CH 125 von WILLEBRAND DISEASE Flashcards
the most common inherited bleeding disorder in humans.\
von Willebrand disease (vWD)
The overall prevalence of vWD has been estimated to be as high as ___% of the general population
1
vWD is associated with either
quantitative deficiency (type _ and type _) or qualitative abnormalities of vWF (type _).
1,3
2
type ___ variant is the most severe form of vWD and is characterized by clinically undetectable levels of vWF, a severe bleeding diathesis, and usually an autosomal recessive pattern of inheritance.
3
the vWF is abnormal in structure, function, or both
type 2 vWD
Type ____ vWD is associated with selective loss of the largest and most functionally active vWF multimers.
results from variants that interfere with vWF biosynthesis and secretion or variants that produce a form of vWF that exhibits an increased sensitivity to proteolysis in plasma.
Type 2A vWD
Caused by variants clustered within the vWF A1 domain in a segment critical for binding to the platelet glycoprotein Ib receptor.
These variants produce a “gain of function,” resulting in spontaneous vWF binding to platelets and clearance of the resulting platelet complexes, leading to thrombocytopenia and loss of the most active (large) vWF multimers.
Type 2B vWD
Characterized by variants within the FVIII binding domain of vWF, leading to disproportionately decreased blood levels of FVIII and a disorder resembling mild to moderate hemophilia A but with autosomal rather than X-linked inheritance.
Type 2N vWD
T/F
Type 1,2,3 vWD and symptomatic low vWF can often be effectively managed by treatment with DDAVP (deamino D-arginine vasopressin), which produces a two- to threefold increase in plasma vWF level.
FALSE
Type 1 vWD and symptomatic low vWF only can often be effectively managed by treatment with DDAVP (deamino D-arginine vasopressin), which produces a two- to threefold increase in plasma vWF level.
T/F
Type 3 and some type 2 vWD variants often require treatment with vWF replacement.
TRUE
What VWD type?
- Partial quantitative deficiency of vWF that is otherwise normal in structure and function
- the most common variant.
type 1 vWD
Type 1 vwd
Molecular Characteristics
Inheritance
Factor VIII Activity
vWF Antigen
Platelet- Dependent vWF Activity
vWF Collagen Binding
RIPA
Plasma vWF Multimer Structure
Molecular Characteristics - Partial quantitative vWF deficiency (<30 IU/dL)
Inheritance - Autosomal dominant, incomplete penetrance
Factor VIII Activity (VIII:C) - Decreased to normal
vWF Antigen (VWF:Ag)- D
Platelet- Dependent vWF Activity (VWF:act) - D
vWF Collagen Binding (VWF:CB) - D
RIPA - Dec or N
Plasma vWF Multimer Structure - Normal distribution
Type 3
Molecular Characteristics
Inheritance
Factor VIII Activity
vWF Antigen
Platelet- Dependent vWF Activity
vWF Collagen Binding
RIPA
Plasma vWF Multimer Structure
Molecular Characteristics -Undetectable vWF
Inheritance - Autosomal recessive (or codominant)
Factor VIII Activity (VIII:C) - Markedly decreased
vWF Antigen (VWF:Ag)- Clinically undetectable
Platelet- Dependent vWF Activity (VWF:act) - Clinically undetectable
vWF Collagen Binding (VWF:CB) - Clinically undetectable
RIPA - Absent
Plasma vWF Multimer Structure - Absent
Type 2A
Molecular Characteristics
Inheritance
Factor VIII Activity
vWF Antigen
Platelet- Dependent vWF Activity
vWF Collagen Binding
RIPA
Plasma vWF Multimer Structure
Molecular Characteristics -Qualitative vWF defect; loss of large vWF multimers,
- decreased vWF-dependent platelet adhesion
Inheritance - Usually autosomal dominant
Factor VIII Activity (VIII:C) - D to N
vWF Antigen (VWF:Ag)- Usually low
Platelet- Dependent vWF Activity (VWF:act) - Markedly decreased
vWF Collagen Binding (VWF:CB) - Markedly decreased
RIPA - Decreased
Plasma vWF Multimer Structure - Largest and intermediate multimers absent
Type 2B
Molecular Characteristics
Inheritance
Factor VIII Activity
vWF Antigen
Platelet- Dependent vWF Activity
vWF Collagen Binding
RIPA
Plasma vWF Multimer Structure
Molecular Characteristics
- Qualitative vWF defect; increased vWF-platelet interaction (GPIb)
Inheritance: Autosomal dominant
Factor VIII Activity (VIII:C) : Decreased (D) to normal
vWF Antigen (VWF:Ag): D
Platelet- Dependent vWF Activity (VWF:act) :
D to N
vWF Collagen Binding (VWF:CB): D to N
RIPA: Increased to low concentrations of ristocetin
Plasma vWF Multimer Structure: Largest multimers often reduced or absent
Type 2M
Molecular Characteristics
Inheritance
Factor VIII Activity
vWF Antigen
Platelet- Dependent vWF Activity
vWF Collagen Binding
RIPA
Plasma vWF Multimer Structure
Molecular Characteristics
- Qualitative vWF defect; decreased platelet-dependent vWF activity or vWF-collagen binding, no loss of large vWF multimers
Inheritance: Usually autosomal dominant
Factor VIII Activity (VIII:C) : D to N
vWF Antigen (VWF:Ag): Variably decreased
Platelet- Dependent vWF Activity (VWF:act) :
Variably decreased
vWF Collagen Binding (VWF:CB): Variably decreased
RIPA: Variably decreased
Plasma vWF Multimer Structure: Normal and occasionally ultra-large forms
Type 2N
Molecular Characteristics
Inheritance
Factor VIII Activity
vWF Antigen
Platelet- Dependent vWF Activity
vWF Collagen Binding
RIPA
Plasma vWF Multimer Structure
Qualitative vWF defect; decreased vWF–FVIII binding capacity
Autosomal recessive
Decreased
Normal
Normal
Decreased to normal
Normal
Normal
Management:
For patients with type 3 vWD, other patients with vWD unresponsive to DDAVP, major bleeding, or situations requiring precise control over therapeutic levels
vWF replacement therapy
(virus-inactivated, vWF-containing FVIII concentrates)
T/F
most standard FVIII concentrates and all RFVIII products are not effective in vWD because they lack clinically significant quantities of vWF
True
The objective of VWF treatment is to
elevate FVIII:C and vWF:RCo until bleeding stops and healing is complete
Replacement goals of FVIII:C and vWF:RCo should be initial replacement to greater than ____IU/dL and maintenance of greater than ___ IU/dL for ___–___ days for major trauma, surgery, or central nervous system hemorrhage
100 IU/dL
50 IU/dL for 7–14 days
Replacement Goals
minor surgery or bleeding:
greater than ____ IU/dL for ____ days
delivery
greater than ____ IU/dL for and continued for at least _____ days in the postpartum period (at least one more recent guideline recommends >____ IU/dL for the initial delivery)
minor surgery or bleeding:
greater than 30–50 IU/dL for 3–5 days
delivery
greater than 50 IU/dL for and continued for at least 3–7 days in the postpartum period (at least one more recent guideline recommends >100 IU/dL for the initial delivery)
Replacement Goals
dental extractions and minor surgery
mucous membrane bleeding/menorrhagia
greater than 30–50 IU/dL for 1–5 days for dental extraction
greater than 20–50 IU/dL
Laboratory monitoring of posttreatment FVIII:C and vWF levels is important in guiding therapy and avoidance of supra- therapeutic replacement doses (>____IU/dL vWF:RCo, >____ IU/dL FVIII)
200
250
Treatment options for patients with type 3 vWD who have developed anti-vWF antibodies:
Immunosuppression, rFVIII, and rFVIIa
Management for patients who have concomitant thrombocytopenia associated with or in addition to vWD
transfuse platelets in addition to factor concentrates.
T/F
In pregnancy, vWF levels are increased.
True
Postpartum hemorrhage within the first few days after parturition may be related to the
relatively rapid return of FVIII and vWF activities to prepregnancy levels
postpartum hemorrhage in all forms of vWD may occur as long as ____ weeks postpartum
4–6
True or False
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. Tranexamic acid is useful to reduce bleeding after delivery.
True
T/F
Type 2M patients generally do have a satisfactory response to DDAVP
False
Type 2M patients generally do not have a satisfactory response to DDAVP. (p.2275)
T/F
Many experts consider DDAVP to be contraindicated in the treatment of type 2B vWD because the high-molecular-weight vWF released from storage sites has an increased affinity for binding to GPIb and might worsen thrombocytopenia
True
Common side effects of DDAVP administration are
mild cutaneous vasodilatation resulting in a feeling of heat, facial flushing, tachycardia, tingling, and headaches
potential for dilutional hyponatremia,
T/F
DDAVP: 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.
T
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 bod- ies in endothelial cells
DDAVP
Therapy with DDAVP often increases the (3) to two to five times the basal level.
FVIII activity,
vWF:Ag, and
platelet- dependent vWF activity
How to administer DDAVP
DDAVP 0.3 mcg/kg by continuous IV infusion over 30 minutes or subcutaneous injection or in intranasal form at a fixed dose (300 mcg for adults or 150 mcg for children)
in patients for whom DDAVP is potentially the treatment of choice, a test dose should be given at the planned therapeutic dose and route in advance of the first required course of treatment with measurements of before and after (2) levels to ensure an adequate therapeutic response.
vWF and FVIII:C
Features of acquired von Willebrand syndrome (AVWS)
Decreased levels of FVIII, vWF:Ag, and platelet-dependent vWF activity are common, and vWF multimers can be abnormal
AVWS is usually associated with another underlying disorder and has been reported to occur in patients with
myeloproliferative neoplasms
amyloidosis
benign or malignant B-cell disorders
hypothyroidism
autoimmune disorders
several solid tumors (particularly Wilms tumor)
cardiac or vascular defects (eg, aortic stenosis)
ventricular assist devices
association with several drugs (ciprofloxacin and valproic acid)
In cases of malignancy, AVWS is thought to be caused by
selective adsorption of vWF to the tumor cells
In AVWS associated with valvular heart disease, ventricular assist devices, or certain
drugs, vWF may be
lost by accelerated destruction or proteolysis under shear
T/F
Hypothyroidism results in decreased vWF synthesis.
T
T/F
A variety of B-cell disorders have been associated with the development of anti-vWF autoantibodies. In most cases, the AVWS appears to be caused by rapid clearance of vWF induced by the circulating inhibitor.
T
The mainstays of therapy for vWD are
DDAVP, which induces secretion of both vWF and FVIII and replacement therapy with vWF-containing plasma concentrates.
T/F
treatment with DDAVP with type 2 and type 3 vWD often requires a vWF-containing FVIII product
T
T/F
A vWF variant is required for the diagnosis of vWD, in part because not all patients who meet criteria for vWD have an identifiable vWF variant and in part because of lack of uniform access to testing.
False
A vWF variant is not required for the diagnosis of vWD, in part because not all patients who meet criteria for vWD have an identifiable vWF variant and in part because of lack of uniform access to testing. However, most patients with vWD do have an identifiable vWF gene variant, and genotype correlates strongly with vWD phenotype.
Can be used to confirm the diagnosis of type 2N vWD
Specific assays of FVIII binding to vWF (vWF:FVIIIB)
T/F
The PFA-100 system, which measures platelet binding under high shear is controversial in the diagnosis or monitoring of vWD.
T
Hyperresponsiveness to ristocetin-induced platelet agglutination results either from a type 2B vWD variant or an intrinsic defect in the platelet (platelet-type or pseudo-vWD).
In these disorders, patient platelet-rich plasma agglutinates spontaneously or at low ristocetin concentrations of only ____ mg/mL. At these concentrations, normal platelet-rich plasma does not agglutinate.
0.2–0.7
Type 2B and platelet-type vWD can be distinguished by RIPA experiments performed with
separated patient platelets or plasma mixed with the correspond- ing component from a normal individual or paraformaldehyde-fixed platelets
type 2B vWD plasma transfers the enhanced RIPA to normal platelets, whereas plasma from patients with platelet- type vWD interacts normally with control platelets.
Factor VIII Levels in type 3 vWD generally range from ___% to ___%
3-10
FVIII level in type 2N vWD is more severely decreased but rarely to less than X___.
FVIII level in type 2N vWD is more severely decreased but rarely to less than 5%.
is a measure of the ability of vWF to interact with its platelet ligand, GPIb.
Platelet-dependent vWF activity
In the initial laboratory evaluation of patients suspected by history of having vWD, the following tests are routinely performed:
assay of FVIII activity (FVIII:C),
vWF antigen (vWF:Ag), and
a measure of platelet- dependent vWF activity,
