8.2.4 Regulatory systems

 It is crucial for coagulation reaction not to spin out of control. It must remain localised to the site of the vascular injury in order to stop bleeding, but must not trigger thrombosis throughout the vascular tree. Several mechanisms are involved in this control (see Figure 8.7).

  • Fibrinolysis;
  • Circulating inhibitors;
  • The endocrine activity of platelets;
  • A healthy vascular endothelium;
  • The constraint for the coagulation chain to unfold on platelets surface activated by an endothelial injury.

Fibrinolysis

Once haemostasis has been achieved and the vessel wall is sealed, thrombus must disappear. Fibrinolysis consists in cleavage of fibrin into fragments without coagulant activity (D-dimers). It is carried out by plasmin, transformed from circulating plasminogen by two main triggers [1].

  • Tissue plasminogen activator (t-PA), synthesised in the vascular endothelium in response to thrombus and stasis;
  • Serum plasminogen activator, or urokinase (u-PA, urokinase plasminogen activator), activated from pro-urokinase by plasmin, factor XIIa and kallikrein; it is found in great quantities in the urinary system.

Fibrinolysis is also controlled by two braking systems: plasminogen activator inhibitors (PAI-1 and PAI-2), and thrombin-activated fibrinolysis inhibitor (TAFI), which reduces the attachment points for plasmin.

Fibrinolysis can also get out of control and become excessive, to the extent that plasmin also degrades fibrinogen. It is therefore regulated by an inhibitor of its specific activators. In clinical cases, it can be slowed by antifibrinolytic agents such as aprotinin, tranexamic acid or ε-aminocaproic acid. Tranexamic acid and ε-aminocaproic acid bind to the lysine of plasminogen and block plasmin activation. Aprotinin is a non-specific protease inhibitor, which directly blocks plasmin. In cardiac surgery, these substances reduce blood loss by 30% and redo operation for hemostasis  by 60% [2,6].

Inhibitors

As mentioned earlier, several mechanisms associated with the coagulation cascade play a key role in limiting clot extension. When they escape into circulation, coagulation factors are thus rapidly controlled [1,5,7].

  • Proliferation of the TF/VIIa complex outside the endothelial lesion is limited by its circulating inhibitor (TFPI, tissue factor pathway inhibitor), which is mainly produced by endothelium; it rapidly inhibits any complex escaping outside the lesion area.
  • Endothelial thrombomodulin (TM) inhibits thrombin.
  • TM-thrombin complex activates protein C and protein S which block factors Va and VIIIa.
  • Antithrombin III (AT III) rapidly inactivates thrombin and factor Xa, more slowly factors IXa, XIa and XIIa; it is responsible for more than half of the total inhibitory effect. Heparin acts as a cofactor for AT III and makes the thrombin inhibitory reaction 2000 times more active.
  • Excess thrombin is bound to newly formed fibrin (antithrombin I).
  • Factor VIIIa is unstable and dissociates spontaneously.

Endothelium

Endothelium is a highly active cell layer that plays a crucial role in protection against thrombosis. The endothelium secretes substances that inhibit coagulation and modify local perfusion.

  • Tissue factor pathway inhibitor (TFPI).
  • Tissue plasmin activator (tPA): activation of fibrinolysis.
  • Thrombomodulin: inhibition of factors IIa (thrombin) and Xa.
  • Protein C receptor: inhibition of factors Va and VIIIa.
  • NO : main distal vasodilator (decrease in intracellular ionised Ca2+ ), inhibition of platelet aggregation.
  • Prostacyclin PGI2 : increased cAMP, decreased platelet aggregation.
  • Ecto-ADPase: suppression of the platelet recruitment phase.
  • Endothelin: a potent vasconstrictor, whose secretion is stimulated by thrombin, angiotensin II, adrenaline and vasopressin.

A diseased endothelium reacts in a pathological manner. In major inflammatory reactions or atheromatosis, for example, the physiological balance between the effects of NO• and endothelin is altered in favour of vasocontriction and platelet stimulation [9]. Thus, stimuli that normally lead to vasodilation (e.g. hypoxia, exercise and increased O2 demand ) can lead to vascoconstriction and increased platelet adhesiveness in arteriosclerotic vessels. In some abnormal situations, the endothelium may express tissue factor (TF), and thus become a trigger for coagulation. Which happens with certain bacterial lipopolysaccharides (sepsis), inflammatory cytokines or oxidised LDL [1]. Furthermore, TF is a major component of atheromatous plaques [8].

Platelets

When stimulated, platelets release coagulation activating agents (TXA2 , ADP, serotonin, thrombin), some of which are also local vasoconstrictors (TXA2 , serotonin), while the endothelium secretes substances that inhibit platelet activity and have a vasodilatory effect: NO• , prostacyclin PGI2 and ecto-ADPase. Situation may evolve in two different ways [4].

  • Predominance of vasodilating agents and platelet inhibitors: spontaneous resolution of the thrombus; circulation is restored, but scarring and fibrosis of the atheromatous plaque which progressively increase in size.
  • Predominance of vasoconstrictive and platelet stimulating agents such as stress, smoke or inflammation: massive recruitment of thrombocytes and coagulation factors; thrombus becomes occlusive and causes distal ischaemia or necrosis.

The opposing endocrine activity of platelets and endothelium maintains a dynamic balance at the arteriolar level. However, certain situations come along with exaggerated platelet excitability: obesity, smoking, hyperlipidaemia, hypercholesterolaemia, hypertension, ageing, diabetes, renal failure [3]. The balance is then tipped in favour of thrombosis.

 

Coagulation regulatory systems 
Several mechanisms allow coagulation to remain confined to the site of the vascular lesion without dissemination risk  :
- Fibrinolysis: cleavage of fibrin by plasmin
- Circulating inhibitors: anti-thrombin (AT III), thrombomodulin (thrombin inhibitor)
  TF/VIIa complex inhibitor
- Spontaneous dissociation: factor VIIIa
- Endothelium (inhibitory action): inhibition of TF/VIIa complex, activation of plasmin, secretion of NO, prostacyclin PGI2 , endothelin
- Platelets must be present: only activated and locally fixed platelets provide an adequate surface for the coagulation cascade to unfold
 

 

   © CHASSOT PG, MARCUCCI Carlo, last update November 2019.

 

References

  1. ADAMS RLC, BIRD RJ. Review article: Coagulation cascade and therapeutic update: Relevance to nephrology. Part I: Overview of coagulation, thrombophilia and history of anticoagulants. Nephrol 2009; 14:462-70
  2. BROWN JR, BIRKMEYER NJO, O'CONNOR GT. Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation 2007; 125:2801-13
  3. DAVI G, PATRONO C. Platelet activation and atherothrombosis. N Engl J Med 2007; 357:2482-94
  4. FALK E, SHAH PK, FUSTER V. Coronary plaque disruption. Circulation 1995; 92:657-71
  5. INNERHOFER     P, KIENAST J. Principles of perioperative coagulopathy. Best Pract Res Clin Anaesthesiol 2010; 24:1-14
  6. KOSTER A, SCHIRMER U. Re-evaluation of the role of antifibrinolytic therapy with lysine analogs during cardiac surgery in the post aprotinin era. Curr Opin Anaesthesiol 2011; 24:92-7
  7. MOSESSON  MW. Update on antithrombin I (fibrin). Thromb Haemost 2007; 98:105-8
  8. VILES-GONZALEZ  JF, ANNAND SX, ZAFAR MU, et al. Tissue factor coagulation pathway: A new therapeutic target in atherothrombosis. J Cardiovasc Pharmacol 2004; 43:669-76
  9. ZAUGG M, SCHAUB MC, FOËX P. Myocardial injury and its prevention in the perioperative setting. Br J Anaesth 2004; 93:21-33