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Von Willebrand Disease

Von Willebrand disease (vWD) is the most common inherited abnormality of hemostasis and is usually inherited in an autosomal dominant fashion. Currently, vWD is divided into 3 types (type 1, 2 and 3) and type 2 vWD is further divided into 4 subclasses (2A, 2B, 2M, and 2N). Estimates of prevalence vary from 1 per 10,000 persons to 1 per 100 persons, with Type 1 vWD being the most common type.

Von Willebrand Disease Characteristics

VWD is due to a qualitative or quantitative abnormality of von Willebrand factor (vWF), leading to a disruption of primary hemostasis. Normally, vWF mediates the adhesion and aggregation of platelets to subendothelium in blood vessels with high shear force, such as arteries. In addition, vWF binds to factor VIIIc and protects it against degradation. Substantial deficiency of vWF (levels <30%) results in a primary hemostatic defect and most patients present with mild mucocutaneous bleeding including easy bruising, epistaxis, posttraumatic and postsurgical bleeding and menorrhagia in women. Cases of Type 3 vWD with very low vWF also have very low factor VIII levels and may experience soft tissue and joint hemorrhages.

A panel of tests is required to screen adequately for the disorder, because routine screening tests such as the aPTT may be normal. The aPTT is abnormal only in those cases of vWD with low levels of factor VIIIc. The initial panel includes factor VIIIc assay, von Willebrand factor antigen, and ristocetin cofactor (RcoF). VWF antigen test measures the quantity of vWF in plasma. RcoF assesses vWF function by measuring the binding activity of vWF to platelet glycoprotein 1b. Patient plasma is added to fixed donor platelets, ristocetin is added, and the rate of platelet aggregation is measured. Ristocetin is a small glycopeptide antibiotic that binds to both vWF and GP1b, resulting in a vWF dependent platelet agglutination. Factor VIII coagulant activity provides information about the ability of vWF to function as a carrier protein for factor VIII. Factor VIII is always decreased in patients with Type 2N and Type 3 vWD. Factor VIII coagulant activity does not always parallel vWF antigen levels.

If one or more of the initial tests are abnormal, additional testing may performed to further classify vWD. Ristocetin induced platelet aggregation (RIPA) is particularly useful to distinguish ttype 2A from type 2B vWD, because it can demonstrate the higher than normal affinity of vWF for the platelet GP1b/IX complex that occurs in Type 2a. In this assay, varying concentrations of ristocetin (0.5, 1.0, & 1.5 mg/mL) are mixed together with platelet rich plasma. The minimal concentration of ristocetin able to cause 30% platelet aggregation is recorded. Platelets from unaffected individuals require 1.0 – 1.5 mg/dL of ristocetin for aggregation. Platelets from patients with type 2A will not aggregate with 0.5 mg/mL ristocetin, but platelets from patients with type 2B do.

VWF multimer analysis involves the separation of vWF molecules by protein electrophoresis and detection of all molecular weight forms by Western Blot. This test is used to subclassify Type 2 vWD into types 2A, 2B and 2M. Types 2A and 2B have a decrease in high molecular weight multimers, while type 2M has a normal distribution.

Based on the levels of RcoF, vWF antigen, factor VIII activity and distribution of vWF multimers, vWD can be classified into quantitative (Types 1 & 3) and qualitative (Type 2) abnormalities. Quantitative abnormalities include a mild to moderate reduction of vWF (Type 1) or complete absence of vWF (Type 3). In contrast, Type 2A & 2B vWD have a normal quantity of vWF, which is functionally and structurally defective as manifested by a discordant decrease in RcoF activity. Panel results are interpreted as follows:

Classification of von Willebrand’s Disease

 

Type I vWD is the mildest form of the disease and is characterized by a concordant mild quantitative decrease in vWF level and ristocetin cofactor activity (30-50%). Factor VIIIc may be normal or decreased.

Type 2 vWD is caused by a qualitative defect in vWF that may be associated with deficient multimerization. VWF antigen level and RcoF activities are often discordant; Rcof is usually low and vWF and FVIII are usually borderline. Type 2 vWD can be further subclassified into as type 2A, 2B, 2M, or 2N.

• Type 2A is a qualitative variant of vWF characterized by absence of high molecular weight multimers. The absence of these high molecular weight multimers results in decreased RcoF activity. Factor VIIIc activity may be normal to moderately reduced. Platelet rich plasma from patients with Type 2A do not aggregate in the presence of dilute ristocetin.
• Type 2B vWD is characterized by a dysfunctional vWF that has increased platelet avidity, resulting in increased platelet aggregation with dilute ristocetin. Patients with Type 2B often have mild thrombocytopenia. Platelet rich plasma from patients with Type 2B does aggregate with dilute ristocetin.
• Type 2M (M for multimers) has a normal vWF multimer distribution, but the binding of vWF to platelets is decreased.
  • Type 2N (N for Normandy) resembles hemophilia A in that plasma factor VIIIc levels are decreased. A defect in binding of vWF to Factor VIII results in increased clearance of Factor VIIIc.

Type III vWD is the most severe form of vWD. There is almost total absence of vWF in the plasma and platelets and markedly decreased factor VIIIc.

Mild vWD may be difficult to detect because assay values in a patient may vary at different times. Repeat testing after an interval of 2 to 4 weeks may be required to confirm or exclude the diagnosis. Inflammation, stress, pregnancy or estrogen therapy may increase vWF levels above baseline and potentially mask diagnosis of mild vWD. Short term physical exertion causes a rapid increase in vWF levels. Combined oral contraceptive pills increase vWF levels. Repeat testing should be undertaken 4 to 6 weeks after discontinuation of oral contraceptives. Hyperthyroidism increases vWF levels and hypothyroidism is associated with decreased levels. People with blood group O have 25% lower vWF levels than patients with non-O blood groups.

Myeloproliferative disorders and monoclonal gammopathies are associated with acquired abnormalities of vWF, often due to immune clearance. The high shear stress associated with aortic stenosis causes proteolysis of high molecular weight multimers and mimics type 2 vWD.

Treatment Options

Treatment of vWD can be accomplished by stimulating the release of endogenously stored vWF or infusing exogenous vWF.

Treatment Recommendations for vWD

DDAVP promotes accelerated release of endogenous vWF from storage sites and is the treatment of choice for Type 1 vWD. It can be used prophylactically prior to surgery and to treat bleeding. Type 1 vWD patients with baseline plasma levels of vWF antigen in the 10 to 20 IU/dL range or higher are those who are more likely to reach post-DDAVP levels sufficient to attain hemostasis. DDAVP is usually ineffective for Type 2 variants and Type 3. It can cause thrombocytopenia in Type 2B patients. A therapeutic trial of DDAVP before an elective procedure is advisable. Factor VIII and vWF are measured before and 1, 4 and 8 hours after infusion. Responsive patients have will have a three-fold increase in Factor VIII:C and a two-fold increase in vWF within 30 minutes. Increased levels should persist for 8 to 10 hours. Baseline and post-infusion platelet counts should be measured in unclassified patients to screen for thrombocytopenia. If the trial is successful, the same dose can be used for prophylaxis or treatment of bleeding. Doses should be repeated on a daily basis for most bleeding episodes. Tachyphylaxis may occur with more frequent dosing or after 3 to 4 consecutive days. It can be overcome by waiting 24 to 48 hours before giving the next dose. Side effects include flushing, headache, hyponatremia, and hypotension. Hypotension is most often associated with rapid infusion. It is especially important to monitor Infants and surgical patients for hyponatremia.

Antifibrinolytic amino acids, such as epsilon aminocaproic acid (Amicar) are often prescribed as an adjunct to desmopressin therapy when treating epistaxis, oral cavity bleeding, bleeding associated with dental procedures, and menorrhagia. Amicar interferes with the lysis of newly formed clots by saturating the binding sites on plasminogen and preventing its attachment to fibrin.

Factor Replacement Therapy for vWD

Factor replacement is recommended for patients with Types 2 and 3 vWD and for Type 1 patients who do not respond adequately to DDAVP. The FDA has licensed some Factor VIII concentrates containing multimeric vWF, such as Humate P and Koate-DVI, for treatment of vWD.

Humate P is labeled in RCof units and in Factor VIII units. The recommended dosage of Humate or 40–80 IU vWF:RCoF per kg depending on the vWD type and bleeding severity. One vWF:RCoF unit per kg should raise the plasma vWF:RCoF level by 1.5 IU/dL.

Humate P Dosage Guidelines for vWD Based on RCoF

Examples of minor bleeding include epistaxis, oral mucosal bleeding and menorrhagia. Examples of major bleeding include GI, CNS and trauma. If RCoF units are not known, dosage should be based on Factor VIII levels. The recommended dosage based on Factor VIII is 20–40 IU FVIII:C per kg

Humate P Dosage Guidelines for vWD Based on Factor VIII:C

The plasma half life of vWF:RCoF is much shorter than Factor VIII, 8 hours versus 24 hours. Plasma Factor VIII levels should be monitored daily and the dose adjusted accordingly. The patient’s plasma Factor VIII level should increase 2U/dL for each 1 IU/kg infused. A patient’s own FVIII level will begin to rise within 4 to 8 hours after infusion of vWF.

Factor VIII concentrate is preferred over cryoprecipitate because of the decreased risk of viral transmission. Cryoprecipitate should not be used except in life and limb-threatening emergencies when vWF-containing Factor VIII concentrate is not immediately available. A reasonable dose of cryoprecipitate is 1 bag for every 5 Kg of body weight. This dose should be repeated every 8 to 12 hours. The amount of von Willebrand factor contained within a given unit of cryoprecipitate is highly variable and dependent upon the donor’s plasma level. Additional therapeutic intervention is indicated in certain clinical situations. Type 3 patients who continue to bleed and have a prolonged bleeding time should receive platelets.

Pregnancy causes a progressive increase in vWF. Determination of which obstetrical patients will require therapy for delivery should be based on the factor VIII level and not the vWF level. Patients with factor VIII levels >50% usually do not experience increased bleeding with vaginal delivery or C-section. Bleeding can be significant when the Factor VIII level is <20%. A patient with Factor VIII levels <50% should receive DDAVP or Factor VIII concentrate prior to delivery. If prolonged bleeding occurs during delivery, then Factor VIII concentrate should be given regardless of the Factor VIII level. Three to 4 daily doses of Factor VIII concentrate are usually necessary to avoid postpartum bleeding. Pregnant patients with type 2B vWD may develop thrombocytopenia due to increasing vWF levels. Factor concentrate can be given just prior to delivery to reverse thrombocytopenia.