Ch 19, pt 2

Hemostasis

  • Hemostasis is defined as the process to stop blood loss from severed blood vessels, maintaining blood volume homeostasis.

Phases of Hemostasis

  • Hemostasis is composed of three main phases:

    • Vascular Phase

    • Platelet Phase

    • Coagulation Phase

Vascular Phase

  • The vascular phase initiates immediately after vessel injury.

    • Specifically:

    • When a cut occurs, smooth muscle cells in the vessel wall contract causing a vascular spasm.

    • This vascular spasm:

      • Occurs primarily in arterioles, as capillaries lack smooth muscle.

      • Reduces the diameter of the vessel at the injury site, effectively “pinching” it shut.

      • Serves to slow or stop blood loss.

      • Lasts approximately 30 minutes.

Endothelial Response

  • The endothelial cell layer at the cut site contracts simultaneously with smooth muscle spasms, this action:

    • Reveals proteins in the underlying basal lamina.

    • Exposes additional proteins that promote platelet binding and endothelial-endothelial binding, resulting in endothelial cells becoming “sticky.”

    • Releases local hormones and substances such as ADP, calcium ions (Ca^{2+}), and clotting factors to further promote clot formation, including:

    • Prostacyclin: A compound that inhibits platelet aggregation.

    • Endothelins: Hormones that stimulate smooth muscle contraction and endothelial cell division.

    • ADP (Adenosine diphosphate): Stimulates platelet aggregation.

    • Tissue Factor: Joins with Ca^{2+} and clotting factor VII (circulating in blood) to activate the enzyme involved in the clotting cascade.

Platelet Phase

  • The platelet phase begins shortly after the vascular phase, characterized by:

    • Initiation: Occurs within 15 seconds post-injury.

    • Key Processes:

    • Platelet adhesion: Platelets bind to “sticky” endothelial cells, the basal lamina, and exposed collagen at the site of injury.

    • Platelet aggregation: Activated platelets bind to one another.

    • Platelet plug formation: A mass of platelets which serves as a temporary seal at the site.

Activation and Release of Chemicals

  • Upon exposure to adhered substrates, platelets undergo activation:

    • Activated platelets release various compounds, which include:

    • ADP: Promotes further platelet aggregation.

    • Thromboxane A2: A potent vasoconstrictor and promotes platelet aggregation.

    • Calcium ions (Ca^{2+}): Essential for various clotting processes.

    • Clotting factors and serotonin: Aid in the promotion of clot formation.

    • Platelet-derived growth factor (PDGF): Promotes vessel repair.

Positive Feedback Mechanism

  • The activation of platelets leads to a positive feedback loop where:

    • Released ADP and Thromboxane A2 promote further platelet activation and aggregation.

  • Mechanisms are in place to limit platelet aggregation and clot formation only to the injury site, preventing excessive clotting.

Coagulation Phase

  • The coagulation phase involves transforming liquid blood into a gel-like (clot) state via:

    • Formation of insoluble proteins that cover the platelet plug and trap more platelets and other blood cells.

Enzymatic Activation

  • The enzymes required for clot formation are present in the circulation in an inactive form, called proenzymes.

    • Upon cleaving, these proenzymes become active enzymes.

    • Some proteins necessary for clot formation are also in inactive forms called proproteins.

Coagulation Cascade

  • This process involves the transformation of proenzymes into enzymes.

    • The cascade effect leads to an exponential increase, rapidly generating a large number of active enzymes.

Clotting Factors

  • Clotting factors are identified with Roman numerals according to their order of discovery, not function in the cascade:

    • Some key factors include:

    • Calcium ion (Ca^{2+}): Essential for clotting mechanism.

    • Tissue Factor (lipoprotein): Initiates the extrinsic pathway.

    • Various enzymes and proteins: Including fibrinogen, which converts to fibrin during clot formation.

    • The synthesis of several clotting factors depends on Vitamin K, a lipid-soluble vitamin which acts as a co-factor for enzymes synthesizing these proteins.

Pathways to Clot Formation

  • The coagulation process can occur via two distinct pathways, both leading to a common destination:

    1. Extrinsic Pathway:

    • Triggered when endothelial cells release tissue factor (TF).

    • Tissue factor combined with Ca^{2+} and another clotting factor activates factor 10 (X), initiating clotting.

    • This pathway is shorter and faster, ideal for initial clot formation.

    1. Intrinsic Pathway:

    • Triggered by exposure to collagen, activating the first enzyme in a cascade.

    • This process, while slower, reinforces the clot formation initiated by the extrinsic pathway.

    • Ends up activating factor 10 (x).

Common Pathway (need more detail)

  • This pathway shares components from both intrinsic and extrinsic pathways, involving:

    • Formation of prothrombinase (often referred to as factor X).

    • Conversion of prothrombin to thrombin (enzyme), which subsequently converts (insoluble)fibrinogen into (soluble) fibrin.

    • Clotting times can vary based on situation:

    • Small wound clotting time ranges from 1-4 minutes.

    • Using a surface like a glass blood collection tube can extend the time to 8-18 minutes.

    • To prevent clotting in samples, chelators such as EDTA or citrate are added to the tubes.

Positive Feedback in Clot Formation

  • An additional aspect of the common pathway is a positive feedback mechanism where:

    • Activated thrombin can stimulate the synthesis or release of upstream factors like tissue factor and PF-3, which are necessary for the intrinsic pathway activation.

Clot Retraction

  • Once formed, the clot undergoes retraction due to:

    • Platelets containing myosin and actin fibers contracting, pulling the edges of the vessel closer together.

    • This action facilitates area repair by fibrocytes, smooth muscle cells, and endothelial cells.

Limiting Clot Formation

  • It is vital to limit clot formation outside of the injury site.

  • Several mechanisms exist for this:

    • Prostacyclins (produced by endothelial cells) prevent platelet aggregation.

    • Inhibitory factors released by white blood cells (WBCs).

    • Degradation of ADP by circulating enzymes.

    • Chemical actions that inhibit the plug formation and limit activation factor release into overall circulation.

Anticoagulants and Antiplatelets

  • Anticoagulants: Substances that inhibit clotting include:

    • Heparin: Released by basophils and mast cells, enhances the activation of antithrombin-III, used clinically for blood thinning.

    • Antithrombin III: A serum enzyme that inhibits various clotting factors, including thrombin.

    • Thrombomodulin and Protein C: Inactivate clotting factors and stimulate plasmin (enzyme) formation, which degrades fibrin. This breaks up the clot.

    • Prostacyclins: Inhibit aggregation and counteract thrombin and ADP.

Fibrinolysis

  • Fibrinolysis is the process of clot dissolution:

    • Initiated by thrombin and tissue plasminogen activator (t-PA). Then..

    • Plasminogen (inactive) converts to active plasmin, which degrades fibrin.

    • t-PA is particularly significant and is utilized to treat conditions like ischemic strokes (w/o oxygen) and myocardial infarctions (MIs): heart attack

  • This dissolves the clots.

Summary of Hemostasis Phases

  1. Vascular Phase: Smooth muscle contraction and endothelial cell secretion of chemical factors and hormones.

  2. Platelet Phase: Formation of a platelet plug, accompanied by the release of factors that promote clotting.

  3. Coagulation Phase: Activation of cascade enzymes leading to the creation of fibrin; fibrin overlays the platelet plug, capturing additional platelets and blood cells to form a stable blood clot.

Pathways Overview

  • The two pathways (extrinsic and intrinsic) converge to activate prothrombinase, facilitating the conversion of fibrinogen to fibrin.

  • Clotting first occurs with positive feedback to enhance response speed.

  • Clotting processes are constrained to the injury site by factors from plasma or released by platelets or blood cells.

  • Fibrinolysis occurs post-repair of the wound.

Clotting Factors and the Liver - The liver plays a crucial role in hemostasis, producing most of the clotting factors necessary for the coagulation cascade. These factors include prothrombin and fibrinogen, both essential for blood clot formation.

Plasmin and Fibrin - Fibrin is a protein that plays a key role in blood coagulation. It forms fibrous strands that create a mesh-like structure in the blood clot, trapping platelets and blood cells, thus stabilizing the clot.

  • Fibrin is derived from its precursor, fibrinogen, which is produced in the liver and is an essential component of the clotting process.

  • The conversion of fibrinogen to fibrin is catalyzed by thrombin during the coagulation phase.

    • Plasmin is an enzyme that is crucial for the process of fibrinolysis, the breakdown of fibrin in blood clots. It helps to dissolve clots once they are no longer needed, allowing for normal blood flow to be restored after a vessel has healed.

  • Plasmin is generated from its precursor, plasminogen, which is also produced by the liver. The activation of plasminogen to plasmin occurs through the action of tissue plasminogen activator (t-PA), especially during wound healing or when the clot has fulfilled its purpose.

  • The balance between clot formation (via fibrin) and clot dissolution (via plasmin) is vital for maintaining proper hemostasis in the body.

Hemostasis is defined as the process to stop blood loss from severed blood vessels, maintaining blood volume homeostasis. It is crucial for preventing excessive bleeding and enabling wound healing. Certain diseases can significantly affect hemostasis, leading to disorders in blood clotting or excessive bleeding.

Diseases Related to Hemostasis

  • Hemophilia: A genetic disorder that impairs the body’s ability to make blood clots, leading to prolonged bleeding. People with hemophilia often experience spontaneous bleeding, particularly into joints and muscles.

  • Von Willebrand Disease: The most common inherited bleeding disorder, caused by a deficiency of von Willebrand factor, which is necessary for platelets to stick to blood vessels and clot properly.

  • Thrombocytopenia: A condition characterized by low platelet counts, which can be due to conditions like aplastic anemia or side effects of certain medications, increasing the risk of bleeding.

  • Deep Vein Thrombosis (DVT): A condition where a blood clot forms in a deep vein, often in the legs, which can lead to further complications like pulmonary embolism if the clot dislodges.

What is Serum?

Serum is the clear, yellowish fluid that separates from blood when it clots. It contains electrolytes, antibodies, antigens, hormones, and various proteins including albumin and globulins. Unlike plasma, which contains clotting factors such as fibrinogen, serum does not have these factors because they are consumed in the clotting process. Serum is often used in diagnostic tests as it provides insights into various bodily functions and helps detect diseases.