Blood Coagulation, Transfusion, and Conservation

Heparin

Heparin is the mainstay agent used to prevent clotting during cardiovascular surgery. Heparin is isolated from porcine intestine and previously from beef lung, where it is bound to histamine and stored in the mast cell granules. When heparin is isolated, the purification leads to a heterogeneous mixture of molecules. Heparin is an acidic molecule with side groups, either sulfates or N -acetyl groups, attached to individual sugar groups. These structural characteristics are important for producing its anticoagulant activity. Heparin acts as an anticoagulant by binding to antithrombin III (AT), which enhances the rate of thrombin-AT complex formation by 1000- to 10,000-fold. Other factors in the clotting cascade, including factor Xa, are also inhibited by AT. Anticoagulation thus depends on the presence of adequate amounts of circulating AT.

Heparin anticoagulation can be reversed immediately by removing heparin from AT with the highly basic molecule protamine. Heparin also binds to a number of other blood and endothelial proteins. Each of these proteins can influence the ability of heparin to act as an anticoagulant, and may, along with AT levels, affect heparin dose responses in patients. Heparin can also produce platelet dysfunction following acute or constant administration, especially with high-dose administration during cardiac surgery. Severe adverse reactions to heparin can also occur because of immune-related causes, including hypersensitivity (allergic) and heparin-induced thrombocytopenia (discussed later).

In January 2008, the U.S. Food and Drug Administration (FDA) received reports of clusters of acute hypersensitivity reactions in patients undergoing dialysis. The Centers for Disease Control and Prevention identified heparin as a common feature of the cases, leading to a recall of affected lots. After the initial recall, there were continuing reports of allergic-type reactions from patients in other clinical settings. The contaminant was recently identified as an unusual, oversulfated form of chondroitin sulfate. Highly charged molecules like this can activate enzymatic cascades in plasma. Activation of kinin pathways produced vasodilation via contact activation, the mechanism of the reported adverse reactions.

Protamine Administration and Heparin Reversal

Protamine, the mainstay neutralizing agent, is a basic polypeptide isolated from salmon sperm. Composed mostly of arginine, protamine reverses heparin by a nonspecific acid-base interaction (polyanionic-polycationic). Protamine can immediately reverse the anticoagulation effect of unfractionated heparin by nonspecific polyionic-polycationic (acid-base) interactions. Different methods can be used to calculate the reversal dose of protamine, but using a ratio of 1.0 to 1.3 mg protamine to 100 units of the initial dose of unfractionated heparin administered is a useful estimate. Protamine has the potential to function as an anticoagulant when excessive doses have been administered ( Fig. 51-2 ). Additional considerations about protamine and potential adverse effects will be considered later.

Fondaparinux

Fondaparinux (Arixtra), a synthetic pentasaccharide with a duration of action longer than LMWH, selectively binds antithrombin and causes rapid and predictable inhibition of factor Xa. Fondaparinux is more effective than enoxaparin in preventing venous thrombosis in patients undergoing orthopedic surgery, and it is similar in effectiveness to enoxaparin or unfractionated heparin in patients with pulmonary embolism. Pilot trials involving patients with acute coronary syndromes and those undergoing percutaneous coronary intervention suggest that fondaparinux may be as effective as enoxaparin or safer than unfractionated heparin. The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-5; NCT00139815) trial compared the efficacy and safety of fondaparinux and enoxaparin (Lovenox, Sanofi-Aventis) in high-risk patients with unstable angina or myocardial infarction without ST-segment elevation. The result of this study indicated that fondaparinux reduces the risk of ischemic events similar to enoxaparin, but with less risk of major bleeding.

Warfarin

Warfarin is the most commonly used oral anticoagulant; it is a member of the family of drugs known as vitamin K antagonists . Warfarin has major limitations, including slow onset and offset, a narrow therapeutic window, and metabolism affected by diet, concomitant drug therapy, and genetic polymorphisms. Warfarin also requires careful monitoring. Warfarin is a vitamin K analog that interferes with the transformation of coagulation factors to an active form. Vitamin K is required in the posttranslational carboxylation required for the synthesis of active coagulation factors II, VII, IX, and X. Without vitamin K, these coagulation factors are incapable of chelating calcium that is required for their binding to phospholipid membranes during the normal clotting process, thereby decreasing prothrombin activation. Warfarin also inhibits the carboxylation of protein C and protein S, thus impairing the function of the anticoagulant proteins. Warfarin is often a mainstay in preventing thromboembolic complication in patients with prosthetic heart valves, atrial fibrillation, atrial mural thrombi, deep vein thrombosis, or prior pulmonary embolic problems. Warfarin is rapidly absorbed from the gastrointestinal tract with peak plasma concentrations reached 1 to 4 hours after ingestion; its anticoagulant effect occurs only after a significant decrease in the concentration of normal vitamin K–dependent clotting factors.

The NOAC agent ximelagatran was the first oral anticoagulant, but it was withdrawn from the market in Europe because of hepatic toxicity. A next-generation direct thrombin inhibitor, dabigatran (Pradaxa), is now recommended for atrial fibrillation and VTE prophylaxis. Additional agents include rivaroxaban and apixaban, also approved for paroxysmal atrial fibrillation and VTE prophylaxis. Rivaroxaban and apixaban target factor Xa, whereas dabigatran etexilate inhibits thrombin. Rivaroxaban is a small molecule directed against the active site of factor Xa. After oral administration, all the agents have a rapid onset of action within a few hours. Although monitoring is not required for the NOAC agents, their effects can be determined using readily available coagulation assays. For dabigatran, this includes thrombin times and partial thromboplastin times, and if possible a dabigatran-specific assay that is a diluted thrombin time (HemoClot assay). For rivaroxaban and apixaban, an antiXa assay, similar to LMWH assay but calibrated for the specific drug, is the assay used to measure levels of the Xa inhibitors including edoxaban. All the agents have some renal elimination, but dabigatran is the agent most dependent on renal function, and for all of the NOAC agents dose alterations must be made with renal dysfunction. For more information about the NOAC agents and bleeding, a recent review has discussed this as therapeutic modalities continue to evolve.

Heparin-Induced Thrombocytopenia and New Anticoagulants

Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening, adverse effect of heparin produced by antibodies (IgG) induced to the composite antigen of heparin-platelet factor 4 (PF4). Later exposure of seropositive patients to heparin risks forming the heparin-PF4 antigen and immune complexes. These immune complexes bind to platelets via platelet Fc-receptors (CD 32); this produces intravascular platelet activation, thrombocytopenia, and platelet activation with potential thromboembolic complications that can result in limb loss or death. HIT can occur after 5 to 10 days of heparin therapy, but can occur earlier because of occult heparin exposure from prior hospitalizations or in the cardiac catheterization laboratory.

This serious, yet treatable, prothrombotic disease develops in 1% to 3% of heparin-treated patients and dramatically increases their risk of thrombosis. HIT antibodies (IgM and IgG), occur more often than the overt disease itself. Even without thrombocytopenia, the IgG subclass may be associated with increased thrombotic morbidity and mortality. HIT should be suspected whenever the platelet count drops greater than 50% from baseline more than 4 to 5 days after starting heparin (or sooner if there was prior heparin exposure) or when new thrombosis occurs during, or soon after, heparin treatment, with other causes excluded. When HIT is strongly suspected, with or without complicating thrombosis, heparin should be discontinued and a fast-acting, nonheparin alternative anticoagulant, such as a direct thrombin inhibitor (argatroban or bivalirudin), should be initiated immediately, because HIT is a prothrombotic disease that carries significant morbidity and mortality.

Despite their association with long-term adverse effects, circulating heparin-PF4 antibodies are transient. Should a patient require cardiac surgery and have a history of HIT, antibody titers should be checked. If the patient is currently seronegative, heparin is the anticoagulant of choice. Bivalirudin has emerged as the agent most studied for use during on- or off-pump surgery in patients with HIT. For prophylaxis in the intensive care unit in patients with HIT, fondaparinux is a potential alternative, but its long duration of effect makes it impractical. Rivaroxaban can have a role for prophylaxis and can be given via a nasogastric tube. Eventually the patient should be switched to warfarin for long-term anticoagulation. Warfarin should not be started until the platelet count has recovered. A minimum of a 5-day overlap of the direct thrombin inhibitor and warfarin should be used before stopping the direct thrombin inhibitor. The role of NOAC agents is yet to be determined.

Risk Factors for Bleeding

Ferraris and colleagues summarize variables associated with increased transfusion requirements caused by patient-related, procedure-related, and process-related factors in their inclusive review. However, most studies do not distinguish between red blood cell (RBC) transfusion and hemostatic factor transfusion. Ferraris and colleagues identified a high-risk profile associated with increased postoperative blood transfusion. Six variables were identified as important indicators of the risk of bleeding: (1) advanced age, (2) low preoperative RBC volume (preoperative anemia or small body size), (3) preoperative antiplatelet or antithrombotic drugs, (4) reoperative or complex procedures, (5) emergency operations, and (6) certain patient comorbidities. The web site of the review can be found at www.sts.org/sites/default/files/documents/pdf/guidelines/BloodConservationUpdate0311.pdf .

Patient-Related Causes of Bleeding

Certain patients are at greater risk for bleeding, such as those with acquired or congenital coagulopathies, patients scheduled for re-do or complex procedures (e.g., combined valve and coronary revascularization, and aortic dissection with deep hypothermic circulatory arrest). There is evidence that certain patients have an accentuated response to antiplatelet drugs. Patients with thrombocytopenia from any cause (defined as platelet count less than 50,000) are at a high risk of excessive bleeding after CABG. Patients with preoperative anemia have a lower starting RBC mass. Anemia in complex ways can also contribute to bleeding. Patients with other congenital or acquired qualitative platelet defects, such as von Willebrand disease, Bernard-Soulier syndrome, and Glanzmann thrombasthenia, are at increased risk of bleeding. Acquired qualitative defects occur with hepatic and renal failure, as well as following the administration of some drugs.

Physician-Related Causes of Bleeding

One important factor in surgical bleeding and blood transfusion is the surgeon. Surgical practices differ widely and influence morbidity and mortality. Cardiopulmonary bypass times influence platelet function and postoperative bleeding. Meticulous attention to surgical technique and to intraoperative hemostasis will affect bleeding and transfusion requirements. Differences in practice patterns relative to the diagnosis and therapy of postoperative hemorrhage also contribute to variability in transfusion practices. Transfusion practices also vary among centers.