Von Willebrand Disease and Pregnancy

Abstract

A 26-year-old woman (gravida 1) was seen when she was 33½ weeks pregnant. She was healthy except for easy bruising, which had been a problem since childhood. The patient did not have nosebleeds or prolonged bleeding after toothbrushing, flossing, or minor cuts.

Menarche had occurred at age 13, with a 28-day cycle. Her heavy menstrual periods usually lasted 7 to 10 days. She underwent tonsillectomy and adenoidectorny at age 7 and bilateral bunionectomy at age 20; hemorrhage did not occur after the operations. The patient did not smoke or abuse drugs or alcohol. She took no medications except for prenatal vitamins.

Mild von Willebrand disease (vWD) had recently been diagnosed in her mother. Her father had anemia of unknown cause; his family history included thalassemia, and his father had Hodgkin disease that was diagnosed when he was 30 years old. Her 23-year-old brother was healthy and had no bleeding disorders.

The patient appeared well-nourished and was in no distress. Vital signs were stable, and site was afebrile. Heart sounds were normal; lungs were clear. Her abdomen was soft and rumtender. There was no spine tenderness, mucosal bleeding, ocular hemorrhage, or skin bruising.

Because of the patient’s history of easy bruising and heavy menstrual bleeding and her mother’s recently diagnosed vWD, testing for the disorder was ordered.

Laboratory results revealed von Willebrand factor (vWF) antigen activity of 75 U/dL, activated partial thromboplastin time (aPTT) of 32 seconds, factor VIII activity of 100%, and bleeding time of 9 minutes. (Normal values are vWF antigen level, 50 to 200 U/dL; aPTT) 20 to 32 seconds; factor VIII activity, 60% to 150%; and bleeding time, 5.5 minutes.) A ristocetin-induced platelet aggregation test did not show aggregation at tow concentrations of ristocetin, and vWF multimers showed a normal distribution. These laboratory data suggested that the patient had type 1 vWD. She was closely monitored during the rest of her pregnancy.

At full term, the patient went into labor. About 1 to 2 hours before the delivery, she was given intravenous desmopressin at a dosage of 0.3 μg/kg in 50 mL of saline over 30 minutes. When vaginal bleeding (approximately 150 mL) occurred on postpartum day 3, the patient was given nasal desmopressin and advised to limit her physical activity. No excessive bleeding occurred thereafter.

Von Willebrand disease, die most common inherited bleeding disorder, is transmitted in an autosomal dominant pattern with variable penetrance. Its prevalence is estimated to be 0.5% to 1 %.¹ In most patients, the disease is mild or moderate and remains undiagnosed until they sustain trauma or undergo surgery. Women of childbearing age may be at risk particularly during delivery or the postpartum period.

Von Willebrand factor is an acute phase reactant, and plasma levels may be high during stress, in pregnant women, and in newborns after vaginal delivery. The levels may be reduced in hypothyroid patients but return to normal when patients become euthyroid.

Von Willebrand factor is a large, multimeric glycoprotein encoded on chromosome 12. It is synthesized in endothelial cells and megakaryocytes and circulates as a series of multimers. The size of vWF varies from 500,000 to 20 million daltons. The factor serves to:

• Support primary hemostasis, including platelet adherence to the subendothelium and platelet-platelet aggregation in vessels with high shear flow.

• Support secondary hemostasis (fibrin formation), in which vWF serves as a carrier for factor VIII (antihemophilic factor), protecting it from premature proteolysis and clearance from the circulation.

Variability of symptoms.

Patients with vWD may present at any age because of the variable expressivity and wide variation in bleeding severity. Most patients are heterozygous, and they present with mild or moderate disease. Because a primary function of vWF is the support of normal platelet function, bleeding manifestations are similar to those of platelet disorders, such as bruising and mucous membrane bleeding (epistaxis, menorrhagia, and GI bleeding).² The last may be associated with angiodysplasia and can be life-threatening.³ Excessive bleeding may occur after surgery (for example, tooth extraction or tonsillectomy) or with menses.

The rare homozygous or doubly heterozygous patients (2% to 10% of persons with vWD) are severely affected and have low levels of factor VIII in addition to low levels of vWF. The levels are low because vWF does not afford the usual protection to factor VIII.⁴ Examples of severe bleeding include hemarthrosis, soft tissue bleeding, and profuse bleeding from mucous membranes.

Because of the variable expressivity, affected family members may have different levels of severity of bleeding.^5,6 In addition, levels of vWF are labile and may change for various reasons (Table 1). For example, healthy persons with type O blood have vWF levels of approximately 75 U/dL, whereas persons with other blood types tend to have normal readings that are higher.⁷ Estrogen, pregnancy, exercise, adrenergic stimuli, and inflammation increase vWF levels.^8-10

Table 1-.

Factors that affect levels of von Willebrand factor

Factors that decrease levels
Type O blood group
Factors that increase levels
Adrenergic stimuli
Estrogen
Exercise
Inflammation
Pregnancy

Testing.

The diagnosis of vWD is based on a pertinent family history of mucosal bleeding, prolonged aPTT, and prolonged bleeding time. The aPTT and bleeding time may be normal in patients with milder forms of vWD). More specific tests include ristocetin cofactor activity (vWF activity), vWF antigen, and factor VIII activity.^11,12

Once you make die diagnosis, order electrophoresis for a vWF multimer pattern and ristocetin-induced platelet aggregation (RIPA) to determine the disease subtype.^13,14 which will direct the type of therapy (Table 2). Because test results can be influenced by physiologic (eg, pregnancy) and laboratory variables, test persons with borderline levels 2 or 3 times within 1 to 3 months before you make a diagnosis.¹⁵ The distribution of vWF multimers can be directly visualized by low-concentration agarose gel electrophoresis when labeled antibodies are used to develop the gel.¹⁶

Table 2-.

Classification of von Willebrand disease

Type	Ristocetin-induced platelet aggregation	Moltimer pattern
1	Reduced	Quantity of all types of multimers is uniformly decreased; all multimers are present
2A	Reduced	Quantity of high and intermediate molecular weight multimers is decreased
2B	Increased	Quantity of high molecular weight multimers is decreased
2M	Reduced	Quantity of multimers is normal
2N	Normal	Quantity of all multimers is normal
3 (severe)	Markedly reduced	Multimers are undetectable

Classification of vWD.

The disease is classified into 3 types (Box). Clinical presentations of types 1 and 2 are indistinguishable^17-20; type 3 is usually more severe, involving soft tissue bleeding, hemarthrosis, and mucosal bleeding.

Treatment.

Select therapy based on the patient’s vWD subtype, factor VIII and vWF levels, bleeding history, and current medications that might inhibit platelet function (eg, aspirin or other NSAIDs).

Although the general therapeutic goal is to raise and maintain vWF levels above 50%, specific levels do not correlate well with the risk of bleeding.^21,22 Correction of the bleeding time is probably not necessary but continues to be controversial. Many patients have undergone surgery without excessive bleeding after factor VIII and vWF were increased to normal levels that were not sufficient to correct bleeding time.

The availability of desmopressin (1-deamino-8-D-arginine vasopressin) has allowed most patients with vWD to be treated with a non–plasma-derived product and thus avoid exposure to viral diseases transmitted by blood products (Table 3).²³ This synthetic analogue of vasopressin increases the levels of vWF and factor VIII by stimulating the release of vWF from the storage granules of endothelial cells. The released vWF also includes very high molecular weight multimers.

Table 3-.

Treatment of von Willebrand disease

Medication	Dose	Comments
Desmopressin	0.3 μg/kg IV in 50 mL of saline over 30 min; also administered subcutaneously and by nasal spray	Effective in most patients with type 1; usefulness varies for type 2*; not useful for type 3. May repeat dose after 12 h and every 24 - 48 h. Monitor for hyponatremia.
Factor VIII/vWF (concentrates containing all vWF multimer or cryoprecipitate)	20 - 30 U/kg IV q 12h (to keep vWF and factor VIII levels above 50% or to control clinical bleeding); maintain levels 3 - 10 d after major surgery	Dose and duration may vary based on clinical experience
Antifibrinolytic agents		Used alone or in conjunction with other therapy; indicated for mucosal bleeding
Epsilon-aminocaproic acid	50 mg/kg qid (maximum 5 g/dose) PO or IV. Acute bleeding: 4 - 5 g is infused during the 1st hour, then 1 g/h continuously until control is attained. Chronic bleeding: 5 - 30 g/d every 3 or 6 h, adjusted to lowest level that controls bleeding.
Tranexamic acid	25 mg/kg PO† or IV every 6 - 8 h for 2 - 8 d

vWD, von Willebrand disease; vWF, von Willebrand Factor.

^*Thrombocytopenia may worsen in some patients with type 2B vWD.

^†In general, oral administration is preferable, particularly for GI bleeding, because of the stomach’s fibrinolytic activity.

The intravenous dosage of desmopressin is 0.2 to 0.3 μg/kg in a volume of 50 to 100 mL over 30 minutes.²⁴ The dosage by the subcutaneous route is the same, with injection of no more than 1.5 mL per site (a single treatment may require 3 or 4 subcutaneous injections).

Two intranasal preparations are available; the more concentrated type (1.5 mg/mL) is preferred for vWD.^25,26 Clinical trials show that a dosage of 150 μg in each nostril produces results equivalent to 0.2 μg/kg given intravenously. The usual intranasal dosage is 300 μg (0.1 mL or 1 spray into each nostril of a solution containing 1.5 mg/mL). A dosage of 150 μg (0.1 mL or 1 spray into a single nostril of a solution containing 1.5 mg/mL) may be sufficient for patients weighing less than 50 kg (110 lb). It is administered 2 hours before a minor procedure, such as tooth extraction, in patients with type 1 vWD; thereafter, once daily for 2 or 3 days is usually adequate.

The levels of vWF and factor VIII usually reach a maximum of 2 to times the baseline approximately 45 minutes after the intravenous infusion. persist for about 4 hours, and then decrease. The bleeding time usually decreases within 1 to 2 hours of administration and increases again at approximately 4 to 6 hours. Doses may be given again after 12 hours, and then every 24 to 48 hours, although responses to the repeated doses may be decreased.²⁷

Observe the patient’s clinical response. and use laboratory indicators (eg, levels of factor VIII and factor VIII/ristocetin cofactor activities, factor VIII/vWF antigen, and bleeding time) to determine the need for additional doses. Keep in mind the tendency toward tachyphylaxis (decreased responsiveness) when desmopressin is given more frequently than every 48 hours.

Adverse effects include flushing, hypotension or hypertension, headaches and, rarely, angioedema. Although desmopressin does not appear to increase the risk of myocardial infarction beyond that in the normal population,²⁸ use the drug cautiously in patients with cardiovascular disease. Monitor for hyponatremia, particularly if patients are receiving intravenous fluids and will be given desmopressin for several days.²⁷

Desmopressin is useful in most patients with type 1 and in some patients with type 2A vWD. The drug is controversial for type 2B vWD because increasing the level of abnormal vWF may intensify the severity of thrombocytopenia.²⁹ Type 3 vWD does not respond to desmopressin because patients usually do not have a storage pool of vWF.

In a pregnant patient with vWD. administer desmopressin approximately 1 to 2 hours before delivery. The drug may also be given intravenously or nasally immediately after delivery. If serious bleeding does not respond to desmopressin, give a vWF concentrate (approximately 1500 to 2500 ristocetin units).³⁰ The dose can be repeated every 8 to 12 hours if needed. If bleeding recurs 7 to 10 days postpartum, advise the patient to limit her physical activities and use intranasal desmopressin.

Replacement therapy is appropriate for patients with type 2A and type 2B disease that does not respond to desmopressin. Such therapy usually consists of factor VIII concentrates that contain vWF (including the high molecular weight multimers). The concentrates are rendered relatively safe by viral inactivation during manufacture. Two concentrates are available in the United States: one contains approximately 2 to 2.5 times as much vWF as factor VIII, and the other contains approximately 0.5 times as much vWF as factor VIII.³⁰

Cryoprecipitate may also be employed for replacement therapy, but its use is not generally recommended because the product does not undergo viral inactivation. Cryoprecipitate from 1 unit of blood contains approximately 100 to 150 units of vWF.

Doses recommended for replacement therapy depend on the type of bleeding or surgery. Maintain levels of both factor VIII and vWF above 50% during episodes of major bleeding, usually for a total of 3 to 10 days.²² Platelet transfusion has also been helpful if therapy results in adequate levels of factor VIII and vWF but bleeding persists.

Epsilon-aminocaproic acid and tranexamic acid are fibrinolytic inhibitors that have been useful adjunctively, particularly for patients with mucous membrane bleeding.^21,22

Estrogens increase the synthesis of vWF and have been used successfully in women with mild to moderate vWD. Doses now commonly used for prevention of postmenopausal osteoporosis are effective.³¹

Characteristics of the 3 Types of von Willebrand Disease.

• Type 1 affects 75% of patients with vWD. The quantitative abnormalities are expressed as a concordant decrease in vWF antigen, ristocetin cofactor, and factor VIII. All vWF multimers are present in decreased quantity.

• Type 2 affects 15% to 25% of patients with vWD. Qualitative abnormalities in vWF can be seen on multimer studies and/or in functional studies that assess binding affinities for platelet receptors (RIPA) or binding affinity of factor VIII. Most patients with type 2 vWD have subtype 2A or 2B.

• Type 2A—the most common type 2 variant (10% to 15% of patients with vWD)—is characterized by decreased vWF antigen levels and reduced ristocetin cofactor activity; the activity is usually decreased to a greater extent than the antigen level. Factor VIII levels may be normal or reduced. The high molecular weight and intermediate-sized multimers are reduced on gel electrophoresis studies of plasma platelet vWF, and the density of the smaller multimers is often increased.

• Type 2B accounts for approximately 5% of vWD cases.This subtype represents a “gain of function” mutation in which the vWF binds to platelet glycoprotein Ib more readily than normal. The decrease in plasma multimers of high molecular weight is less severe than in type 2A; the levels of vWF antigen and activity are decreased; and the level of factor VIII may be normal or decreased. Because the abnormal vWF has a tendency to attach to platelets, small aggregates of platelets form and are cleared from the circulation, causing thrombocytopenia in these patients.

• Type 2M is characterized by a defect in the vWF that leads to decreased binding to platelets. However, patients have normal high molecular weight multimers in their plasma on gel electrophoresis.

• Type 2N is clmracterized by a defect in the binding region of vWF for factor VIII but normal vWF function for platelet adhesion and aggregation. Factor VIII is rapidly cleared because of the decreased binding and protection by vWF. Consequently, patients have the phenotype of mild or moderate classic hemophilia A. Because their factor VIII levels fall to less than 5% to 10%, they are susceptible to soft tissue hemorrhages and hemarthrosis without the accompanying symptoms of abnormal primary hemostasis usually seen in vWD. Be alert to a family history that indicates autosomal inheritance and includes females with low factor levels. Order a specific assay for the binding function of vWF for factor VIII, and be aware that other tests of vWF function will show normal results.

• Type 3, which is rare, is characterized by unmeasurable levels of vWF antigen and ristocetin cofector and low levels of factor VIII. Patients may be homozygous or doubly heterozygous.