von Willebrand’s Disease

vWD Family of bleeding disorders Family of bleeding disorders Caused by a deficiency or an abnormality of von Willebrand Factor Caused by a deficiency or an abnormality of von Willebrand Factor VWF gene : short arm of chromosome 12 VWF gene : short arm of chromosome 12

vWF Production Vascular endothelial cells Vascular endothelial cells Megakaryocytes Megakaryocytes Most vWF is secreted Most vWF is secreted Some vWF is stored Some vWF is stored Weibel-Palade bodies in endothelial cells Weibel-Palade bodies in endothelial cells Alpha granules of platelets Alpha granules of platelets Constitutive and stimulus- induced pathways Constitutive and stimulus- induced pathways Release stimuli (EC) Thrombin Histamine Fibrin C5b-9 (complement membrane attack complex) Release stimuli (platelets) Thrombin ADP Collagen

vWF Function Adhesion Mediates the adhesion of platelets to sites of vascular injury (subendothelium) Mediates platelet to platelet interaction Binds GPIb and GPIIb-IIIa on activated platelets Stabilizes the hemostatic plug against shear forces

vW Factor Functions in Hemostasis Carrier protein for Factor VIII (FVIII) Carrier protein for Factor VIII (FVIII) Protects FVIII from proteolytic degradation Protects FVIII from proteolytic degradation Localizes FVIII to the site of vascular injury Localizes FVIII to the site of vascular injury

vWD History 1931: Erik von Willebrand described novel bleeding disorder 1931: Erik von Willebrand described novel bleeding disorder Hereditary pseudohemophilia Hereditary pseudohemophilia Prolonged BT and normal platelet count Prolonged BT and normal platelet count Mucosal bleeding Mucosal bleeding Both sexes affected Both sexes affected 1950s: Prolonged BT associated with reduced FVIII 1970s: Discovery of vWF 1980s: vWF gene cloned

Frequency Most frequent inherited bleeding disorder Most frequent inherited bleeding disorder Autosomal inheritance pattern Autosomal inheritance pattern Males and females are affected equally Males and females are affected equally

vWD Classification  Disease is due to either a quantitative deficiency of vWF or to functional deficiencies of vWF  Due to vWF role as carrier protein for FVIII, inadequate amount of vWF or improperly functioning vWF can lead to a resultant decrease in the available amount of FVIII

vWD Classification 3 major subclasses 3 major subclasses Type I: Partial quantitative deficiency of vWF Type I: Partial quantitative deficiency of vWF Mild-moderate disease Mild-moderate disease 70% 70% Type II: Qualitative deficiency of vWF Type II: Qualitative deficiency of vWF Mild to moderate disease Mild to moderate disease 25% 25% Type III: Total or near total deficiency of vWF Type III: Total or near total deficiency of vWF Severe disease Severe disease 5% 5% Additional subclass Additional subclass Acquired vWD Acquired vWD

Clinical Manifestations Most with the disease have few or no symptoms Most with the disease have few or no symptoms For most with symptoms, it is a mild manageable bleeding disorder with clinically severe hemorrhage only with trauma or surgery For most with symptoms, it is a mild manageable bleeding disorder with clinically severe hemorrhage only with trauma or surgery Types II and III: Bleeding episodes may be severe and potentially life threatening Disease may be more pronounced in females because of menorrhagia Bleeding often worsen by the ingestion of aspirin Severity of symptoms tends to decrease with age due to increasing amounts of vWF

vWD Screening PT PT aPTT aPTT (Bleeding time) (Bleeding time) 1- aPTT: 1. Mildly prolonged in approximately 50% of patients with vWD 2. Normal PTT does not rule out vWD 3. Prolongation is secondary to low levels of FVIII

2-PT: Usually within reference ranges Prolongations of both the PT and the aPTT signal a problem with acquisition of a proper specimen or a disorder other than or in addition to vWD Prolongations of both the PT and the aPTT signal a problem with acquisition of a proper specimen or a disorder other than or in addition to vWD 3-Bleeding time is prolonged. 4-vWF level : When suspected, blood plasma of a patient needs to be investigated for quantitative and qualitative deficiencies of vWF. blood plasmablood plasma

vWD Diagnostic Difficulties vWF levels vary greatly vWF levels vary greatly Physiologic stress Physiologic stress Estrogens Estrogens Growth hormone Growth hormone vWF levels may be normal irregularly in patients with vWD vWF levels may be normal irregularly in patients with vWD Measurements should be repeated to confirm abnormal results Measurements should be repeated to confirm abnormal results Repeating tests at intervals of more than 2 weeks is advisable to confirm or definitively exclude the diagnosis, optimally at a time remote from hemorrhagic events, pregnancy, infections, and strenuous exercise Repeating tests at intervals of more than 2 weeks is advisable to confirm or definitively exclude the diagnosis, optimally at a time remote from hemorrhagic events, pregnancy, infections, and strenuous exercise vWF levels vary with blood type?? vWF levels vary with blood type??

5. vWF Antigen: Quantitative immunoassay or an ELISA using an antibody to vWF 5. vWF Antigen: Quantitative immunoassay or an ELISA using an antibody to vWF 5-Multimer analysis 5-Multimer analysis 6- FVIII activity assay: Factor VIII and vWF levels arc reduced (Factor VIII levels are also performed as factor VIII is bound to vWF which protects the factor VIII from rapid breakdown within the blood. Deficiency of vWF can therefore lead to a reduction in factor VIII levels). 6- FVIII activity assay: Factor VIII and vWF levels arc reduced (Factor VIII levels are also performed as factor VIII is bound to vWF which protects the factor VIII from rapid breakdown within the blood. Deficiency of vWF can therefore lead to a reduction in factor VIII levels).Factor VIIIFactor VIII

Defective platelet function, reduced aggregation with ristocetin, A platelet aggregation assay will show an abnormal response. Mild thrombocytopenin may occur Other tests performed in any patient with bleeding problems are a full blood count (especially platelet counts), thrombin time and fibrinogen level.full blood countplatelet thrombinfibrinogen

vWD Treatment DDAVP DDAVP Cryoprecipitate Cryoprecipitate FVIII concentrate FVIII concentrate

Factor VIII Concentrates Concentrates are purified to reduce the risk of blood- borne disease Concentrates are purified to reduce the risk of blood- borne disease Contain a near-normal complement of high molecular weight vWF multimers Contain a near-normal complement of high molecular weight vWF multimers

vWD Treatment Platelet transfusions Platelet transfusions May be helpful with vWD refractory to other therapies May be helpful with vWD refractory to other therapies Cryoprecipitate Cryoprecipitate Fraction of human plasma Fraction of human plasma Contains both FVIII and vWF Contains both FVIII and vWF Medical and Scientific Advisory council of the National Hemophilia Foundation no longer recommends this treatment method due to its associated risks of infection Medical and Scientific Advisory council of the National Hemophilia Foundation no longer recommends this treatment method due to its associated risks of infection FFP FFP An additional drawback of fresh frozen plasma is the large infusion volume required An additional drawback of fresh frozen plasma is the large infusion volume required

VW DiseaseHaemophilia B Haemophilia A DominantSex-linked Inheritance Mucous membranes, skin cuts, post trauma or operative Muscles, joints, post trauma or operative. Main sites of haemorrhage Normal Platelet count ProlongedNormal Bleeding Time Normal PT Prolonged or normal Prolonged PTT LowNormalLowFactor VIII NormalAbnormalNormalFactor IX ImpairedNormal Restoctin induced platelet aggregation AbnormalNormal Platelet aggregation LowNormal vWF