Thrombotic (Clotting) Disorders: Two categories—Primary and Secondary Hypercoagulability.
Presenter: Phil Jones, DO
Context: Part of the Hematology and Circulatory Course.
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.
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.
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.
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.
Illustration detailing plasminogen activators and inhibitors involved in fibrinolysis, contributing to hemostatic balance.
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.
Overview of natural anticoagulants affecting coagulation and fibrinolysis.
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.
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.
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.
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.
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.
Mutation leading to a 3-fold increase in prothrombin levels and associated venous thrombosis risk.
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.
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.
Secondary causes include various acquired conditions and often multifactorial.
Examples include HIT, antiphospholipid antibodies, and DIC.
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.
HIT corresponds with development of antibodies leading to paradoxical thrombosis.
Antibodies bind to PF4 and cause further platelet activation despite thrombocytopenia, resulting in a prothrombotic state.
Autoimmune disorder causing thrombosis with presence of antiphospholipid antibodies.
Clinical manifestations include recurrent thrombosis and miscarriages.
Primary APS: Hypercoagulability without autoimmune evidence.
Secondary APS: Associated with autoimmune conditions like SLE, showing prolonged PTT.
Acute or chronic thrombohemorrhagic disorder characterized by excessive coagulation activation.
Leads to consumption of platelets and clotting factors and triggers widespread fibrinolysis.
Initiated by exposure to tissue factor; can result from various sources, leading to widespread fibrin thrombi.
Typically shows prolonged PT and PTT, thrombocytopenia, and elevated D-dimer levels.
Thrombi can affect multiple organs, causing issues like ischemia and hemorrhage.
Often associated with pregnancy-related complications, malignancy, and severe trauma.
Key disorders to know: Factor V Leiden, HIT, APS, DIC.
Understand pathogenesis, clinical presentation, laboratory findings, and associated clinical conditions.
Emphasis on comprehensive understanding of clinical presentation, laboratory characteristics, and risk factors for thrombotic disorders.