Pathophysiology
Summary
Von Willebrand disease is the most common inherited coagulopathy and is characterized by a deficiency in von Willebrand factor (vWf). Von Willebrand factor is found in the sub-endothelium of arteries and veins and is crucial for blood clotting. When endothelial injury occurs, vWf aids in platelet aggregation by linking glycoprotein 1b (GP1b) on platelets to exposed collagen on the endothelium. A deficiency in vWf results in prolonged bleeding time and symptoms like easy bruising, epistaxis, prolonged skin bleeding, & heavy menstrual bleeding in females.
In von Willebrand disease, both platelet function and the intrinsic coagulation pathway are affected. Specifically, reduced levels of von Willebrand factor (vWf) increase the susceptibility of factor VIII to degradation, thereby shortening its half-life. As a result, the activity of the intrinsic coagulation pathway is diminished, manifesting as a prolonged activated partial thromboplastin time (aPTT).
The ristocetin test assesses vWf's ability to mediate platelet aggregation by adding ristocetin to a blood sample, activating GP1b receptors on platelets. In von Willebrand disease, this test is negative due to low vWf levels, resulting in decreased GP1b receptor binding and reduced platelet aggregation.
The synthetic vasopressin analog desmopressin (DDAVP) stimulates endothelial cells to release stored vWf and can be used for treatment. For severe hemorrhages, cryoprecipitate is employed.
Acquired von Willebrand disease can be due to aortic stenosis, which degrades vWf multimers, or coexist with angiodysplasia, causing persistent gastrointestinal bleeding.
Hemophilia represents a group of inherited coagulopathies predominantly affecting the intrinsic coagulation pathway. Two main types of this disorder are hemophilia A and hemophilia B, each distinguished by the deficiency of specific clotting factors.
Hemophilia A is an X-linked recessive disorder caused by a factor VIII deficiency, affecting both the intrinsic and common coagulation pathways by reducing factor X activation. Clinically, the disorder leads to ‘coagulopathic' bleeding, commonly manifesting as hemarthrosis, as well as intramuscular and intracranial hemorrhages. Even dental procedures can trigger bleeding episodes. Diagnosis is confirmed by a prolonged aPTT, indicative of intrinsic pathway disruption. Desmopressin can also be used to treat hemophilia A, as it induces platelets and endothelial cells to release factor VII.
Hemophilia B is similar to hemophilia A but is caused by a deficiency in factor IX. Hemophilia B is also an X-linked recessive disorder that affects the intrinsic pathway, leading to a prolonged aPTT and ‘coagulopathic’ bleeding similar to hemophilia A.
Acquired hemophilia is a phenomenon that can occur in conditions including SLE, pregnancy, postpartum, rheumatoid arthritis, and drugs like penicillin. These conditions promote the formation of anti-factor VIII antibodies that accelerate the clearance of factor VIII, resulting in the clinical manifestations of hemophilia. Diagnosis involves a mixing study, where normal serum is combined with the patient's serum. If aPPT remains prolonged, this suggests factor VII inactivation due to antibodies. Treatment includes corticosteroids to counteract the antibody-mediated degradation of factor VIII.
Lesson Outline
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FAQs
Von Willebrand disease is the most prevalent inherited coagulopathy, characterized by a quantitative deficiency of von Willebrand factor (vWF). This deficiency leads to impaired platelet function and a prolonged bleeding time. vWF is located in the sub-endothelium and becomes exposed during endothelial injury. It plays a crucial role in platelet aggregation by linking glycoprotein 1b on the platelet surface to exposed collagen on the endothelium, thereby aiding in the coagulation process.
Individuals with von Willebrand disease often experience mild ‘platelet-like' bleeding symptoms. These can include easy bruising, frequent nosebleeds (epistaxis), prolonged bleeding from minor skin injuries, and heavy menstrual bleeding in women. Von Willebrand presents with a prolonged activated partial thromboplastin time (aPTT) due to decreased levels of factor VIII, which impairs the intrinsic coagulation pathway.
The ristocetin test is a standard diagnostic tool for von Willebrand disease. In this test, ristocetin is added to a blood sample to activate GP1b receptors on platelets. These receptors then bind to von Willebrand factor multimers, leading to platelet aggregation. A negative result, characterized by decreased platelet aggregation due to low levels of von Willebrand factor, is indicative of the disease.
Desmopressin, a synthetic analog of vasopressin, is commonly used to treat von Willebrand disease. It stimulates endothelial cells to release stored von Willebrand factor, thereby improving coagulation. For severe hemorrhage related to the disease, cryoprecipitate can be administered as a treatment option.
Although all three conditions are inherited coagulopathies, they result from different deficiencies and have distinct inheritance patterns. Von Willebrand disease arises from a deficiency in von Willebrand factor and is an autosomal dominant disorder. Hemophilia A and B are due to deficiencies in factor VIII and factor IX, respectively, and follow an X-linked recessive inheritance pattern. These deficiencies affect different parts of the coagulation pathway, leading to varying symptoms. For instance, hemophilia A frequently causes bleeding in joints, a symptom less commonly seen in von Willebrand disease.
