von Willebrand's Disease

Question 1

What is the most common inherited bleeding disorder?

Answer 1

von Willebrand disease (vWD)
Usually autosomal dominant
Affects 1% of screened population

Question 2

What is von Willebrand factor?

Answer 2

Binds to platelets and endothelial components, forming an adhesive bridge at sites of endothelial injury.
Contributes to fibrin clot formation by acting as a carrier protein for factor VIII, which has a greatly shortened 1/2 life and abnormally low concentration unless it is bound to vWF.

Question 3

What is ristocetin?

Answer 3

Ristocetin is an antibiotic previously used to treat staphylococcal infections. It is no longer used clinically because it caused thrombocytopenia and platelet agglutination. It is now used solely to assay those functions in vitro in the diagnosis of conditions such as vWD and Bernard-Soulier syndrome. Platelet agglutination caused by ristocetin can occur only in the presence of von Willebrand factor multimers, so if ristocetin is added to blood lacking the factor or its platelet receptor, the platelets will not clump.

Question 4

What are the 3 initial tests for vWD?

Answer 4

Plasma vWF antigen (vWF:Ag)
Plasma vWF activity (ristocetin cofactor activity, vWF:Rco - bind to platelets in presence of ristocetin, or vWF:CB - binding to collagen)
Factor VIII activity

Question 5

If one of the 3 initial tests for vWD is abnormal, what should be done next?

Answer 5

vWF multimer distribution using gel electrophoresis
Ristocetin-induced platelet aggregation (RIPA - tests ability of pt’s vWF to bind to platelets in suboptimal ristocetin concentrations)

Question 6

What is Type 1 vWD?

Answer 6

Most common variant (75%), AD inheritance
Partial quantitative deficiency of vWF
Clinical presentation varies from mild to severe
Labs: concordant decr in vWF antigen, vWF activity (ristocetin cofactor), factor VIII activity, all vWF multimers are present but decreased

Question 7

What is Type 2A vWD?

Answer 7

10-15% of cases, AD, mod-severe bleeding
Decreased high & intermediate molecular weight multimers of vWF
Labs: Ristocetin cofactor activity lower than the vWF antigen (ratio <0.5 ot 0.7); antigen may be in nl range; factor VIII levels nl or reduced; RIPA is reduced.

Question 8

What is Type 2B vWD?

Answer 8

5% of cases, AD, mod-severe bleeding
vWF has a gain of fxn mutation -> the larger multimers bind more readily to the platelet receptor, taking them out of circulation. May also have thrombocytopenia.
Labs: discordant vWF:Ag & ristocetin cofactor activity, nl or decr Factor VIII

Question 9

What are Type 2M & 2N vWD?

Answer 9

Uncommon variants with severe bleeding

Question 10

What is Type 3 vWD?

Answer 10

Rare, severe bleeding involving skin, mucosal membranes, soft tissues, joints
Labs: marked decr or absence of detectable vWF, Factor VIII activity 1-10% of nl, ristocetin cofactor not detectable, RIPA is absent.

Question 11

What is the difference between low vWF vs Type 1 vWD?

Answer 11

A diagnosis of Type 1 vWD requires vWF activity & antigen < 30 IU/dL. Individuals with mild bleeding symptoms and mildly decr vWF levels are referred to as having “low vWF.”

Question 12

What is the presentation of vWD?

Answer 12

Easy bruising, skin bleeding, prolonged bleeding from mucosal surfaces, menorrhagia.
Exceptions:
-Type 2N vWD - mimics classic hemophilia (soft tissue, joint, urinary bleeding, bleeding after invasive procedures)
-Type 3 vWD - both mucocutaneous and joint/soft tissue bleeding

Question 13

What can precipitate bleeding in patients with mild vWD?

Answer 13

Ingestion of aspirin or NSAIDS

Question 14

What disorders are associated with acquired vWD?

Answer 14

SLE - antibodies to vWF
Hypothyroidism - decreased synthesis
Aortic stenosis - intravascular shear forces
Leukemia
Uremia
Hemoglobinopathies
Valproic acid, ciprofloxacin

Question 15

When should acquired vWD be suspected?

Answer 15

Onset of bleeding later in life

• Hx of prior uneventful surgery prior to bleeding episode
• Presence of an inhibitor to vWF or vWF-binding antibodies
• Remission of bleeding after tx of an underlying acquired VWD-associated disorder
• Response to treatment with IVIG
• Short-lived Response to vWF-containing concentrates or desmopressin

Question 16

How is inherited vWD treated?

Answer 16

5 classes of meds:
Desmopressin (dDAVP) - promotes release of vWF
Replacement therapy with vWF-containing concentrates
Antifibrinolytic drugs
Topical therapy w/ thrombin or fibrin sealan
Estrogen therapy

There is a role for recombinant human factor VIIa in pts with severe Type 3 vWD who develop inhibitors to replacement vWF.

Question 17

How is acquired vWD treated?

Answer 17

Depends on pathogenesis, may consider trial of dDAVP, vWF replacement, IVIG, recombinant VIIa

Question 18

How does pregnancy affect vWD?

Answer 18

• Levels of VWF rise in normal individuals and in most patients with VWD during the second and third trimesters to two to three times baseline. Consequently, many patients with VWD reach normal levels of both VWF and factor VIII at term. However, the qualitative abnormalities in type 2 VWD will persist and thrombocytopenia in type 2B VWD may worsen.
• Procedures such as amniocentesis, chorionic villus sampling, and regional anesthesia are generally safe if these levels are maintained and the coagulation screen is otherwise normal.
• Since desmopressin has a theoretical possibility of initiating uterine contractions, it is not generally used prior to delivery. However, limited data indicate that dDAVP has been used “without mishap” in 31 pregnant women for prophylaxis before invasive procedures.

Question 19

What are delivery considerations for women with vWD?

Answer 19

• Although treatment is not needed during pregnancy in the majority of women with VWD, many require treatment during delivery and during the following one to three weeks thereafter.
• It is recommended that levels of VWF and factor VIII be maintained at 50 IU/dL or higher during delivery and for at least three to five days after delivery.
• An anesthesia consultation should be obtained prior to the onset of labor to discuss options for regional anesthesia or analgesia. —
• Regional anesthesia may be considered when VWF and factor VIII levels are maintained at about 50 IU/dL.
• Low factor VIII appears to be the most important determinant of increased bleeding during delivery. It is generally recommended that factor VIII levels be at or above 50 percent for a cesarean section.
• Cesarean delivery should be reserved for the usual obstetrical indications; fetal intraventricular hemorrhage due to maternal or fetal VWD is rare.
• Elective surgical procedures on the newborn (eg, circumcision) should be delayed until the infant’s VWD and factor VIII status have been determined.

Question 20

How should women with VWD be managed postpartum?

Answer 20

• Plasma levels of factor VIII and VWF fall quickly after delivery and excessive bleeding may occur at this time.
• The average time of onset for postpartum hemorrhage in women with VWD is from 11 to 23 days post delivery.
• Thus, dDAVP or VWF replacement may be required during or shortly after delivery, and for the first 2-4 weeks thereafter.