von Willebrand disease is caused by either a quantitative or qualitative defect in von Willebrand factor (VWF). Patients may have extensive mucosal bleeding (because of platelet dysfunction) and prolonged bleeding after surgery (because of factor VIII deficiency). Up to 6 different subtypes of the disease have been described, and diagnosis is based on clinical suspicion and laboratory confirmation. Accurate diagnosis is of paramount importance because therapy will vary according to the subtype. Bleeding complications during pregnancy are more frequent when levels of the von Willebrand ristocetin cofactor assay and factor VIII levels are <50 IU/dL. In such cases, therapy before any invasive procedure or delivery must be instituted. The mainstays of therapy are desmopressin and plasma concentrates that contain von Willebrand factor. Delayed postpartum hemorrhage may occur, despite adequate prophylaxis. Frequent monitoring and continued prophylaxis and/or treatment are recommended for at least 2 weeks after delivery.
A 26-year-old patient was seen for routine prenatal care. She had a history of delayed postpartum hemorrhage 4 years earlier after an uncomplicated vaginal delivery. During a recent visit to the dentist, she experienced increased bleeding after a tooth extraction. Bleeding diathesis was considered, and the question is how to evaluate and treat this patient during the current pregnancy.
In 1926, Erik von Willebrand first described a familial bleeding disorder in which symptoms were more severe in children and young women. He also noted that the condition had autosomal inheritance and that blood transfusions improved bleeding symptoms. Since then, knowledge of this disease has grown exponentially and is currently recognized as the most common inherited bleeding disorder.
Pathogenesis
Now known as von Willebrand disease (VWD), this disorder is caused by either a quantitative or qualitative defect in von Willebrand factor (VWF). The prevalence of VWD is as high as 1-2% in the general population.
VWF, a large multimeric glycoprotein, is encoded by a gene that is located in the short arm of chromosome 12 and is synthesized and released from the endothelium and megakaryocytes. As a result of vascular injury, VWF adheres to the subendothelial matrix that is exposed; with shear stress, the multimeric VWF uncoils, which leads to platelet adhesion, activation, and aggregation.
Besides the predominant role in platelet-induced hemostasis, VWF also binds factor VIII (FVIII) in plasma, thereby preventing its degradation and clearance. The latter action explains the reason that VWD is characterized by both extensive mucosal bleeding (because of platelet dysfunction) and prolonged bleeding after surgery (because of FVIII deficiency).
Interestingly, the disease is disproportionately symptomatic in women of child-bearing age and appears in the form of menorrhagias and/or postpartum hemorrhage. Numerous case series of pregnancies that have been complicated with VWD have been reported in the literature. Overall, such women are at a higher risk of bleeding that is associated with invasive procedures, delivery, and both immediate and delayed postpartum hemorrhage.
Consequently, it is of utmost importance that the obstetrician is familiar with this condition.
The classification of VWD was updated in 2006 ( Table 1 ) in an attempt to correlate disease subtype and optimal therapy.
| Type | Explanation |
|---|---|
| 1 | Type 1 VWD is the classic and most common form that accounts for nearly 80% of all cases. This subtype is characterized by a partial quantitative deficiency in VWF. Inheritance is autosomal dominant, and the bleeding propensity is mild to moderate. |
| The laboratory evaluation of this disease will typically show a decrease in plasma concentration of both VWF protein (von Willebrand factor antigen [VWF:Ag]) and factor VIII (FVIII). Qualitative functional assays of VWF function (von Willebrand factor ristocetin cofactor activity [VWF:RCo]) show a decrease in function that parallels the quantitative deficit of the protein. | |
| 2 | Type 2 VWD is mainly a qualitative/functional problem of the VWF (plasma concentrations of VWF are normal or near normal). Four variants of type 2 VWD have been described. |
| Type 2A VWD is a variant in which, despite normal (or mildly reduced) plasma concentrations of VWF:Ag and FVIII, VWF-dependent platelet aggregation is compromised. This is demonstrated by a significantly decreased VWF functional test (VWF:RCo). The main problem here is a deficit in the proportion of large VWF multimers. These large multimers are the ones that ultimately interact with platelets to achieve aggregation. The condition may be inherited in either autosomal dominant or recessive fashion. | |
| Type 2B VWD is due to a pathologic increase in binding between platelets (through glycoprotein Ib) and VWF. Platelets bind to the mutant large multimers, and these complexes are sequestered in the microcirculation and subsequently dissolved by the metalloproteinase ADAMTS 13. This then leads to a decrease in large multimers and thrombocytopenia. Pregnancy and surgery frequently aggravate thrombocytopenia in these patients. Laboratory diagnosis rests on demonstration of a pathologically increased ristocetin-induced platelet aggregation. Inheritance is autosomal dominant. | |
| Type 2M VWD is characterized by decreased platelet adhesion to VWF due to minimal affinity between VWF and the platelet surface glycoprotein Ib. Unlike types 2A and 2B, the concentration of large VWF multimers is normal in this subtype. The diagnosis rests on the demonstration of poor platelet aggregation in vitro (VWF:RCo) in the presence of a normal amount of large VWF multimers on gel electrophoresis. Inheritance of this subtype may be autosomal dominant or recessive. | |
| Type 2N VWD is caused by minimal binding between VWF and FVIII. Quantitative (VWF:Ag) and qualitative (VWF:RCo) testing for VWF are normal; however, the FVIII level is low. The main differential diagnosis in this situation is hemophilia A. Inheritance is autosomal recessive. | |
| Type 3 | Type 3 VWD is rare. The prevalence has been estimated at 1 per 1,000,000. This is a severe quantitative defect in VWF that is characterized by undetectable levels of VWF:Ag in plasma. Consequently, FVIII levels will also be very low. Bleeding propensity in this subgroup is obviously very high. Inheritance is autosomal recessive. |
| Acquired | Acquired VWD has also been described. Autoimmune diseases may lead to increased clearance or inhibition of VWF (mediated by autoantibodies that cross-react with VWF). Certain conditions (such as ventricular septal defects, aortic stenosis, and pulmonary hypertension) will increase fluid shear stress and may lead to increased proteolysis of VWF by ADAMTS 13. Certain medications (hydroxyethylstarch, valproic acid, ciprofloxacin) may induce acquired VWD. |
Diagnosis
Suspicion for the presence of VWD usually arises from a patient’s personal history of excessive bleeding and/or a similar family history. Importantly, a family history is frequently not present because family members may be affected by the milder forms of the disease and have minimal-to-no symptoms.
Symptoms usually involve mild-to-moderate mucocutaneous bleeds, such as epistaxis, menorrhagia, bleeding after dental extractions, ecchymoses, gingival bleeding, and prolonged bleeding from minor cuts. Patients with menorrhagia and no documented pelvic anomalies should undergo testing for VWD. Postoperative and delayed postpartum hemorrhage may also be present. Most of these events do not require blood transfusions or even doctor visits.
Patients with the rare type 3 disease may have life-threatening bleeding episodes, such as intracranial and gastrointestinal hemorrhages.
Once the clinical suspicion is present, the next step is laboratory confirmation. At the University of Texas in Galveston, we use the following protocol. We start with a basic hemostasis evaluation that includes a complete blood cell count, platelet count, activated partial thromboplastin time (aPTT), prothrombin time, and fibrinogen levels. The initial workup is mainly to rule out other potential causes of bleeding (eg, severe thrombocytopenia) and not particularly directed specifically at the diagnosis of VWD. The aPTT is often normal in VWD, and only the most severe deficiencies with very low levels of FVIII will have a prolonged aPTT. If on initial evaluation the aPTT is prolonged, it should correct on a 1:1 mixing with normal plasma to be consistent with VWF (if it does not correct, the presence of a FVIII inhibitor should be suspected).
If the initial test results return normal or show a prolonged aPTT that corrects with mixing, further testing is indicated. The following 3 tests should follow. The first test is the VWF protein (VWF:Ag) assay, which is an immunoassay that measures the VWF protein in plasma. The second test to be performed is a functional assay (VWF:RCo) that measures the interaction between VWF and platelets. The binding between these 2 and subsequent formation of platelet clumps is stimulated by the addition of the antibiotic ristocetin. Platelets bind mainly to the large VWF multimers through their surface glycoprotein 1b.The third test, the FVIII assay, measures the activity of FVIII, which is a surrogate for the activity of VWF as a carrier protein for FVIII.
Other specialized tests may follow to further classify the disease. Gel electrophoresis may provide information on the abundance of different-sized VWF multimers, which would aid in the diagnosis of subtypes 2A and 2B, where large multimers are decreased.
A binding assay is available to evaluate interaction between VWF and FVIII. Minimal interaction will point towards type 2N VWD.
The low-dose ristocetin-induced platelet aggregation test is valuable in diagnosing type 2B VWD. In this test, low doses of the antibiotic ristocetin are added to the patient’s sample. In type 2B disease, because of the high affinity of VWF and platelets, even such low concentrations of ristocetin will induce platelet aggregation. This test will be negative in all other subtypes of the disease.
Reference laboratories frequently will perform a ratio to compare the amount of qualitative-to-quantitative dysfunction present (VWF:RCo/VWF:Ag). This will be useful in the differentiation of type 1 and type 2 VWD variants. If the ratio is <0.5-0.7, the patient is most likely affected with type 2 disease, because such a low ratio is consistent with dysfunctional VWF (a higher ratio is consistent with type 1 disease because the VWF:Ag will be lower).
Both the VWF:Ag and VWF:RCo assays are reported in international units per deciliters. A value <30 IU/dL is diagnostic for VWD; however, some patients with VWD may have values between 30 and 50 IU/dL. This subgroup of patients should be treated in the same fashion as other patients with VWD before any invasive procedure during pregnancy.
Occasionally, repeated testing for VWD is needed because conditions such as pregnancy, stress, surgery, and inflammation will increase levels of VWF and mask lower baseline values.
Table 2 shows the typical laboratory findings according to the various VWD subtypes.
| Subtype a | von Willebrand factor antigen | von Willebrand factor ristocetin cofactor activity | von Willebrand factor ristocetin cofactor activity/von Willebrand factor antigen | Factor VIII | Low dose ristocetin-induced platelet aggregation | Multimer assay |
|---|---|---|---|---|---|---|
| Type 1 | Low | Low | >0.5-0.7 | Low or normal | No reaction | Normal |
| Type 2A | Low | Low | <0.5-0.7 | Low or normal | No reaction | Decrease in large multimers |
| Type 2B | Low | Low | <0.5-0.7 | Low or normal | Positive | Decrease in large multimers |
| Type 2M | Low | Low | <0.5-0.7 | Low or normal | No reaction | Normal |
| Type 2N | Normal to low | Normal to low | >0.5-0.7 | Low | No reaction | Normal |
| Type 3 | Absent | Absent | Low | No reaction | Absent |
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