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  1. Coagulopathy of massive transfusion is unusual with transfusions less than 1 to 1.5 BVs, assuming the patient has a normal coagulation profile, platelet count, and platelet function initially.
    1. Thrombocytopenia. Diffuse oozing and failure to form clots after massive transfusion may be precipitated in part by thrombocytopenia, which is typically due to the transfusion of platelet-poor blood products. However, clinically significant bleeding is unlikely with platelet counts above 50,000 cells/mm3. If the loss of one BV or more is expected, platelets should be transfused to maintain a count of 50,000 cells/mm3 or greater.
    2. Coagulation factor deficiencies. The normal human body has tremendous reserves of clotting factors. In addition, the patient receives small amounts of the most stable clotting factors in the plasma of each unit of red cells. Bleeding from factor deficiency in the face of massive transfusion is therefore typically due to decreased levels of fibrinogen and labile factors with shorter storage half-lives (especially factors V, VIII, or IX). Bleeding from hypofibrinogenemia is unusual unless the fibrinogen level is below 75 mg/dL. In some patients, factor VIII levels increase with massive transfusion because of increased release from endothelial cells. Additional labile clotting factors are best repleted in the form of FFP. Six units of platelets contain coagulation factor levels equivalent to 1 unit of FFP. Cryoprecipitate may also provide a source of concentrated fibrinogen for the patient who cannot tolerate FFP owing to volume overload.
  2. DIC refers to the abnormal, diffuse systemic activation of the clotting system. The pathophysiology involves excessive generation of thrombin (factor IIa), resulting in unrestrained fibrin cross-linking throughout the circulation accompanied by platelet activation, fibrinolysis, and coagulation factor consumption. The profound consumptive coagulopathy produced by DIC often results in hemorrhage.
    1. Causes of DIC include infection, shock, trauma, burns, pancreatitis, and fat or cholesterol embolism. DIC is also common in extensive head injury and complications of pregnancy (eg, amniotic fluid embolism, placental abruption, or septic abortion) because of the high concentrations of tissue factor (thromboplastin) in brain and placental tissues, respectively. A chronic form of DIC may accompany cirrhotic liver disease, nephrotic syndromes, aortic dissection, and malignancy.
    2. Clinical features include petechiae, ecchymoses, bleeding from venipuncture sites, and frank hemorrhage from operative incisions. Although the hemorrhagic manifestations of DIC are clinically most obvious, complications related to diffuse microvascular and macrovascular thromboses are more common, more difficult to treat, and more potentially life-threatening because of the resulting ischemia of vital organs. Systemic bradykinin release in DIC may also cause acute hypotension.
    3. Laboratory features of DIC universally include an elevated D-dimer level and increased fibrin degradation products, although these abnormalities are nonspecific. The PT and PTT are typically prolonged, and serial measurements reveal decreased fibrinogen levels and platelet counts. After an initial PTT value is obtained, the waveform used to generate the PTT result can be reviewed for an early negative slope that is suggestive of DIC. Various TEG parameters, usually first indicating a hypercoagulable state followed by severe coagulation factor deficiencies, can also be followed as point-of-care assessments of a patient’s coagulation profile.
    4. Treatment of DIC involves addressing the precipitating cause and transfusing appropriate blood products (eg, FFP, platelets, and cryoprecipitate) to correct bleeding. It is now generally recommended that blood products not be withheld out of concern for “feeding the fire” of the consumptive coagulopathy, particularly if significant hemorrhage is present. However, inhibitors of fibrinolysis (eg, TXA) are contraindicated in DIC owing to the risk of exacerbating or precipitating further thrombotic complications.
  3. Chronic liver disease. With the notable exceptions of factor VIII and vWF, which are produced by the endothelium, the liver synthesizes all coagulation factors. Assessment of serum factor VIII levels may thus be useful in distinguishing hepatic synthetic dysfunction from other coagulopathies. Patients with hepatic dysfunction may exhibit decreased production of inactive coagulation factors with decreased clearance of activated factors. If circulating levels of activated clotting factors are increased, patients may develop an ongoing consumptive coagulopathy similar to that seen in DIC. Because the liver is also instrumental in removing the by-products of fibrinolysis, levels of fibrin degradation products may be elevated. Note that, although the INR provides a reliable indicator of hepatic synthetic dysfunction, it does not correlate well with surgical bleeding risk in patients with significant liver disease.
  4. Vitamin K deficiency. The fat-soluble vitamin K (phylloquinone) is required by the liver as a cofactor for the gamma-carboxylation of factors II, VII, IX, and X as well as anticoagulant proteins C and S. Because vitamin K cannot be synthesized endogenously, decreased vitamin K intake or malabsorption may cause a coagulopathy with a prolonged PT (see Chapter 6). In addition, because humans rely on gastrointestinal (GI) flora for some production of vitamin K, vitamin K deficiency is also commonly found in patients receiving broad-spectrum antibiotics, neonates who lack a mature GI microbiome, and patients with short bowel syndrome. Patients on warfarin therapy also exhibit a functional vitamin K deficiency (see Section IX.E.3). Patients with poor absorption or limited GI flora can be treated with subcutaneous vitamin K (eg, 10 mg daily for 3 days), whereas malnourished patients or those on warfarin may be given vitamin K orally. Intravenous administration of vitamin K (2.5-10 mg) may result in a faster correction of the PT but is accompanied by a greater risk of anaphylaxis. If used, IV vitamin K should be administered slowly. If faster correction of PT than by using vitamin K is required (as in active intracranial hemorrhage), FFP (5-8 mL/kg) or other blood products such as prothrombin complex concentrate (PCC or Kcentra) should be coadministered.
  5. Coagulopathy associated with cardiopulmonary bypass (CPB) has long been recognized as a consequence of abnormal activation of the coagulation cascade and platelet dysfunction, which are likely precipitated by contact of blood with CPB circuit components. This increases the likelihood of bleeding in patients after cardiac surgery despite a lack of clear correlation with coagulation studies such as platelet counts. More recently, there has been an increased interest in the use of point-of-care platelet function assays as a metric of the risk of hemorrhagic complications associated with CPB.
  6. Pharmacologic interventions
    1. Heparin acts by accelerating the effects of antithrombin III, thus inhibiting both factors IIa (thrombin) and Xa. It prolongs the PTT and has a short half-life; therefore, its anticoagulant effect is usually reversed approximately 4 to 6 hours after discontinuation of the infusion. If faster reversal is required, protamine sulfate, a natural antagonist, may be administered.
    2. Low-molecular-weight heparins (LMWHs) such as enoxaparin (Lovenox) are commercially prepared by fractionating heparin into molecules of 2000 to 10,000 Da. They exert their anticoagulant effect primarily by inhibiting factor Xa and usually do not require monitoring of the PTT. These drugs have longer half-lives than heparin and are incompletely reversed by protamine, yet protamine reversal may be indicated in the setting of a major bleeding episode. Faster reversal may require FFP transfusion.
    3. Warfarin (Coumadin) is an oral vitamin K antagonist that inhibits vitamin K epoxide reductase. This produces a deficiency of activated vitamin K, preventing the hepatic gamma-carboxylation of factors II, VII, IX, and X and proteins C and S to their active forms. The PT and the INR are prolonged in patients taking warfarin. The onset and offset of warfarin’s effects are slow due to the drug’s half-life and the half-lives of vitamin K–dependent factors. If quick reversal of warfarin is required, vitamin K–dependent factors can be repleted in the form of FFP (5-15 mL/kg) or PCC. Vitamin K (2.5-10 mg by mouth, intravenously, or subcutaneously) can also be given to accelerate warfarin reversal.
    4. Platelet inhibitors (or antiplatelet agents) target multiple pathways of platelet adhesion, activation, and aggregation. Irreversible inhibitors such as aspirin and clopidogrel generally impair the function of the platelets throughout their 7- to 10-day lifespan. Thus, immediate reversal of certain platelet inhibitors may require platelet transfusion and may not be effective if the inhibitor is still present in the plasma.
    5. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit platelet aggregation by interfering with cyclooxygenase function. Non-aspirin NSAIDs reversibly inhibit the cyclooxygenase pathway, and their effects typically dissipate within 3 days of discontinuation.
    6. Ticlopidine, clopidogrel, prasugrel, ticagrelor, and cangrelor are agents that inhibit ADP-mediated platelet aggregation by antagonizing the P2Y12 receptor. Clopidogrel remains the most commonly coprescribed antiplatelet agent with aspirin in patients requiring dual antiplatelet therapy, although ticagrelor, a more potent reversible inhibitor, may have greater clinical efficacy in certain contexts. Ticlopidine is now rarely prescribed owing to the associated risk of neutropenia.
    7. Eptifibatide, abciximab, and tirofiban are inhibitors of the platelet glycoprotein IIb/IIIa receptor. Abciximab, notably, is an IV monoclonal Fab antibody fragment directed against the receptor and thus also has the potential to produce thrombocytopenia. Although the drug’s plasma half-life is short, impairment of platelet function may last for days, and reversal of its effects may require multiple platelet transfusions owing to ongoing adsorption of the antibody to donor platelets.
    8. Dipyridamole and cilostazol are selective phosphodiesterase 3 inhibitors that increase platelet and endothelial cAMP levels, thereby inhibiting platelet aggregation and producing a degree of vasodilation. Cilostazol is commonly used in the management of symptomatic peripheral arterial disease.
    9. Thrombolytic agents act by dissolving thrombi via direct conversion of plasminogen to plasmin, which lyses fibrin clots. They are intended to rapidly antagonize thrombosis and thus recanalize blood vessels occluded as a result of thrombotic phenomena (eg, thromboembolic stroke). Two thrombolytic agents, recombinant tissue plasminogen activator and streptokinase, are most commonly used in clinical practice. Each of these drugs results in a hypofibrinogenemic state and carries a substantial risk of bleeding. Therefore, they are generally contraindicated perioperatively, and the benefits of their administration should be carefully weighed against their considerable risks. If emergent surgery is required after thrombolytic therapy, the effect may be antagonized by administration of aminocaproic acid or TXA. Fibrinogen levels may also be restored by transfusion of cryoprecipitate or FFP.
    10. Direct thrombin inhibitors (DTIs) such as dabigatran, argatroban, and bivalirudin inhibit thrombin (factor IIa). Dabigatran is an oral DTI often used for stroke prevention in atrial fibrillation and, unlike warfarin, does not require frequent INR monitoring. It also carries the advantage of an availability of a novel reversal agent called idarucizumab, a monoclonal antibody that targets and inactivates drug. Argatroban (often preferred in renal insufficiency) and bivalirudin are intravenous medications used for anticoagulation as alternatives to heparin in patients with heparin-induced thrombocytopenia. At this time, argatroban and bivalirudin lack specific reversal agents and can thus cause life-threatening bleeding if administered without due caution.
    11. Direct factor Xa inhibitors such as apixaban, edoxaban, and rivaroxaban inhibit factor Xa. This mechanism lies in contrast to that of LMWHs and synthetic agents such as fondaparinux, which inhibit factor Xa indirectly via interaction with antithrombin III. Like dabigatran, these oral agents are also typically used for the prevention and treatment of thromboembolic events, and they have been demonstrated to be efficacious, safe, and convenient alternatives to warfarin therapy in patients with adequate renal function. Although direct factor Xa inhibitors were traditionally irreversible, a novel reversal agent called andexanet alfa (Andexxa), a recombinant derivative of factor Xa that acts as a decoy receptor for the anticoagulant drug, has gained US Food and Drug Administration (FDA) approval. Additional antidotes such as ciraparantag, a “universal” reversal agent potentially capable of counteracting a wide variety of anticoagulants, remain under investigation.
  7. Reversal of perioperative coagulopathy can often be achieved with blood component therapies such as cryoprecipitate, platelets, and FFP, although the choice of therapy depends on the underlying cause of the coagulopathy. In addition, specific clotting factors are available for patients who require rapid reversal of coagulopathy and may not tolerate the large volumes or other risks associated with transfusion of conventional blood products.
    1. Recombinant factor VIIa (rFVIIa) is FDA approved for the treatment of hemophiliacs with antibody inhibitors that prevent factor VIII or IX from normalizing their coagulation. Rather than replenishing factor VII levels directly, it produces direct and rapid platelet activation and can trigger the coagulation cascade with a “thrombin burst.” The apparent efficacy of rFVIIa in massive surgical or traumatic bleeding, primarily shown in case studies, has generated interest in wider applications for the drug. A major trial of rFVIIa administration demonstrated reduced expansion of intracerebral hematoma in cases of nontraumatic hemorrhagic stroke, although a follow-up study showed no improvement in mortality or functional outcome. rFVIIa is expensive and has been associated with adverse thrombotic events.
    2. Prothrombin complex concentrates (PCCs) are preparations of vitamin K–dependent factors II, VII, IX, X, and proteins C and S that are derived from FFP. They are useful for the urgent reversal of warfarin or other serious coagulopathies resulting from specific factor deficiencies. PCCs are expensive, and their use is currently restricted to particular clinical circumstances requiring immediate reversal of anticoagulation. Standard inactive PCC (Kcentra) is currently approved for the rapid reversal of warfarin anticoagulation in patients with severe acute bleeding or those requiring major surgery, whereas an activated form (factor eight inhibitor bypass activity or FEIBA) is primarily administered for uncontrolled hemorrhage in patients with hemophilia A. Key adverse effects include thrombotic sequelae, especially with the use of activated PCC.