Understanding the physiology of blood and its interactions for hemostasis is a critical aspect of managing perioperative bleeding. With the ever increasing application of anticoagulation therapies for cardiovascular diseases, patients also present with multiple underlying acquired coagulation abnormalities. Further, in an acutely bleeding and hemorrhagic patient, additional coagulation changes occur that are covered in the chapter on physiology and management of massive transfusion. Understanding the physiology of coagulation and blood interactions is important in determining the preoperative bleeding risk of patients and in managing hemostatic therapy perioperatively.
At the center of hemostasis is the ability to generate thrombin, a serine protease. Thrombin plays pivotal roles in the activation of additional coagulation factors as shown in Figures 27-1 and 27-2.1 Most coagulation factors circulate in the body as inactive enzymatic precursors that are called zymogens.1 However, there are multiple critical steps in clot formation that involve additional cofactors, humoral proteins, cellular components, and cell surface receptors. Following tissue injury, thrombin is generated in a highly regulated way that keeps the effects of this activation local to the site of injury and prevents uncontrolled systemic thrombosis. In surgical patients, multiple perturbations occur, and the hemostatic and inflammatory systems are closely related and have significant cross talk. Managing perioperative hemostasis also requires consideration of the postoperative hypercoagulability that may follow, and important advances have been made as new pharmacologic strategies are available and used to treat both procoagulation states and cardiovascular disease. This chapter will review the physiology of hemostasis, clot formation, and thrombin generation.
Hemostasis and History
The term hemostasis essentially means to stop bleeding and refers to the physiologic process that keeps blood within damaged blood vessels, the opposite of hemorrhage. Multiple mechanisms are involved in hemostasis, a process critical for survival. The elucidation of models to explain the molecular and cellular interactions of the clotting cascade continue to evolve over time. The best understood clotting cascade is the Waterfall/Cascade model that most clinicians learned in medical school and was developed about 50 years ago but is still used as an educational tool.1 However, this acellular model does not tell the entire story and has been further refined by Hoffman and Monroe2 in their cell-based model that focuses on both cellular and humoral interactions and (see Fig. 27-1). Hemostasis is also a complex inflammatory response that provides host defense mechanisms to prevent exsanguination following injury, trauma, and/or surgery. Many of the hemostatic factors have complex inflammatory signaling properties that orchestrate further host defense mechanisms, healing, and a multitude of other functions. There are multiple aspects of the physiology of hemostasis and clot formation that will be considered separately.
Initiation of Coagulation
Initiation of coagulation by procoagulant activities has been traditionally separated into extrinsic, intrinsic, and common pathways. However, a better understanding of the complex interactions has created a better conceptual integration of these pathways. Following tissue injury and vascular endothelial disruption, activation of hemostasis occurs by tissue factor (TF) expression on the subendothelial vascular basement of the blood vessel as shown in Figures 27-1 and 27-2.1–3 TF is a transmembrane receptor expressed by perivascular/vascular cells that binds factor VIIa.4 Vascular injury with loss of normal endothelial function allows for expression of extravascular TF and initiation of clotting.4 TF is also present in the circulation as microparticles that are small membrane vesicles that appear following cellular injury or death and may contribute to thrombosis with sepsis or other procoagulant states. Activated factor VII (factor VIIa), a serine protease that circulates in blood in low concentrations, allows for formation of the factor VIIa/TF complex, and conversion of factor X to factor Xa.1,3 Subsequently, factor Xa (also a serine protease) generates trace amounts (0.1–1 nM) of thrombin.1,3 Thrombin generation is subsequently amplified by other coagulation factors from the intrinsic cascade that includes factors XI, IX, and VIII dependent activities, although both the extrinsic (factor VIIa/TF) and intrinsic (factors IXa/VIIIa) tenase complexes produce factor Xa, which is also an important target form many anticoagulation agents. “Tenase” is a contraction of the words “ten” and the suffix “-ase” and refers to these factor complexes which activate inactive factor X through enzymatic cleavage. Multiple factors influence the degree of activation including the local TF concentration and type of cell surface supporting enzyme/cofactor complex assembly as platelets also will contribute to this response.1,3 The interaction of both cellular and plasma-dependent mechanisms generates the prothrombinase complex (factors Xa, Va, and prothrombin) assembly that enzymatically cleaves prothrombin to produce thrombin, another critical factor targeted in anticoagulation therapy. The orchestration of hemostasis and factors influencing its balance are shown in Figures 27-1 and 27-2.
As part of the activation, there are also checks and balances in the system to prevent an over exuberant prothrombotic effect from occurring and regulate thrombin generation to localize clot at the site of vascular injury as shown in Figure 27-2. Tissue factor pathway inhibitor (TFPI) neutralizes factor Xa when it is in a complex with TF-factor VIIa.1,3 The other regulator of TF-trigger procoagulant response is antithrombin (AT, formerly called antithrombin III; a serine protease inhibitor; SERPIN), which circulates at a high concentration (150 µg/mL, ~2.7 µM) and neutralizes the initially formed factor Xa and thrombin.1,3 Overall factor VIIa patrols the circulation in search of sites of vascular injury where TF is exposed, and trace quantities of factor Xa and thrombin initiate a procoagulant response. Plasma levels of the different coagulation proteins are listed in Table 27-1.
Propagation of Coagulation
Platelets further amplify or potentially initiate clot formation at the site of vascular injury. Inflammatory cells all contain adhesion molecules to facilitate binding in the rapid flow of blood vessels as shown in Figure 27-1. Following vascular injury and exposure of the subendothelial vascular basement membrane, von Willebrand factor (vWF) that circulates in a multimeric form binds to the damaged blood vessel. Platelets then adhere to subendothelial collagen-vWF via their glycoprotein (GP) Ib receptors and are activated. Thrombin generation that also occurs locally is a potent activator/agonist for platelets by stimulating protease activated receptor (PAR)-1 and PAR-4.1,3 Thrombin activation of platelets further amplifies clot formation by multiple mechanisms. Platelet glycoprotein Ib receptors bind to factor XI, and they also localize factor VIII to the site of endothelial disruption via its carrier protein vWF.5Also, factor V is released from platelet α-granules upon platelet activation, and factors XI, VIII, and V further amplify and sustain procoagulant responses (the “intrinsic pathway”) after thrombin-mediated activation. The serine protease factor XIa mediates the activation of factor IX to factor Xa, and factor VIIIa serves as a cofactor to factor IXa. Factor IXa, a serine protease, activates factor X to factor Xa, and factor Va serves as a cofactor to factor Xa.1,3In the absence of factor VIIIa or factor IXa, as is clinically observed in hemophilia A or B, the initiation of coagulation is normal, but amplification/propagation is altered. Patients with hemophilia clot, but they develop bleeding in muscle and joints due to low TF expression.
Tissue Factor, Thrombin, and Fibrin(ogen) in Clot Formation and Stability
When generated, thrombin facilitates the proteolytic conversion of circulating, soluble fibrinogen to an insoluble fibrin meshwork. This complex mechanism involves the cleavage of N-terminal peptides from fibrinogen, end-to-end polymerization of fibrin monomers to protofibrils, and lateral aggregation of protofibrils to fibers.1,3 Fibrin’s biophysical characteristics provide extensive structural support to the clot; individual fibers can be strained >330% without rupturing. The fibrin network that forms can be influenced by many different factors including fibrin(ogen)-binding proteins (e.g., factor XIII), thrombin, and fibrinogen present during fibrin formation.
Role of Fibrinogen
Fibrinogen is a critical protein for clot formation, and has a critical role in hemostasis.6 Fibrinogen is critical for clot formation and creating the dense lattice structure as shown in Figure 27-3. Fibrinogen also binds to platelet glycoprotein IIb/IIIa receptors to facilitate clot formation and is affected by many antiplatelet agents. In addition, fibrinogen facilitates the cross-linking and network formation for clot and the subsequent fibrin polymerization that is catalyzed by thrombin and thrombin-activated factor XIII that locally at the site of activation. Of all the coagulation factors, fibrinogen circulates at the highest concentration (7.6 µM, ~200 to 400 mg/dL). In pregnancy and during acute inflammatory responses that often occur postoperatively, fibrinogen is an acute-phase reactant.6 Platelets that are activated by multiple agonists express glycoprotein IIb/IIIa receptors. Thrombin catalyzes the conversion of fibrinogen to fibrin monomers after thrombin cleaves the fibrinopeptides from the fibrinogen Aa and B3 chains. Platelets that are activated release factor XIII A subunits that further polymerize fibrin monomers into fibrin. Activated factor XIII also cross-links a2-antiplasmin to fibrin, making fibrin more resistant to degradation. Thrombin released locally modulates the thickness and the fibrinolytic resistance of fibrin fibers.
Thrombin generation is critical to clot formation, platelet activation, and fibrinogen cross linking.1,3 With normal hemostatic function, the peak thrombin level reaches 200 to 500 nM, facilitating the formation of a dense fibrin network for normal clot function and hemostasis. However, in patients with hemophilia and other bleeding abnormalities, lower levels of thrombin generation occur and as a result clot formation is altered, thus hemophiliacs commonly bleed into joints. Thrombin generation at the junction of the injured vasculature and subendothelial basement membrane is amplified by platelet activation and release of procoagulant microparticles.1,3 Thrombin has a complex effect of releasing tissue plasminogen activator (t-PA) to simultaneously initiate fibrinolysis. This occurs by binding to thrombomodulin but also by activated factor XIII and activation of thrombin-activatable fibrinolysis inhibitor (also called TAFI). Fibrin polymerization, thrombin, and activated factor X generated at the site of vascular injury site are released systemically.
Critical Factor Levels for Hemostasis
A critical question is what levels of fibrinogen, platelets, and other coagulation proteins are necessary to optimize hemostasis in the surgical patients. Many blood bank experts as well as older guidelines only recommended treating fibrinogen levels if they have decreased below ~1.0 g/L (100 mg/dL), a level similar to the management of congenital afibrinogenemia.6 There is increasing data about the critical role of fibrinogen and current European guidelines recommend higher fibrinogen levels of 1.5 to 2.0 g/L for treating coagulopathy. Recent studies have demonstrated the critical role of fibrinogen for aortic surgery, postpartum hemorrhage, cardiac surgery, and cystectomy. Of note is that studies suggest that further normalization of fibrinogen to levels more consistent with normal circulating concentrations of 2 to 3 g/L may be important for adequate hemostasis.
Role of Factor XIII
Factor XIII plays a major role in the terminal phase of the clotting cascade that promotes formation of cross-linked fibrin polymers and generation of a stable hemostatic plug.7 Factor XIII exists as a tetrameric precursor (zymogen) of 2 A and 2 B subunits and is converted into an active transglutaminase (factor XIIIa) by thrombin and calcium.7 In this activated form, factor XIIIa mechanically stabilizes fibrin and protects it from fibrinolysis. As a result, patients with a deficiency in factor XIII develop a rare but severe bleeding disorder.8,9 A congenital deficiency in factor XIII is clinically defined as a plasma level of less than 5% of the protein.7 Most cases of factor XIII deficiency are due to lack of the A subunit with less than 1% factor XIII activity. Congenital factor XIII deficiency is inherited as an autosomal recessive disease and was first reported in Switzerland in 1960.10 The incidence of factor XIII deficiency is currently estimated as one in 3 to 5 million births in the United States.11 An acquired deficiency in factor XIII can arise from the development of antibodies against factor XIII. We have also studied factor XIII repletion, and although it did not decrease bleeding or transfusion requirement in cardiac surgery, levels of >50% to 60% may to reduce bleeding in surgical patients with low fibrinogen levels (<1.5 g/L).7
Role of Platelets and von Willebrand Factor
Platelets adhere to sites of vascular injury and to each other by direct and indirect effects that are part of a complex cellular mechanism required for hemostasis. Although platelet aggregation is mediated in part by bridging/binding of the integrin glycoprotein IIb/IIIa on platelet surfaces by the adhesive protein fibrinogen, this process is far more complex than simple interactions and the lattice formation of the two elements.
There are multistep adhesion processes involving distinct receptors and adhesive ligands that are also dependent on flow conditions, especially with the critical role of platelet function in arterial hemostatic mechanisms. Thus, following vascular injury, the subendothelial surface is exposed which then binds to vWF that is synthesized in the endothelium and critical for platelet adhesion in arteries and arterioles that have high shear rates.
vWF is critical to facilitate platelet adhesion in rapid blood flow environments. vWF binds to an adhesion ligand, its platelet membrane receptor, GPIb-IX-V. Once platelets adhere, they are activated by a complex series of steps including release of adenosine diphosphate (ADP) and thromboxane A2, agonists that activate additional platelets and bind P2Y12 receptors and express IIb/IIIa receptors. These important receptors are the target of common pharmacologic agents including clopidogrel, prasugrel, and ticagrelor. Platelets provide a catalytic membrane surface for further thrombin generation and clot formation and mediate additional platelet and leukocyte recruitment by mechanisms that include release of microparticles that mediate leukocyte-leukocyte and leukocyte–endothelial cell interactions. When activated, platelets may also form occlusive thrombi in cardiovascular diseases that result in myocardial infarction, stroke, or other acute ischemic syndromes of other organs.
Endothelial Regulation of Coagulation
The vascular endothelium provides an extensive interface that is critical for both anticoagulant and procoagulants functions as shown in Figure 27-2.12–15 Increased shear forces and flow across the endothelium release important anticoagulation agents (Table 27-2) that include a diverse series of molecules, including nitric oxide, prostacyclin, and ecto-ADPase that degrade the platelet agonist ADP. Additionally, endothelium-derived TFPI is localized on the surface of vascular endothelium, and reduces the procoagulant activities of the TF–factor VIIa initiation step.1,3 Heparin sulfate is located on endothelial surfaces and binds antithrombin in the circulation to further provide anticoagulant activity on the vascular surface. Thrombin is scavenged to keep thrombin activity local at the site of vascular injury by another endothelium-bound protein called thrombomodulin.1,3 Thrombomodulin is used clinically in Japan for DIC and is currently being studied for treatment of sepsis in the United States. Endothelial activation also provides anticoagulation by releasing t-PA from the endothelial stores of the Weibel-Palade bodies. t-PA activates plasmin from plasminogen which, in turn, promotes fibrinolysis, a critical component of vascular patency.1,3
The endothelium is critical for procoagulant effects as well.12–15 Endothelial damage following vascular injury or inflammatory responses initiates an array of procoagulant responses that include release of TF, vWF, plasminogen activator inhibitor (PAI)-1, and PARs. TF as discussed is critical for initiation of clot formation and thrombin generation. vWF allows for platelets to bind and activate locally at the site of vascular injury. PAI-1 prevents plasmin generation and fibrinolysis, or clot cleavage. PARs further signal platelet and a host of other responses by thrombin and other inflammatory mediators.12–15
This complex equilibrium of hemostasis continues and is constantly scavenged by many of these important mechanisms to localize hemostasis to the site of vascular injury through this multitude of regulatory mechanisms. Thrombin that is scavenged and bound to thrombomodulin is an important step in the generation of the anticoagulant protein C and TAFI.12–15 Activated protein C has multiple antiinflammatory and cytoprotective functions by modulating endothelial protein C receptor (EPCR) and PAR-1 (thrombin receptor).16–18 TAFI also exerts antiinflammatory effects by cleaving bradykinin and C5a. Activated protein C has also seen therapeutic use as a therapy in sepsis, along with antithrombin.
Other important factors in hemostatic regulation include the circulating release of vWF that circulates as a multimer complex and is a key adhesive protein for platelets as further discussed in the following text. vWF is also increased during inflammation and is downregulated by ADAMTS-13 (A Disintegrin and Metalloprotease with a ThromboSpondin type 1 motif, member 13), which is also synthesized by endothelial cells.19 In addition to vWD, other vWF abnormalities can occur due to increased degradation that occurs with ventricular assist devices or aortic stenosis, or decreased regulation due to lack of the cleaving enzyme that can occur with hemolytic uremic syndrome or thrombotic thrombocytopenic purpura.
Antithrombin and Proteins C and S
As discussed earlier, thrombin generation for hemostasis is localized because anticoagulant activities of endothelial cells modulate thrombin and other procoagulant proteases as shown in Figure 27-2.20 Other proteins including antithrombin, protein C, and protein S are also important serine proteases that exert anticoagulant and antiinflammatory activities. Protein C circulates in the inactive state in plasma at concentrations of 4 to 5 µg/mL (~0.08 µM) and is proteolytically activated by thrombin to activated protein C.20 Thrombin is again scavenged by binding to endothelial thrombomodulin, activating protein C. Activated protein C binds protein S, and together they function as a critical anticoagulant by inhibiting factor Va and factor VIIIa, two cofactors in thrombin generation and clot formation (see Fig. 27-2). Activated protein C has been studied in sepsis but is no longer available for that indication.
Inflammation and Coagulation: An Important Link
Coagulation is closely linked to inflammatory responses through complex networks of plasma and cellular components including proteases of the clotting and fibrinolytic cascades.21,22 Hemostatic initiation, contact activation, and other pathways amplify inflammatory responses and can collectively produce end-organ damage in the process of their normal function as host defense mechanisms. Coagulation is activated as a central element of both a local and a systemic response to inflammation.22 Surgical injury and additional activation that can occur following cardiopulmonary bypass produces inflammatory responses initiated by contact of blood with the damaged vasculature and other nonendothelial extracorporeal circuits. In vascular surgical and trauma patients, ischemia-reperfusion injury of organs can also occur.23 TF has important proinflammatory effects mediated by thrombin, plasmin, and other proteases. 21,22,24
Coagulation Testing
The two tests most frequently used in the perioperative setting, other than blood counts, include the prothrombin time used to evaluate the extrinsic coagulation cascade and the activated partial thromboplastin time, used to evaluate the intrinsic pathway of the classic coagulation system. The prothrombin time is affected by reductions of factors VII, X, V, and prothrombin and is used to measure the effect of warfarin and other agents with vitamin K antagonist activity or the consequences of decreased synthetic activity resulting from hepatic dysfunction. Although prothrombin time is used commonly for perioperative coagulation screening, its use and target values are still controversial and often based on consensus rather than supportive data. Clinical hemostasis may not be adequately evaluated with prothrombin times alone as is apparent in patients with hemophilia who have isolated factor VIII or IX deficiency despite normal prothrombin times.
The partial thromboplastin time is another widely used coagulation test that assesses the intrinsic coagulation cascade. Most partial thromboplastin times are activated using an agent such as ellagic acid, kaolin, or celite.25 The partial thromboplastin time is used to monitor lower doses of unfractionated heparin (up to ~1.0 unit/mL), argatroban, and bivalirudin. At higher heparin concentrations used during cardiac surgery the activated clotting time is used.
Although these coagulation tests are used to evaluate bleeding, they only examine specific components of the overall coagulation cascade and may not be useful to determine the exact cause of the coagulopathy. As should be apparent from the discussion in this chapter, multiple factors influence normal coagulation and lead to coagulopathy in a perioperative setting including hemorrhage and dilution, fibrinolysis, hypothermia, and vascular injury .26,27These in vitro laboratory tests do not include the important interaction of platelets with coagulation factors or measurement of the stability of a hemostatic plug as these tests actually measure initial clot formation alone.
Whole blood viscoelastic tests including thromboelastography and thromboelastometry provide multiple insights in to coagulation factor interaction and allow assessment of individual characteristics of either individual limbs of hemostasis or global monitoring of coagulation, and they have been widely used in the perioperative and trauma setting. The commonly used thromboelastometric variables include coagulation time (in seconds), clot formation time (in seconds), angle (in degrees), maximum clot firmness (in millimeters), and lysis time (in seconds). Coagulation time represents the onset of clotting, whereas clot formation time and angle both represent the initial rate of fibrin polymerization. Maximal clot firmness is a measure of the maximal viscoelastic strength of clot. Lysis time is used for the diagnosis of premature lysis or hyperfibrinolysis.
Perioperative Changes in Coagulation
In surgical patients, there are multiple perioperative events that influence hemostatic function and produce coagulopathy. Vascular and tissue injury are important contributors to bleeding, but with significant hemorrhage and resuscitation with crystalloids/colloids, a dilutional coagulopathy can occur resulting from significant reductions in platelet counts/dilutional thrombocytopenia and factor deficiencies. The end result is a multifactorial reduction of thrombin generation, hypofibrinogenemia, and lack of other factors that reduce clot formation and this state is accompanied by increased fibrinolysis. The poorly formed fibrin clot contributes to bleeding, and increasing hemodilution simultaneously leads to a reduction in important proteins that balance hemostasis and anticoagulation, including antithrombin, TFPI, protein C, protein S, and thrombomodulin.20 These complex hemostatic changes also contribute to the coagulopathic state.
Hemostatic Therapy
When perioperative bleeding occurs, we use red blood cells and hemostatic factors that include plasma/fresh frozen plasma, platelet concentrates, and cryoprecipitate (see further discussion in Chapter 28, Blood Products and Blood Components and Chapter 29, Procoagulants). Postoperatively, an important anabolic state occurs that increases hemostatic factors for several days. Many of the factors that modulate this acute inflammatory response postoperatively will increase cytokines and other important signaling molecules that will increase cellular and protein synthesis. These changes will increase bone marrow production of red blood cells and platelets; increase fibrinogen and vWF; and create a hypercoagulable, procoagulant response. This is important and also integral to the current practice of use of anticoagulation for postoperative venous thromboembolic prophylaxis because of the increased thrombotic potential postoperatively.
Postoperative Hypercoagulability
The complex balance in hemostatic function can be readily altered in the postoperative setting. Because of loss of vascular endothelial function and other prohemostatic changes, venous and arterial thromboembolic events increase with age.20 Acute myocardial infarction and thrombotic stroke can occur following disruption of atheromatous plaques in coronary and cerebral arteries. The rupture of a lipid core expresses multiple procoagulant molecules that expose TF, lead to thrombin generation, and activate platelets, all leading to coagulation. Embolic and other thrombotic events occurring locally at the site of an atherosclerotic plaque can result in myocardial infarction and ischemic stroke. Additional abnormalities present in cancer patients can also initiate coagulation and other prothrombotic events that increase the risk of venous thromboembolic events.
Congenital coagulation factor deficiencies or polymorphisms of critical proteins including hemophilia A or B, vWF, antithrombin, protein C, protein S, factor V Leiden, and prothrombin (polymorphisms) are more uncommon in the perioperative period but do occur and often require specific management strategies—these conditions can present with either bleeding or thrombosis. Acquired or congenital absence of the anticoagulant proteins reduces normal clot formation and regulation, and untreated patients are at an increased risk for venous thromboembolic problems, including pulmonary embolism. A more common occurrence is the antiphospholipid syndrome that is caused by the lupus anticoagulant, which is a phospholipid binding antibody. Of note is that patients may present with prolonged prothrombin times and partial thromboplastin times, but they are actually hypercoagulable.20
Disseminated Intravascular Coagulation
Disseminated intravascular coagulation (DIC) is a coagulation disorder that occurs when pathologic activation of the hemostatic systems occurs following major tissue injury associated with trauma, sepsis due to bacterial, fungal, or viral causes, or other complex occurrences of vasculopathy that occurs in eclampsia.28,29 Activation of the coagulation system occurs; however, the multiple endothelial and circulating anticoagulation mechanisms that are part of hemostatic mechanisms are unable to inhibit systemic thrombin formation. The pathophysiologic changes of DIC include hemostatic activation characterized by microvascular deposition of clot/fibrin and thrombotic microangiopathy. Platelets are also activated and are sequestered into the pulmonary, renal, hepatic, and other organs, depleting platelets, fibrinogen, antithrombin, and other hemostatic factors. The end result is an imbalance, resulting in either a hemorrhagic coagulopathy or procoagulant state. The diagnosis of DIC is based on clinical and laboratory findings that follow.
Thrombocytopenia occurs in DIC due to the mechanisms described; however, in the perioperative setting and in critically ill patients, thrombocytopenia is common. The most common cause of perioperative thrombocytopenia is the dilutional effect following volume resuscitation; nonetheless, current strategy is to treat massive transfusion coagulopathy in the setting of trauma and surgery, and this strategy includes the administration of platelets and other clotting factors (platelets, fresh frozen plasma, and/or cryoprecipitate). Coagulation factors are also decreased in DIC, and this presents clinically with prolonged prothrombin times or activated partial thromboplastin times. In DIC and other similar syndromes, such as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, decreased levels of the protease ADAMTS-13 can occur. This protease converts ultra-large von Willebrand multimers in plasma that are otherwise prothrombotic. The uncleaved multimers increase vascular platelet sequestration and the subsequent development of thrombotic microangiopathy and organ dysfunction.29 Fibrinogen levels are also used in diagnosing DIC but, despite consumption, plasma levels are affected by multiple factors and may only detect severe cases of DIC.29 D-dimers are also used in the diagnosis of DIC and are fragments of cross-linked fibrinogen that are cleaved by fibrinolysis. D-dimer levels are increased in DIC but also with venous thromboembolism and following any recent trauma or surgery, thus they may not be helpful in the surgical patient. Finally, antithrombin levels decrease in DIC, and have been suggested as a therapeutic target to replete. Overall, in DIC, removal of the underlying source of the problem, treatment with antibiotics for infections, and perhaps instituting anticoagulation in efforts to reduce further consumption of coagulation factors are critical considerations.30
Conclusion
The physiology of coagulation and hemostatic regulation are critical homeostatic mechanisms that are critical to survival. The interaction of the vasculature with both circulating plasma proteins and platelets is important for understanding the physiology of the hemostatic system, and the ability to modulate hemostasis and respond to vascular injury. Multiple disease states including atherosclerosis, acquired coagulation deficiencies, and the pharmacologic effects of many therapies used for atherosclerotic vascular disease may contribute to the problems of perioperative hemostatic management. Our goal is to reduce bleeding without the adverse effects of thrombosis. This concern is complicated by the interaction of coagulation and subsequent inflammatory responses. As discussed in the other chapters on coagulation that follow pharmacologic interventions, based on the authors’ understanding of the physiology of hemostasis, it is critical for the perioperative management and further discussed in other chapters.
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