Blood and Coagulation




Abstract


Hemostasis is a critical homeostatic mechanism of survival that involves vascular, cellular, and plasma components that interact to stop bleeding. Vascular effects include vasoconstriction, expression of procoagulant factors such as tissue factor, and loss of normal anticoagulant functions of the endothelium. Coagulation and clot formation occur by cellular and humoral factors that interact together with local and systemic factors. Surgery produces complex alterations and defects in hemostatic mechanisms, particularly in trauma, cardiac surgery with or without cardiopulmonary bypass, major orthopedic surgery, and neurosurgery. In many patients, multiple quantitative and qualitative hemostatic abnormalities develop as part of surgery, tissue injury, and complex underlying medical conditions. Additionally, the increasing use of multiple anticoagulation agents to treat cardiovascular disease contributes to preexisting perioperative hemostatic defects and increases the potential for bleeding. Furthermore, massive bleeding can produce an acquired hemostatic defect called massive transfusion coagulopathy that is characterized by tissue injury, dilutional hemostatic changes, hypothermia, acidosis, and multiorgan dysfunction.




Keywords

bleeding, blood conservation, coagulation testing, coagulopathy, disseminated intravascular coagulation, hemostasis, hypercoagulability

 





Hemostasis is a critical homeostatic mechanism of survival that involves vascular, cellular, and plasma components that interact to stop bleeding. Vascular effects include vasoconstriction, expression of procoagulant factors such as tissue factor, and loss of normal anticoagulant functions of the endothelium. Coagulation and clot formation occur by cellular and humoral factors that interact together with local and systemic factors. Surgery produces complex alterations and defects in hemostatic mechanisms, particularly in trauma, cardiac surgery with or without cardiopulmonary bypass, major orthopedic surgery, and neurosurgery. In many patients, multiple quantitative and qualitative hemostatic abnormalities develop as part of surgery, tissue injury, and complex underlying medical conditions. Additionally, the increasing use of multiple anticoagulation agents to treat cardiovascular disease contributes to preexisting perioperative hemostatic defects and increases the potential for bleeding. Furthermore, massive bleeding can produce an acquired hemostatic defect called massive transfusion coagulopathy that is characterized by tissue injury, dilutional hemostatic changes, hypothermia, acidosis, and multiorgan dysfunction.


Managing hemostatic dysfunction and bleeding perioperatively requires an understanding of underlying hemostatic mechanisms. Tissue injury and the stress response activate fibrinolysis that can further contribute to coagulopathy and bleeding. This chapter reviews the basis of normal hemostasis, the procoagulant and anticoagulant changes that occur in surgical patients, as well as perioperative coagulation testing and treatment of bleeding.




Normal Hemostatic Mechanisms


Complex interactions among coagulation proteins, platelets, and the vascular endothelium maintain normal hemostasis ( Fig. 43.1 ). The vascular endothelium plays a major role in preventing clotting; it presents an important anticoagulation interface with circulating blood. Multiple substances are released to prevent activation of both cellular and humoral components of hemostasis. Understanding hemostasis, perioperative bleeding, and treatment of coagulopathy in the current era requires knowledge of the multiple interactions that occur between molecular and cellular components of the coagulation cascade.




Fig. 43.1


Schematic summary of procoagulant and anticoagulant processes. Initial plug formation begins with von Willebrand factor (vWF) binding to collagen at the site of injury, which acts as a bridge for platelets to adhere. At the same time, exposed tissue factor (TF) at the site of injury binds with small amounts of circulating activated factor VII (FVIIa) to produce thrombin via the tissue factor (extrinsic) pathway. Thrombin activates a positive feedback loop by producing more of itself, cleaves fibrinogen to insoluble fibrin, and activates platelets that release more procoagulant and inflammatory factors. The process is kept in check by anticoagulant forces. Away from the site of injury, antithrombin (AT) inhibits thrombin. Additionally, activated protein C (APC) destroys factor V ( Va —needed for the tissue factor pathway), and tissue factor pathway inhibitor (TFPI) destroys TF-FVIIa complexes. The endothelium releases tissue plasminogen activator (tPA) that cleaves plasminogen into plasmin to initiate fibrinolysis. PLT, Platelet.


Hemostasis, which means the “halting of blood,” protects the individual from massive bleeding secondary to minor trauma. In pathologic states, however, thrombosis can occlude the microvasculature, leading to organ ischemia. Hemostasis is therefore highly regulated by a number of factors, including (1) vascular extracellular matrix and alterations in endothelial reactivity, (2) platelets, (3) coagulation proteins, (4) inhibitors of coagulation, and (5) fibrinolysis. These involve tissue factor release, generation of factor VIIa, platelet activation, and multiple cellular and humoral amplification pathways. Prostacyclin, tissue plasminogen activator (tPA), heparan sulfate, antithrombin III, protein C, and endothelium-derived relaxing factor are normally expressed or secreted to inhibit platelet activation, fibrin formation, and to provide vascular patency. However, if a blood vessel is cut or damaged, tissue factor and other promoters of coagulation are released or exposed to provide a thrombotic surface. Exposure of subendothelial vascular basement membrane activates platelets, and expression of tissue factor also activates thrombin generation and signals other inflammatory pathways.


Platelet activation is an important mechanism for initiation of the coagulation cascade. Receptors on platelets bind to the damaged blood vessel by forming a bridge with von Willebrand factor (vWF) to initiate platelet adhesion. Once platelets adhere, they undergo surface receptor changes that cause platelets to aggregate. Once platelets aggregate, they expose factors on their surface that provides a substrate for activation of the coagulation cascade and formation of the early hemostatic plug. Platelets play vital roles in maintaining vascular hemostasis. Any abnormality in platelet number or function poses a significant risk for perioperative coagulopathy.


Hypercoagulability


Normal hemostasis is a balance between procoagulant and anticoagulant mechanisms. The coagulation system ensures that bleeding does not continue indefinitely after vascular injury. This is balanced by thromboresistant forces involving anticoagulant proteins to control clot formation and fibrinolytic proteins to remove clot once vascular injury has been repaired. A proper balance between these systems must be maintained to ensure the fluid nature of blood, yet be readily activated when pathologic activation occurs.


In surgical patients, especially postoperatively, there is potential for a hypercoagulable state. Hypercoagulability, also known as thrombophilia or a prothrombotic state , is a condition in which blood clots more readily than normal. It results from a shift of the normal equilibrium of procoagulant and anticoagulant forces in favor of coagulation. Although arterial and venous thrombi were once thought to represent distinct problems, patients with hypercoagulability can be at risk for both, and it has been suggested that hypercoagulability represents a spectrum of disease rather than separate clinical entities. In the perioperative environment, clinicians are usually aware and concerned about the risk of bleeding; however, hypercoagulability is also a potential cause of postoperative adverse outcomes that is often overlooked.


Risk factors for hypercoagulability can be inherited or acquired, and are caused by either increasing procoagulant activity and/or decreasing anticoagulant or fibrinolytic activity. About 80% of patients with venous thromboembolism (VTE) have at least one underlying risk factor. Because of this increased risk, hypercoagulable patients often receive prophylactic anticoagulation therapy.


Inherited Risk Factors


Most patients with inherited risk factors for hypercoagulability are at risk to develop venous thromboembolic events early in life. One of the most common risk factors is inherited antithrombin deficiency. Other conditions, for example, the prothrombin G20210A mutation, are continually being discovered. Inherited risk factors can enhance procoagulant effects, reduce natural anticoagulation, impair fibrinolysis, or have other potential effects. Fig. 43.2 presents an overview of the interaction of coagulation and fibrinolytic pathways and illustrates how different inherited risk factors modify hemostasis.




Fig. 43.2


Inherited risk factors for hypercoagulability. Procoagulant forces (red) and natural anticoagulant/fibrinolytic forces (blue) are shown. Dashed lines indicated an inhibitory effect. Inherited risk factors are presented in diamond shapes with lettering and arrows indicating the mechanism for the hypercoagulable effect. “X” denotes a specific block in a pathway. See text for full details. PAI, Plasminogen activator inhibitor; TF, tissue factor; TFPI, tissue factor pathway inhibitor.

(Modified with permission from Sniecinski RM, Hursting MJ, Paidas MJ, et al. Etiology and assessment of hypercoagulability with lessons from heparin-induced thrombocytopenia. Anesth Analg . 2010;112:46–58.)


Increased Procoagulant Effects


The most common inherited risk factors for VTE are factor V (FV) Leiden, present in approximately 5% of the population, and the prothrombin G20210A mutation, present in approximately 2% of Caucasians. In the FV Leiden mutation, an amino acid replacement modifies activated procoagulant FV so that it is no longer inactivated or inhibited by activated protein C. In patients with FV Leiden, thrombotic risk is increased approximately 3-fold in heterozygotes, 18-fold in homozygotes, and 9-fold overall compared with individuals without the mutation. Patients heterozygous for the prothrombin G20210A mutation have higher plasma levels of prothrombin, the precursor for thrombin, and an approximately threefold greater risk for VTE; homozygous individuals for the G20210A mutation are rare. Whether FV Leiden and prothrombin G20210A carriers have increased risk for arterial thrombosis is less clear.


Other common procoagulant effects include fibrinogen abnormalities caused by increased levels or structural variants that are either more or less susceptible to clot formation, known as dysfibrinogenemia . Fibrinogen is an increasingly important target for therapeutic interventions in bleeding and coagulopathy. Similarly, patients with the highest plasma fibrinogen concentration have an approximately twofold increased risk for arterial thrombosis, and stroke patients with fibrinogen levels of 450 mg/dL or greater have poorer functional outcomes. Hyperfibrinogenemia also increases the risk for VTE. Dysfibrinogenemias can also cause hypercoagulability if the resulting fibrin molecules fail to inhibit thrombin or are less susceptible to cleavage by plasmin. Elevated coagulation factor levels, including vWF and FVIII, can occur in patients with unexplained VTE, and increased FVIII levels are a risk factor for arterial vascular events.


Reduction of Natural Anticoagulant Factors


Two important circulating anticoagulants are protein C and protein S. These are vitamin K–dependent proteins that inhibit the activated procoagulant FV and FVIII. Inherited qualitative or quantitative deficiencies of protein C and protein S increase the risk for VTE by 5- to 10-fold. Importantly, large loading doses of the vitamin K antagonist warfarin, without concomitant heparin therapy, can result in a transient procoagulant state by depleting proteins C and S. This most commonly manifests as microthrombi within cutaneous vessels, a condition known as “warfarin skin necrosis.”


Antithrombin (formerly called antithrombin III) is a serine protease inhibitor that avidly binds to thrombin; this interaction is facilitated by heparin and, along with its inhibition of FXa, the primary mechanism for heparin’s anticoagulant action. Heparin and related glycosaminoglycans are normally present on endothelial surfaces or administered therapeutically. Heterozygous antithrombin deficiency is associated with approximately 50% of normal levels, whereas homozygous antithrombin deficiency is likely always fatal in the newborn or in utero, and is exceedingly rare. Acquired antithrombin deficiency can also occur after prolonged heparin administration, or in patients with sepsis or disseminated intravascular coagulation (DIC). Patients with antithrombin deficiency are at an increased risk for thrombotic events. Whether antithrombin should be replaced in prolonged cardiopulmonary bypass operations remains an area of active investigation.


Fibrinolysis Modulation


Fibrinolysis regulates the extent of clot formation and vascular patency as part of hemostatic regulation. After tissue and vascular injury, multiple hemostatic mechanisms are initiated to modulate fibrinolysis. An important circulating serine protease inhibitor that regulates fibrinolysis is plasminogen activator inhibitor-1 (PAI-1) and a specific polymorphism (4G/5G) correlates with higher plasma levels. The 4G allele is associated with an increased risk of VTE but only when combined with another genetic risk factor for thromboembolic complications. Abnormalities in tPA, another important regulator of fibrinolysis, are associated with a twofold to threefold increased risk of myocardial infarction and thrombotic stroke. Inherited deficiencies of plasminogen and polymorphisms affecting plasma levels of thrombin-activatable fibrinolysis inhibitor are reported, but their associations with thrombotic risk remain unclear.


Other Inherited Conditions


Increased levels of homocysteine are thought to produce endothelial dysfunction and could have variable effects on arterial or venous thrombosis and potentially other vascular ischemic events. Hyperhomocystinemia can also be acquired in individuals with folic acid deficiency, and folate therapy was once thought to reduce ischemic cardiovascular disease. Other important polymorphisms exist for regulatory glycoproteins on platelets. Lack of the glycoprotein Ib/IX complex or vWF receptor results in Bernard-Soulier disease. Common deficiencies include abnormalities of the IIb/IIIa receptor that binds fibrinogen and allows platelet cross-linking, known as Glanzmann thrombasthenia. Patients with these platelet glycoprotein genetic variants can still have ischemic cardiovascular disease despite their relative platelet dysfunction, although some reports suggest reduced cardiovascular risk.


Acquired Risk Factors


Acquired risk factors are usually transient, yet can confer higher thrombotic risk than genetic disorders. Like inherited factors, some acquired conditions enhance procoagulant effects (e.g., heparin-induced thrombocytopenia), whereas others decrease levels of natural anticoagulants (e.g., antiphospholipid antibodies). However, most acquired risk factors are multifactorial and have mechanisms that remain to be fully characterized. We have grouped the acquired risk factors into three broad categories: disease states, patient-related causes, and pharmacologic causes ( Fig. 43.3 ).




Fig. 43.3


Acquired risk factors for hypercoagulability. Procoagulant forces (red) and natural anticoagulant/fibrinolytic forces (blue) are diagrammed. Dashed lines indicate an inhibitory effect. Acquired risk factors are presented in diamond shapes with lettering and arrows indicating the mechanism for the hypercoagulable effect. “X” denotes a specific block in a pathway. Note that some acquired risk factors have multiple effects; see text for full details. CPB, Cardiopulmonary bypass; DDAVP, desmopressin; DIC, disseminated intravascular coagulation; HIT, heparin-induced thrombocytopenia; rFVIIa, recombinant factor VIIa; TF, tissue factor; TFPI, tissue factor pathway inhibitor.

(Modified with permission from Sniecinski RM, Hursting MJ, Paidas MJ, et al. Etiology and assessment of hypercoagulability with lessons from heparin-induced thrombocytopenia. Anesth Analg . 2010;112:46–58.)


Disease States Associated With Hypercoagulability


Antiphospholipid antibodies, including lupus anticoagulants, anticardiolipin antibody, and anti–β 2 -glycoprotein 1 antibody are associated with increased risk of thrombosis. Patients with lupus anticoagulants are actually hypercoagulable despite increased prothrombin times, and have increased risk for both arterial and venous thrombosis and miscarriage. Multiple mechanisms are responsible for increased thrombotic risk with antiphospholipid antibodies and are thought to be due to decreased thrombomodulin expression, increased tissue factor expression, and impairment of the protein C anticoagulant pathway. Patients with thrombosis (arterial or venous) or repeated pregnancy loss plus antiphospholipid antibody detected on at least two occasions at least 12 weeks apart meet diagnostic criteria for antiphospholipid syndrome. Patients with known antiphospholipid antibodies are at risk for recurrent thrombotic events and require ongoing anticoagulation, usually with warfarin.


Other important factors that contribute to hypercoagulability include renal and hepatic dysfunction, although these are commonly considered risks for bleeding. Severe hepatic dysfunction and cirrhosis lead to decreased synthetic capabilities and decreased levels of anticoagulant factors, including antithrombin, protein C, protein S, and plasminogen. Endothelial dysfunction, especially with renal failure and often pulmonary and portal vascular dysfunction, also occur. This, in turn, increases platelet activation and is an important cause of hypercoagulability. In nephrotic syndrome, fibrinogen levels are increased and antithrombin levels are low, increasing the potential for thrombosis.


Another important clinical setting is blood stasis, which commonly occurs with postoperative immobility or low cardiac output associated with heart failure—important risk factors for hypercoagulability. Although a low-flow state is a component of the Virchow triad, it alone does not create thrombosis. The importance of the other two Virchow factors— vessel wall abnormalities and dysfunctional blood constituents—is now becoming clear at the molecular level. Metabolic syndrome characterized by abdominal obesity, hypertension, elevated glucose, and increased cholesterol levels is associated with endothelial dysfunction and increased platelet aggregation. Cancer can have multiple causes for hypercoagulability, including cells that release microparticles to promote fibrin deposition. Advanced age is associated with procoagulant changes, including vascular dysfunction, increased fibrinogen levels, increased FVII, impaired fibrinolytic activity, and increased platelet aggregation. Many of these factors can be additive with complex interactions that are not well understood. Routine VTE prophylaxis is therefore an important part of perioperative management.


Heparin-Induced Thrombocytopenia


Heparin-induced thrombocytopenia (HIT) is an important antibody-mediated prothrombotic complication of heparin therapy that occurs in 0.5% to 5% of patients treated with heparin for at least 5 days (see Chapter 45 ). HIT is characterized by an otherwise unexplained drop in platelet count by 50% or more, often to less than 150,000/µL and frequently accompanied by thrombosis, plus the presence of HIT antibodies. When HIT is suspected, heparin, including low-molecular-weight heparin treatment, should be discontinued, and alternative anticoagulation therapy initiated even before laboratory confirmation.


HIT is mediated by antibodies to a complex of heparin and platelet factor 4 (PF4). Antibodies recognize antigenic sites newly exposed on PF4 when it is conformationally modified by binding to heparin. Platelets are activated by the Fc domain of the immunoglobulin G (IgG) in the heparin-PF4 immune complexes, and release microparticles that promote thrombin formation and thrombosis. Thrombocytopenia, excessive thrombin generation, and a prothrombotic state ensue. Antibody-mediated endothelial injury and tissue factor production further increase the prothrombotic state.


Up to 7% to 50% of heparin-treated patients generate heparin-PF4 antibodies, especially after cardiovascular surgery. HIT antibodies circulate with a median half-life of approximately 90 days. The presence and level of HIT antibodies, regardless of thrombocytopenia, are associated with increased morbidity or mortality in various clinical settings. Clinical HIT occurs in 1% to 5% of patients administered unfractionated heparin and less than 1% of patients administered low-molecular-weight heparin. Cardiac transplant and neurosurgery patients (11% and 15%, respectively), as well as orthopedic patients, are at increased risk of HIT.


HIT increases the risk of thrombosis, including deep VTE, pulmonary embolism, myocardial infarction, stroke, and limb artery occlusion requiring amputation. The overall risk for thrombosis in patients with HIT is 38% to 76%. Other risk factors for HIT-related thrombosis include female gender, malignancy, higher-titer heparin-PF4 antibodies, and more severe thrombocytopenia. Other complications include skin lesions at heparin injection sites, DIC, warfarin-associated venous limb ischemia, and acute systemic reactions after heparin bolus. Although counterintuitive, bleeding is rare even in the presence of severe thrombocytopenia.


HIT should be suspected whenever the platelet count drops by 50%, or new thrombosis occurs in a patient 5 to 14 days after the start of heparin therapy. Other causes of thrombocytopenia (e.g., sepsis, mechanical destruction with an intraaortic balloon pump or with extracorporeal circulation, or another drug-induced thrombocytopenia) should be excluded. In “rapid-onset” HIT, the platelet count begins to drop minutes to hours after heparin exposure, usually owing to heparin-PF4 antibodies from a previous heparin exposure within the prior 3 months. HIT should also be suspected if acute systemic reactions, such as hypotension, pulmonary hypertension, and/or tachycardia, occur 2 to 30 minutes after intravenous heparin bolus. This can be observed intraoperatively and can present as anaphylaxis, usually accompanied by acute thrombocytopenia. HIT can also occur days to weeks after stopping heparin (“delayed-onset HIT”), and should be considered if a recently hospitalized, heparin-treated patient presents with thrombosis. For suspected HIT, laboratory testing for heparin-PF4 antibody is recommended. Because of the high thrombotic risk early in HIT, treatment should not be withheld while awaiting laboratory results.


The recommended treatment for strongly suspected or confirmed HIT, with or without complicating thrombosis, is stopping heparin and initiating a nonheparin alternative anticoagulant. The mainstay agents include intravenous administration of a direct thrombin inhibitor, either argatroban or bivalirudin. Other heparin sources such as catheter flushes and heparin-coated devices should be eliminated. Different direct thrombin inhibitors are approved in the United States for use in HIT patients without initial thrombosis (argatroban), in HIT patients with thrombosis (argatroban), and in patients with or at risk of HIT undergoing percutaneous coronary intervention (argatroban, bivalirudin). Previously used agents that were derivatives of the leech protein hirudin are no longer available (desirudin, lepirudin). The more recently approved direct oral anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban) provide potential alternatives for venous thromboembolic prophylaxis in patients but not as immediate therapies for HIT therapy. Recent evidence-based guidelines from the American College of Chest Physicians for the use of these alternative anticoagulants in patients with HIT in noninterventional and interventional settings have been reported. Alternative nonheparin anticoagulant strategies are required in HIT patients who need intraoperative anticoagulation. If heparin use is unavoidable or planned, the heparin exposure should be limited to the surgery itself, with alternative anticoagulation used preoperatively and postoperatively. If cardiac surgery is required, prospective studies have evaluated bivalirudin as the most investigated and useful alternative, although plasmapheresis has also been reported.




Hypocoagulability: Perioperative Bleeding


Bleeding in surgical patients is a common and multifactorial problem. Surgery-induced tissue injury with both large vessel bleeding and microvascular bleeding can occur. Patients often have acquired defects that can be complicated by the surgical insult, or coagulation abnormalities that occur owing to antiplatelet or anticoagulant drug use or massive blood loss. Major coagulation abnormalities occur perioperatively and are influenced by multiple factors, including type of surgery, cardiopulmonary bypass, and preexisting abnormalities. Coagulopathic states and risk factors predisposing to surgical bleeding are listed in Tables 43.1 and 43.2 .



TABLE 43.1

Coagulopathic States Associated With Increased Risk for Bleeding








  • Hemophilia



  • Inherited platelet disorders



  • von Willebrand disease



  • Liver failure



  • Renal failure (uremia)



  • Disseminated intravascular coagulation



  • Dilutional coagulopathy



  • Anticoagulant and antiplatelet therapy



  • Other coagulation disorders (factor deficiencies)


Apr 15, 2019 | Posted by in ANESTHESIA | Comments Off on Blood and Coagulation
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