Haemostasis — Natural Anticoagulants

• Haemostasis is the natural process that stops blood loss when an injury occurs.
• Intact vascular endothelial cells:
  • fibrinolytic heparin, Thrombomodulin → prevent clotting
  • NO, Prostacyclin → Prevents clotting cascade

Haemostasis following vessel injury

Three steps: Vascular spasm (vasoconstriction), platelet plug formation and coagulation.

• Vasoconstriction:
  • Brief reflexive contraction that decreases local blood flow
  • Caused by signalling molecules from injured endothelial cells, thromboxane A2 from activated platelets, Nervous system reflexes from local pain receptors
  • Vasoconstriction only lasts for a few minutes during haemostasis. During inflammation that follows the injury, it is replaced by vasodilation as the healing process begins.
• Platelet Plug Formation (Primary Haemostasis):
  • Within 20 seconds, coagulation is initiated
  • Platelet Adherence: vWF released from damaged endothelium → change platelet form → adhere to subendothelial collagen
  • Platelet Activation: subendothelial collagen binds to platelet receptors → activates platelets → degranulate → release ADP, vWF, TXA2, PDGF, VEGF, Serotonin, Coagulation factors
  • Platelet Aggregation: Platelets bind to vWF and fibrinogen → aggregate over damaged endothelium
  • Positive feedback mechanism
  • Platelet plug formed in seconds to a few minutes based on extent of injury
• Coagulation Cascade (Secondary Haemostasis):
  • Occurs if platelet plug ineffective in controlling bleeding
  • Platelets degranulate → release ADP, Serotonin, Thromboxane A2
  • Coagulation cascade: Intrinsic, Extrinsic pathway → Common pathway
  • Intrinsic (Contact Activation) Pathway: Primary complex (on collage by High molecular weight kininogen, prekallikrenin, factor XII) → XI → IX (which, along with VIII) → Common pathway
  • Extrinsic (Tissue factor) Pathway: Tissue factor III → VII → Generates thrombin burst – cleaves fibrinogen to fibrin
  • Common pathway: Prothrombin(II) to thrombin (using Factor V) → cleaves fibrinogen to fibrin
    • forms mesh that binds and strengthens platelet plug → coagulation → haemostasis
    • Also activates factor XIII – covalently bonds to fibrin to strengthen attachment to platelets
    • Also activates more factor V which acts as anticoagulant with inhibitor protein C

Fate of the Clot:

One of four outcomes:

• Propagation: Accumulation of additional platelets and fibrin
• Embolization: Thrombus breaks free and becomes mobile
• Dissolution: Fibrinolysis (aided by tissue plasminogen activator, tPA)
• Organization and recanalization: Ingrowth of smooth muscle cells, fibroblasts and endothelium into fibrin-rich thrombus.

Clot lysis and Wound healing:

Over the course of the next few days:

• Clot Retraction: blood clot shrinks.
  • dependent on the release of multiple factors, mostly factor XIIIa crosslinks
  • Cause contraction, knotting and twisting of fibrin mesh
  • Blood clot shrinks
  • Fibrinolysis – Plasmin degrades fibrin to Fibrin degradation products, macrophages consume the expended platelets. FDPs inhibit further thrombin and fibrin formation
• Wound Healing:
  • Inflammation – Tissue proliferation – Collagen and granulation tissue deposition – angiogenesis – Wound contraction – Epithelialization

Source: https://courses.lumenlearning.com/boundless-ap/chapter/hemostasis/

JC 2019

Answer by JC