Von Willebrand Disease Dr. Mohamed Haseen Basha Assistant professor ( Paediatrics) Faculty of Medicine Al Maarefa College of Science and Technology

Physiology of Hemostasis As a result of injury to the blood vessel endothelium, three events take place simultaneously: Vasoconstriction (vascular phase) Platelet plug formation (primary hemostatic mechanism—platelet phase) Fibrin thrombus formation (initiation, amplification, and propagation phases)

Phases of Hemostasis Primary Hemostasis Arteriolar vasoconstriction Formation of platelet plug Secondary Hemostasis Activation of coagulation cascade Formation of permanent fibrin plug

Primary Hemostatic Mechanism

Primary Hemostatic Mechanism (Platelet Phase) This mechanism leads to the formation of a reversible aggregate of platelets: a temporary hemostatic plug. Endothelial injury exposes von Willebrand factor and collagen from the subendothelial matrix to flowing blood and shear forces. Plasma vWF binds to the exposed collagen, uncoils its structure, and, in synergy with collagen, supports the adhesion of platelets.

Initially the vWF interacts with the GPIb platelet receptor, tethering the platelets. platelets adhere and become activated with a resulting release of platelet alpha and dense granule contents. Platelet activation results in a conformational change in the α11bβ3 receptor, activating it and enhancing its avidity for von Willebrand factor, for vessel wall ligands, and for fibrinogen. The enhanced avidity for von Willebrand factor and fibrinogen mediates platelet-to-platelet interactions, which eventually lead to platelet plug formation.

Von Willebrand Disease von Willebrand disease (VWD) is the most common inherited bleeding disorder, with an estimated prevalence cited at 1 : 100 to 1 : 10,000. Patients with VWD typically present with mucosal bleeding. Inherited VWD is caused by genetic mutations that lead to decreased production OR impaired function of Von Willebrand Factor (VWF) Acquired VWD is most commonly associated with immunoproliferative cancer and Autoimmune Disease ( SLE) A family history of either VWD or bleeding symptoms and confirmatory laboratory testing are also required for the diagnosis of VWD.

Von Willebrand’s Factor : is a critical protein in blood clotting. vWF is synthesized in endothelial cells as a monomer that is subsequently made into multimers. These VWF multimers form an adhesive bridge between platelets and injured vascular epithelium. They also form a bridge between adjacent platelets allowing them to bind together and effectively form a platelet plug at sites of endothelial injury. VWF additionally functions as a carrier for factor VIII and it also protects factor VIII from being rapidly broken down thereby extending its half life. Therefore VWF is also extremely important in normal Fibrin clot formation.

Pathophysiology VWD is caused by a defect in von Willebrand factor (VWF) and has several functions in coagulation. First, VWF serves to tether platelets to injured sub endothelium via binding sites for platelets and for collagen. Second, VWF serves as a carrier protein for factor VIII (FVIII), protecting FVIII from degradation in plasma. VWF is stored in endothelial cells and in platelet Weibel-Palade bodies and circulates as a large multimeric glycoprotein. Shear stress induces a conformational change in VWF that facilitates its ability to bind platelets through a binding site on platelet glycoprotein Ib (GPIb). This enables VWF to recruit platelets to the site of clot formation, a function that is dependent on the high-molecular-weight multimer forms of VWF.

Von Willebrand's factor functions as an adhesion bridge between subendothelial collagen and the GpIb platelet receptor. Aggregation involves linking platelets via fibrinogen bridges bound to the platelet GpIIb-IIIa receptors.

Classification Type 1 Partial quantitative deficiency of vWF (70% of cases) Mild-moderate disease Type 2 Qualitative deficiency of vWF (25% of cases ) Mild to moderate disease Type 2A ↓vWF-dependent platelet adhesion with selective deficiency of high molecular weight vWF multimers Type 2B Increased vWF affinity for platelet GPlb; ± ↓platelet numbers Type 2M ↓vWF-dependent platelet adhesion without selective deficiency of high molecular weight vWF multimers Type 2N Markedly decreased vWF binding affinity for FVIII Type 3 Total or near total quantitative deficiency of vWF (5% of cases ) Severe disease

Clinical Presentation Common symptoms of VWD are: • Easy bruising • Bleeding from nose and gums • Prolonged bleeding from skin lacerations • Bleeding from the gums when baby teeth fall out or after tooth extractions • Heavy or prolonged bleeding during menstruation, called menorrhagia.

In children, Symptoms of VWD can begin at any age. The signs are: • bruises from minor bumps • nose bleeds • prolonged bleeding from minor cuts. In cases of severe Type 3 VWD, bleeding can occur in newborns, especially from the umbilical cord and at the time of circumcision. These types of bleeding can also occur with Types 1 and 2 VWD, but only in rare cases.

Lab testing for VWD

VWD Classification

Von Willebrand Disease Testing Condition vWF:RCo (%) vWF:Ag (%) F VIII (%) Ratio of vWF: RCo/vWF:Ag Result Interpretation Normal 51-215 52-214 56-191 >0.5-0.7 Type 1 <30 ↓ or N Partial quantitative deficiency of vWF Type 2A 30-200 < 0.5-0.7 ↓vWF-dependent platelet adhesion with selective deficiency of high molecular weight vWF multimers Type 2B Usually Increased vWF affinity for platelet GPlb; ± ↓platelet numbers Type 2M ↓vWF-dependent platelet adhesion without selective deficiency of high molecular weight vWF multimers Type 2N ↓↓↓ > 0.5-0.7 Markedly decreased vWF binding affinity for FVIII Type 3 <10 N/A Total quantitative deficiency of vWF

VWD Treatment

Stimate: Desmopressin Acetate 1.5 mg/mL

Clinical characteristic Platelet defect Clotting factor deficiency Site of bleeding Skin, mucous membranes (gingivae, nares, GI and genitourinary tracts) Deep in soft tissues (joints, muscles) Bleeding after minor cuts Yes Not usually Petechiae Present Absent Ecchymoses Small, superficial Large, palpable Hemarthroses, muscle hematomas Rare Common Bleeding after surgery Immediate, mild Delayed, severe