb, leading to thrombocytopenia as platelet-VWF aggregates are sequestered by the microcirculation. Type 2N is caused by a mutation that leads to impaired binding of factor VIII to VWF, resulting in increased proteolysis of factor VIII and decreased circulating factor VIII levels on the order of those seen with mild hemophilia A. Type 2N VWD should be suspected in a woman presenting with a low factor VIII level with normal levels of VWF, and can be distinguished from hemophilia A carriership by the VWF-factor VIII binding assay. Type 3 disease is rare, is caused by a complete absence of VWF, and results in a severe bleeding disorder.

Genetic transmission of VWD types 1 and 2A, 2B, and 2M is characterized by an autosomal dominant inheritance pattern with variable penetration. VWD type 2N has an autosomal recessive inheritance pattern, as do rare cases of types 2A and 2M. VWD type 3 is also an autosomal recessive disease, resulting from either compound heterozygosity of 2 VWF gene mutations or homozygosity for a single gene defect.

In the recently updated VWD classification scheme, a distinction is made between genetic type 1 VWD and low levels of VWF that may occur as a result of population variation. For example, ABO blood group influences VWF levels, with type O individuals having mean levels that are roughly 25% lower than individuals with other ABO types. Racial differences have also been reported, with African Americans having higher levels than other groups. The accepted normal range for VWF:Ag is 50 to 200 IU/dL. In general, very low levels of VWF (ie, <20–30 IU/dL) correlate well with VWF gene mutations, bleeding symptoms, and a family history of bleeding (reviewed in Ref. ); however, levels of 30 to 50 IU/dL, while below the “normal range,” do not reliably correlate with genetic VWD and often occur in healthy individuals with type O blood. Levels of VWF between 30 and 50 IU/dL, while not diagnostic of the disease per se, nevertheless constitute a mild risk factor for bleeding. Many clinicians, therefore, elect to refer to these otherwise healthy patients as having “low VWF” rather than labeling them with a disease, which potentially carries adverse psychological, social, and insurance ramifications. The laboratory characteristics of the subtypes of VWD are summarized in Table 1 .

Clinical manifestations

VWD is suspected in individuals with a personal history of unexplained spontaneous bleeding or with excessive bleeding after seemingly minor insults. Of note, although VWD is a hereditary disorder, often there may be no relevant family history of bleeding, due to variability in expression of symptoms, especially in milder forms of the disorder. Many patients with types 1 and 2 VWD are asymptomatic in everyday life but may experience mild to moderate bleeding after hemostatic challenges such as trauma or surgery. The character of bleeding in patients with VWD is generally mucocutaneous, with epistaxis and easy bruisability as frequent manifestations. Affected individuals will describe bleeding that persists after injury or surgery, thus indicating a defect in primary hemostasis rather than that which stops initially and starts up again later as is typical with defects in secondary hemostasis or the fibrinolytic pathway. In women, menstruation is a monthly hemostatic challenge, and menorrhagia is common in those with VWD. Patients with type 2N or type 3 VWD experience more severe bleeding that can resemble that of patients with factor VIII deficiency. These patients are more often at risk for deep tissue and joint bleeds, intracranial hemorrhage, or gastrointestinal bleeding.

Von Willebrand factor levels during pregnancy

Complex physiologic adaptations occur in the maternal hemostatic system during pregnancy (reviewed in Ref. ). Establishment of the uteroplacental circulation occurs early, and its maintenance is critical to fetal survival. The integrity of the uteroplacental circulation is dependent on local conditions, and mandates that the maternal hemostatic system be readily responsive to bleeding or thrombotic events that pose a threat to normal blood flow. By the third trimester the hemostatic adaptations result in a net prothrombotic state that is designed to mitigate life-threatening bleeding at parturition. At the time of delivery uterine myometrial contractions initially limit bleeding associated with parturition, while at the cessation of contractions a hypertophied hemostatic system takes over to form clots in injured blood vessels. As a consequence of the physiologic changes in the coagulation system in response to the hemostatic demands of pregnancy and parturition, normal pregnancy and the puerperium are associated with an increased risk for both bleeding and thrombosis.

Levels of many of the coagulation factors increase during a normal pregnancy under the influence of an increasing level of estradiol. Both VWF and factor VIII levels start to increase during the second trimester (and possibly as early as 6 weeks’ gestation for VWF:Ag), peak at term, and return to baseline levels shortly after delivery in normal women as well in the majority of those with VWD. Although the magnitude of the increase in coagulation factors is variable, some investigators have documented an average twofold increase for factor VIII and a threefold increase for VWF, while others have noted lesser increases throughout the pregnancy. Most women with type 1 VWD will experience a progressive climb in VWF:Ag, VWF:RCo, and factor VIII levels throughout pregnancy, such that they notice an improvement in their baseline bleeding symptoms as the pregnancy progresses. This phenomenon is responsible for the difficulty in making a diagnosis of type 1 VWD in pregnancy, as VWF levels increase into the normal range in all but the most severe cases. Although women with type 2 VWD may show increased levels of VWF:Ag and factor VIII, this reflects an increase in the level of abnormal VWF protein and does not necessarily produce a concurrent increase in VWF:RCo activity. In fact, type 2B VWD is reported to worsen during pregnancy as increased levels of abnormal VWF result in progressive thrombocytopenia. Accordingly, type 2B VWD should be ruled out in any pregnant woman presenting with thrombocytopenia, especially if there is a family history of abnormal bleeding. Although factor VIII levels have been reported to increase and normalize in pregnant women with type 2N disease, often they do not despite increased levels of both VWF:Ag and VWF:RCo (reviewed in Ref. ). Most women with type 3 VWD will have no improvement in VWF or factor VIII levels in pregnancy.

VWF and factor VIII levels decline after delivery and there is substantial interindividual variability in the rate at which the factors return to their baseline levels. Although levels of VWF and factor VIII generally begin to decline 1 week postpartum and return to baseline by 4 to 6 weeks, the decrease can be precipitous and has been reported as early as 24 hours after delivery.