Haemostasis and thrombosis: an overview

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1 European Heart Journal Supplements (2001) 3 (Supplement Q), Q3 Q7 Haemostasis and thrombosis: an overview Department of Hematology, Center of Internal Medicine, Zentralkrankenhaus, Bremen, Germany The present review provides a review of haemostasis and thrombosis. It describes the basic mechanisms of the blood s coagulable states, as well as their associated bleeding and thromboembolic disorders. Endothelial cells present a nonthrombogenic surface. In contrast, after contact of blood with a synthetic surface (e.g. mechanical heart valves) local thrombus formation and embolism can occur. Anticoagulant therapy is required to prevent these complications in patients with artificial implants. (Eur Heart J Supplements 2001; 3 (Suppl Q): Q3 Q7) 2001 The European Society of Cardiology Key Words: Haemostasis, thrombosis, bleeding disorders, thrombophilia. Introduction Maintenance of blood fluidity within the vascular system is an important human physiological process. The term haemostasis refers to the normal response of the vessel to injury by forming a clot that serves to limit haemorrhage. Thrombosis is pathological clot formation that results when haemostasis is excessively activated in the absence of bleeding ( haemostasis in the wrong place ). Essential components of fluidity, haemostasis and thrombosis are the blood flows produced by the cardiac cycle, the vascular endothelium and the blood itself. Under normal physiological conditions there is a delicate equilibrium (eucoagulability) between the pathological states of hypercoagulability and hypocoagulability in the circulating blood (Fig. 1). Astrup [1], in 1958, first described the phenomenon of socalled haemostatic balance. It would appear that, at that time, the prevalent notion regarding the haemostatic balance was that a clot that formed in response to injury orchestrated its own destruction by stimulating fibrinolytic activity. This concept has now been extended by the observations that blood has a strong tendency to clot and that the intact vasculature requires major antithrombotic systems to prevent clot formation [2,3]. Under normal circumstances, endothelial cells present a non-thrombogenic surface that does not attract plasma proteins and blood cells. Following contact of blood with damaged tissue or a synthetic surface, however, deposition of proteins and thrombus formation is observed. Indeed, thrombosis and related events such as embolization remain the greatest obstacles to the use of artificial devices in a clinical setting (e.g. after heart valve replacement) [4]. Correspondence: Prof. Dr, Department of Hematology, Center of Internal Medicine, Zentralkrankenhaus St.-Jürgen-Str. 1, D Bremen, Germany X/01/0Q $35.00/0 T hr o m bo s i s Hypercoagulable state Blood flow Vascular endothelium Blood constituents Normal haemostasis Hypocoagulable state Figure 1 The balance of normal haemostasis (eucoagulable state). Hypercoagulable states and thrombosis are induced by altered blood flow (e.g. stasis, turbulences), defects in the endothelium and changes in the blood constituents (e.g. reduced inhibitor capacity of the coagulation system, reduced activity of the fibrinolytic system). Hypocoagulable states and bleeding are caused primarily by reduced activity of procoagulant factors (e.g. in haemophilia), thrombocytopenia and antithrombotic drugs. The eucoagulable state and haemostasis Vascular endothelium, the cellular monolayer that lines the entire cardiovascular system, is strategically located at the interface between blood and tissues. It provides a protective barrier that separates blood from highly reactive elements in the deeper layers of the vessel wall [5,6]. Endothelial cells are exposed to a variety of biochemical and biomechanical stimuli. The finding that specific fluid mechanical forces, including shear stress, influence endothelial structure and function has provided a framework for a mechanistic understanding of flow-dependent processes in haemostasis and thrombosis [7,8]. Inert platelets, as well as plasma factors, normally circulate in close contact with the endothelium The European Society of Cardiology B le e d i n g

2 Q4 Table 1 Antithrombotic properties of endothelium contributing to vascular patency Vessel injury Endothelial factors Biological functions Collagen Contact activation XIa Tissue factor Surface, ICAM Absent activation of hemostasis VIIa PL ADPase Prostacyclin (prostaglandin I 2 ) Nitric oxide Thrombomodulin Heparan sulphate Inhibitors of platelet activation Inhibitors of blood coagulation Activated platelets vwf Platelet adhesion VIIIa IXa PL TFPI Xa t-pa, u-pa, PAI Modulators of fibrinolysis TM PC, PS Va PL Endothelin Prostacyclin Vasoconstriction and vasodilatation Fibrinogen Thrombomodulin is a membrane protein which binds to thrombin to form the protein C activation complex. ADPase=adenosine diphosphatase; ICAM=inter-cellular adhesion molecule; PAI=plasminogen activator inhibitor; t-pa=tissue plasminogen activator; u-pa=urokinase plasminogen activator. Platelet aggregation Thrombin t-pa/u-pa PAI Under normal physiological conditions, platelets do not adhere to the endothelial cells or to one another, nor do they bind adhesive proteins that are present in the surrounding plasma. On encountering temporary dysfunction of the vessel wall related, for example, to desquamation of endothelial cells, the latent activation of the haemostatic mechanisms plays a major role in maintaining the structural and functional integrity of the vascular system. Excessive activation of haemostatic mechanisms is prevented by protective endothelial factors (Table 1), inhibitors of the coagulation system (Fig. 2) and the diluting effects of the flowing blood. In the case of traumatic vascular injury with endothelial disruption (e.g. the cut end of a divided vessel), activation of platelets and coagulation factors evokes a vigorous response [9]. Platelets are anchored to the subendothelium by links formed between cellular adhesion molecules/adhesive receptors and adhesive ligands/counter-receptors in the blood and connective tissues (Table 2). Once adherent to the subendothelium the platelets spread out over the surface, and additional platelets, which are delivered by the flowing blood, adhere first to the basal layer and then to one another through inter-platelet bridges provided by fibrinogen, forming a clot of aggregated cells (first phase of haemostasis). Platelet aggregation requires activation of platelets by adenosine diphosphate, which is released from platelet storage organelles. Fibrin formation represents the second phase of haemostasis. It is triggered by pro-coagulant factors (e.g. fibrinogen, factor V, von Willebrand factor) secreted by the platelets, by tissue factor as a critical component of vascular elements (extrinsic pathway), and by contact activation (intrinsic pathway) of the coagulation system. Once factor Xa is formed it converts pro-thrombin to thrombin (common pathway), which induces fibrin strand formation. The platelet membranes provide sites for orderly surface Fibrin CLOT Wound healing Recanalization Figure 2 Basic mechanisms in haemostasis and thrombosis. Injury induces activation of platelets and initiation of the clotting cascade. Activation of coagulation is triggered by contact and by tissue factor, an intrinsic membrane protein. Key events are the formation of factor Xa, and the prothrombin thrombin and fibrinogen fibrin conversions. There are remarkable feedback reactions. Circles indicate sites of inhibitor action. The protein C anticoagulant pathway (thrombomodulin [TM], protein C [PC] and protein S [PS]) inactivates factors Va and VIIIa, thereby shutting down thrombin formation and preventing clot extension. AP=antiplasmin; = antithrombin; PAI = plasminogen activator inhibitor; PL=phospholipid; TFPI=tissue factor pathway inhibitor; t-pa=tissue plasminogen activator; u-pa= urokinase plasminogen activator; vwf=von Willebrand factor. packing of activated coagulation proteins (factors V and VIII) that urge them to generate thrombin at high rates. The fibrin mesh binds the platelets together and contributes to their attachment to the vessel defect, mediated by binding the platelet receptor glycoproteins and by interactions with other adhesive proteins such as thrombospondin, fibronectin and vitronectin. The definitive haemostatic plug that seals off the haemorrhagic leak is a platelet fibrin thrombus. Over- XIIIa AP Plasmin

3 Haemostasis and thrombosis Q5 Table 2 Synergistic interaction of the major platelet glycoprotein receptors with constituents of the vessel wall and blood in cases of vascular injury Plasma/vessel wall: Biological function in Platelets: adhesion molecules/receptors ligands/counter-receptors haemostasis and thrombosis GPIa/Iia Collagen, Adhesion and activation of platelets GPIb/IX/V von Willebrand factor (shape change, secretion) GPIIb/IIIa Fibrinogen, von Willebrand factor, Platelet aggregate formation vitronection Activation of platelet ligand-binding sites is also achieved through agonists (serotonin, thromboxane A 2, adenosine diphosphate, adrenaline, thrombin) that bind to G-protein-coupled seven-transmembrane receptors. GP=glycoprotein. whelming thrombosis induced by activated haemostasis in the vascular bed outside the region of vascular defect is counteracted by the dilution effects of the flowing blood, by the antithrombotic capacity of the haemostatic system and by local activation of fibrinolysis. Furthermore, fibrinolysis with clot solution paves the way for wound healing (third phase of haemostasis). Hypocoagulable states and bleeding disorders Abnormal bleeding is the result of defective vascular function or disturbed haemostasis after injury. Endothelial cell permeability is influenced by the functional adaptations that join the cells to their neighbours. Vessel permeability is increased by vasodilatation, by thrombocytopenia and by antithrombotic drugs. The great variety of congenital bleeding disorders provides clear evidence of the key role played by single participants of normal haemostasis. Bernard Soulier syndrome is caused by abnormality of the glycoprotein (GP)Ib/V/IX complex, which results in decreased platelet adhesion to vessel wall subendothelium. In patients with Glanzmann thrombasthenia, platelet aggregation is absent because of a deficiency in GPIIa/IIIb. The bleeding tendency in patients with von Willebrand disease (deficiency of the ligand), storage pool disease (deficiency of platelet granules containing adenosine triphosphate/adenosine diphosphate) and in the haemophilias (deficiency in factors VIII or IX) is very well known. From these examples, is it apparent that all of the factors referred to above (along with some that are not) are needed for normal haemostasis, because a severe deficiency of one cannot be compensated for by normal activity/concentration of the others. Antithrombotic drugs induce a hypocoagulable state and a bleeding tendency. Haemorrhage is an important and often preventable side effect of anticoagulant and antiplatelet therapy. Models have been developed to estimate the risk of major bleeding. They are based on the identification of independent risk factors for drug-related bleeding, such as a history of stroke, a history of gastrointestinal bleeding, older age and higher levels of anticoagulation [10]. Hypercoagulable states and thromboembolic disorders Injury to the vessel wall or endothelial dysfunction, a decrease in blood flow and thrombophilia of the blood (Virchow s triad) induce thrombosis. Hypercoagulable states arise from an imbalance between the procoagulant/ pre-thrombotic and anticoagulant/antithrombotic forces of the blood. A noticeable feature in all of these conditions is the focal nature of the pathological event. In general, although congenital thrombophilia is an established risk factor for venous thromboembolic disease [11], the association with arterial thrombosis is not so evident [12,13]. This is probably due to the complexity of pathogenesis of arterial thrombosis. Furthermore, even the clinical phenotypes of venous thrombosis differ in the various forms of thrombophilia (Tables 3 and 4). In fact, systemic alterations in the haemostatic mechanism typically give rise to local thrombotic lesions in discrete segments of the vascular bed. The pathophysiological basis for this observation is not completely understood [14]. In most thrombophilias, impaired neutralization of thrombin or a failure to control the generation of thrombin causes thrombosis (Fig. 2). Whether platelet hyperaggregability ( sticky platelet syndrome ) is a risk factor for venous or arterial thrombosis is under discussion [15]. The clinical significance of gene polymorphisms of platelet glycoproteins must be established. The demonstration that congenital factor VIII deficiency is associated with decreased mortality from ischaemic heart disease [16,17], and the association of elevated factor VIII levels with venous thrombotic disease [18] support the hypothesis that factor VIII concentration has a direct impact on the occurrence of thrombotic events. The same might be true for factors VII, IX and XI, and fibrinogen. Paradoxically, several recent studies suggest that increased plasma activity levels due to gene polymorphism of factor XIII may be associated with a decreased risk for arterial and venous thrombosis [19,20]. The haemodynamics of the flowing blood and surface properties influence local thrombus formation in patients following prosthetic heart valve replacement [21,22]. Many different materials (e.g. pyrolytic carbon coatings on rigid substrates) have been used to improve the biocompatibility

4 Q6 Table 3 Genetic susceptibility to thromboembolic discorders Frequency in a Hereditary thrombophilia normal white population Clinical significance Platelet receptor polymorphisms Approximately 15% Not established Homocysteinuria Very rare Premature arterial and venous thrombosis Hyperhomocysteinaemia 5 20% Possible association with vte Antithrombin deficiency, protein C deficiency, <0 5% Established risk factors for vte; associated with arterial protein S deficiency thrombotic disease, particularly in young individuals with cerebral ischaemia Activated protein C resistance/factor V Leiden 3 5% Established risk factors for vte Prothrombin G20210A 2% No major cardiovascular risk factor; possible association in young women with myocardial infarction or cerebrovascular events in children vte=venous thromboembolic disease. Table 4 Sites of thrombosis in acquired hypercoagulable states Acquired thrombophilia Paroxysmal nocturnal hemoglobinaemia, myeloproliferative disorders Antiphospholipid antibody syndrome Thrombotic thrombocytopenic purpura Coumarin induced L-Asparaginase induced Sites of thrombosis Visceral veins Arteries and veins (including retina, placenta); recurrent thrombosis of MHV? Microvessels (exceptions: liver, lung) Subcutaneous microvessels Cerebral veins and sinuses Taken together with the types of thrombosis in congenital thrombophilia (Table 3), it becomes evident that there is a systemic defect local phenotype paradox [14]. MHV=mechanical heart valve. of the mechanical valves. Some form of activation of the haemostatic system remains inevitable, however. Low-flow areas, stagnation zones, turbulent flow fields and cell damage, including haemolysis [23], may all promote adhesion and aggregation of platelets, as well as fibrin formation. Patients with mechanical heart valves have an incidence of inheritable thrombophilic disorders that is comparable to that in the general population. There are no prospective data available concerning whether congenital thrombophilia is prevalent in patients who have recurrent thrombosis after valve implantation despite adequate antithrombotic therapy. However, a retrospective analysis has described a group of patients with high prevalence of acquired hypercoagulable state, the so-called antiphospholipid syndrome [24,25]. Conclusion Blood vessels and blood circulation affect quality of life in many ways. They provide an essential nutritive function for tissues, but can also become affected by disorders or trauma, resulting in bleeding and thrombosis. Our understanding of these physiological and pathophysiological conditions has improved significantly over recent years. Our insight is broadening from simple vessel leakage or vessel occlusion to the basic mechanical, cellular, biochemical and molecular mechanisms. Whereas once only 2% of all hereditary thrombophilias could be explained, we are now able to identify the cause of venous thromboembolism in the majority of cases. However, we still lack a complete understanding of the correlation between thrombophilia and the tendency for thrombi to develop in other parts of the vascular tree or thrombosis in patients with artificial implants that are in contact with blood (e.g. mechanical heart valves). Nevertheless, current insights will give rise to future research in the field of drug development [26]. In the past, efforts to develop antiplatelet agents focused on substances that blocked the biochemical reactions that are involved in platelet activation and aggregation. Advances can be expected in the development of substances that inhibit platelet recruitment and adhesion at sites of vascular injury [27]. Conventional anticoagulant strategies focus on blocking the initiation of coagulation, preventing thrombin generation and inhibiting thrombin activity. Another approach to attenuate thrombogenesis is to enhance endogenous anticoagulant pathways [28], rather than to block specific clotting factors. It is reasonable to assume that we can look forward to an exciting era of novel antithrombotic drugs that will augment the treatment options for venous thromboembolic, as well as for cardiovascular diseases.

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