VON WILLEBRAND DISEASE (VWD)

DR ODE I.C

INTRODUCTION

• Von Willebrand disease (VWD) is the most common inherited bleeding disorder
• It was first described in 1926 by Erik Von Willebrand who named it ״pseudohaemophilia״
• It was later discovered after many years that there is a factor in the plasma that corrects this bleeding disorder in the affected individuals.
• The factor was then named after Von Willebrand as Von Willebrand factor (VWF)

INTRODUCTION

• Von Willebrand factor is an important component of haemostasis
• Abnormality in function or deficiency of Von Willebrand factor results in Von Willebrand disease
• Von Willebrand factor gene (VWF gene) is located on the short arm of chromosome 12
• VWF is synthesized in the megakaryocyte and the endothelial cells
• After biosynthesis VWF is assembled into multimers and is stored in α (alpha)-granules of platelets and the Weibel-Palade bodies in the endothelial cells

INTRODUCTION

• VWF mediates platelet adhesion and aggregation
• VWF carries and protects factor VIII (FVIII) from premature degradation
• Aside carrying and protecting factor VIII from premature destruction, once VWF binds to factor VIII, the bound VWF-FVIII moves to cells or sites where they can more readily be involved in promoting blood coagulation
• VWF adheres to collagen types and may play a role in inflammation
• VWF is an acute phase reactant to injury and is increased in inflammation, pregnancy and neoplasia

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CAUSES OF VWD

• VWD can be inherited or acquired
• The inherited VWD is autosomal dominant in nature
• Mutation of the VWF gene mutation is identified in some cases and it is found that cases with mutation tend to be more severe and highly inheritable
• Missense mutations at the various domains of the VWF accounts for types 1,2A,2B,2M and 2N VWD
• Acquired VWD is rare, however it is caused by various mechanisms that result in rapid degradation or clearance of VWF

VWD CLASSIFICATION

• VWD is classified into 3 types (types 1,2 and 3)
• VWD types 1 and 3 are characterized by quantitative deficiency of functionally normal VWF
• VWD type 1 is due to partial quantitative deficiency of VWF in contrast to VWD type 3 where there is complete deficiency of VWF

VWD CLASSIFICATION

• Type 2 VWD is due to functional abnormality of VWF and it is further classified into four subtypes:
• Type 2A
• Type 2B
• Type 2M and 2N respectively

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VWD CLASSIFICATION

• VWD type 1 is the most common variant of VWD and accounts for about 70% or more of VWD with incidence of 1-30 per 1000
• Inheritance is autosomal dominant , the mechanism underlying VWD type 1 is reduced synthesis of normal VWF, decreased release of VWF from the cells as well as increased clearance of VWF
• There is reduced factor VIII activity in addition to decreased ristocetin induced platelet aggregation

VWD CLASSIFICATION

• VWD type 3 is characterized by complete absence of VWF
• It is inherited as autosomal recessive with prevalence of 1-5 per 1000,000
• Ristocetin induced platelet aggregation is absent, and there is also marked decrease in factor VIII activity

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VWD CLASSIFICATION

• Type 2A VWD is due to a qualitative deficiency of high molecular weight VWF multimers, there is decreased platelet adhesion and enhanced proteolysis by ADAMTS13
• VWF retains its capability to bind factor VIII in VWD type 2A
• Ristocetin induced platelet adhesion is decreased and high molecular weight VWF multimers are absent

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VWD CLASSIFICATION

• VWD type 2B is a qualitative VWF abnormality characterized by increased affinity for glycoprotein Ib (GPIb)
• Ristocetin induced platelet aggregation is increased even with low concentrations of ristocetin
• It is not a common variant, it constitutes less than 5% of clinical VWD
• There is normal VWF-FVIII binding and decreased to absent high molecular weight multimers

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VWD CLASSIFICATION

• VWD type 2M is a qualitative defect of VWF
• VWD TYPE 2M is rare, inheritance is autosomal dominant and is characterized by the presence of high molecular weight VWF multimers and normal VWF-FVIII binding with decreased VWF-platelet interaction
• Platelet aggregation to ristocetin is decreased

VWD CLASSIFICATION

• VWD type 2N is autosomal recessive disease, rare and results from a qualitative defect in VWF
• It is characterized by normal high molecular weight VWF multimers and reduced VWF-FVIII binding as well as decreased FVIII activity
• There is normal platelet function and platelet aggregation to ristocetin is normal

ROLE OF VWF IN PLATELET ADHESION AND AGGREGATION

• In an intact, uninjured vessel there is no spontaneous interaction between VWF and platelet while in circulation
• Following vessel wall injury, VWF adheres to the injured vessel and because of higher shear stress it is subjected to, the platelet binding site in the VWF is exposed and it now interacts with receptor glycoprotein 1bα (GPIbα), GPIIb and GPIIIa
• Activated platelets undergo conformational change and recruits more of its fellow platelets leading to platelet aggregation and formation of platelet plug to arrest bleeding at the site of vessel injury

CLINICAL FEATURES OF VON WILLEBRAND DISEASE

• Von Willebrand disease presentations and symptoms vary among patients
• VWD symptoms may depend on the level of residual Von Willebrand factor activity, the disease subtype, age, sex and the ABO blood group of the patient
• Women are worse affected than men at a given VWF level

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CLINICAL FEATURES OF VON WILLEBRAND DISEASE

• Mucous membrane bleeding is the most common symptom and may present as:
• Bruising
• Epistaxis
• Gingival bleeding
• Prolonged bleeding after minor cuts
• Menorrhagia in women
• Postpartum haemorrhage

CLINICAL FEATURES OF VON WILLEBRAND DISEASE

• Gastrointestinal bleeding
• Excessive bleeding after bruises, superficial cuts and abrasions as well as after trauma and surgical procedures e.g dental extraction are typical findings
• Bleeding into the joints (haemarthroses) is not a common finding as it is in haemophilia but may be seen in VWD type 3
• Severely affected patients may present with arthropathy and joint deformity

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LABORATORY FINDINGS IN VON WILLEBRAND DISEASE

• Full blood count (FBC): shows normal white blood cell count, haematocrit may be normal or reduced depending on the frequency of bleeding episodes and the severity of bleeding
• Red blood cell indices levels will be determined by the degree of bleeding and frequency of bleeding episodes
• Reticulocyte count may be increased in cases of severe bleeding or remain normal

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LABORATORY FINDINGS IN VON WILLEBRAND DISEASE

• Platelet count is normal except in VWD type 2B where there is thrombocytopenia
• Coagulation studies e.g activated partial thromboplastin time test (APTT) may be prolonged
• FVIII level may be low when FVIII-VWF binding assay is done
• Platelet function analysis/aggregometry-100 test is abnormal (PFA-100 test)

LABORATORY FINDINGS IN VON WILLEBRAND DISEASE

• Defective platelet aggregation when patients plasma is reacted with ristocetin (VWF:Rco) but with normal aggregation to adenosine diphosphate (ADP), thrombin and adrenaline
• High molecular weight multimers analysis may be reduced, absent or normal depending on the VWD subtype
• Von Willebrand factor collagen binding function (VWF:CB) is reduced

DIAGNOSIS OF VWD

• Diagnosis of VWD is based on a personal history of bleeding, a family history of bleeding, or both, in combination with abnormal laboratory test results of VWF, factor VIII or both
• The nature of bleeding may also serve as a rough guide to which type of bleeding disorder it may be

TREATMENT OF VWD

• Treatment of VWD is aimed at bleeding control or prevention
• This is achieved by ensuring normal VWF and FVIII levels either as corrective therapeutic or prophylactic measure
• Desmopressin in the dose of about 0.3μg given intravenous or subcutaneous and a dose of 300μg intranasal should be given to increase the endgenous VWF levels in addition to tranexamic acid during bleeding episodes
• Desmopressin is known to cause release of VWF from the endothelial cells 30min after intravenous infusion

TREATMENT OF VWD

• Infusion of high-purity VWF concentrate in those with very low VWF levels is also given and in acute bleeding episode or surgery both of which require immediate normalization of VWF and factor VIII levels additional factor VIII concentrate should be administered together with high-purity VWF concentrate

TREATMENT OF VWD

• Recombinant VWF/FVIII concentrates help reduce risk of viral infection and are better options where licensed or approved
• For mild bleeding, antifbrinolytic agents like tranexamic acid, ε-aminocaproic acid and local measures to arrest bleeding should be given

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TREATMENT OF VWD

• VWF/FVIII concentrate is recommended as a treatment modality in type 3 VWD where there is complete deficiency of VWF
• To prevent or minimize bleeding during major surgery the factor levels (VWF, FVIII) should be maintained above 100 IU per deciliter
• In women with type 2 VWD, at the third trimester gestational period with VWF or FVIII level below 50 IU per deciliter, it is advised that they be treated with VWF/FVIII concentrate to levels higher than 100 IU to avoid postpartum haemorrhage

TREATMENT OF VWD

• In recalcitrant VWD that neither responds to VWF concentrate nor FVIII concentrate in combination to VWF concentrate, platelet concentrate should be transfused, and in type 2B where there is thrombocytopenia severe enough to cause bleeding

ACQUIRED VON WILLEBRAND SYNDROMD(AVWS)

• It is acquired, not common and presents late in life with bleeding
• No previous history of bleeding in patients or the family
• AVWS is usually due to an underlying disease condition e.g hypothyroidism, autoimmune disease, B-cell disorders, amyloidosis, myeloproliferative neoplasms, drugs e.g ciprofloxacin, in which decrease synthesis of VWF, autoantibodies to VWF, increase clearance of VWF may be the underlying mechanisms

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ACQUIRED VON WILLEBRAND SYNDROMD(AVWS)

• Distinguishing AVWS from VWD in the clinical setting is difficult but diagnosis is based on the late onset of bleeding history in the patient as well as lack of family history of bleeding and the presence of an underlying medical condition
• There may be reduction of the high molecular weight multimers

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ACQUIRED VON WILLEBRAND SYNDROMD(AVWS)

• Treatment of the underlying medical condition improves VWF levels and bleeding symptoms in patients with AVWS
• In patients whose VWF level and bleeding do not respond to treatment of the underlying medical disorder, treatments involving intravenous gamma globulin, glucocorticoids, desmopressin, rituximab, plasma exchange and VWF-FVIII concentrate be given