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Blood Clotting and Disorders

Overview of Blood

  • Composition: Consists of ~50% blood cells (erythrocytes, leukocytes, platelets) and ~50% plasma.

    • Platelets (Thrombocytes): Mediate clotting, formed from megakaryocytes in bone marrow. Normal concentration: 150,000-300,000/\mu L. Contain contractile proteins (actin, myosin, thrombosthenin), enzymes for prostaglandins/thromboxane A2 (TXA_2), fibrin-stabilizing factor, PDGF.

    • Platelet Receptors: Glycoprotein Ib (GPIb) for adhesion; Glycoprotein IIb/IIIa (GPIIb/IIIa) for fibrinogen (aggregation).

    • Platelet Granules: Dense (\delta) granules (calcium, ATP/ADP, serotonin); Alpha (\alpha) granules (fibrinogen, vWF, plasminogen, PDGF, factors V & VIII).

  • Plasma: Liquid portion (90% water, 10% solutes), including plasma proteins (immunoglobulins, albumin, apolipoproteins, transferrin, clotting proteins like fibrinogen, prothrombin).

  • Endothelium: Intact endothelium prevents platelet activation and clotting by:

    • Smooth surface, glycocalyx (proteoglycans), thrombomodulin (binds thrombin, activates protein C), proPGI2 and NO release, heparin sulfate (activates anti-thrombin III), tissue plasminogen activator (tPA).

  • Clotting Factors: >50 substances; pro-coagulants (proteins, mostly liver-produced, some require Vitamin K) and anti-coagulants. Balance determines coagulation.

Blood Clotting (Hemostasis)

  • Hemostasis: Cessation of blood loss from damaged vessels; depends on vessel wall integrity, adequate and functional platelets, adequate and functional clotting factors, and a functioning fibrinolytic pathway.

  • Stages of Hemostasis:

    • Primary Hemostasis: Vascular constriction and platelet plug formation.

      • Vascular Constriction: Due to nervous reflexes, local mediators (TXA2), and decreased vasodilator production (NO, PGI2).

      • Platelet Plug: Platelets adhere to damaged vessels (via collagen/vWF), release mediators (ADP, TXA_2) to activate and aggregate more platelets, forming a temporary plug.

    • Secondary Hemostasis (Clot Formation/Coagulation): Blood clotting using intrinsic and extrinsic pathways convergent to a common pathway.

      • Pathways: Involved intravascular and extravascular elements, platelets, active proteins/factors.

      • Common Pathway: Prothrombin converted to thrombin; thrombin converts fibrinogen to fibrin monomers; fibrin polymerizes to insoluble meshwork, forming a stable clot (thrombus).

        • Ca^{++} ions are essential for most steps in the clotting cascade.

        • Prothrombin: Unstable plasma protein from liver; requires Vitamin K.

        • Fibrinogen: Large protein from liver; converted to fibrin by thrombin.

        • Fibrin-stabilizing factor (Factor XIIIa): Strengthens the fibrin meshwork by covalent bonding.

      • Fibrinolysis (Clot Lysis): Plasminogen (trapped in clot) is converted to plasmin by tPA; plasmin digests fibrin threads and other clotting factors. \alpha_2-antiplasmin inactivates plasmin.

  • Homeostasis Maintenance: Delicate balance between pro-coagulants (Vitamin K) and anti-coagulants (PGI_2, NO, thrombomodulin, protein C, tPA, antithrombin III, heparin).

Bleeding Disorders

  • Common Conditions of Impaired Hemostasis:

    • Vitamin K Deficiency: Leads to insufficient prothrombin, factors VII, IX, X, and protein C, increasing bleeding risk. Causes: malnutrition, malabsorption, antibiotic therapy, biliary obstruction.

    • Hemophilia: Inherited, X-linked disorders, primarily affecting males.

      • Hemophilia A: Deficiency of Factor VIII (~85% of cases).

      • Hemophilia B: Deficiency of Factor IX (\approx 15\% of cases).

      • Characterized by abnormal bleeding (mild to severe), e.g., hemarthrosis.

    • Thrombocytopenia: Deficiency in platelet number or function (<150,000/\mu L). Causes bleeding from small vessels, small puncture hemorrhages (thrombocytopenic purpura). Lethal at \% \leq 10,000 counts.

    • Idiopathic Thrombocytopenic Purpura (ITP): Autoimmune destruction of platelets. Acute (children post-viral), Chronic (adults related to immune disorders).

    • Thrombocytosis: High platelet counts (>400,000/\mu L). Primary (myeloproliferative disease) or Secondary (stress, exercise, hemorrhage).

    • Von Willebrand Factor (vWF) Related Disorders: vWF anchors platelets to subendothelium and carries Factor VIII. Deficiency leads to prolonged bleeding from skin/mucosa.

    • Bernard-Soulier Syndrome: Lack of platelet receptor glycoprotein Ib/IX, impairing adhesion to vWF.

    • Glanzmann's Thrombasthenia: Deficiency in glycoprotein IIb/IIIa complex, preventing fibrinogen binding and platelet aggregation.

  • Signs/Symptoms of Bleeding Disorders:

    • Petechiae: Small, pinpoint red/purple hemorrhages (primary hemostasis defects).

    • Ecchymosis: Large bruises (>3mm) (secondary hemostasis defects).

    • Purpura: Purple spots (3-10mm) from bleeding under skin.

    • Hematoma: Localized blood collection outside vessels.

    • Hemarthrosis: Bleeding into joint space.

  • Inappropriate Coagulation (Thromboembolic Conditions):

    • Disseminated Intravascular Coagulation (DIC): Systemic activation of coagulation leading to widespread microclot formation (thrombosis) and subsequent depletion of clotting factors and platelets, causing secondary hemorrhage (bleeding).

      • Triggered by trauma, sepsis, malignancy. Can lead to organ failure and circulatory shock.

    • Thrombus: Abnormal clot forming in a blood vessel.

    • Embolus: A free-flowing thrombus or other substance (tissue, air, fat, etc.) that can circulate and block vessels (embolism).

    • Virchow's Triad for thrombus formation: Endothelial injury, sluggish blood flow, increased coagulability.

  • Bleeding Disorders Caused by Other Diseases:

    • Vascular Wall Disorders: Fragility due to vessel damage or abnormal formation (e.g., scurvy-Vitamin C deficiency, Cushing's syndrome, geriatric atrophy).

    • Liver Disease: Impairs synthesis of clotting factors, inhibitors, and affects fibrinolytic system; can also lead to thrombocytopenia and reduced Vitamin K effectiveness.

  • Medications (Anticoagulants):

    • Heparin: Increases effectiveness of antithrombin III; rapid effect.

    • Warfarin: Blocks Vitamin K-dependent synthesis of clotting factors (prothrombin, VII, IX, X).

    • Antiplatelet Drugs: Inhibit platelet aggregation.

Blood Coagulation Tests

  • Bleeding Time: Assesses platelet count and function. Normal: 2-8 min.

  • Clotting Time: Measures clotting process. Normal: 6-10 min.

  • Prothrombin Time (PT) and International Normalized Ratio (INR): Indicates prothrombin concentration; INR standardizes PT measurements.