Transfusion Therapy - Perioperative Coagulopathy That May Alter Management

Coagulopathy of massive transfusion

Coagulopathy of massive transfusion is unusual with transfusions less than 1 to 1.5 blood volumes, assuming the patient had a normal coagulation profile, platelet count, and platelet function initially.

  1. Thrombocytopenia. Diffuse oozing and failure to form clots after massive transfusion are often at least in part due to thrombocytopenia. The decreased platelet count is due to the transfusion of platelet-poor blood products. Clinical bleeding is unlikely with platelet counts above 50,000 cells/mm3. If loss of one BV or more is expected, platelets should be available and transfused to maintain a count of more than 50,000 cells/mm3 or greater if ongoing blood loss is expected.
  2. Clotting factors. The normal human body has tremendous reserves of clotting factors. In addition, the patient receives small amounts of the stable clotting factors in the plasma of each unit of red cells. Bleeding from factor deficiency in the face of massive transfusion is usually due to decreased levels of fibrinogen and labile 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. Labile clotting factors are administered in the form of FFP. Six units of platelets contain the equivalent of 1 unit of FFP. Cryoprecipitate provides a source of concentrated fibrinogen for the patient who cannot tolerate FFP due to volume overload.

Disseminated intravascular coagulation (DIC)

Disseminated intravascular coagulation (DIC) refers to the abnormal, diffuse systemic activation of the clotting system. The pathophysiology involves excessive formation of thrombin, resulting in fibrin formation throughout the vasculature accompanied by platelet activation, fibrinolysis, and consumption of coagulation factors. The profound consumptive coagulopathy produced by DIC often results in hemorrhage.

  1. Causes of DIC include infection, shock, trauma, complications of pregnancy (e.g., amniotic fluid embolism, placental abruption, or septic abortion), burns, and fat or cholesterol embolism. DIC is common in extensive head injury because of the high content of thromboplastin in brain tissue. A chronic form of DIC may accompany cirrhotic liver disease, aortic dissection, and malignancy.
  2. Clinical features include petechiae, ecchymoses, bleeding from venipuncture sites, and frank hemorrhage from operative incisions. The bleeding manifestations of DIC are most obvious, but the diffuse microvascular and macrovascular thromboses are usually more common, more difficult to treat, and more frequently life threatening because of ischemia to vital organs. Bradykinin release in DIC may also cause hypotension.
  3. Laboratory features of DIC include an elevated d-dimer, indicating fibrin degradation by plasmin, in all cases. Fibrinogen degradation products (FDPs) are increased, but this is not specific to DIC because FDPs may be present from the formation of fibrin by fibrinogen or from the degradation of fibrinogen by plasmin. The PT and PTT typically are prolonged and serial measurements reveal falling fibrinogen levels and platelet counts. After acquisition of the PTT, the waveform that is used to generate the PTT result can be reviewed for an early negative slope that is suggestive of DIC.
  4. Treatment of DIC involves treating the precipitating cause and transfusion of appropriate blood products (e.g., FFP, platelets, and cryoprecipitate) to correct bleeding. Inhibitors of fibrinolysis (e.g., aminocaproic acid and tranexamic acid) are contraindicated in DIC.

Chronic Liver Disease

With the exception of factor VIII and vWf, which are manufactured by the endothelium, the liver synthesizes all coagulation factors. Patients with hepatic dysfunction may have decreased production of coagulation factors and decreased clearance of activated factors. Patients may have an ongoing consumptive coagulopathy, similar to DIC, if circulating activated clotting factors are increased. Because the liver is also instrumental in removing the by-products of fibrinolysis, circulating fibrin degradation products may be elevated.

Vitamin K Deficiency

Vitamin K is required by the liver for production of factors II, VII, IX, and X and proteins C and S. Because vitamin K cannot be synthesized by humans, interference with vitamin K absorption will cause a coagulopathy (see Chapter 5) and a prolonged PT. Because we rely on GI flora for the production of vitamin K, vitamin K deficiency is commonly found in patients receiving broad-spectrum antibiotics, neonates who lack GI flora, and patients with short bowel syndrome. These patients can be treated with vitamin K, 10 mg SC daily for 3 days. IV administration of vitamin K may result in a slightly faster correction of the PT but is accompanied by a rare risk of anaphylaxis. If used, IV vitamin K should be administered very slowly. If faster correction of PT than vitamin K is required, FFP (5 to 8 mL/kg) can be used.

Pharmacologic Intervention

Pharmacologic Intervention

  1. Heparin acts by accelerating the effect of antithrombin III. It prolongs the PTT and has a short half-life so that its anticoagulant effect is usually fully reversed approximately 4 hours after discontinuation of the infusion. If faster reversal is required, protamine, a natural antagonist, may be administered.
  2. Low molecular weight heparins are commercially prepared by fractionating heparin into molecules of 2,000 to 10,000 Da. They exert their anticoagulant effect primarily by inhibiting factor X and usually do not prolong the PTT. These drugs have a longer half-life than heparin and are incompletely reversed by protamine, yet protamine reversal is indicated in the setting of a major bleeding episode. Fast reversal may require FFP transfusion.
  3. Warfarin (Coumadin) inhibits vitamin K epoxide reductase. This causes a deficiency of vitamin K, preventing the hepatic carboxylation of factors II, VII, IX, and X and proteins C and S to the active form. The PT and the INR are prolonged in patients taking warfarin. The drug's half-life is approximately 35 hours, requiring days for reversal. If quick reversal of warfarin is required, active factors can be given in the form of FFP (5 to 15 mL/kg). Vitamin K (2.5 to 10 mg IV or SC) can also be given for warfarin reversal, but its effect requires 6 or more hours.
  4. Platelet inhibitors. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit platelet aggregation by interfering with the cyclooxygenase pathway. Aspirin permanently inhibits the pathway for the 10-day life span of the platelet. The other NSAIDs reversibly inhibit the cyclooxygenase pathway; their effects are reversed within 3 days of discontinuing the drug. Dipyridamole is a phosphodiesterase inhibitor that increases platelet cAMP, thereby inhibiting platelet aggregation. Ticlopidine, clopidogrel, prasugrel, and ticragalor are antiplatelet agents that inhibit ADP-mediated platelet aggregation. Abciximab is an IV monoclonal antibody against the platelet glycoprotein IIb/IIIa receptor. It causes profound platelet inhibition and produces thrombocytopenia. Although the drug's plasma half-life is short, impairment of platelet function may last for days and reversal of the effect may require multiple platelet transfusions due to adsorption of the antibody to donor platelets. Immediate reversal of platelet inhibitors may require platelet transfusion and may not be effective if the inhibitor is still present in the plasma.
  5. Thrombolytic agents act by dissolving thrombi via conversion of plasminogen to plasmin, which lyses fibrin clot. They are intended to reverse thrombosis and recanalize blood vessels. Two thrombolytic agents, tissue plasminogen activator and streptokinase, are commonly used in clinical practice, each with slightly different pharmacodynamic and side effect profiles. Each of these drugs results in a hypofibrinogenemic state and carries a substantial risk of bleeding. They are generally contraindicated perioperatively. If emergent surgery is required after thrombolytic therapy, the effect may be antagonized by administration of aminocaproic or tranexamic acid. The fibrinogen level may be restored by transfusion of cryoprecipitate or FFP.
  6. Direct thrombin inhibitors (DTIs). Dabigatran and argatroban are among the increasingly popular DTIs, which inhibit thrombin (factor II). Dabigatran is an oral DTI often used for stroke prevention in atrial fibrillation and, unlike warfarin, does not require frequent INR monitoring. Argatroban is an IV medication used for anticoagulation in patients with heparin-induced thrombocytopenia. At this time, DTIs lack a specific reversal agent and can thus cause life-threatening bleeding if taken incorrectly.
  7. Direct factor Xa inhibitors, such as apixaban and rivaroxaban, directly inhibit factor Xa (as opposed to LMWHs that inhibit factor Xa via antithrombin III). Like DTIs, these drugs are also typically used for the prevention and treatment of thromboembolic events. They also lack a specific reversal agent.

Reversal of Perioperative Coagulopathy

Reversal of Perioperative Coagulopathy

  1. Reversal of perioperative coagulopathy can often be achieved with cryoprecipitate, platelets, and FFP depending on the cause of 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 large amounts of blood products.
  2. 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. The apparent efficacy of the drug in massive surgical or traumatic bleeding from case studies had generated intense interest for a wider applicability of the drug. In addition, one major trial demonstrated reduced expansion of intracerebral hematoma in cases of nontraumatic, hemorrhagic stroke, which has created enthusiastic support for the use of rFVIIa in these patients by some neurointensivists. However, a follow-up prospective randomized controlled study by the same group showed no improvement in mortality or functional outcome after intracerebral hemorrhage although they confirmed a reduction in the size of the hematoma. There is currently no clearly defined role for rFVIIa except for treating hemophiliacs with inhibitors.
  3. Prothrombin Complex Concentrates (PCC, also by various brand names) are preparations of factors II, V, 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 coagulopathy resulting from factor deficiency. They are extremely expensive, and their use is currently limited to patients who require immediate reversal of anticoagulation, such as those with life-threatening intracerebral hemorrhage.