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Overview of hemostasis - UpToDate

Official reprint from UpToDate® www.uptodate.com ©2019 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Overview of hemostasis Author: Lawrence LK Leung, MD Section Editor: Pier Mannuccio Mannucci, MD Deputy Editor: Jennifer S Tirnauer, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Oct 2019. | This topic last updated: Oct 01, 2019.

INTRODUCTION Hemostasis is the process of blood clot formation at the site of vessel injury. When a blood vessel wall is disrupted, the hemostatic response must be quick, localized, and carefully regulated. Abnormal bleeding or thrombosis (ie, nonphysiologic blood clotting not required for hemostatic regulation) may occur when specific elements of these processes are missing or dysfunctional. ●

The pathways of thrombin-stimulated fibrin clot formation and plasmin-induced clot lysis are linked and carefully regulated (figure 1 and figure 2 and figure 3) [1]. When they work in coordinated harmony, a clot is laid down initially to stop bleeding, followed by eventual clot lysis and tissue remodeling.

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Abnormal bleeding can result from diminished thrombin generation (eg, due to factor VIII deficiency) or enhanced clot lysis (eg, due to alpha-2-antiplasmin deficiency). Conversely, excessive production of thrombin (eg, due to an inherited thrombophilia) can lead to thrombosis.

The elements responsible for normal hemostasis will be reviewed here. Approaches to the patient with abnormal bleeding or abnormal thrombosis are discussed separately. (See "Approach to the adult with a suspected bleeding disorder".) The uses of platelet function testing and coagulation assays to diagnose hemostatic abnormalities are discussed separately. (See "Platelet function testing" and "Clinical use of coagulation tests".)

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Although the clotting process is a dynamic, highly interwoven array of multiple processes [2], it can be viewed as occurring in phases, which are discussed in detail in the following sections: ●

Endothelial injury and formation of the platelet plug. (See 'Formation of the platelet plug' below.)

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Propagation of the clotting process by the coagulation cascade. (See 'Clotting cascade and propagation of the clot' below.)

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Termination of clotting by antithrombotic control mechanisms. (See 'Control mechanisms and termination of clotting' below.)

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Removal of the clot by fibrinolysis. (See 'Clot dissolution and fibrinolysis' below.)

FORMATION OF THE PLATELET PLUG Platelets are activated at the site of vascular injury to form a platelet plug that provides the initial hemostatic response to stop bleeding. (See "Congenital and acquired disorders of platelet function", section on 'Normal platelet function' and "Platelet biology".) Injury to the endothelium leads to exposure of the circulating blood to subendothelial elements from which it would normally be protected, and endothelial cell activation may further promote recruitment of platelets, other cell types, and procoagulant factors. (See "The endothelium: A primer".) The functional response of activated platelets involves four different processes: ●

Adhesion – The deposition of platelets on the subendothelial matrix

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Aggregation – Platelet-platelet cohesion

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Secretion – The release of platelet granule proteins

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Procoagulant activity – The enhancement of thrombin generation

Platelet activation — There are a number of physiologic platelet stimuli including adenosine diphosphate (ADP), epinephrine, thrombin, and collagen. ADP and epinephrine are relatively weak platelet activators, while collagen and thrombin are the most potent platelet activators. The spatial hierarchy of platelet agonists under flow conditions begins with thrombin, which activates a core of platelets in the core of the hemostatic plug [3]. ADP activates more loosely packed platelets in a shell overlying the core, and thromboxane provides a critical activation in the shell region. (See 'Platelet secretion' below and 'Prostacyclin and thromboxane' below.) Collagen — The intact endothelium prevents the adherence of platelets by the production of nitric oxide and prostacyclin. Intimal injury impairs these processes and exposes subendothelial elements https://www.uptodate.com/contents/overview-of-hemostasis/print?search=coagulation

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such as microfibrils, laminin, and collagen. These factors lead to the adherence of platelets, platelet activation, and secretion. Integrins are a superfamily of adhesive protein receptors that are found in many different cell types. They typically exists as a heterodimer composed of an alpha subunit and a beta subunit. The integrin glycoproteins GPIa/IIa (also known as alpha2 beta1) and GPVI are the two major platelet collagen receptors, playing critical roles in platelet adhesion and activation, respectively [4]. Patients with GPIa/IIa deficiency generally have mild bleeding diathesis, while severe spontaneous bleeding has been reported with platelet GPVI deficiency. Thrombin — Thrombin activation of cells is mediated by a family of G-protein coupled proteaseactivated receptors (PARs) [5-8]. Platelets have a dual receptor system for thrombin, with two distinct receptors (PAR-1 and PAR-4). Thrombin cleaves the amino-terminal exodomain of PAR, exposing a new amino-terminus, which then serves as a tethered ligand that binds intramolecularly to the body of the receptor to initiate transmembrane signaling [9]. PAR-1 is a high-affinity receptor that mediates the effect of thrombin at low concentrations; PAR-4 is a low-affinity receptor that requires high levels of thrombin for activation [5]. Vorapaxar is an oral PAR-1 antagonist developed as an antiplatelet agent [10,11]. In an animal model of laser-induced vascular injury, it was shown that thrombin, rather collagen, is the major agonist leading to platelet activation [12]. ADP — ADP binds to two G-protein coupled purinergic receptors, P2Y1 and P2Y12. Activation of P2Y1 leads to calcium mobilization, platelet shape change, and rapidly reversible aggregation; activation of P2Y12 leads to platelet secretion and more stable aggregation [13]. ADP is released from platelets upon platelet activation and functions in a paracrine/autocrine fashion to recruit additional platelets and amplify platelet aggregation. Clopidogrel blocks the activation of P2Y12. Platelet adhesion — Following activation, platelets undergo significant shape changes, producing elongated pseudopods that make the platelets extremely adhesive. Platelet adhesion is primarily mediated by the binding of platelet surface receptor GPIb/IX/V complex to von Willebrand factor (VWF) in the subendothelial matrix [14]. Deficiency of any component of the GPIb/IX/V complex or VWF leads to congenital bleeding disorders: Bernard-Soulier disease [15] and von Willebrand disease, respectively. (See "Biology and normal function of von Willebrand factor" and "Approach to the adult with unexplained thrombocytopenia", section on 'Causes of thrombocytopenia'.) In addition, there are other adhesive interactions that contribute to platelet adhesion. One example is binding of the platelet collagen receptor GPIa/IIa to collagen fibrils in the matrix [16].

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Platelet aggregation — Platelet activation results in both exposure of and conformational changes in the GPIIb/IIIa receptor on the platelet surface, leading to binding of VWF and fibrinogen, resulting in platelet-platelet cohesion or aggregation [17-19]. GPIIb/IIIa is also a member of the integrin superfamily. The GPIIb/IIIa complex (integrin alpha IIb beta 3) is the most abundant receptor on the platelet surface, with about 80,000 complexes per platelet. GPIIb/IIIa does not bind fibrinogen on nonstimulated platelets. However, following platelet stimulation (eg, by thrombin, collagen, or ADP), GPIIb/IIIa undergoes a conformational change and is converted from a low-affinity to a high-affinity fibrinogen receptor, a process referred to as "inside-out" signaling (since the conformational change in the external cell surface exposed GPIIb/IIIa complex is mediated by changes in the intracellular cytosolic portion ["cytoplasmic tail"] of the complex). Fibrinogen is a divalent symmetrical molecule, able to bind to two activated GPIIb/IIIa complexes on two different platelets, thus crosslinking them. (See "Platelet biology", section on 'GPIIb/IIIa activation' and "Disorders of fibrinogen".) In addition to mediating platelet aggregation, when GPIIb/IIIa binds to immobilized VWF, the cytosolic portion of the activated GPIIb/IIIa complex binds to the platelet cytoskeleton, resulting in platelet spreading and clot retraction, which has been referred to as "outside-in" integrin signaling. Thus, the GPIIb/IIIa complex integrates receptor-ligand interactions that occur on the external face of the membrane with cytosolic events in a bidirectional fashion [20,21]; it is the final common pathway for platelet aggregation, irrespective of the mode of platelet stimulation. The importance of GPIIb/IIIa is illustrated by the congenital bleeding disorder Glanzmann thrombasthenia, which is characterized by mutations in the gene for either the alpha IIb or the beta-3 subunit [22], as well as the clinical utility of GPIIb/IIIa antagonists in the treatment of coronary heart disease. (See "Congenital and acquired disorders of platelet function", section on 'Glanzmann thrombasthenia' and "Early trials of platelet glycoprotein IIb/IIIa receptor inhibitors in coronary heart disease".) Platelet secretion — Platelets contain two types of granules: alpha granules and dense granules (which appear dense on transmission electron micrographs). The alpha granules contain many proteins including fibrinogen, von Willebrand factor, thrombospondin, platelet-derived growth factor (PDGF), platelet factor 4, and P-selectin. Dense granules contain ADP, ATP, ionized calcium, histamine, and serotonin. Platelets secrete a variety of substances from their granules upon cell stimulation: ●

ADP and serotonin stimulate and recruit additional platelets [23]. Platelet-released serotonin normally causes vasodilation; however, it can induce vasoconstriction in the presence of

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damaged or abnormal (dysfunctional) endothelium. ADP-activated platelets increase the surface expression of intercellular adhesion molecule (ICAM)-1 on endothelial cells [24]. ●

Fibronectin and thrombospondin are adhesive proteins that may reinforce and stabilize platelet aggregates.

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Fibrinogen is released from platelet alpha granules, providing a source of fibrinogen at sites of endothelial injury in addition to that present in plasma [25].

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Thromboxane A2, a prostaglandin metabolite, promotes vasoconstriction and further platelet aggregation.

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Growth factors, such as PDGF, have potent mitogenic effect on smooth muscle cells. The release of PDGF from platelets at the site of vascular injury probably mediates tissue repair physiologically and, at a site of repeated injuries, may contribute to the development of atherosclerosis and coronary reocclusion following angioplasty. (See "The role of platelets in coronary heart disease".)

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Release of the thiol isomerase, protein disulfide isomerase (PDI), by platelets and disrupted vessel wall cells may serve to activate tissue factor and enhance the generation of fibrin and platelet thrombus formation at sites of vascular injury [26,27].

Procoagulant activity — Platelet procoagulant activity is an important aspect of platelet activation and involves both exposure of procoagulant phospholipids, primarily phosphatidylserine, and the subsequent assembly of the enzyme complexes in the clotting cascade on the platelet surface [28]. These complexes are an important example of the close interrelationship between platelet activation and activation of the clotting cascade that has been referred to as "cell-based" coagulation [29]. (See 'Multicomponent complexes' below.)

CLOTTING CASCADE AND PROPAGATION OF THE CLOT Overview of clot propagation — The central feature of the clotting cascade is the sequential activation of a series of proenzymes or inactive precursor proteins (zymogens) to active enzymes, resulting in significant stepwise response amplification. As an example, the generation of a small number of factor VIIa molecules will activate many molecules of factor X, which in turn generates even larger numbers of thrombin molecules, which then converts fibrinogen to fibrin (figure 2). The resultant local generation of fibrin, in turn, enmeshes and reinforces the platelet plug. The function of the active enzymes is markedly facilitated by the formation of multiple component macromolecular complexes, such as the tenases (X-ase) that activate factor X and the https://www.uptodate.com/contents/overview-of-hemostasis/print?search=coagulation

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prothrombinase which produces thrombin from prothrombin. (See 'Multicomponent complexes' below.) All of the procoagulants are synthesized in the liver except for von Willebrand factor (VWF), which is synthesized in megakaryocytes and endothelial cells, and factor VIII, which is produced in endothelial cells in the liver as well as other tissues such as lymphatics and renal glomeruli [30-32]. VWF and factor VIII are co-expressed in postcapillary high endothelial venules but not in most other endothelial cells. VWF stabilizes factor VIII. (See "Biology and normal function of von Willebrand factor" and "Biology and normal function of factor VIII and factor IX".) Post-translational modification of these factors is known to occur [33]. The best characterized modifications occur in the vitamin K-dependent procoagulants (ie, prothrombin, factors VII, IX, and X) and anticoagulants (ie, protein C and protein S). For each of these factors, vitamin K-dependent carboxylated glutamic acid residues function as calcium-binding sites that are important in the assembly of the membrane-bound macromolecular procoagulant complexes [34]. (See "Vitamin K and the synthesis and function of gamma-carboxyglutamic acid".) Traditionally, the clotting cascade is depicted as consisting of an intrinsic and extrinsic pathway (figure 1). This view of coagulation is useful for interpreting in vitro tests of coagulation. (See "Clinical use of coagulation tests".) ●

The intrinsic pathway is initiated by the exposure of blood to a negatively charged surface (such as celite, kaolin, or silica in the in vitro activated partial thromboplastin clotting time [aPTT]).

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The extrinsic pathway is activated by tissue factor exposed at the site of injury or tissue factorlike material (thromboplastin, TPL in the in vitro prothrombin clotting time [PT]).

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Both pathways converge on the activation of factor X which, as a component of prothrombinase, converts prothrombin to thrombin, the final enzyme of the clotting cascade. Thrombin converts fibrinogen from a soluble plasma protein into an insoluble fibrin clot (tested in the in vitro thrombin time [TT]).

Thrombin generation — While the classical view of the clotting cascade based on intrinsic and extrinsic pathways has been useful in the interpretation of in vitro coagulation tests (eg, PT and aPTT), it may not be physiologically accurate. It is now established that the generation or exposure of tissue factor at the wound site and its interaction with activated factor VII (factor VIIa) (figure 2) is the primary physiologic event in initiating clotting [35]. The small initial amount of thrombin generated then activates factor XI in a feedback manner, leading to amplification of thrombin generation. This was shown via the time course of https://www.uptodate.com/contents/overview-of-hemostasis/print?search=coagulation

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thrombin generation, which demonstrated an initiation phase with only a small amount of thrombin being generated, followed by a propagation phase consisting of the bulk of thrombin generation, and finally cessation of thrombin generation [36]. Standard laboratory clotting tests, which detect initial fibrin clot formation, primarily measure the initiation and not the propagation phase of clotting. The initiation phase is largely mediated by the activation of factor X by tissue factor/factor VIIa, giving rise to a small amount of thrombin (figure 4), which in turn activates factor V, factor VIII, factor XI, and platelets, exposing anionic phospholipids on the platelet surface to support the assembly of the multi-component enzyme complexes (intrinsic tenase and prothrombinase) [37]. Thus, the initial small amount of generated thrombin primes the clotting cascade and activates platelets, which then leads to explosive thrombin generation. This is illustrated in the Amplification and Propagation phases in the figure (figure 5). At least two cell types play important roles in the initial phases of thrombin generation. ●

Activated platelets in the initial platelet plug adherent to the endothelium provide a phospholipid surface that promotes assembly of multicomponent complexes. (See 'Multicomponent complexes' below.)

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Endothelial cells at the site of injury provide binding sites for coagulation factors and other procoagulant effects.

The prominent role of endothelial cells rather than platelets to thrombin generation was illustrated in a study using a mouse model of arteriolar injury in which accumulation of fluorescently labeled activated clotting factors was imaged in vivo [38]. Fluorescently labeled factors Xa and Va bound to the endothelium outside the edges of the initial platelet plug and did not bind to platelets a small distance from the site of injury. When platelet thrombus formation at the injured site was blocked extensively, using an inhibitor of platelet aggregation or an animal lacking the platelet thrombin receptor PAR4, accumulation of factors Xa, Va, and fibrin at the site of injury was virtually unaffected. These findings may explain why patients with severe thrombocytopenia or inherited platelet defects do not have typical findings associated with impaired coagulation such as tissue hematomas and joint bleeding (table 1). Multicomponent complexes — Four multicomponent macromolecular complexes play a major role in the coagulation pathways: three procoagulant complexes (extrinsic and intrinsic X-ase and prothrombinase) and one anticoagulant complex. These complexes consist of the enzyme, a cofactor protein, the enzyme substrate, assembled on cellular membrane components (anionic phospholipid surfaces) in the presence of calcium (figure 1):

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Extrinsic X-ase (ten-ase) – Consists of activated factor VII (factor VIIa) as the protease, tissue factor as the cofactor, and factor X (Stuart factor) as the substrate [39-41]. The extrinsic X-ase activates both factor X and factor IX [42,43].

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Intrinsic X-ase (ten-ase) – Consists of factor IXa as the protease, activated factor VIII (factor VIIIa) as the cofactor, and factor X as the substrate [44]. Factor IXa can be generated by the extrinsic X-ase or via activation of the intrinsic pathway, either directly or indirectly via thrombininduced activation of factor XI.

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Prothrombinase – Consists of factor Xa as the protease, factor Va as the cofactor, and prothrombin (factor II) as the substrate.

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The protein C anticoagulant complex – Consists of thrombin (factor IIa) as the enzyme, thrombomodulin as the cofactor, and protein C as the substrate. In addition, endothelial protein C receptor (EPCR), which is primarily expressed on the endothelium of large blood vessels, functions as a receptor for protein C and further accelerates the activation of protein C by the thrombin/thrombomodulin complex [45].

All the activated clotting factors in the clotting cascade (ie, factors VIIa, XIa, IXa, Xa, and thrombin [IIa]) are trypsin-like serine proteases (with serine as a major component of their catalytic site). Despite their structural relatedness, they display remarkable specificity towards their substrates (eg, FIXa activates factor X but not prothrombin (factor II) or fibrinogen). This substrate specificity results from the structural requirement of the substrate to be aligned properly ("docked") with the enzyme before proteolytic cleavage of the substrate can take place. This docking is mediated by an exosite on the enzyme surface that lies outside the active catalytic site (figure 4) [46]. The advantages of these multicomponent enzyme complexes can be illustrated by the prothrombinase complex [47]. When platelets are activated, anionic lipids – primarily phosphatidylserine – become exposed on the platelet surface, and factor V, stored in platelet granules, is released and bound to these anionic lipids. Factor V is activated to factor Va by the initial trace amount of thrombin generated from interactions between tissue factor and factor VIIa at the wound site. Together with the appropriate anionic membrane phospholipids and calcium, this activated factor Xa and its cofactor, factor Va, form the prothrombinase complex, which cleaves prothrombin (factor II) to thrombin (factor IIa). Because of its extremely favorable local proximity, thrombin generation by the prothrombinase complex is approximately 300,000 times more efficient compared with that generated by factor Xa and prothrombin alone. In addition, factor Xa bound to factor Va is also relatively protected from

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inhibition by circulating inhibitors such as antithrombin. The net effect is that thrombin generation is dramatically enhanced on the surface of activated platelets and restricted to sites of vascular injury. The importance of the procoagulant effect of platelets in the assembly of multicomponent complexes is illustrated by congenital platelet function disorders in which the platelet membrane phospholipids do not change in response to platelet activation. Scott syndrome is an autosomal recessive disorder caused by mutation of TMEM16F, a protein partly responsible for lipid scramblase activity [28,47-51]. This protein forms a calcium-activated channel that promotes the "scrambling" (ie, disrupting the membrane gradient) of phosphatidylserine, moving it from the inner leaflet of the platelet plasma membrane to the outer leaflet [51]. Activated platelets with phosphatidylserine on their surface bind factor Va and initiate assembly of the prothrombinase complex. Patients with Scott syndrome have impaired thrombin generation, clinically prolonged bleeding, and a reduced tendency to form thromboses. Extrinsic pathway Tissue factor — Vessel wall damage leads to expression of tissue factor (TF, tissue thromboplastin), an integral membrane glycoprotein [52]. Tissue factor is not normally expressed on vascular endothelial cells or monocytes but is constitutively expressed on certain biological surfaces, such as skin, organ surfaces, vascular adventitia, and many of their malignant counterparts. Normally, TF is exposed to blood flow only after endothelial damage [53]. The mechanism may be either via direct exposure of the subendothelial matrix and/or via cytokine- (especially interleukin [IL]-6-) induced expression of TF on activated monocytes and endothelial cells [54]. The majority of the TF is in a functionally inactive ("encrypted") state. Upon cell lysis or certain in vitro conditions, such as stimulation by calcium ionophore, TF will become activated ("de-encrypted") and support FVIIa binding and activation of factor X. The encrypted state may be due to a pair of free cysteine residues (Cys186 and Cys209) which would become linked into a disulfide bond upon cell perturbation, leading to an allosteric change in the conformation of TF resulting in its active deencrypted state [55,56]. Protein disulfide isomerase (PDI), glutathione, and nitric oxide have all been implicated in mediating this process [56]. However, not all of the data are consistent and whether Cys186 and Cys209 are involved in the de-encryption of TF remains controversial [57-59]. TF may also circulate in the blood, associated with cell-derived membrane microvesicles as well as in a soluble, alternatively-spliced form [60,61]. These microvesicles derive from lipid rafts on the surface of stimulated monocytes/macrophages, and are capable of fusing with, and initiating coagulation on, activated platelets [62]. (See 'White blood cell contributions' below.)

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In addition to assembling clotting reactions on their surface, platelets may also synthesize their own tissue factor in order to generate thrombin in a timely and spatially circumscribed process [63], although this has been called into question [64]. (See "Pathogenesis of the hypercoagulable state associated with malignancy", section on 'Tissue factor-bearing microparticles'.) Activation of factors VII, X, and IX — TF serves as the cofactor required for the production of activated factor VII (FVIIa) [65,66]. The TF-FVIIa complex activates factors X [39,40] and IX [42,43]. Activation of factor X occurs at the Arg52-Ile53 peptide bond in the heavy chain of factor X, leading to the formation of the serine protease Xa [41]. Factor IXa in complex with its cofactor factor VIIIa also activates factor X (the intrinsic X-ase as noted above) (figure 1) [40]. This dual pathway of factor X activation (ie, directly and indirectly via activation of factor IX) is necessary because of the limited amount of TF generated in vivo and the presence of the tissue factor pathway inhibitor (TFPI) which, when complexed with factor Xa, inhibits the TF/FVIIa complex [67]. Thus, sustained generation of thrombin depends upon the activation of factor IX and its cofactor factor VIII. This process is amplified because factor VIII is activated by both factor Xa and thrombin [39,68] and factor IXa by thrombin-induced activation of factor XI [69-73]. As a result, there is a progressive increase in factor VIII and factor IX activation as factor Xa and thrombin are formed. In vitro studies using human plasma have also demonstrated a feed-forward loop in which the TF/FVIIa complex can activate factor VIII, a component of the intrinsic (contact activation) pathway [74]. (See 'Intrinsic or contact activation pathway' below.) Intrinsic or contact activation pathway — The initial phase of the intrinsic or contact activation pathway consists of several plasma proteins including factor XII (Hageman factor), prekallikrein (Fletcher factor) and high molecular weight kininogen (HMWK, Fitzgerald factor). These factors are activated by contact with negatively charged surfaces, leading to the term "contact activation pathway." Contact with negatively charged surfaces initiates the following sequence: ●

Enhanced auto-activation of factor XII. Activated factor XII (factor XIIa) in conjunction with HMWK activates factor XI, which in turn, activates factor IX.

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Factor IXa in complex with factor VIIIa forms the intrinsic X-ase, leading to the formation of factor Xa (see 'Multicomponent complexes' above). Factor VIII is activated by both factor Xa and thrombin [39,68]. Thus, there is a progressive increase in factor VIII activation as factor Xa and thrombin are formed. Thrombin also increases the generation of factor IXa via the activation of factor XI [69,70,72,73].

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Factor XIIa activates plasma prekallikrein (PPK) to plasma kallikrein (PK), which liberates bradykinin (BK) from HMWK. BK is a major inflammatory peptide that induces pain and

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vasodilation (see 'Blood coagulation as part of the host defense system' below). PK also activates factor XII, thus forming a positive feedback loop of activation [75]. The remainder of the intrinsic pathway uses the same cascade as the extrinsic pathway (the common pathway), which involves factors V, prothrombin, and fibrinogen. As noted above, in vitro studies suggest that this pathway can also be activated by the TF/FVIIa complex. (See 'Extrinsic pathway' above.) Critical role of polyphosphate in initiating blood clotting via the intrinsic contact pathway — Inorganic polyphosphate (polyP) is a linear highly anionic polymer of orthophosphates linked by high-energy phosphoanhydride bonds. It is ubiquitous in biology and can vary from a few to several thousand phosphate units in polymer length, depending on the organisms and tissues from which it is derived. In microorganisms, polyP is synthesized from ATP and may serve as an energy store allowing the bacteria to resynthesize ATP in times of starvation [76]. PolyP is also stored in human platelet dense granules and is efficiently released upon platelet activation [77]. In contrast to microbial polyP, platelet polyP is smaller, consisting of 60 to 100 phosphate units. With its multiple anionic charges, polyP is a potent procoagulant, and it likely represents the "physiological" or "pathological" negatively charged surface that triggers blood coagulation via the intrinsic pathway. The source of polyP in this setting may derive from injured tissues at the wound site or a microbial source in the case of an infection. In addition to triggering intrinsic pathway activation, polyP has other effects on blood clotting. It accelerates factor V activation, abrogates the inhibitory effect of tissue factor pathway inhibitor (TFPI), enhances fibrin polymerization (making the fibrils thicker), and accelerates factor XI activation by thrombin. The potency of polyP is dependent on its chain length. Long-chain polyP (from a microbial source) is efficient in carrying out all four functions, while medium-size polyP (from platelets) is less effective in triggering the intrinsic pathway but effective in accelerating blood clotting once it is initiated [78]. Deficiencies of intrinsic contact pathway proteins — The physiologic relevance of the initial complex of the intrinsic contact pathway is not fully established. Deficiencies in these proteins (prekallikrein, HMWK, and factor XII) are not associated with bleeding tendencies, suggesting that the initiation portion of the intrinsic pathway (the contact phase) is not very important in vivo [79,80]. Mutations in factor XII have been seen in a subset of patients with hereditary angioedema (HAE) and normal C1 inhibitor levels, an autosomal dominant disease characterized by recurrent attacks of upper respiratory tract edema, although the bleeding phenomena and coagulation defects in these patients have not been well characterized. (See "Hereditary angioedema with normal C1 inhibitor".)

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However, injury-related bleeding is seen with deficiency of factor XI [81], suggesting that factor XI plays an important hemostatic role, independent of contact activation and factor XII. One likely mechanism is that thrombin feedback activates factor XI, with polyP, released from activated platelets or derived from injured tissues, serving as a cofactor [69-71,82]. Factor XIa then activates factor IX, which leads to further thrombin formation after the clot has been formed [70]. This interpretation is also consistent with the phenotype observed in mice deficient in either factor XII or factor XI. These mice do not exhibit any bleeding problems under normal circumstances, similar to patients deficient in factor XII or factor XI, but surprisingly, they are protected from arterial thrombosis in experimental thrombosis models [83,84]. In this regard, it is notable that patients severely deficient in factor XI (