Patient Factors

Patients may have acquired or inherited disorders of hemostasis. Of these, antithrombotic (anticoagulant and antiplatelet) drugs are the most important.

Intraoperative Factors

Intraoperative factors that contribute to postoperative bleeding include the effects of cardiopulmonary bypass (CPB), the type and duration of the surgical procedure, and the management of anticoagulation. The effects of CPB and surgery on hemostasis are complex.⁴ CPB and surgical trauma elicit a marked systemic inflammatory response characterized by leukocyte activation, release of inflammatory mediators, and activation of platelets and the coagulation and complement cascades (see Chapter 2). Activation of platelets and coagulation occurs through blood contact with the CPB circuit, through surgical trauma, and through the reinfusion of pericardial blood. Platelets are also activated by heparin and hypothermia. Hemodilution of platelets and coagulation proteins occurs because of the CPB prime solution and other intravenous fluids. Platelets are sequestered onto Dacron grafts. Fibrinolysis is stimulated by hypothermia, contact activation of thrombin and factor XII, and the release of tissue plasminogen activator from the vascular walls. These adverse effects are more pronounced when CPB is prolonged and deep hypothermia is utilized.

Various intraoperative strategies may be employed to reduce bleeding and allogenic (i.e., donor) blood transfusion. They include: (1) antifibrinolytics; (2) heparin-coated CPB circuits; (3) avoidance of deep hypothermia; (4) autologous (i.e., the patient’s) blood donation; (5) normovolemic hemodilution; (6) intraoperative blood recovery and reinfusion through a cell saver. Surgical strategies to reduce postoperative blood loss include meticulous surgical hemostasis and the use of topical agents such as surgical adhesives (e.g., BioGlue) and thrombin preparations (e.g., Thrombostat).

Postoperative Factors

In the early postoperative period, the major contributors to postoperative bleeding are inadequate surgical hemostasis, hypothermia, residual heparin effect (sometimes referred to as heparin rebound), platelet dysfunction, thrombocytopenia, and dilutional coagulopathy. In particular, platelet dysfunction—usually in association with thrombocytopenia, but not always—is a major cause of postoperative bleeding. Less commonly, excessive fibrinolysis is present, although the widespread preemptive use of antifibrinoltyics minimizes this as a cause. Assuming there are no specific concerns regarding neurologic function, patients who are bleeding excessively should be actively warmed to 36°C. Massive transfusion causes coagulopathy by several different mechanisms; it is discussed later in this chapter.

Beyond the early postoperative period, pathologic bleeding is usually related to antithrombotic drugs. Acute gastrointestinal stress ulceration and hemorrhage is the most common nonsurgical cause of bleeding. Stress ulcer prophylaxis is discussed in Chapter 34. Thrombocytopenia is common in patients with critical illness. The causes include: (1) heparin-induced thrombocytopenia (see subsequent material); (2) drugs (see Table 30-2); (3) platelet destruction due to intraaortic balloon counterpulsation, renal replacement therapy, or mechanical cardiac support; (4) sepsis and disseminated intravascular coagulation (see subsequent material); (5) posttransfusion purpura (see subsequent material). Usually, platelet transfusion is required only to treat bleeding or before invasive procedures.

Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is a generalized disorder of the coagulation system involving the inappropriate activation of platelets, coagulation, and fibrinolysis, resulting in a consumptive coagulopathy and pathologic thrombosis. It is characterized by pathologic bleeding from surgical sites, intravenous cannula sites, and mucosal surfaces and, rarely, by clinically significant thrombosis. Following an initiating event, there are normally two stages of DIC. Stage 1 (early) involves excessive activation of platelets and coagulation proteins, resulting in generalized microvascular thrombosis and obstruction. This obstruction leads to red cell fragmentation and coagulation factor and platelet consumption, resulting in bleeding due to hemostatic factor and platelet depletion (stage 2, late). DIC has multiple causes, including trauma, hemolytic transfusion reaction, obstetric complications and, most important, sepsis. In addition, the consumptive coagulopathy that accompanies prolonged CPB or extracorporeal membrane oxygenation (ECMO) shares many of the hemostatic features of late DIC, namely, low platelet numbers, low fibrinogen, prolonged prothrombin time, prolonged aPTT, elevated D-dimer, and characteristic changes on the thromboelastogram (see Fig. 30-4).⁵ Management of DIC involves treating the underlying causes and controlling bleeding by means of blood component therapy. In the relatively rare circumstance of clinically important thrombosis, systemic heparinization is indicated.

Figure 30.4 Normal and abnormal thromboelastograms. DIC, disseminated intravascular coagulation. (See page 441 for explanation of DIC stages 1 and stage 2.)

Activated Partial Thromboplastin Time

The aPTT monitors primarily the competency of the intrinsic coagulation pathway (i.e., high molecular weight kininogen, prekallikrein, and factors VIII, IX, X, XI, XII) and, to a lesser extent, the common pathway. The test involves adding a phospholipid tissue extract—which activates factor XII and calcium ions—to citrated plasma. The aPTT is used to monitor the effectiveness of anticoagulation with unfractionated heparin and direct thrombin inhibitors (see subsequent material). The normal range is 20 to 35 seconds but values vary slightly among laboratories. The therapeutic range for systemic heparinization is 50 to 80 seconds. Causes of prolonged aPTT include (1) deficiency of intrinsic pathway factors (e.g., due to consumptive coagulopathy or hemophilia); (2) unfractionated heparin; (3) the presence of acquired inhibitors (i.e., antibodies) of factors VIII and IX; and (4) the presence of lupus anticoagulant. Although typically associated with an elevated prothrombin time (PT), a mildly elevated aPTT may also be seen with warfarin overdose, liver disease, and vitamin K deficiency.

If the aPTT is prolonged preoperatively, correction studies in which the patient’s plasma is mixed with pooled normal plasma may be performed. Normalization of the aPTT suggests that there is a coagulation factor deficiency; partial or no correction suggests a heparin effect or the presence of an inhibitor or lupus anticoagulant. A heparin effect can be excluded by adding protamine to the sample. Although the aPTT is often measured after cardiac surgery, abnormalities may not always correlate with bleeding.

Prothrombin Time, Prothrombin Ratio, and International Normalized Ratio

The PT monitors the competency of the extrinsic (tissue factor, factor VII) and common (factors V, X, II, and I) pathways. The test involves adding tissue factor and calcium ions to citrated plasma. The prothrombin ratio (PR) is the patient’s PT divided by the mean PT obtained from healthy individuals using the laboratory’s reagents. The normal value for PT is 10 to 14 seconds; the normal PR is 0.8 to 1.2, but values vary among laboratories. Causes of a prolonged PT include: (1) consumptive coagulopathy, (2) warfarin anticoagulation, (3) vitamin K deficiency, (4) liver disease, and (5) hypofibrinogenemia. Large amounts of heparin also elevate the PT but not to the same extent as the aPTT is raised. Inhibitors of extrinsic pathway factors can occur but are much less common than those of factors VIII and IX, which affect the aPTT. Although the PT is commonly measured after cardiac surgery, abnormalities may not always correlate with bleeding.

The international normalized ratio (INR) pertains to monitoring warfarin anticoagulation; it is the patient’s PT divided by the result that would have been obtained if the PT were measured using standardized reagents (the international reference preparation). An individual laboratory’s reagents have a specific sensitivity relative to the international reference preparation. Thus, the INR avoids differences in PR due to differences in the reagents used by various laboratories.

Fibrinogen

The normal range for the plasma fibrinogen concentration is 200 to 400 mg/dl. Levels increase as part of the acute-phase response and decrease with consumptive coagulopathy and advanced liver and renal disease. Several days following cardiac surgery, fibrinogen levels can increase to more than 500 mg/dl and remain elevated for up to a month.⁹

D-Dimer

D-dimer is a degradation product of cross-linked fibrin. Levels are normally low (<500 μg/l). Higher levels occur in any situation in which there is excess clotting followed by fibrinolysis; in particular, higher levels occur with venous thromboembolism (see Chapter 23), major hemorrhage, therapy, and DIC. Moderate elevations in the D-dimer are also seen in patients with severe systemic illness. Following cardiac surgery, the fibrinolytic D-dimer concentration is commonly greater than 1000 μg/l and remains elevated for as long as 60 days.⁹

Thrombin Clotting Time

The thrombin clotting time is a measure of the rate of conversion of fibrinogen to fibrin by thrombin. The normal range is 15 to 20 seconds. It is higher when fibrinogen levels are low (<100 mg/dl) and after the administration of unfractionated heparin and direct thrombin inhibitors.

Activated Clotting Time

The activated clotting time (ACT) is a bedside test that is used to assess the effectiveness of heparin anticoagulation. Whole blood is added to a tube or cartridge containing an activator (celite, kaolin, glass beads, or phospholipid tissue extract), which stimulates contact activation of the intrinsic coagulation pathway. The activated blood sample is then placed in a device that warms the blood and records the time it takes for clot to form. Devices from different manufacturers use different activators and different methodologies of assessing clot formation; thus, ACT values from different machines cannot be used interchangeably. The normal range for ACT depends on the device being used, but it is usually within the range of 70 to 150 seconds. Values above 400 seconds are generally used for CPB; values of 160 to 180 seconds are used for continuous renal replacement therapy (CRRT; see Chapter 33) and ECMO (see Chapter 22).

The ACT has the advantage of being able to be rapidly performed at the bedside. Most ACT devices have two channels, one of which can be used with a heparinase-containing cartridge. Heparinase is an enzyme that neutralizes heparin. An elevated ACT with a normal heparinase ACT indicates a heparin effect; if both ACTs are elevated, coagulopathy is suggested. The ACT has several limitations. First, as outlined earlier, values vary among devices and may not reliably correlate with plasma heparin concentrations.¹⁰ Second, values for ACT (more so than values for aPTT) are influenced by factor depletion, thrombocytopenia, platelet dysfunction, and antifibrinolytic therapy. Finally, as a point-of-care test, a quality assurance program must be maintained, but most ACT machines do not allow patient and user identification to be recorded.

Platelet Count and Platelet Function Tests

The normal value for the platelet count is 140,000 to 450,000/mm³. This parameter is easily measurable, but specific tests of platelet function are not widely available. Currently available point-of-care tests of platelet function, such as the PFA-100 and the HemoSTATUS analyzers, have proved disappointing as sole measures of hemostatic function in cardiac surgery patients.^11–13 Important information about platelet function can be inferred from the thromboelastogram (see subsequent material).

The causes of thrombocytopenia in preoperative and postoperative patients are listed in the early part of this chapter. A raised platelet count (thrombocytosis) has a number of causes, which may be classified as primary or reactive. Infection, inflammation, and surgical stress are common reactive causes.

Thromboelastography

Thromboelastography is a hemostatic test that measures the shear elasticity and the dynamics of clot formation and the strength and stability of formed clot. In one method (TEG 5000 Thromboelastograph Hemostasis Analyzer, Hemoscope, Niles, IL), whole blood is placed in a heated oscillating cup into which a pin, suspended from a torsion wire, is lowered. Initially, the pin is undisturbed by the oscillating cup, but as fibrin strands develop, the pin becomes progressively constrained by the developing clot, creating tension in the wire, which is transduced and displayed on a computer screen. This is represented as an increasing deflection from the midline. In another device (ROTEM Whole Blood Haemostasis Analyser, Pentapharm, Basel Switzerland), the sensor shaft, rather than the cup, rotates; otherwise the principles are similar.

Various activators (celite, tissue factor) can be added to the cups to accelerate initial coagulation, and heparinase cups are commonly paired with plain cups to identify a heparin effect. Thromboelastography provides information about all components of hemostasis (coagulation, platelet function, fibrinolysis) but offers a particular advantage in diagnosing fibrinolysis. Also, the diagnosis of platelet dysfunction can be inferred by the findings of an abnormal thromboelastogram (in particular, a maximum amplitude <45 mm) in combination with a normal platelet count and normal tests of coagulation.

Standard thromboelastogram parameters are shown in Figure 30-3; typical abnormal patterns are shown in Figure 30-4. Point-of-care thromboelastogram-guided blood transfusion algorithms, either alone^7,14 or in conjunction with other tests,⁸ have been shown to reduce transfusion requirements. As with ACT, point-of-care thromboelastogram analysis requires a quality assurance program.

Figure 30.3 Thromboelastogram parameters. The reaction (R) time is the time from the start of the test until the first significant levels of detectable clot formation (amplitude 2 mm). The normal range is 15 to 23 minutes (5 to 7 minutes for a kaolin-activated sample). The R time is increased by factor deficiency and anticoagulants. The kinetic (K) time is the time to achieve a certain level of clot strength (amplitude of 20 mm). The normal value is 5 to 10 minutes (1 to 3 minutes for a kaolin-activated sample). The K time is increased by factor deficiency and anticoagulants and, to a lesser extent, by thrombocytopenia and platelet dysfunction. The α angle is the angle between the baseline and the outer edge of clot envelope. The normal range is 22 to 38 degrees (or 53 to 67 degrees for kaolin-activated blood). The α angle measures the rapidity of fibrin formation and cross-linking (clot strengthening). It is reduced by factor deficiency, anticoagulants and, to a lesser extent, by thrombocytopenia and platelet dysfunction. The maximum amplitude (MA) is the maximum strength of developed clot. The normal range is 47 to 58 mm. The MA is determined mainly by platelet number and function and, to a lesser extent, by the concentration of coagulation factors. The amplitude 30 minutes after the MA allows for estimation of the percent clot lysis. The normal value is less than 7.5%. The percent clot lysis is increased with fibrinolysis.

Red Blood Cells

Red blood cells are usually administered as packed cells from which much of the non-red-cell component has been removed and the blood has been resuspended in an anticoagulant storage solution, usually citrate-phosphate-dextrose-adenine. A unit of packed red cells has a volume of about 300 ml and a hematocrit of about 60%. Without continuing blood loss, transfusion of 4 to 5 ml/kg of packed red cells increases hemoglobin concentration by about 1 g/dl. Packed red cells are stored at 4°C and have a shelf life of 35 to 42 days. During storage, red cells metabolize dextrose into lactate, resulting in a fall in pH and an increase in lactate. Red cell fragility increases progressively, and temperature-sensitive failure of the red cells’ sodium-potassium pump occurs, resulting in an increase in the concentrations of free hemoglobin and extracellular potassium. There is also progressive loss of cellular 2,3-diphosphoglycerate (2,3-DPG), which is probably responsible for the short-lived (12 to 24 hours) leftward shift in patients’ oxygen-hemoglobin curves (and therefore the reduced tissue unloading of oxygen) that occurs with the transfusion of old blood. Despite these effects, no convincing data indicate an association between length of storage of red blood cells and adverse outcomes in cardiac surgery patients.¹⁵