125 Von Willebrand Disease

Question 1

Associated with undetectable levels of vWF and severe bleeding

Answer 1

Type 3 vWD

Question 2

Partial quantitative vWF deficiency, which is subdivided into

Answer 2

• Low vWF: between 30 and 50 IU/dL
• Type 1 vWD: less than 30 IU/dL.

Question 3

Characterized by qualitative abnormalities of vWF structure, function, or both

Answer 3

Type 2 vWD

Question 4

Abnormal vWF secretion or proteolysis and is characterized by a disproportionately low level of platelet-dependent vWF activity relative to vWF antigen and absence of large and intermediate-sized multimers

Answer 4

Type 2A vWD

Question 5

Abnormal vWF molecule with increased affinity for platelet glycoprotein (GP) Ib and can also be associated with reduced high-molecular-weight vWF multimers and thrombocytopenia.

Answer 5

Type 2B vWD

Question 6

Defective interactions with platelets or collagen

Answer 6

Type 2M vWD

Question 7

Decreased FVIII binding to vWF characterized by mild to moderate FVIII deficiency

vWF antigen is normal

Answer 7

Type 2N vWD

Sometimes misdiagnosed as hemophilia

Named after the Normandy province

Question 8

An intrinsic platelet disorder caused by variants in GPIb

Answer 8

Platelet-type (pseudo-) vWD

Question 9

Occur resulting in accelerated loss of circulating vWF

Answer 9

Acquired forms of vWD

Question 10

vWD that are autosomal recessive

Answer 10

Type 3
Type 2N

Question 11

vWF is synthesized exclusively in

Answer 11

Endothelial cells and megakaryocytes

Question 12

Two major functions in hemostasis

Answer 12

1. Serves as the initial critical bridge between circulating platelets and the injured blood vessel wall
2. Serves as the carrier in plasma for FVIII

Question 13

vWF is encoded by the vWF gene on human chromosome 12

Answer 13

Chromosome 12

Meanwhile FVIII is encoded by the F8 gene on the X chromosome

Question 14

TRUE OR FALSE

In general, the higher levels of vWF mRNA and antigen were found in the endothelial cells of large vessels rather than in microvasculature and in venous rather than arterial endothelial cells.

Answer 14

TRUE

In general, the higher levels of vWF mRNA and antigen were found in the endothelial cells of large vessels rather than in microvasculature and in venous rather than arterial endothelial cells.

Question 15

vWF is unusually rich in _________, which accounts for 8.3% of its amino acid content.

Answer 15

Cysteine

Question 16

Derived from the Golgi apparatus and are found in most endothelial cells and contain vWF

Answer 16

Weibel-Palade bodies

Question 17

The concentration of vWF in plasma is approximately ________, with approximately _____% of circulating vWF localized to the platelet compartment.

Answer 17

10 mg/mL

15%

Question 18

A specific protease that cleaves vWF resulting in reduction in the size of the largest multimers

Answer 18

ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs-13)

Decreased ADAMTS13 activity, either caused by congenital deficiency or acquired inhibitors, plays a central role in the pathophysiology of thrombotic thrombocytopenic purpura

Question 19

vWF performs this bridging function by binding to two platelet receptors

Answer 19

GPIb and GPIIb/IIIa

Question 20

Type 1 vWD with accelerated vWF clearance phenotype

Answer 20

vWF type 1C

The Tyr1584Cys variant is associated with decreased vWF survival, likely caused by increased susceptibility to proteolysis by ADAMTS13.

Question 21

Features of Low von Willebrand Factor

Answer 21

• More variable bleeding
• Less likely to have an identifiable vWF gene variant
• More likely to be blood group O
• More consistently responsive to DDAVP
• More likely to have vWF levels correct with aging

Different than in type 1 vWD, vWF levels did not inversely correlate with bleeding, and bleeding appeared to be disproportionate to the reduction in vWF level.

Question 22

The most common qualitative variant of vWD

Cause selective loss of the large and intermediate vWF multimers from plasma

Answer 22

Type 2A von Willebrand Diseas

Question 23

Type 2A vWD variants

Answer 23

• Group 1: a defect in intracellular transport, with retention of mutant vWF in the ER
• Group 2: mutant vWF is normally processed and secreted in vitro, but with increased susceptibility to proteolysis in plasma at the Tyr1605-Met1606 site cleaved by ADAMTS13

Question 24

The peculiar functional abnormality characteristic of type 2B vWD suggested a molecular defect within the__________

Answer 24

GPIb binding domain of vWF

Question 25

Mean vWF antigen levels are low in what ABO blood group

Answer 25

Type O

75%

Question 26

The most common event in patients with type 1 vWD

Answer 26

Mucocutaneous bleeding

Question 27

In the initial laboratory evaluation of patients suspected by history of having vWD:

Answer 27

• Assay of FVIII activity (FVIII:C)
• vWF antigen (vWF:Ag)
• Ristocetin cofactor activity (vWF:RCo): measure of platelet-dependent vWF activity

Other tests that are commonly used include the ristocetin-induced platelet aggregation (RIPA), vWF collagen-binding assay (vWF:CB), and vWF multimer analysis.

Question 28

TRUE OR FALSE

Routine coagulation studies, such as prothrombin time (PT) or activated partial-thromboplastin time (aPTT), are generally not useful in the evaluation of vWD.

Answer 28

TRUE

Routine coagulation studies, such as prothrombin time (PT) or activated partial-thromboplastin time (aPTT), are generally not useful in the evaluation of vWD.

However, the aPTT can be prolonged in subjects with vWF deficiency because of the secondary reduction in FVIII level.

Question 29

FVIII levels in patients with vWD are generally coordinately decreased along with plasma vWF except in:

Only mildly or moderately decreased

Answer 29

• Type 3 vWD: range from 3% to 10%
• Type 2N vWD: more severely decreased but rarely to less than 5%

Question 30

A measure of the ability of vWF to interact with its platelet ligand, GPIb

Has been tested with the ristocetin cofactor assay (vWF:RCo)

The ristocetin cofactor assay is limited by high coefficients of variation and low sensitivity.

Answer 30

Platelet-dependent vWF activity

The platelet-dependent vWF activity/vWF:Ag ratio has been proposed as a means to distinguish between type 1 and type 2 vWD, with a ratio of less than 0.7 indicative of a qualitative (type 2) vWF defect.

Question 31

A nomenclature for categories of platelet-dependent vWF activity methods has been proposed by the SSC of ISTH as follows:

Answer 31

• **vWF:RCo **refers to all assays that use platelets and ristocetin
• vWF:GPIbR assays use a recombinant GPIb fragment to bind vWF in the presence of ristocetin
• vWF:GPIbM assays are based on vWF binding to a gain-of-function mutant recombinant GPIb fragment
• vWF:Ab assays measure binding of a monoclonal antibody to a vWF A1 domain epitope

Question 32

Measures vWF binding to collagen (usually type I, type III, or mixed) by ELISA

Answer 32

vWF collagen-binding assay (vWF:CB)

Abnormalities in vWF:CB can reflect loss of high-molecular-weight multimers and/or the discrete loss of collagen binding caused by a type 2M variant.

Inclusion of vWF:CB in the vWD diagnostic assessment minimizes the risk of misclassifying patients with type 2 vWD.

Question 33

Hyperresponsiveness to ristocetin-induced platelet agglutination (RIPA) results either from

Answer 33

• Type 2B vWD variant or
• An intrinsic defect in the platelet (platelet-type or pseudo-vWD)

Question 34

Analysis of plasma vWF multimers is critical for the proper diagnosis and subclassification of vWD

This is generally accomplished by

Answer 34

Agarose gel electrophoresis of plasma vWF

Question 35

Has been the primary method of vWF gene sequencing for more than 30 years.

Answer 35

Sanger-based DNA sequencing

Question 36

Uses of vWF gene sequencing

Answer 36

• Differentiate type 1 from type 2 vWD
• To distinguish vWD from genocopies (ie, type 2B from platelet type vWD and type 2N from hemophilia A)
• To inform alloantibody risk in type 3 vWD

Question 37

Used when type 2N vWD is suspected

Answer 37

vWF:FVIII binding capacity

Question 38

Can be used to calculate the vWF propeptide:antigen ratio (vWFpp:Ag ratio) to detect a subset of patients with vWD with decreased vWF survival

Answer 38

vWF propeptide (vWFpp)

The presence of detectable vWFpp can also help distinguish severe type 1 from type 3 vWD.

Question 39

TRUE OR FALSE

The bleeding time is no longer recommended in the evaluation of patients with vWD or other conditions.

Answer 39

FALSE

The bleeding time is no longer recommended in the evaluation of patients with vWD or other conditions.

It was used as a screening test for vWD and other abnormalities of platelet function.

Varied considerably with the experience of the operator and a variety of other factors, did not prolong with FVIII deficiency, and correlated poorly with clinical bleeding risk

Question 40

A platelet defect that phenotypically mimics vWD

Molecular analysis has identified variants within the GPIbα chain as the molecular basis of disease

Answer 40

Platelet-type (pseudo-) vWD

Question 41

Should be performed at low ristocetin concentrations to distinguish type 2B and platelet-type vWD from type 2A vWD

Answer 41

Specialized RIPA test

In type 2B vWD patient platelets aggregate only at higher ristocetin concentrations
Type 2B vWD plasma transfers the enhanced RIPA to normal platelets

Question 42

A relatively rare acquired bleeding disorder that usually presents as a late-onset bleeding diathesis in a patient with no prior bleeding history and a negative family history of bleeding

Answer 42

Acquired vWD, or acquired von Willebrand syndrome (AVWS)

Management of AVWS is generally aimed at treating the underlying disorder.

Refractory patients have been treated with corticosteroids, plasma exchange, intravenous immunoglobulin, rituximab, DDAVP, and vWF-containing FVIII concentrates.

Question 43

The mainstays of therapy for vWD are:

Answer 43

• DDAVP
• Replacement therapy with vWF-containing plasma concentrates

Patients with low VWF and type 1 may be able to be treated with DDAVP alone, but treatment in those with type 2 and type 3 vWD often requires a vWF-containing FVIII product.

Question 44

An analog of antidiuretic hormone that acts through type 2 vasopressin receptors to induce secretion of FVIII and vWF, likely via cAMP-mediated secretion from the Weibel-Palade bodies in endothelial cells

Answer 44

Desmopressin (DDAVP)

Has become a mainstay for the treatment of mild hemophilia and vWD because it is relatively inexpensive and widely available.

Patients with type 2 vWD are less likely to have a response than type 1 patients, and nearly all patients with type 3 vWD cannot respond

Question 45

Patients with type 1 vWD treated with DDAVP release unusually high-molecular-weight vWF multimers into the circulation for ______ hours after the infusion.

Answer 45

1–3 hours

Question 46

Dose of DDAVP

Answer 46

• 0.3 mcg/kg by continuous IV infusion over 30 minutes or subcutaneous injection
• Intranasal form at a fixed dose (300 mcg for adults or 150 mcg for children)

Question 47

Patients should be monitored for response of FVIII and platelet-dependent vWF activity and side effects, particularly

Answer 47

Hyponatremia

Common side effects of DDAVP administration are mild cutaneous vasodilatation resulting in a feeling of heat, facial flushing, tachycardia, tingling, and headaches.

Question 48

DDAVP is contraindicated in patients with

Answer 48

Unstable coronary artery disease

Because of increased risk of thrombotic events, such as myocardial infarction

Question 49

Patients receiving DDAVP at closely spaced intervals of less than 24–48 hours can develop _______________.

Answer 49

Tachyphylaxis

Question 50

vWF replacement therapy is appropriate among:

Answer 50

• Type 3 vWD
• Other patients with vWD unresponsive to DDAV
• Major bleeding, or situations requiring precise control over therapeutic levels

Question 51

Acceptable commercial vWF-containing plasma concentrates

Answer 51

Humate-P, Alphanate, Wilate, and Koate

A low FVIII plasma-derived vWF replacement product, Wilfactin, has a vWF:RCo/FVIII ratio of greater than 10 and is approved for use in Europe.

It is important to note that most standard FVIII concentrates and all RFVIII products are not effective in vWD because they lack clinically significant quantities of vWF.

Question 52

Dosing of vWF replacement

In practice, the dosing and timing of vWD replacement therapy have been largely empiric.

Answer 52

• Greater than 100 IU/dL and maintenance of greater than 50 IU/dL for 7–14 days for major trauma, surgery, or central nervous system hemorrhage
• Greater than 30–50 IU/dL for 3–5 days for minor surgery or bleeding
• Greater than 50 IU/dL for delivery and continued for at least 3–7 days in the postpartum period (although at least one more recent guideline recommends >100 IU/dL for the initial delivery)
• Greater than 30–50 IU/dL for 1–5 days for dental extractions and minor surgery
• Greater than 20–50 IU/dL for mucous membrane bleeding or menorrhagia

Question 53

Increased or Decreased

In pregnancy, vWF levels are ___________.

Answer 53

Increased

In patients with low vWF, the FVIII and platelet-dependent vWF activities nearly always increase into the normal range, and most patients do not require specific treatment for delivery.

Question 54

More recently, target vWF levels of greater than ____________ IU/dL have been recommended for childbirth and the immediate postpartum period.

Answer 54

Greater than 100 IU/dL

Some guidelines have recommend to treat to vWF levels over 50 IU/dL.

Question 55

Laboratory testing is recommended in the

Answer 55

Third trimester and in the postpartum period

Patients who have “self-corrected” their vWF levels by the time of delivery usually do not require any specific therapy at the time of parturition