Platelets and Clotting Factors

Lecture #8: Platelets and Clotting Factors

Thrombocytes

  • Definition: Thrombocytes are also known as platelets, which play a crucial role in hemostasis (the process of stopping bleeding).

Hemostasis

  • Definition: Hemostasis is a fast series of reactions to stop bleeding and involves:

    • Mechanical and chemical substances released by thrombocytes, injured tissues, or are circulating in plasma.

    • Comprised of three main steps:

    1. Vascular spasm (vasoconstriction)

    2. Platelet plug formation

    3. Coagulation mediated by plasma clotting factors

Hemostasis Disorders

  • These can be categorized generally into:

    • Thromboembolic disorders: undesirable clot formation

    • Bleeding disorders: abnormalities preventing normal clot formation

Thrombocyte Development and Structure

  • Platelets arise from:

    • Cytoplasmic fragments of megakaryocytes

  • Appearance:

    • Blue/purple staining outer region, with purple granules (large vesicles) which contain numerous signaling molecules.

  • Functions of signaling molecules:

    1. Activating other platelets

    2. Increasing vascular spasm

    3. Promoting the formation of platelet plug

    4. Promoting regrowth of blood vessels

    5. Attracting immune cells to the site of injury

  • Thrombopoietin:

    • A hormone involved with stimulating platelet formation, produced by the liver and kidneys.

    • Stimulates production and maturation of megakaryocytes.

    • Takes approximately one week to make and one week to break down.

  • Normal platelet levels:

    • 150 to 400 billion platelets per liter of blood (~1/10 the levels of RBCs).

Developmental Pathway

  • Stages in the development of thrombocytes:

    1. Stem cell

    2. Hematopoietic stem cell (hemocytoblast)

    3. Megakaryoblast (Stage I megakaryocyte)

    4. Megakaryocyte (Stage II/III)

    5. Platelets (Stage IV)

Platelet Function

  • Role of platelets:

    • Form temporary plugs that help seal breaks in blood vessels.

  • Mechanism preventing unnecessary clotting:

    • Platelets are kept inactive and mobile by the release of nitric oxide (NO, a gas) and prostacyclin (a lipid) from endothelial cells lining blood vessels.

Vascular Spasm (Hemostasis Step 1)

  • Definition: Vascular spasm involves vasoconstriction of a damaged blood vessel.

  • Triggers for vascular spasm:

    1. Mechanical injury to smooth muscle surrounding blood vessels

    2. Chemicals released by endothelial cells and platelets that promote smooth muscle contraction

  • Effectiveness:

    • Most effective in smaller blood vessels (not effective in capillaries).

    • Progressive vasoconstriction can be mimicked by applying pressure to damaged vessels.

Platelet Plug Formation (Hemostasis Step 2)

  • Process:

    • Damaged endothelium exposes collagen fibers, leading to platelet adhesion.

  • Mechanism of adhesion:

    • Platelets stick to collagen fibers via plasma protein von Willebrand factor (a “glue”)

    • Clinical correlation:

    • von Willebrand disease is the most common inherited clotting disorder.

  • Activation of platelets:

    • Platelets swell, become spiked and sticky, releasing chemical messengers from granules.

    • Key molecules released:

    • Platelet activating factor (PAF) and ADP, which cause further platelet activation and aggregation.

    • Serotonin and thromboxane A2: enhance the vascular spasm and promote platelet activation.

    • Positive feedback loop is established during this process.

    • Note: Aspirin inhibits thromboxane A₂, which diminishes platelet aggregation and vasoconstriction.

Coagulation (Hemostasis Step 3)

  • Definition: Coagulation is the process where clotting factors in plasma work to form a stable clot.

  • Pathways involved:

    • Intrinsic Pathway: Triggered by contact activation via collagen, involves factor XII.

    • Extrinsic Pathway: Triggered by cell injury; damage exposes tissue factor (III) and involves factor VII.

  • Common Pathway:

    • Involves formation of prothrombin activator (factor X) from either pathway.

    • Prothrombin (factor II) is converted to thrombin, which then catalyzes the conversion of fibrinogen (factor I) to fibrin.

    • Fibrin, in conjunction with Ca²⁺ and factor XIII, causes cross-linking to form a stable clot.

  • Summary of Coagulation Events:

    1. Formation of prothrombin activator (factor X) via intrinsic and extrinsic pathways.

    2. Conversion of prothrombin (factor II) to thrombin.

    3. Thrombin catalyzes the conversion of fibrinogen (factor I) to fibrin.

    4. Cross-linking of fibrin occurs with the aid of Ca²⁺ and factor XIII, producing a sticky web.

Clot Retraction

  • Definition: Clot retraction is a process facilitated by actin and myosin in platelets, leading to contraction and shrinkage of the platelet plug.

  • Timeline: Occurs within 30-60 minutes of clot formation.

  • Functions:

    • Stabilizes clot by squeezing serum from the clot, drawing ruptured blood vessel edges together.

Vessel Repair

  • Definition: Vessel repair occurs simultaneously with clot retraction.

  • Mediators of repair:

    • Platelet-derived growth factor (PDGF) stimulates cell division in smooth muscle cells and fibroblasts to rebuild blood vessel walls.

    • Vascular endothelial growth factor (VEGF) stimulates proliferation of endothelial cells to restore the lining of blood vessels.

Fibrinolysis

  • Definition: Fibrinolysis is the process of breaking down the fibrin clot that is no longer needed after healing.

  • Timeline: Begins within two days post-injury and may continue for several days.

  • Mechanism: Plasminogen within the clot is converted to plasmin by tissue plasminogen activator (tPA). Plasmin is a fibrin-digesting enzyme (often referred to as a “clot buster”).

Factors Limiting Clot Growth or Formation

  1. Dilution: Swift removal and dilution of clotting factors by blood flow.

  2. Inhibition of thrombin:

    • Anti-thrombin III inactivates unbound thrombin.

    • Heparin, released by basophils and mast cells, enhances the activity of anti-thrombin III, inhibiting thrombin.

    • Dabigatran is a drug that directly inhibits thrombin.

  3. Missing Clotting Factors:

    • Hemophilia A, B, and C are conditions resulting from missing factors VIII, IX, and XI, respectively in the intrinsic coagulation pathway.

    • Classification of Vitamin K as essential for synthesizing four clotting factors (II, VII, IX, and X), which is obtained from dark green vegetables (e.g., kale, spinach, collard greens, broccoli, Brussels sprouts).

    • Warfarin is a drug that blocks formation of vitamin K-dependent clotting factors.

Disorders of Hemostasis

  • Thromboembolic disorders:

    • Undesirable clot formation within unbroken blood vessels.

    • Thrombus: Clot that develops and persists in an unbroken vessel (e.g., deep vein thrombosis).

    • An embolus is a thrombus that has broken free and is floating in the bloodstream.

    • An embolism refers to the obstruction of a vessel by an embolus (e.g., cardiac, pulmonary, or cerebral embolism).

Bleeding Disorders

Bleeding Disorders (1)

  • Thrombocytopenia:

    • Characterized by a deficient number of circulating platelets.

    • Petechiae, tiny red spots, appear due to spontaneous and widespread capillary breakage.

    • Causes include suppression or destruction of the red bone marrow due to conditions like malignancy, radiation, or drugs.

Bleeding Disorders (2)

  • Hemophilia:

    • Encompasses several related hereditary disorders resulting in deficiencies of clotting factors VIII, IX, and XI (the intrinsic coagulation pathway).

    • Symptoms: Prolonged bleeding.

    • Treatment includes plasma transfusions and injections of missing factors.

  • Impaired Liver Function:

    • An inability to synthesize pro-coagulants causing bleeding disorders.

    • Causes may include Vitamin K deficiency, hepatitis, and cirrhosis.

    • Issues with fat absorption from liver disease can share similar implications, impairing absorption of vitamin K, and subsequently affecting clotting factor synthesis.