125 Von Willebrand Disease Flashcards
Associated with undetectable levels of vWF and severe bleeding
Type 3 vWD
Partial quantitative vWF deficiency, which is subdivided into
- Low vWF: between 30 and 50 IU/dL
- Type 1 vWD: less than 30 IU/dL.
Characterized by qualitative abnormalities of vWF structure, function, or both
Type 2 vWD
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
Type 2A vWD
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.
Type 2B vWD
Defective interactions with platelets or collagen
Type 2M vWD
Decreased FVIII binding to vWF characterized by mild to moderate FVIII deficiency
vWF antigen is normal
Type 2N vWD
Sometimes misdiagnosed as hemophilia
Named after the Normandy province
An intrinsic platelet disorder caused by variants in GPIb
Platelet-type (pseudo-) vWD
Occur resulting in accelerated loss of circulating vWF
Acquired forms of vWD
vWD that are autosomal recessive
Type 3
Type 2N
vWF is synthesized exclusively in
Endothelial cells and megakaryocytes
Two major functions in hemostasis
- Serves as the initial critical bridge between circulating platelets and the injured blood vessel wall
- Serves as the carrier in plasma for FVIII
vWF is encoded by the vWF gene on human chromosome 12
Chromosome 12
Meanwhile FVIII is encoded by the F8 gene on the X chromosome
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.
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.
vWF is unusually rich in _________, which accounts for 8.3% of its amino acid content.
Cysteine
Derived from the Golgi apparatus and are found in most endothelial cells and contain vWF
Weibel-Palade bodies
The concentration of vWF in plasma is approximately ________, with approximately _____% of circulating vWF localized to the platelet compartment.
10 mg/mL
15%
A specific protease that cleaves vWF resulting in reduction in the size of the largest multimers
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
vWF performs this bridging function by binding to two platelet receptors
GPIb and GPIIb/IIIa
Type 1 vWD with accelerated vWF clearance phenotype
vWF type 1C
The Tyr1584Cys variant is associated with decreased vWF survival, likely caused by increased susceptibility to proteolysis by ADAMTS13.
Features of Low von Willebrand Factor
- 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.
The most common qualitative variant of vWD
Cause selective loss of the large and intermediate vWF multimers from plasma
Type 2A von Willebrand Diseas
Type 2A vWD variants
- 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
The peculiar functional abnormality characteristic of type 2B vWD suggested a molecular defect within the__________
GPIb binding domain of vWF
Mean vWF antigen levels are low in what ABO blood group
Type O
75%
The most common event in patients with type 1 vWD
Mucocutaneous bleeding
In the initial laboratory evaluation of patients suspected by history of having vWD:
- 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.
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.
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.
FVIII levels in patients with vWD are generally coordinately decreased along with plasma vWF except in:
Only mildly or moderately decreased
- Type 3 vWD: range from 3% to 10%
- Type 2N vWD: more severely decreased but rarely to less than 5%
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.
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.
A nomenclature for categories of platelet-dependent vWF activity methods has been proposed by the SSC of ISTH as follows:
- **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
Measures vWF binding to collagen (usually type I, type III, or mixed) by ELISA
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.
Hyperresponsiveness to ristocetin-induced platelet agglutination (RIPA) results either from
- Type 2B vWD variant or
- An intrinsic defect in the platelet (platelet-type or pseudo-vWD)
Analysis of plasma vWF multimers is critical for the proper diagnosis and subclassification of vWD
This is generally accomplished by
Agarose gel electrophoresis of plasma vWF
Has been the primary method of vWF gene sequencing for more than 30 years.
Sanger-based DNA sequencing
Uses of vWF gene sequencing
- 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
Used when type 2N vWD is suspected
vWF:FVIII binding capacity
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
vWF propeptide (vWFpp)
The presence of detectable vWFpp can also help distinguish severe type 1 from type 3 vWD.
TRUE OR FALSE
The bleeding time is no longer recommended in the evaluation of patients with vWD or other conditions.
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
A platelet defect that phenotypically mimics vWD
Molecular analysis has identified variants within the GPIbα chain as the molecular basis of disease
Platelet-type (pseudo-) vWD
Should be performed at low ristocetin concentrations to distinguish type 2B and platelet-type vWD from type 2A vWD
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
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
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.
The mainstays of therapy for vWD are:
- 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.
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
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
Patients with type 1 vWD treated with DDAVP release unusually high-molecular-weight vWF multimers into the circulation for ______ hours after the infusion.
1–3 hours
Dose of DDAVP
- 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)
Patients should be monitored for response of FVIII and platelet-dependent vWF activity and side effects, particularly
Hyponatremia
Common side effects of DDAVP administration are mild cutaneous vasodilatation resulting in a feeling of heat, facial flushing, tachycardia, tingling, and headaches.
DDAVP is contraindicated in patients with
Unstable coronary artery disease
Because of increased risk of thrombotic events, such as myocardial infarction
Patients receiving DDAVP at closely spaced intervals of less than 24–48 hours can develop _______________.
Tachyphylaxis
vWF replacement therapy is appropriate among:
- Type 3 vWD
- Other patients with vWD unresponsive to DDAV
- Major bleeding, or situations requiring precise control over therapeutic levels
Acceptable commercial vWF-containing plasma concentrates
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.
Dosing of vWF replacement
In practice, the dosing and timing of vWD replacement therapy have been largely empiric.
- 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
Increased or Decreased
In pregnancy, vWF levels are ___________.
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.
More recently, target vWF levels of greater than ____________ IU/dL have been recommended for childbirth and the immediate postpartum period.
Greater than 100 IU/dL
Some guidelines have recommend to treat to vWF levels over 50 IU/dL.
Laboratory testing is recommended in the
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
