Advanced Pathophysiology Class Notes: Clotting System & Hematologic Disorders
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University of Utah
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Summary
These class notes from an Advanced Pathophysiology course cover the clotting system, including extrinsic and intrinsic pathways, as well as fibrinolysis. Specific disorders such as Hemophilia A, von Willebrand Disease, Immune Thrombocytopenic Purpura (ITP), Thrombotic Thrombocytopenic Purpura (TTP), and Hemolytic Uremic Syndrome (HUS) are also discussed, outlining their etiologies, clinical consequences and underlying pathophysiologies.
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Review - Clotting System ***Formation of a stable clot is dependent on the clotting system and formation of fibrin*** [Overview of Clotting System] **Extrinsic pathway** Activated by injury to endothelial cells or the tissues surrounding the blood vessels and the release of tissue factor (factor...
Review - Clotting System ***Formation of a stable clot is dependent on the clotting system and formation of fibrin*** [Overview of Clotting System] **Extrinsic pathway** Activated by injury to endothelial cells or the tissues surrounding the blood vessels and the release of tissue factor (factor III) **Intrinsic pathway** Activated by endothelial injury and exposure of subendothelial substances (such as collagen, fibronectin) to Factor XII npo0000d3 *See handout of full clotting system posted on Canvas.* Fibrinolytic System *Promotes clot resolution* XIIa (+ others) activates plasminogen via tissue plasminogen activator (tpA) Plasmin dissolves fibrin End products of plasmin\'s breakdown of fibrin are called fibrin degradation products (FDPs)  Hemophilia A *Deficiency of clotting factor VIII* [Note] Hemophilia B = deficiency of clotting factor IX Hemophilia C = deficiency of clotting factor (XI) [Etiology] X-linked recessive disorder - primarily affects males (1/5000), females are carriers High rate of spontaneous mutations (i.e., not inherited) 10% of female carriers have an increased bleeding tendency [Pathophysiology] Factor VIII deficiency prevents completion of the intrinsic pathway of the clotting cascade Increased risk of bleeding [Clinical Consequences] Prolonged bleeding times Ecchymoses/hematoma formation Hemarthroses - bleeding in the synovial joints Chronic anemia requiring transfusions von Willebrand Disease *Deficiency of von Willebrand factor, caused by multiple known gene defects* [Pathophysiology] *Normal functions of von Willebrand factor (vWf)* Binds to factor VIII and prevents its degradation, therefore promoting the activity of the intrinsic pathway Helps promote platelet aggregation *Deficiency of vWf* Leads to low levels of factor VIII and decreased platelet activity Results in increased risk of bleeding Immune Thrombocytopenic Purpura (ITP) *Immune-mediated platelet consumption* [Types] **Chronic ITP** Most prevalent among females age 20-40 years old **Acute ITP** More prevalent in children - 80% associated with viral illnesses (RSV, CMV, EBV, HIV, rubella, varicella\...) Most prevalent in children \> 3 months, peak incidence 3-5 years Onset of symptoms within 1 to 4 weeks after infection [Pathophysiology] Antibodies (IgG) produced in response to viral infection leads to cross-sensitization of antibodies to circulating platelets with IgG binding to platelets  Enhanced phagocytosis of platelets by WBC in spleen **\ ** **Clinical Consequences** Thrombocytopenia - platelet count can be \< 5000/ul in acute ITP Splenomegaly, lymphadenopathy **Thrombotic Thrombocytopenic Purpura (TTP)** *A rare thrombohemorrhagic disorder that leads to thrombus formation in large arteries and microangiopathic hemolytic anemia* [Pathophysiology] *Cause:* Deficiency of von Willebrand factor-cleaving protease. (also known as ADAMTS13), an enzyme that breaks \'ultra large\' fragments of vWf into smaller fragments. Increased amounts of ultra large fragments of vWf circulate in plasma and stimulate clot formation Etiologies **Inherited - Upshaw-Schulman Syndrome** Defect in the formation of von Willebrand factor-cleaving protease (genetic) **Acquired** *Acquired TTP is associated with various conditions & diseases. In almost all cases, the condition leads to the formation of autoantibodies that target von Willebrand factor-cleaving protease.* Pregnancy (prior to 24 weeks gestation) Autoimmune disease of unknown etiology HIV Bacterial infection (*E. coli, Shigella*), vasculitis Drugs (quinine, cyclosporine, others) [Clinical Consequences] Formation of thrombi in arteries with high shear forces (e.g., carotid, cerebral, & renal arteries) Formation of small blood clots Platelets are consumed in blood clots leading to thrombocytopenia Hemolytic Uremic Syndrome (HUS) *A disorder similar to TTP that is characterized by hemolysis, renal failure, and thrombocytopenia.* [Types/Etiologies] **Childhood HUS** Often occurs after infection with particular strains of E. Coli and release of Shiga-like toxin **Adult HUS** HIV Antiphospholipid syndrome Postpartum renal failure Malignant hypertension Scleroderma Drugs - chemotherapy, immunosuppressive drugs [\ ] [Pathophysiology] *The pathogenesis is not well described for all etiologies.* **Childhood HUS** Bacterial exotoxin damages the glomerular endothelium in the kidneys causing clots to form resulting in renal failure and thrombocytopenia. Also see some inactivation of the vWf-cleaving protease, similar to TTP. **Adult HUS** In some cases, HUS has the same underlying pathophysiology as TTP with increased levels of the ultra-large vWf fragments causing clot formation, although the clots mainly form in the renal arteries. [Clinical Consequences] Thrombotic microangiopathy Microangiopathic hemolytic anemia Acute renal failure Thrombocytopenia
