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22. Circular of Information Regarding Transfusions from the Choosing Wisely Campaign. American Association of Blood Banks, 2014. Available at http://www.aabb.org/pbm/Documents/Choosing-

Wisely-Five-Things-Physicians-and-Patients-Should-Question. pdf. Accessed October 26, 2020.

23. Munoz M, Acheson AG, Auerbach M, Besser M, Habler O, Kehlet H, et al. International consensus statement on the perimanagement of anaemia and iron deciency. Anaesthesia. 2017;72(2):233–47.

24. Chong MA, Krishnan R, Cheng D, Martin J. Should transfusion trigger thresholds differ for critical care versus perioperative patients? A meta-analysis of randomized trials. Crit Care Med. 2018;46(2):252–63.

25. Hendrickson JE, Hillyer CD. Noninfectious serious hazards of transfusion. Anesth Analg. 2009;108(3):759–69.

26. Vamvakas EC, Blajchman MA. Blood still kills: six strategies to further reduce allogeneic blood transfusion-related mortality. Transfus Med Rev. 2010;24(2):77–124.

27. Rudmann SV. Textbook of blood banking and transfusion medicine. 2nd ed. Philadelphia: Elsevier/Saunders; 2005.

28. Scott E, Puca K, Heraly J, Gottschall J, Friedman K.Evaluation and comparison of coagulation factor activity in fresh-frozen plasma and 24-hour plasma at thaw and after 120 hours of 1 to 6 degrees C storage. Transfusion. 2009;49(8):1584–91.

29. Fresh Frozen Plasma Leucocyte Depleted. Guidelines for the blood transfusion services. 8th ed: Joint United Kingdom: The Stationary Ofce; 2013.

30. Smith JF, Ness PM, Moroff G, Luban NL.Retention of coagulation factors in plasma frozen after extended holding at 1-6 degrees C.Vox Sang. 2000;78(1):28–30.

31. Shehata N, Blajchman M, Heddle N. Coagulation factors in FFP and cryosupernatant. Transfus Med. 2001;11:391–401.

32. MacLennan S, Williamson LM.Risks of fresh frozen plasma and platelets. J Trauma. 2006;60(6 Suppl):S46–50.

33. Khawar H, Kelley W, Guzman N. Fresh frozen plasma (FFP). Treasure Islands: StatPearls; 2019.

34. O’Shaughnessy DF, Atterbury C, Bolton Maggs P, Murphy M, Thomas D, Yates S, etal. Guidelines for the use of fresh-frozen

operative

plasma, cryoprecipitate and cryosupernatant. Br J Haematol. 2004;126(1):11–28.

35. Dean L, National Center for Biotechnology Information (U.S.). Blood groups and red cell antigens. Bethesda: NCBI; 2005.

36. Pandey S, Vyas GN. Adverse effects of plasma transfusion. Transfusion. 2012;52(Suppl 1):65S–79S.

37. Jhang JS, Spitalnik SL.Glycosylation and cold platelet storage. Curr Hematol Rep. 2005;4(6):483–7.

38. Rao GH, Smith CM 2nd, Escolar G, White JG.Inuence of heat on platelet biochemistry, structure, and function. J Lab Clin Med. 1993;122(4):455–64.

39. Haematology BCfSi, Force BTT.Guidelines for the use of platelet transfusions. Br J Haematol. 2003;122(1):10–23.

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43. Centers for Disease C, Prevention. Fatal bacterial infections associated with platelet transfusions– United States, 2004. MMWR Morb Mortal Wkly Rep. 2005;54(7):168–70.

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The Coagulation System andBlood Clot

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Stability

NikitaNayyar, HaigMannasian, LongqiuYang, andHenryLiu

Introduction

Hemorrhage is a very common complication in perioperative settings and other invasive procedures. This complication can be caused by various factors, usually by surgical technical difculties and coagulation abnormalities [1, 2]. Reduction of surgery-related blood loss will be addressed in other chapters in this book. Here we will discuss normal coagulation system, coagulation regulations, and clot stability. The coagulation system is a series of enzymatic reactions that plays an important role in hemostasis and normal human life. Coagulation cascade is a very dynamic process that involves multiple enzymes that propagate to the clot formation [2]. A delicate balance between the coagulation system and the brinolytic system is critical in order to maintain a normal blood circulation. Hemostasis is to stop bleeding after an injury. It is categorized as primary hemostasis and secondary hemostasis [3, 4]. In primary hemostasis, the blood vessel contracts and platelets adhere to the site of injury. In a series of integrative reactions, the platelets form a temporary hemostatic plug that prevents extravasation from the site of injury. The nal step is secondary hemostasis [5]. In secondary hemostasis, the coagulation system is activated and a series of enzymatic reactions and a cascade of factor activations take

N. Nayyar New York University Langone School of Medicine, Department of Anesthesiology, New York, NY, USA

H. Mannasian Thomas Jefferson University Hospital, Department of Anesthesiology, Philadelphia, PA, USA

L. Yang Huangshi Central Hospital, Department of Anesthesiology, Huangshi, Hubei, China

H. Liu (

Department of Anesthesiology and Perioperative Medicine, Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA, USA

place to form brin which subsequently reinforces the primary platelet plug [6].

Blood maintains its uidity in the vascular system and its ability to clot when a blood vessel is damaged by various etiologies. In 1905, Morawitz described the classic theory of blood coagulation (Fig.4.1), in which he rst described the conversion of prothrombin to thrombin and then the conversion of brinogen to brin, utilizing thromboplastin and calcium ions [7]. More intricacies and details of the coagulation cascade were discovered via clinical observations and experimental studies in subsequent decades. It was unveiled that there was an abnormality in the blood of patients with hemophilia that leads to the prolongation of clotting time in 1936. Both invivo and invitro investigations led to the discovery of Factor VIII deciency [8]. Furthermore, heparin and antithrombin were discovered after multiple experiments looking into the coagulation of blood with enzymes derived from the livers of dogs [9]. Each of the new factors that were discovered were given their own name by different researchers which led to enormous confusion regarding the interplay between various factors and their roles in coagulation cascade. An international committee for the nomenclature of blood coagulation factors was established in 1954 with a goal of creating common terminology for the known clotting factors at that time [10]. With the discovery of procoagulants also came the discovery of anticoagulants. The role of Protein C in anticoagulation was also discovered after signicantly lower Protein C levels were found in a family with many members prone to thrombosis as opposed to normal Protein C levels in those without coagulation issues [11]. After the discovery of Protein C deciencies, laboratory tests were developed and revealed that deciencies in Protein S also lead to procoagulant tendencies [6, 12].

As our understanding of clotting factors deepened, adjustments to the classic theory were made and the role of the coagulation factors was more specically dened.

https://doi.org/10.1007/978-3-030-59295-0_4

N. Nayyar et al.

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Fig. 4.1 The classic theory

of blood coagulation by Morawitz (1905) [7]

Table 4.1 Coagulation factors and their functions [15]

Factor number Coagulation actor name Biological function

I Fibrinogen Clot formation 3000 90 II Prothrombin Activates I, V, VII, VIII, protein C, platelet 100 65 III Tissue factor Cofactor of VIIa IV Calcium Facilitates factor binding to phospholipids V Labile factor/Proacclerin Cofactor of X-prothrombinase complex 10 15 VI Unassigned VII Stable factor/Proconvertin Activates IX, X 0.5 5 VIII Antihemophilic factor A Cofactor of IX-tenase complex 0.1 10 IX Antihemophilic factor B/Christmas

factor

X Stuart-power factor Prothrombinase complex with factor V,

XI Plasma thromboplastin antecedent Activates IX 5 45 XII Hageman factor Activates factor XI, VII, Prekallikrein XIII Fibrin-stabilizing factor Cross-link brin 30 200 XIV Prekallikrein(F Fletcher) Serine protease zymogen 35 XV HMWK- (F Fitzgerald) Cofactor 150 XVI vWF Binds to VIII, mediates platelet adhesion 10ug/ml 12 XVII Antithrombin III Inhibits IIa, Xa, other proteases 0.15–0.2mg/ml 72 XVIII Heparin cofactor II Inhibits IIa 60 XIX Protein C Inactivates Va, VIIIa 0.4 XX Protein S Cofactor for activated protein C

Activates X: forms tenase complex with factor VIII

activates II

Plasma concentration (mg/L)

5 25

10 40

Plasma T (h)

1/2

The waterfall hypothesis, which was developed in 1964 by Davie and Rantoff, provided a detailed schematic for the interactions of the factors leading to clot formation and is the basis of coagulation cascade today [13]. As the roles of the various factors began to be better dened, the waterfall hypothesis has also been continually modied [6].

The coagulation cascade can be broken down into two pathways, the intrinsic pathway and the extrinsic pathway. The intrinsic pathway, so named because all of the components in the cascade are found in plasma, it is triggered when plasma comes into contact with an articial surface, such as a glass test tube. The extrinsic pathway requires blood to come into contact with an extrinsic molecule, tissue factor, which then triggers the clotting cascade [3]. Both pathways are explained in greater depth in subsequent sections.

Coagulation Factors andTheir Functions

Most of the coagulation factors are zymogens which are inert precursors of enzymes. Zymogens are activated by limited proteolysis which results in active serine proteases with low inherent enzymatic activity. When these active proteases bind specic protein cofactors, the activity of the proteases increases signicantly. The cofactors of the clotting cascade also circulate in the plasma as inert procofactors, which must be converted to active cofactors via proteolysis. So, both the enzymes and cofactors of the coagulation cascade require an activation process prior to exerting their biological effects. Once these enzymes and cofactors become active, they are appended with a lower case ‘a’ [14]. Table 4.1 lists all the coagulation factors currently known and their physiological functions (Table4.1) [15].

4 The Coagulation System andBlood Clot Stability

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Thromboplastin (TF) is a glycosylated integral membrane protein and it is unique because it does not require activation. It functions as a receptor (for involved in inammation, apoptosis, cell migration) and also as a cofactor for Factor VII/VIIa [3, 14]. It is expressed in many extravascular tissues as in the brain, heart, lungs, and kidneys. Furthermore, it can also be expressed on vascular endothelium in response to inammatory stimulation, lipopolysaccharides in sepsis, adhesion molecules, and inammatory cytokines. TF expression has also been found on some cancer tissues [14]. Factor VII/VIIa, Factor VII is synthesized in the liver. Factor VII contains a gamma-carboxyglutamic acid-rich (GLA) domain which allows calcium-dependent binding of Factor VII to membranes containing negatively charged phospholipids. Factor VII circulates in both active VIIa and inactive VII form in the blood. VIIa is not susceptible to most plasma protease inhibitors and has a half-life of 2hours. Factor VII can be activated by IXa, Xa, XIIa, thrombin, plasmin, and TF:VIIa complex [3, 14]. TF:VIIa Complex can activate Factors IX and X, and it can be inhibited by Tissue Factor pathway inhibitor XII/XIIa (thrombin).

Thrombin is produced in the liver and is activated by kallikrein, plasmin, Factor XIIa. XII/XIIa activates Protein C, so thrombin can be both procoagulant and anticoagulant. PK/Kallikrein is produced in the liver and activated by XIIa. High-molecular-weight kininogen (HK) is synthesized in

liver but also contained in granulocytes, platelets, and endothelial cells. HK binds to cell surface in a zinc-dependent manner. HK activates Factor XII to XIIa.

Normal Coagulation Cascade

Intrinsic pathway depends on the activation by a negatively changed surface and involves coagulation Factors XII, XI, IX, VIII, and V.The extrinsic pathway depends on the activation by TF and tissue factor (Factor III) and Factor VII.Both pathways converge on a common pathway to activate Factor X, which leads to the conversion of prothrombin (Factor II) to thrombin (IIa). This subsequently converts brinogen to form brin. The Partial thromboplastin time (PTT) can be used to assess the intrinsic pathway and the Prothrombin time (PT) can be used to assess the function of the extrinsic pathway. The three stages of coagulation are initiation, amplication, and propagation [2, 16], (Fig.4.2).

The initiation phase begins with the exposure of TF to the blood by damage to or activation by the endothelium. TF then forms a complex with Factor VIIa on the surface of the cell membrane and activates the zymogens Factors IX and X.Activated Factor X then generates Factor IIa (thrombin). Tissue Factor pathway inhibitor neutralizes Factor Xa and TF:VIIa complexes. The duration of the initiation phase is

Fig. 4.2 Coagulation

pathways [2, 14]

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N. Nayyar et al.

Fig. 4.3 Stages of

coagulation [

2, 14]

dependent on the balance between the concentration of TF:VIIa and tissue Factor pathway inhibitor [2, 17], (Fig.4.3).

In the amplication phase, Factor IXa and Factor VIIa form an intrinsic Factor tenase complex (FIXa:FVIIa) in the presence of calcium. This process greatly enhances the production of Factor Xa which signicantly accelerates thrombin production. The prothrombinase complex (FXa:FVa) is also increased by its proximity to the tenase complex and the presence of calcium, resulting in more thrombin production. A positive feedback loop forms between the tenase and prothombinase complexes to generate substantial quantity of thrombin to stabilize the newly formed clot [2, 17]. Thrombin also interacts with platelets via platelet receptor GPIb which allows interaction of other platelet components and activates GPIIb/IIIa receptor, further promoting platelet aggregation. Thrombin also increases Factor VIIIa by releasing it from vWF:VIII complex and also activates Factor XI to XIa. Subsequently, Factor XIa adheres to platelets and causes activation of the intrinsic pathway. The platelets in the hemostatic plug are stimulated by both collagen and thrombin and then generate more thrombin by further activating tenase and prothombinase complexes. The main result of the amplication phase is to generate as much thrombin as possible [2, 4,

14, 18], (Fig.4.3).

The propagation phase is the nal step in stabilizing the clot. It involved the recruitment of all components, tenase complex, platelets, prothrombinase complexes, calcium to the phospholipid surface. Then platelets are activated by thrombin and the “thrombin burst” leads to the accelerated formation of brin from brinogen. These brin monomers form brin layers. Thrombin also activates Factor XIII to Factor XIIIa which then covalently crosslinks the brin strands to form a more stable brin network. Thrombin also activates thrombin-activatable brinolysis inhibitor which

protects the clot from plasmin brinolysis [2, 4, 14, 18], (Figs.4.3 and 4.4).

The intrinsic or contact pathway is generally activated by Factor XII.Contact of plasma with an articial surface leads to activation of Factor XII to XIIa. Factor XIIa then activates Factor XI to XIa. Factor XIa activates Factor IX to IXa and it allows for the formation of tenase complexes with VIIIa. This then activates Factor X to Factor Xa. The generation of Factor Xa leads to the common pathway of thrombin generation and blood clot stabilization. The intrinsic pathway also produces bradykinin when kallikrein cleaves HK. Subsequently, bradykinin binds to its receptors and results in vasodilation, increased vascular permeability, pain, and neutrophil activation [14, 18], (Fig.4.2).

Regulation ofCoagulation

The coagulation cascade is regulated at every step in order to maintain a balance between procoagulation and anticoagulation. The most important regulation mechanisms are multiple zymogens and cofactors requiring activation prior to exerting their effects. Tissue factor pathway inhibitor (TFPI) neutralizes Factor Xa and it inhibits the TF:VIIa complex. TFPI is primarily produced by the endothelium and it can also be found on platelets. When heparin is administered, the endothelial form of TFPI is released [2, 14]. In mice whose TFPI have been knocked out, these mice do not survive, indicating that lack of TFPI is incompatible with life [19]. Endothelial cells secrete heparan sulfate which activates antithrombin. This antithrombin heparan complex can inhibit multiple coagulation enzymes [2, 14]. When Protein C is activated by thrombin, Protein C inhibits the procoagulant functions of Factors VIIIa and Va. Protein C is vitamin K dependent. Protein S further supports the activity of protein C in inactivating Factors

4 The Coagulation System andBlood Clot Stability

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tal principle of clot stability is that it is a balance between clot formation and brinolysis. This balance can be skewed in either direction by a multitude of factors, including those molecular, metabolic, mechanical, and pharmacologic in nature. Furthermore, the processes of coagulation and brinolysis occur simultaneously in many clinical scenarios. It is necessary to rst mitigate the inherent complexity of this topic by providing a global roadmap for how coagulation and brinolysis interrelate to afford hemostasis. We will then point to specic factors in this framework that inuence clot stability, and brinolysis and its role in disease process. After the blood coagulation cascade is initiated and subsequently thrombin is activated, which then catalyzes the formation of brin from its parent zymogen, brinogen. Fibrin creates a hemostatic milieu in the blood vessels due to its low solubility in the blood. The brin peptides are then cross-linked at lysine residues by the action of Factor XIIIa in the process known as “polymerization”. Simultaneously, leukocytes, erythrocytes, and platelets assimilate into the brin cross- link network to enhance the structural integrity of the clots [20–22]. Once the injured tissue has healed, then the process of brinolysis begins to take effect. The core of brinolysis process is the enzyme plasmin, which is converted from plasminogen via tissue plasminogen activator (tPA) or urokinase- type plasminogen activator (uPA) on the surface of the brin clot, and one of its main functions is to “dissolve” the brin clot through its serine protease activity [23, 24]. However, a brinolytic cross-talk mechanism may potentially bypass the requirement for their molecular co assembly on the same surface, plasmin can be formed by uPA [25].

Fig. 4.4 Regulation of coagulation cascade [2, 14]

VIIIa and Va. Deciencies of both protein C and S will clinically present signicant prothrombotic conditions [19].

Mechanisms ofClot Stability andFibrinolysis

Precise regulation of clot stability is of paramount importance, as an insubstantial or excessively robust clot can lead to hemorrhage or thrombosis, respectively. The fundamen-

Factors Aecting Clot Stability

The stability of a clot is dependent on the structural integrity with which it was formed, as well as external factors. Fibrin ber diameter and the specic geometry of the brin network are the main determinants of clot stability [21]. Even the local blood ow rate in the vessel affects how brin networks are oriented as the thrombus forms [26]. Higher concentrations of thrombin also seem to have an impact on the quality of the brin structure [21]. Understandably, if the newly formed clot is loose and fragile to begin with, then it is more susceptible to brinolysis. Fibrinogen polymorphisms can also impact brin clot architecture and create a prothrombotic or antithrombotic state [27]. The biological environment in which the clot forms can also affect the various reactions involved in forming and stabilizing a clot, including local calcium concentration, pH, and platelet count [21, 26].

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N. Nayyar et al.

Fibrinolysis: Regulation andIts Role inDisease Process

As above mentioned, plasmin is the primary molecular factor in brinolysis, and it is activated from plasminogen by either tPA or uPA. The function of endothelial cells and monocytes that produce tPA and uPA, respectively have signicant impact on the rate of brinolysis. Plasminogen activator inhibitor-1 (PAI1) is an important serine protease inhibitor (“serpin”) that protects against excessive brinolysis by inhibiting tPA and uPA and ultimately limiting their half- lives. Serpins are present in the blood in excess concentrations to ensure that tPA and uPA are rapidly neutralized [28]. There is also thrombin-activated brinolysis inhibitor (TAFI), which is a nonserpin and is activated by thrombin as the name suggests [29]. TAFI serves as just one of the many molecular links between coagulation and brinolysis, illustrating the inter relatedness of the two processes.

Clinical applications of brinolysis in perioperative period are vast. The brinolytic system itself is usually subject to perturbations from the level of organ system functions (e.g., organ failure) to that of genetic polymorphisms (e.g., brinogen). These “acquired” disorders of brinolysis can be categorized into hyperbrinolysis and hypobrinolysis. Examples of acquired hyperbrinolysis include disseminated intravascular coagulation, coagulation factor deciency secondary to chronic liver disease, and nephrotic syndrome [30, 31]. Examples of acquired hypobrinolysis include multiple myeloma, antiphospholipid syndrome, and diabetes [30]. There are also pharmaceutical means of intentionally altering brinolysis to achieve a desirable clinical outcome, such as administering tPA in the setting of early ischemic stroke and tranexamic acid to prevent excessive bleeding in surgical procedures and in patients with hemophilia.

Summary

Normal coagulation is a very dynamic process involving a series of enzymatic reactions. Activation of either intrinsic pathway or extrinsic pathway will lead to brin production and clot formation. Coagulation has three stages (initiation, amplication, and propagation). A delicate balance between clot formation and brinolysis, which often occurs simultaneously, is critical to normal blood circulation and hemostasis. Coagulation system is regulated by ways of multiple zymogens and cofactors all requiring activation prior to exerting their effects. And the clot stability is also regulated by numerous factors. The many steps in coagulation and brinolysis pathways also offer targets for pharmacological interventions.

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. PMID: 6193754.

Fibrinolysis, Antifibrinolytic Agents,

https://t.me/medicina_free

andPerioperative Considerations

AaronN.Primm

Abbreviations

A2AP Alpha-2-antiplasmin ACT Activated clotting time APTT Activated partial thromboplastin time ATC Acute traumatic coagulopathy BART Blood conservation using antibrinolytics in a

randomized trial CABG Coronary artery bypass graft CPB Cardiopulmonary bypass CRASH Clinical randomization of an antibrinolytic in

signicant hemorrhage EACA Epsilon-aminocaproic acid FDA Food and drug administration GABA/A Gamma-aminobutyric acid type A INR International normalized ratio IV Intravenous LY30 Lysis measurement 30minutes MATTERs Military application of tranexamic acid in

trauma emergency resuscitation study PAI-1 Plasminogen activator inhibitor-1 PAI-2 Plasminogen activator inhibitor-2 PATCH Prehospital antibrinolytics for traumatic

coagulopathy and hemorrhage PPH Postpartum hemorrhage RCT Randomized control trial ROTEM Rotational thromboelastometry SAH Subarachnoid hemorrhage TAFI Thrombin-activated brinolysis inhibitor TBI Traumatic brain injury TEG Thromboelastography THA Total hip arthroplasty TKA Total knee arthroplasty tPA Tissue plasminogen activator

A. N. Primm (*) NYU Langone Health, Department of Anesthesiology, Perioperative Care and Pain Medicine, New York, NY, USA e-mail: aaron.primm@nyulangone.org

TXA Tranexamic acid ULTRA Ultra-early tranexamic acid after subarachnoid

hemorrhage uPA Urokinase plasminogen activator WHO World health organization

Introduction

Fibrinolysis is a process that works to limit clot formation and is tightly controlled by cofactors, receptors, and inhibitors. Its actions are integrally counterbalanced by the coagulation process, maintaining physiologic homeostasis and protecting against excessive clot formation or hemorrhage. When plasmin or plasminogen is produced in excess quantities through, for example, trauma and surgery, multiple inammatory responses can be generated, leading to coagulopathy and unwanted pathophysiology. To combat these unwanted events, clinicians have employed antibrinolytic agents to reduce surgical blood loss, allogenic blood transfusion, and other potential adverse outcomes. Of the antibrinolytic agents, tranexamic acid has been the most widely studied and utilized and will be the focus going forward. This chapter will review brinolysis and its measurement, antibrinolytic agents, and the role of tranexamic acid in the most studied perioperative settings.

Fibrinolysis andMolecular Regulation

Fibrinolysis is an integral component of hemostasis that acts to regulate brin formation. Generally, hemostasis is the process of maintaining the integrity of the vascular system after damage [1]. Vessel wall injury and extravasation of blood from the circulation will trigger multiple processes to begin the repair. To do this, expressed tissue factor and circulating platelets combine to achieve vascular hemostasis and thrombin is generated through the coagulation cascade

https://doi.org/10.1007/978-3-030-59295-0_5

https://t.me/medicina_free

A. N. Primm

[2]. More specically, after endothelial cell disruption, platelets are activated when they come in contact with subendothelial matrix proteins such as collagen, bronectin, and von Willebrand factor [3]. This activation exposes anionic phospholipids, which attract procoagulant proteins to the cell surface. A sequential series of enzymatic cleavage events lead to thrombin activation from its zymogen prothrombin [4, 5]. Thrombin will catalyze the conversion of soluble brinogen to insoluble brin, and hence achieves hemostasis [4]. Fibrin will be cross-linked through Factor XIIIa, a transglutaminase, as more platelets, red blood cells, and white blood cells are incorporated for greater clot stability to resist brinolysis [6].

As the clot forms, the brinolytic system is activated to counterbalance the coagulation response at the site of injury, as well as throughout the body. Plasmin is formed on the surface of the brin clot, or cell surfaces, from plasminogen [7]. Plasmin is the primary brinolysin that is activated by two primary serine proteases, tissue plasminogen activator (tPA) and urokinase (uPA) (Fig. 5.1) [4]. Endothelial cells synthesize and release tPA, while uPA is made in macrophages, monocytes, and urinary epithelium. Both are cleared by the liver [8]. Plasminogen also exhibits positive feedback on its activation because plasmin increases activator activity by converting single-chain tPA and uPA to their two-chain counterparts [4]. In response to vascular injury, tPA and uPA are released in high concentrations, although they exist in plasma at a low, “surveillance,” concentration [9].

Plasmin is the key enzyme of brinolysis, acting to cleave brin and release brin degradation products. This action is facilitated by sites in the plasminogen molecule that can bind brin’s lysine residues [10]. However, plasmin can also be involved in multiple enzymatic pathways leading to worsening coagulopathy, bleeding, and inammation [10]. Plasmin, especially when bound to the surface of macrophages, is critical in monocyte activation and inammation. Activated plasmin conveys chemotaxis and actin polymerization in monocytes leading to cytokine release [11]. Also, plasmin can be generated from inammation secondary to bacterial infection and exposure to lipopolysaccharide, which can contribute to disseminated intravascular coagulation and sepsis [12]. By whatever means, these actions can occur when plasmin is present in concentrations that exceed its physiologic inhibitors and is the basis for the use of antibrinolytic therapy [10, 13]. Bursts of free plasmin lead to degradation of coagulation factors like brinogen and factors V and VII.Additionally, the cleavage of glycoprotein Ib and IIb/IIIa receptors on platelets through brinolysis will hinder platelet adhesion and aggregation [14]. By all of these processes, plasmin can bring on a serious pathophysiologic state that will lead to poor clinical outcomes if left unchecked.

Molecular inhibitors are vitally important in brinolysis to control any surplus of plasmin or plasminogen activator. Serine protease inhibitors form covalent complexes with circulating plasmin and plasminogen activators, neutralizing their effects [15]. The most important serine protease inhibi-

Fig. 5.1 Schematic of hemostasis and brinolysis with inhibitors.

After vessel wall injury (red dashed arrow), expressed tissue factor (TF) binds with factor VIIA, leading to the generation of thrombin and hemostasis. Thrombin will catalyze the conversion of soluble brinogen into an organized brin meshwork that will lead to clot formation. Thrombin also stimulates release of tissue plasminogen activator (tPA) from the endothelium (black dashed arrow) that will form a complex with plasminogen on the surface of brin to release active plasmin. Plasmin formation can also be achieved with urokinase plasminogen

activator (uPA), which is released from macrophages, monocytes, and urinary epithelium. Plasmin will cleave brin to soluble brin degradation products. Tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA) inhibit brinolysis intravascularly by competitive inhibition on plasminogen’s lysine-binding site. This prevents plasmin release and allows for a stable brin clot. Aprotinin reversible inhibits free plasmin. Fibrinolysis is inhibited by plasminogen activator inhibitors (PAI-1 and PAI 2), alpha-2-antiplasmin (A2AP), and thrombin-activated brinolysis inhibitor (TAFI)

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