Von Willebrand disease Summary

Pathophysiology:

·         Most common bleeding disorder.

·         Prevalence of symptomatic disease ranges from 1/100 to 1/10,000.

·         The transition is autosomal dominant for most types and rarely inherited in a recessive manner.

·         vWF is a large multimeric glycoprotein produced in megakaryocytes and endothelial cells.

·         Plasma vWF, mostly released from stored vWF in Weibel-Palade bodies in endothelial cells.

·         Platelet vWF is stored in alpha granules and is released upon platelet activation.

·         The main roles of vWF in hemostasis are:

o   Promote platelet adhesion to the exposed subendothelium.

o   Serve as a chaperone for factor VIII in plasma, protecting it from proteolytic degradation

·         Classification of VWD:

o   Type 1: Partial quantitative defect in vWF

o   Type 3: Absolute quantitative defect in vWF

o   Type 2: Qualitative defect in vWF

vWD type 1:

·         Partial quantitative deficiency of vWF

·         A family history of the disease is usually present

·         Patients with vWF levels < 20 IU/dL usually have identifiable mutations in the vWF gene and commonly are associated with significant bleeding symptoms.

·         75% of cases of type 1 are due to mutations that result in decrease vWF secretion

·         Type 1C is a variant of type 1 that is caused by rapid clearance of vWF from the circulation because of specific mutations in the vWF gene.

·         Patients with type 1C have a robust initial response to desmopressin, but they exhibit an abrupt vWF level decrease within 2-4 hours.

·         Low penetrance: Not all individuals that inherit a mutation in vWF show signs of clinical disease.

·         Variable expressivity: Not all individuals that inherit the same mutation show the same signs.

·         More than 50% of individuals with vWF levels in the mildly decreased range (30-50 IU/dL) are asymptomatic or have minimal bleeding symptoms.

·         Individuals with blood group O have 25%-30%  lower vWF levels as compared with those who have blood group A; therefore, 14% of blood group O individuals in the U.S. are expected to have vWF levels < 50 IU/dL

·         < 30 IU/dL is designated as the level for a definitive diagnosis of vWD.

vWD type 2:

·         Type 2A: Loss of intermediate and high molecular weight multimers because of decreased secretion or increased susceptibility to ADAMTS 13.

·         Type 2B: Gain of function mutation resulting in spontaneous vWF-platelet binding under physiologic shear conditions, resulting in clearance of highest moelcular weight multimers and mild thrombocytopenia

·         Type 2M: Loss of function mutations that decrease the interaction of vWF with its platelet receptor and decreased ristocetin cofactor activity.

·         Type 2N: Mutations in vWF causing reduced binding to FVIII allowing for increased clearance.

vWD type 3:

·         Inherited in an autosomal recessive mode

·         Complete lack of vWF protein with undetectable levels of vWF antigen assay and ristocetin cofactor assay and resultant very low FVIII levels

·         The bleeding pattern is usually severe

Clinical presentation:

·         Mucocutaneous bleeding, specifically easy and excessive bruising, nose, mouth, GI and GU bleed.

·         Epistaxis or oral-pharyngeal bleeding sufficient to result in anemia suggests the presence of hemostatic disorder.

·         Excessive bleeding after procedures, the most common is childbirth and oral surgery.

·         Type 3 bleeding events is similar to severe hemophilia

Diagnosis:

·         Screening tests:

o   Have several limitations.

o   aPTT is only noticeably abnormal in patients with types 2N & 3 vWD, and sometimes in type 2B.

·         Diagnostic tests:

o   Quantitative measurement of vWF antigen, platelet binding function (vWF:RCo), Factor VIII activity and binding to vWF.

o   Also vWF multimers distribution is used to differentiate subtypes.

·         Both vWF and FVIII are acute phase reactants and may increase 2 to 5 times above baseline because of variety of conditions as for example elevated estrogen levels. Therefore normal levels do not completely rule out vWD.

·         vWF:RCo assay is widely used and is accepted as the gold standard for vWF activity however recent report suggests that this assay can be abnormal in a subset of otherwise healthy African Americans

·         The FVIII activity level and binding assay provide a more accurate diagnosis of vWD type 2N.  

·         Abstract 3567 presented in ASH meeting 12/13:

o   Novel rapid screening assay for the diagnosis of the phenotypic variants of vWD

o   Assay takes 3 hours

o   It has a diagnostic accuracy of 89.7%

Condition	Description	vWF:RCo (IU/dL)	vWF:Ag (IU/dL)	Factor VIII	vWF:RCO/vWF:Ag
Type 1	Partial quantitative vWF deficiency	< 30	< 30	Decrease  or normal	< 0.5-0.7
Type 1C	Increased clearance (increased propeptide)
Type 2A	Decreased high & med mol wt multimers	< 30	< 30-200	Decrease  or normal	< 0.5-0.7
Type 2B	Increased platelet binding	< 30	< 30-200	Decrease  or normal	< 0.5-0.7
Type 2M	Decreased binding to platelets	< 30	< 30-200	Decrease  or normal	< 0.5-0.7
Type 2N	Decreased binding to FVIII	30-200	30-200	Decrease	< 0.5-0.7
Type 3	Virtually complete deficiency of vWF	< 3	< 3	Markedly decreased	Not applicable
Low vWF		30-50	30-50	Normal	< 0.5-0.7
Normal		50-200	50-200	Normal	< 0.5-0.7

Acquired von Willibrand syndrome:

·         Rare disorder in which vWF is synthesized normally but cleared from the circulation more rapidly via 1 of 3 mechanisms:

o   Auto-antibodies against vWF and immune complex formation (e.g., Hashimoto’s thyroiditis)

o   vWF binding to cancer cells (e.g., Wilms tumor, lymphoproliferative disorders)

o   Increased proteolytic activity of HMWM under pathological high shear stress conditions (e.g., congenital heart disease, aortic stenosis, angiodysplasia)

·         Treatment is directed to underlying disorder.

Treatment:

·         Desmopression:

o   Mild to moderate bleeding associated with type 1 vWD is managed with desmopressin, most commonly intranasal preparation, and antifibrinolytic agents as required.

o   Desmopressin mechanism of action is based on the secretion of stored vWF from Weibel-Palade bodies in endothelial cells into the plasma.

o   Repeated administration of desmopressin in proximity may lead to tachyphylaxis, with decreased response levels with repeated  use likely resulting from depletion of the storage pool

o   Use of desmopressin no more than once daily and no more than on 2-3 consecutive days serves as an acceptable clinical guideline for home use

o   Less effective in type 2 vWD & can precipitate thrombosis or result in significant thrombocytopenia

o   Ineffective in type 3 vWD

o   Dose

§  IV: 0.3 mcg/kg in 50 mL saline over 20 min

§  Nasal spray: weight > 50 kg; 300 mcg, < 50 kg; 150 mcg, (1 spray in each nostril)

·         vWF concentrate:

o   Prepared from cryoprecipitate

o   type 2 vWD most commonly treated with exogenous normal vWF replacement

o   It is also the main treatment for type 3 vWD

o   Dose:

§  Major bleeding or surgery: Initial dose 40-60 ristocetin cofactor units per kg followed by 20-40 ristocetin cofactor/kg q 12-24 hrs to keep vWF level 50 to 100 IU/dL for 7 to 14 days

§  Minor bleeding or surgery:  Initial dose 30-60 ristocetin cofactor units per kg followed by 20-40 ristocetin cofactor units/kg q 12 to 48 hrs to keep vWF level > 30 IU/dL for 3 to 5 days.

·         Antifibrinolytic agents:

o   Aminocaproic acid: 24 to 50 mg/kg (maximum 5 g dose) 4x daily by mouth

o   Tranexamic acid: 10 mg/kg 3x daily IV

o   Are useful as adjunctive therapies

o   They are lysine analogues and inhibit plasmin mediated thrombolysis and exert their effect through clot stabilization and prevention of early dissolution

o   Use with caution in patients with history of thrombosis or atherosclerosis and are contraindicated when hematuria is present as obstructive uropathy 2ry to ureteral clots may develop