Haemostasis: General Pathways

Abstract

Haemostasis protects the organism from bleeding due to tissue and vascular injury. It is a complex system of interconnected mechanisms that have the purpose of halting blood loss and reconstituting the integrity of the damaged tissue. The haemostatic process begins with a vascular damage that results in the exposure of the subendothelial collagen; this component is recognised by platelet receptors that initiate a series of events resulting in platelet aggregation with the formation of the primary unstable thrombus. Tissue damage also sets off the activation cascade of the coagulation factors, which results in the transformation of fibrinogen into fibrin, stabilising the thrombus. The final phase of haemostasis is the removal of the fibrin clot by plasmin, followed by wound healing of the damaged tissue. In normal conditions, haemostasis is controlled by sophisticated mechanisms that trigger the activation of the coagulation process to block blood loss, preventing unnecessary thrombus formation.

Key Concepts

  • Haemostasis is a system of highly interconnected mechanisms aimed at protecting the organism from blood loss.
  • Four phases occur in haemostasis: (1) tissue and vessel wall damage, (2) platelet activation, (3) blood clotting and (4) fibrinolysis and wound healing.
  • Injury of the vessel wall initiates the mechanisms responsible for platelet activation and coagulation factor activation.
  • Coagulation factors are plasma proteins that in the absence of tissue damage circulate in blood in an inactive form. Tissue lesion provokes a proteolytic cascade that sequentially activates all the factors, resulting in the formation of the stable fibrin clot.
  • The haemostatic mechanisms are limited to the area in which tissue injury and platelet adhesion occurred.
  • Upon definitive arrest of bleeding, the fibrin network is dissolved by plasmin deriving from proteolytic activation of plasminogen.
  • Plasminogen activation is strongly stimulated by fibrin, and therefore plasmin is active only in the areas in which fibrin is present.
  • Alterations of the different haemostatic mechanisms result in severe pathologic conditions that represent one of the main causes of death in modern society.
  • The haemostatic process is controlled by sophisticated mechanisms aimed at maintaining a functionally correct balance between prothrombotic and antithrombotic pathways.

Keywords: haemostasis; platelets; vessel wall; blood clotting; endocannabinoids; fibrinolysis; wound healing; extracellular matrix; thrombosis

Figure 1. Overview of the haemostatic process. (a) When the endothelium is intact, platelets and coagulation factors circulate into the bloodstream in an inactive state. (b) When the endothelium is disrupted by injury, platelets along with the intrinsic and extrinsic pathways are activated in order to promote a series of events that culminate in the formation of a primary clot of platelets stabilised by a network of fibrin (formed by cross‐linked monomer). (c) The clot is then degraded only when the fibrinolytic system is activated. Details for all the reactions are described in the text. Yellow arrows, intrinsic pathway; blue arrows, extrinsic pathway; vWF, von Willebrand factor; tPA, tissue‐type plasminogen activator (t‐PA).
Figure 2. Overview of platelet activation pathways. Stimulation of platelet agonist receptors results in platelet activation and consequent exposure of platelet ligand receptors, finally resulting in platelet aggregation. PGI2, prostaglandin I2; IP, prostacyclin receptor; ADP, adenosine diphosphate; P2Y, purinergic receptor; TxA2, thromboxane A2; TP, thromboxane receptor; PAR, protease‐activated receptor; vWF, von Willebrand factor; GP, glycoprotein; NO, nitric oxide; GC, guanylate cyclase; cGMP, cyclic guanosine monophosphate; AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; c‐PLA2, cytosolic phospholipase A2; COX‐1, cycloxygenase‐1; PLCβ, phospholipase Cβ; PLCγ, phospholipase C γ; DAG, diacylglycerol; PKC, protein kinase C; IP3, inositol trisphosphate; IP3R, inositol trisphosphate receptor; Ca2+, calcium; ER, endoplasmic reticulum; MLCK, myosin light‐chain kinase; MLC‐P, phosphorylated myosin light‐chain. Green arrows, activation; red line, inhibition.
Figure 3. Graphical representation of the coagulation cascade model. After the initiation of blood coagulation, the coagulation factor proenzymes (red circle) are activated sequentially (green circle). Red boxes indicate blood coagulation inhibitors (TFPI, tissue factor pathway inhibitor). Yellow arrows, intrinsic pathway; blue arrows, extrinsic pathway; green arrows, common pathway; red line, inhibition pathway.
Figure 4. Schematic representation of fibrinogen and fibrinogen‐derived products. NH2, N‐terminus; COOH, C‐terminus; pink, Aα chain; blue, Bβ chain; yellow, γ chain; FPA, fibrinopeptide A; FPB, fibrinopeptide B.
Figure 5. Schematic view of the fibrinolytic system. Plasminogen can be activated to plasmin by urokinase, tissue‐type plasminogen activator (t‐PA) or streptokinase. Urokinase and t‐PA are inhibited by plasminogen activator inhibitor type I (PAI‐1) and t‐PA inhibitor, respectively. Plasmin degrades fibrin to its degradation products. Green arrows, activation; red line, inhibition; Lys, Lysine; Arg, Arginine; Val, Valine; NH2, N‐terminus; COOH, C‐terminus.
Figure 6. Schematic view of D‐dimer formation. The D‐dimer is a fibrin degradation product that results from the cleavage operated by plasmin during fibrinolysis.
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References

Ali MR, Salim Hossain M, Islam MA, et al. (2014) Aspect of thrombolytic therapy: a review. Scientific World Journal 2014: 586510.

Baldassarri S, Bertoni A, Bagarotti A, et al. (2008) The endocannabinoid 2‐arachidonoylglycerol activates human platelets through non‐CB1/CB2 receptors. Journal of Thrombosis and Haemostasis 6 (10): 1772–1779.

Broos K, Feys HB, De Meyer SF, et al. (2011) Platelets at work in primary hemostasis. Blood Reviews 25 (4): 155–167.

Chapin JC and Hajjar KA (2015) Fibrinolysis and the control of blood coagulation. Blood Reviews 29 (1): 17–24.

De Angelis V, Koekman AC, Weeterings C, et al. (2014) Endocannabinois control platelet activation and limit aggregate formation under flow. PLoS One 9 (9): e108282.

Gremmel T, Frelinger AL 3rd and Michelson AD (2016) Platelet physiology. Seminars in Thrombosis and Hemostasis 42 (3): 191–204.

Gross PL, Murray RK, Beuder DA, Botham KM, et al (2012) Harper illustrated Biochemistry, 29th, chap. 51 edn, pp. 660–670. New York: McGraw Hill.

Kolev K and Longstaff C (2016) Bleeding related to disturbed fibrinolysis. British Journal of Haematology 175 (1): 12–23.

Longstaff C and Kolev K (2015) Basic mechanisms and regulation of fibrinolysis. Journal of Thrombosis and Haemostasis 13 (Suppl 1): S98–S105.

Lowe G (2009) Hemostasis and thrombosis. In: Baynes WB and Dominiczak MH (eds) Medical Biochemistry, 3rd, chap. 7 edn, pp. 73–86. Amsterdam: Mosby‐Elsevier.

Macarrone M, Bari M, Menichelli A, et al. (2001) Human platelets bind and degrade 2‐arachidonoglycerol, which activate these cells through a cannabinoid receptor. European Journal of Biochemistry 268 (3): 819–825.

Macarrone M, Bab I, Birò T, et al. (2015) Endocannabinoid signalling at the periphery: 50 years after THC. Trends in Pharmacological Sciences 36 (5): 277–296.

Okafor ON and Gorog DA (2015) Endogenous fibrinolysis: an important mediator of thrombus formation and cardiovascular risk. Journal of the American College of Cardiology 65 (16): 1683–1699.

Panteleev MA, Dashkevich NM and Ataullakhanov FI (2015) Hemostasis and thrombosis beyond biochemistry: roles of geometry, flow and diffusion. Thrombosis Research 136 (4): 699–711.

Pettersen AA, Arnesen H and Seljeflot I (2015) A brief review on high on‐aspirin residual platelet reactivity. Vascular Pharmacology 67‐69: 6–9.

Randall MD (2007) Endocannabinoids and the haematological system. British Journal of Pharmacology 152 (5): 671–675.

Schenone M, Furie BC and Furie B (2004) The blood coagulation cascade. Current Opinion in Hematology 11 (4): 272–277.

Smith SA, Travers RJ and Morrissey JH (2015) How it all starts: initiation of the clotting cascade. Critical Reviews in Biochemistry and Molecular Biology 50 (4): 326–336.

Stalker TJ, Welsh JD and Brass LF (2014) Shaping the platelet response to vascular injury. Current Opinion in Hematology 21 (5): 410–417.

Vercauteren E, Gils A and Declerck PJ (2013) Thrombin activatable fibrinolysis inhibitor: a putative target to enhance fibrinolysis. Seminars in Thrombosis and Hemostasis 39 (4): 365–372.

Versteeg HH, Heemskerk JW, Levi M, et al. (2013) New fundamentals in hemostasis. Physiological Reviews 93 (1): 327–358.

Yun SH, Sim EH, Goh RY, et al. (2016) Platelet activation: the mechanisms and potential biomarkers. BioMed Research International 2016: 9060143.

Further Reading

Gresele P, Kleiman NS, Lopez JA and Page CP (2017) Platelets in Thrombotic and Non‐Thrombotic Disorders. UK: Cambridge University Press.

Kasper D, Fauci A, Hauser S, et al. (2016) Harrison's Principle of Internal Medicine. USA: Tinsley R. Harrison.

Kaushansky K, Lichtman MA, Prchal JT, et al. (2015) Williams Hematology. Milan, Italy: McGraw‐Hill Medical.

Kolev K and Machovich R (2003) Molecular and cellular modulation of fibrinolysis. Thrombosis and Haemostasis 89 (4): 610–621.

Stamatoyannopoulos G, Nienhuis AW, Leder P and Majerus PW (2000) The Molecular Basis of Blood Diseases. USA: Wiley.

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Balduini, Alessandra, and Balduini, Cesare(Apr 2018) Haemostasis: General Pathways. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001408.pub2]