Page 1: Introduction to Thrombotic Disorders

  • Thrombotic (Clotting) Disorders: Two categories—Primary and Secondary Hypercoagulability.

  • Presenter: Phil Jones, DO

  • Context: Part of the Hematology and Circulatory Course.

Page 2: Learning Objectives

  • Familiarity with laboratory testing methods:

    • Emphasis on the evaluation of secondary hemostasis (coagulation studies).

    • Ability to interpret laboratory tests.

  • Description of thrombotic disorders:

    • Factor V Leiden

    • Heparin-induced Thrombocytopenia (HIT)

    • Antiphospholipid Syndrome

    • Disseminated Intravascular Coagulation (DIC)

  • Bleeding patterns:

    • Differentiate between platelet disorders vs. coagulation factor deficiencies.

Page 3: Basic Definitions

  • Hemostasis: Process of blood clot formation at sites of vascular injury.

    • Essential for life; dysregulation leads to various disorders.

  • Types of disorders:

    • Hemorrhagic (Bleeding) Disorders: Excessive bleeding.

    • Thrombotic (Clotting) Disorders: Formation of thrombosis within intact blood vessels.

    • Note: Some disorders blur these lines, e.g., DIC.

Page 4: Hemodynamic Disorders Overview

  • Vasoconstriction: Reduces blood flow.

  • Primary Hemostasis: Formation of platelet plug via vWF and collagen adhesion.

  • Secondary Hemostasis:

    • Involves deposition of fibrin through tissue factor and factor VII activation.

    • Leads to clotting cascade resulting in thrombin formation and fibrinogen cleavage.

  • Thrombus formation: Concludes with antithrombotic events.

Page 5: Regulation of Hemostasis

  • Normal conditions maintain a balance between the formation and dissolution of hemostatic plugs.

  • Coagulation is limited by:

    • Fibrinolytic Cascade: Limits clot size and promotes dissolution via plasmin, impacting fibrin polymerization.

    • Dilution: Blood flow washes out coagulation factors.

    • Need for negatively charged phospholipid, provided by activated platelets.

Page 6: Fibrinolytic System

  • Illustration detailing plasminogen activators and inhibitors involved in fibrinolysis, contributing to hemostatic balance.

Page 7: Anticoagulation Systems

  • Major Anticoagulant Systems:

    • Protein C/S System: Reduces thrombin, stimulates fibrinolysis, initiates inflammation.

    • Plasma Serine Protease Inhibitor System: Antithrombin (AT III) inhibits factors IIa and Xa, interacts with heparin.

    • TFPI: Tissue factor pathway inhibitor.

Page 8: Natural Inhibitors of Coagulation

  • Overview of natural anticoagulants affecting coagulation and fibrinolysis.

Page 9: Thrombosis

  • Definition: Abnormal clotting characterized by Virchow's triad.

    • Components include:

      • Endothelial injury

      • Stasis or turbulent blood flow

      • Hypercoagulability

  • Importance of Endothelial Integrity: Promotes normal blood flow and prevents thrombosis.

Page 10: Endothelial Injury

  • Normal Endothelial Functions:

    • Platelet inhibition, anticoagulant effects, fibrinolytic effects.

  • Consequences of Injury:

    • Exposes vWF and tissue factor leading to thrombus formation by activating platelets, reducing anticoagulant properties.

Page 11: Alterations to Normal Blood Flow

  • Turbulence:

    • Arterial/cardiac issues promoting endothelial injury.

  • Stasis:

    • Venous issues leading to thrombus formation.

  • Impacts: Endothelial activation and increased coagulation activity.

    • Examples include ulcerated atherosclerotic plaques, aneurysms.

Page 12: Hypercoagulability (Thrombophilia)

  • Definition: Disorders that predispose individuals to thrombosis.

  • Primary Factors (Genetic): Abnormalities in coagulation or fibrinolytic pathways, including Factor V Leiden and prothrombin mutations.

  • Secondary Factors (Acquired): Often multifactorial, including conditions like vascular injury and hyperestrogenic states.

Page 13: Factor V Leiden

  • Mutation prevalent in 2-15% of Caucasians resulting in increased thromboembolic events.

  • Mechanism: Resistance to cleavage by Protein C.

    • Heterozygotes have a 5x risk; homozygotes have a 50x risk for venous thrombosis.

Page 14: Prothrombin Gene Mutation

  • Mutation leading to a 3-fold increase in prothrombin levels and associated venous thrombosis risk.

Page 15: Antithrombin Deficiency

  • Can be hereditary or acquired, associated with conditions such as DVT and PE.

  • Genetic and acquired deficiencies of Protein C/S also entail increased thrombosis risk.

Page 16: Risk Profiles in Hypercoagulability

  • Elevated risks when primary hypercoagulability factors are accompanied by acquired triggers (e.g., pregnancy, bed rest).

  • Important to consider hereditary factors in patients under 50 presenting with thrombotic events.

Page 17: Secondary Hypercoagulability Overview

  • Secondary causes include various acquired conditions and often multifactorial.

  • Examples include HIT, antiphospholipid antibodies, and DIC.

Page 18: Heparin-Induced Thrombocytopenia (HIT)

  • Pathogenesis involves antibodies against PF4 complexes, leading to thrombosis rather than bleeding.

  • Types of HIT:

    • Type I: Non-immune, transient thrombocytopenia.

    • Type II: Immune-mediated, life-threatening.

Page 19: Diagnostic Mechanism for HIT

  • HIT corresponds with development of antibodies leading to paradoxical thrombosis.

Page 20: Pathophysiology of HIT

  • Antibodies bind to PF4 and cause further platelet activation despite thrombocytopenia, resulting in a prothrombotic state.

Page 21: Antiphospholipid Syndrome (APS)

  • Autoimmune disorder causing thrombosis with presence of antiphospholipid antibodies.

  • Clinical manifestations include recurrent thrombosis and miscarriages.

Page 22: Classification of Antiphospholipid Syndrome

  • Primary APS: Hypercoagulability without autoimmune evidence.

  • Secondary APS: Associated with autoimmune conditions like SLE, showing prolonged PTT.

Page 23: Disseminated Intravascular Coagulation (DIC)

  • Acute or chronic thrombohemorrhagic disorder characterized by excessive coagulation activation.

  • Leads to consumption of platelets and clotting factors and triggers widespread fibrinolysis.

Page 24: Etiology of DIC

  • Initiated by exposure to tissue factor; can result from various sources, leading to widespread fibrin thrombi.

Page 25: Laboratory Findings in DIC

  • Typically shows prolonged PT and PTT, thrombocytopenia, and elevated D-dimer levels.

Page 26: Morphological Features of DIC

  • Thrombi can affect multiple organs, causing issues like ischemia and hemorrhage.

  • Often associated with pregnancy-related complications, malignancy, and severe trauma.

Page 27: Summary of Thrombotic Disorders

  • Key disorders to know: Factor V Leiden, HIT, APS, DIC.

  • Understand pathogenesis, clinical presentation, laboratory findings, and associated clinical conditions.

Page 28: Study Guide - Essential Disorders

  • Emphasis on comprehensive understanding of clinical presentation, laboratory characteristics, and risk factors for thrombotic disorders.