Coagulation Pathways Overview

Coagulation Pathways Overview

• The intrinsic pathway initiates when vascular endothelium is damaged, exposing clotting factors to negatively charged subendothelial surfaces.
• Kallikrein mediates the activation of the intrinsic pathway.
• Key reactions in this pathway:
  • Factor XII is activated by surface contact.
  • Factor XIIa activates factor XI, which activates factor IX.
  • Factor IXa, along with factor VIIIa, platelet membrane phospholipids, and Ca2+, activates factor X.

Common Pathway Mechanism

• Factor Xa is produced through both intrinsic and extrinsic pathways and combines with factor V, phospholipids, and Ca2+.
• This combination converts prothrombin into thrombin.
• Thrombin then converts fibrinogen to fibrin strands, forming a structural component of a thrombus.
• Fibrin monomers polymerize to create fibrin strands, forming a mesh-like matrix in blood clots.
• Factor XIII, activated by thrombin, further stabilizes the clot by cross-linking fibrin.

Actions of Thrombin

• Thrombin facilitates fibrin generation by converting fibrinogen to fibrin.
• It initiates a positive feedback loop, enhancing the intrinsic pathway and leading to the production of a significant amount of thrombin ("thrombin burst").

Extrinsic Pathway Characteristics

• The extrinsic pathway is activated externally and begins with tissue factor (TF) exposure due to vascular injury.
• TF binds to plasma factor VIIa, initiating biochemical reactions that activate factor X.
• This leads to clot formation through the common pathway.

Fibrinolytic Phase

• Fibrinolysis is the process of clot disintegration and involves converting plasminogen to plasmin.
• Plasmin is responsible for digesting fibrin, thereby limiting thrombosis.
• Tissue plasminogen activator (t-PA) is secreted by endothelial cells at injury sites, converting plasminogen to plasmin.
• Plasmin activity is regulated by inhibitors like PAI-1, PAI-2, and α2-AP.

Natural Regulation Mechanisms

• Maintaining balance between procoagulant and anticoagulant processes is crucial for normal vessel function.
• Endothelial cells release prostacyclin (PGI2) to inhibit thrombus formation and control platelet activity.
• Factors influencing platelet aggregation:
  • Activators include ADP, collagen, thrombin, and thromboxane A2 (TXA2).
  • Inhibitors include PGI2, nitric oxide, and cyclic AMP (cAMP).

Summary of Factors Involved

• Activation of coagulation factors primarily involves:
  • Proteases that cleave zymogens to active forms.
  • Nonenzymatic protein cofactors that provide binding sites on platelets.
  • Calcium ions necessary for protease binding.
• Each coagulation step requires preceding factors or zymogens to progress efficiently, leading ultimately to thrombin and fibrin formation.

Coagulation and Hemostasis

• Red clots form in slow-moving (venous) or stagnant blood, primarily consisting of fibrin strands intertwined with blood cells.
• White clots, primarily composed of aggregated platelets, develop in rapidly flowing (arterial) blood.

Treatment of Blood Clots

• Antiplatelet drugs and anticoagulants are used for treating white clots.
• Red clots require anticoagulants and fibrinolytic agents for treatment.

Deep Vein Thrombosis (DVT)

• DVT arises in veins, influenced by stasis, endothelial damage, and hypercoagulability.
• Overactive hemostasis can lead to disseminated intravascular coagulation (DIC).

Anticoagulants

• Classified into three categories:
  • Anticoagulants: drugs lowering blood coagulability.
  • Antiplatelet agents: drugs interfering with platelet function.
  • Thrombolytics: drugs dissolving thrombin clots.

Types of Anticoagulant Drugs

• Parenteral Anticoagulants:

  • Unfractionated Heparin (UFH)
  • Low Molecular Weight Heparins (e.g., Enoxaparin, Dalteparin)
  • Fondaparinux
  • Direct thrombin inhibitors (e.g., Hirudin, Argatroban)

• Oral Anticoagulants:

  • Warfarin
  • Dabigatran etexilate
  • Rivaroxaban
  • Apixaban
  • Edoxaban
  • Betrixaban

• Reversal Agents:

  • Idarucizumab for dabigatran
  • Andexanet alfa for factor Xa inhibitors

Antiplatelet Agents

• Key agents include:
  • Aspirin
  • Clopidogrel
  • Prasugrel
  • Ticagrelor
  • Abciximab
  • Eptifibatide
  • Vorapaxar

Thrombolytics

• Include:
  • Streptokinase
  • Tissue plasminogen activator (tPA)
  • Tenecteplase
  • Reteplase
  • Urokinase

Antifibrinolytic Agents

• Aminocaproic acid
• Tranexamic acid
• Aprotinin

Hemostasis Definition

• Hemostasis is a complex process halting bleeding via clotting factor activation, occurring in four phases: vascular, platelet, coagulation, and fibrinolytic.

Normal Hemostasis Phases

• Vascular Phase: Vasospasm reduces blood flow; facilitated by endothelin.
• Platelet Phase: Platelet aggregation forms a plug to stop bleeding.
• Coagulation Phase: Fibrin clot formation stabilizes the plug.
• Fibrinolytic Phase: Breakdown of clot occurs post-vessel repair.

Factors Influencing Hemostasis

• Integrity of vessel walls, functionality and count of platelets, levels of clotting factors, and efficacy of the fibrinolytic pathway.

Regulation of Hemostasis

• Inactivation of coagulation proteins occurs through:
  • α2-macroglobin
  • α2-antiplasmin
  • Antithrombin III
  • Protein C and Protein S.

Pathological Thrombus Formation

• Thrombus: A clot adhered to a vessel wall; can obstruct blood vessels.
• Embolus: A clot that circulates and can lead to pulmonary embolism.

Clot Characteristics

• White clots: Formed in arteries and consist mainly of platelets.
• Red clots: Formed mainly in veins and consist of fibrin and blood cells.

Explore the intricate mechanisms of coagulation pathways, focusing on the intrinsic and common pathways. Understand how factors interact to form blood clots and the role of thrombin in this essential biological process. This quiz will deepen your knowledge of hemostasis and related factors involved in coagulation.