VON WILLEBRAND DISEASE

It is the most common mucocutaneous inherited bleeding disorder described first by Erik Von willebrand (Finnish professor in 1926).
It has autosomal dominant inheritance found in approximately 1% of population.
It results due to germline mutations which cause either structural or quantitative abnormalities of vWF leading to decreased adhesion by platelets to injured vessel wall causing impaired primary hemostasis.

Von Willebrand factor (vWF):

vWF is a glycoprotein (plasma concentration is 0.5 to 1.0mg/dl) with its gene located on chromosome 12.
VWF is secreted by
- The endothelial and stored as weibel palede bodies.
- Megakaryocytes and stored in the α granules of platelets.
vWF and factor VIII (synthesized in liver and kidney) form complex in the circulation. This prevents the degradation of Factor VIII.
vWF is also present in the sub endothelial matrix which is secreted by endothelial cells
Circulating VWF are present as multimers which interact with factor VIII, collagen, heparin and also platelet membrane glycoprotein
When there is endothelial injury platelet adhesion to sub endothelial matrix occurs through interaction between platelet glycoprotein Ib-1X, vWF and matrix component such as collagen.
In addition platelets and endothelial cells also release vWF in circulation which further augments platelet adhesion. vWF released into circulation is cleaved by ADAMTS13 at the site of A2 domain of vWF.
VWF multimers also cause platelet aggregation by binding to activated Gp IIb/IIIa integrins.

Pathophysiology of Von Wille brand disease:

Quantitative or structural (qualitative) abnormalities in VWF leads to reduced platelet adhesion producing mucocutaneous haemorrhage of varying severity.
Severe quantitative deficiency creates in addition factor VIII deficiency which is protected from proteolysis when it is bound to VWF
When VWF levels are 30% to 50% of normal sufficient levels of factor VIII is maintained for coagulation.
When the VWF levels are less than 30% of normal than the mucocutaneous and soft tissue bleeding occurs.

Types of vWD:

Type 1 VWD:

Due to quantitative VWF deficiency
Autosomal domiant disorders characterised by mild to moderate VWF deficiency.
Accounts for 70% of all cases.

Type 2 VWD:

Due to qualitative defects in VWF.
Subtypes: 4 subtypes of type 2 vWD exists, out of which subtype 2A is most common
- Subtype 2A vWD:
  - Accounts for 25% of all cases and is associated with mild to moderate bleeding.
  - Arises from autosomal dominant inheritance with point mutations in A2 structural domain of vWF molecules which increases the susceptibility of vWF proteolysis by ADAMTS-13 producing small molecular weight multimers in the plasma which have less platelet adhesion activity than normal.
- Subtype 2B vWD:
  - Mutations in A1 domain increases the affinity of vWF to platelet glycoprotein 1b/IX/V. Due to this large multimers of vWF bind to resting platelets and vWF is not available for normal platelet adhesion.
  - Chronic platelet activation leads to moderate thrombocytopenia.

Type 3 vWD:

It is an autosomal recessive disorder.
VWF is very less or absent in this condition. Factor VIII is also proportionately reduced in this condition
It is caused by deletion or frame shift mutation of both alleles.
Patients present with severe mucocutaneous or anatomic hemorrhage.

Clinical Features:

Mostly patient presents with mucocutaneous bleed
Common presentations are
- Epistaxis (Nasal bleed)
- Menorrhagia (Heavy, prolonged menstrual periods)
- Gastro intestinal bleeding
- Easy bruising
- Bleeding after surgery (especially involving mucus
  membranes)
- Prolonged or excessive bleeding after dental procedures
- Prolonged bleeding after delivery of a baby
- May vary in each person from time to time, throughout life depending on type of von Willebrand disease

Laboratory diagnosis:

CBC to rule out thrombocytopenia as a cause of mucocutaneous bleeding.
PT and APTT to assess coagulation system.
Standard vWD test panel includes 3 stages.
- Quantitative VWF test by employing enzyme immunoassay or automated latex immune assay methodology.
- vWF activity test which determines the factors ability to bind to platelets. vWF function is assessed by Ristocetin agglutination test
  - This assay is performed by mixing the patients plasma with formalin fixed platelets and Ristocetin, a small molecule that binds and activate VWF.
  - Ristocetin induces multivalent VWF multimers to bind platelet glycoprotein –Ib-1X and form interplatelet” bridges”
  - The resulting clumping (agglutination) of platelets is measured in a device called an aggregometer.
  - Degree to which patient plasma promotes ristocetin dependent platelet aggulatination reflects the vWF activity of the sample.
- vWF multimer analysis by sodium doclecy sulphate polyacrylamide gel electophoresis to further differentiate between vWD subtypes 2A & 2B.

References

Elaine M. Keohane, Larry J Smith, Jeanine M. Walenga. Rodaks Haematology: Clinical Principles and Applications. Fifth edition
Vinay kumar, Abul K.Abbas, Jon C. Aster. Robbins and Cotran. Pathologic Basis of Disease. 9th edition
Shirish M.Kawthalkar. Essentials of Haematology. Second edition

VON WILLEBRAND DISEASE

It is the most common mucocutaneous inherited bleeding disorder described first by Erik Von willebrand (Finnish professor in 1926).

It has autosomal dominant inheritance found in approximately 1% of population.

It results due to germline mutations which cause either structural or quantitative abnormalities of vWF leading to decreased adhesion by platelets to injured vessel wall causing impaired primary hemostasis.

Von Willebrand factor (vWF):

vWF is a glycoprotein (plasma concentration is 0.5 to 1.0mg/dl) with its gene located on chromosome 12.

VWF is secreted by

The endothelial and stored as weibel palede bodies.

Megakaryocytes and stored in the α granules of platelets.

vWF and factor VIII (synthesized in liver and kidney) form complex in the circulation. This prevents the degradation of Factor VIII.

vWF is also present in the sub endothelial matrix which is secreted by endothelial cells

Circulating VWF are present as multimers which interact with factor VIII, collagen, heparin and also platelet membrane glycoprotein

When there is endothelial injury platelet adhesion to sub endothelial matrix occurs through interaction between platelet glycoprotein Ib-1X, vWF and matrix component such as collagen.

In addition platelets and endothelial cells also release vWF in circulation which further augments platelet adhesion. vWF released into circulation is cleaved by ADAMTS13 at the site of A2 domain of vWF.

VWF multimers also cause platelet aggregation by binding to activated Gp IIb/IIIa integrins.

Pathophysiology of Von Wille brand disease:

Quantitative or structural (qualitative) abnormalities in VWF leads to reduced platelet adhesion producing mucocutaneous haemorrhage of varying severity.

Severe quantitative deficiency creates in addition factor VIII deficiency which is protected from proteolysis when it is bound to VWF

When VWF levels are 30% to 50% of normal sufficient levels of factor VIII is maintained for coagulation.

When the VWF levels are less than 30% of normal than the mucocutaneous and soft tissue bleeding occurs.

Types of vWD:

Type 1 VWD:

Due to quantitative VWF deficiency

Autosomal domiant disorders characterised by mild to moderate VWF deficiency.

Accounts for 70% of all cases.

Type 2 VWD:

Due to qualitative defects in VWF.

Subtypes: 4 subtypes of type 2 vWD exists, out of which subtype 2A is most common

Subtype 2A vWD:

Accounts for 25% of all cases and is associated with mild to moderate bleeding.

Arises from autosomal dominant inheritance with point mutations in A2 structural domain of vWF molecules which increases the susceptibility of vWF proteolysis by ADAMTS-13 producing small molecular weight multimers in the plasma which have less platelet adhesion activity than normal.

It is an autosomal recessive disorder.

VWF is very less or absent in this condition. Factor VIII is also proportionately reduced in this condition

It is caused by deletion or frame shift mutation of both alleles.

Patients present with severe mucocutaneous or anatomic hemorrhage.

Clinical Features:

Laboratory diagnosis:

CBC to rule out thrombocytopenia as a cause of mucocutaneous bleeding.

PT and APTT to assess coagulation system.

Standard vWD test panel includes 3 stages.

Quantitative VWF test by employing enzyme immunoassay or automated latex immune assay methodology.

vWF activity test which determines the factors ability to bind to platelets. vWF function is assessed by Ristocetin agglutination test

This assay is performed by mixing the patients plasma with formalin fixed platelets and Ristocetin, a small molecule that binds and activate VWF.

Ristocetin induces multivalent VWF multimers to bind platelet glycoprotein –Ib-1X and form interplatelet” bridges”

The resulting clumping (agglutination) of platelets is measured in a device called an aggregometer.

Degree to which patient plasma promotes ristocetin dependent platelet aggulatination reflects the vWF activity of the sample.

References

Elaine M. Keohane, Larry J Smith, Jeanine M. Walenga. Rodaks Haematology: Clinical Principles and Applications. Fifth edition

Vinay kumar, Abul K.Abbas, Jon C. Aster. Robbins and Cotran. Pathologic Basis of Disease. 9th edition

Shirish M.Kawthalkar. Essentials of Haematology. Second edition