COAGULATION MONITORING (also see Chapter 47 and Chapter 50 )

In contrast to hemodynamic monitoring, assessment of perioperative coagulation remains, at present, entirely an ex vivo process. Traditionally, coagulation monitoring in surgical patients has focused on preoperative testing to identify those at increased risk for perioperative bleeding and intraoperative monitoring of heparin therapy during cardiac and vascular surgery. More recently, the availability of increasingly sensitive and specific point-of-care coagulation monitors has provided an opportunity to guide the administration of blood components and hemostatic drugs more specifically, without the delays inherent in standard laboratory testing.

Monitoring heparin anticoagulation during cardiac and vascular surgery is widely recognized as essential for the safe performance of these operations. Heparin is a biopharmaceutical derived from bovine lung or porcine intestinal mucosa and is composed of a heterogeneous mixture of compounds with diverse anticoagulant activities.^[814]

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The ideal test of perioperative coagulation would be simple to perform, accurate, reproducible, diagnostically specific, and cost-effective. Although no single monitoring device available to date has all these ideal operating characteristics, many provide useful information to guide patient management. Particularly when combinations of these devices are used, they provide valuable diagnostic insight into the mechanism of a patient's perioperative coagulopathy. The importance of integrated monitoring described earlier for hemodynamic assessment is equally applicable to coagulation monitoring.

The commercially available point-of-care coagulation monitors used in the perioperative setting may be divided into four categories: functional measures of coagulation or assays that measure the intrinsic ability of the blood to clot, monitors of heparin concentration, viscoelastic measures of coagulation, and platelet function analyzers ( Table 32-16 ).

Functional Measures of Coagulation

The activated coagulation time (ACT), described by Hattersley in 1966,^[817] is a version of the Lee-White whole blood clotting time that is modified to include an initiator for contact activation of the coagulation system. This activator, frequently diatomaceous earth, is used to accelerate clot formation and reduce the time to completion of the assay.

Hattersley's original assay required manual mixing of a blood sample with the contact activator, followed by repeated visual assessment of the tube to determine the

TABLE 32-16 -- Point-of-care coagulation monitors

Functional measures of coagulation

Activated coagulation time (ACT)

Heparin management test (HMT)

High-dose thrombin time (HiTT)

Prothrombin time (PT)

Activated partial thromboplastin time (aPTT)

Monitors of heparin concentration

Protamine titration

Ion-selective electrodes

Viscoelastic measures of coagulation

Thromboelastograph (TEG)

Sonoclot

Platelet function analyzers

time to visible clot formation. More recent commercial ACT monitors simplify testing by automating clot detection. One of the more widely available ACT monitors uses a glass test tube that contains a small magnet at the bottom (Hemochron; International Technidyne, Inc., Edison, NJ). After adding a sample of blood, the tube is placed into the analyzer, where a constant temperature of 37°C is maintained, and the tube is rotated slowly while the magnet maintains contact with a proximity detection switch. As fibrin clot forms, the magnet becomes enmeshed and is pulled away from the detection switch, thereby triggering an alarm and providing an end time for the ACT measurement. Another ACT device uses a "plumb bob" flag assembly that is raised and dropped repeatedly through the sample vial containing blood and contact activator (Hepcon and ACT II; Medtronic Blood Management, Parker, CO). As clot forms, the rate of descent of the flag through blood slows and triggers an optical detector and alarms to signify the end time for the ACT.

Because each patient's baseline ACT measurement serves as a control for subsequent determinations, the method selected for ACT testing might appear to be unimportant. However, drugs used in the perioperative period, such as the antifibrinolytic drug aprotinin, may dramatically alter the times measured with different ACT monitoring systems. Aprotinin inhibits contact activation by celite (diatomaceous earth)^[818] and produces an artifactual elevation of the celite ACT. If this interaction is not considered, an insufficient dose of heparin may be administered. Kaolin, an alternative contact activator, should be used to measure ACT in patients receiving aprotinin because it will bind the aprotinin and remove it from plasma.^[818] It is not clear whether excess concentrations of aprotinin will overwhelm the kaolin-binding capacity and thereby affect the kaolin-activated ACT.

The ACT in normal individuals is approximately 107 ± 13 seconds (mean ± SD).^[817] However, the time at which a patient's "baseline" ACT is measured can influence the result. After surgical incision, the baseline ACT decreases by more than 2 SD in patients undergoing cardiac surgery, perhaps because of release of tissue factor after tissue injury.^[819] Heparin clearly prolongs the ACT because this test measures the clotting potential of the intrinsic and common pathways of coagulation. In addition to prolongation of the ACT by heparin, a prolonged ACT signifies an impaired ability of the blood sample to generate clot, for whatever reason. However, the ACT is relatively resistant to platelet dysfunction and is affected only by severe thrombocytopenia and platelet inhibitors such as prostacyclin or monoclonal antibodies directed against glycoprotein IIb/IIIa surface receptors. ^{[820] [821] [822]}

ACT testing is probably the most widely used perioperative coagulation monitor because of its simplicity, low cost, and ability to monitor anticoagulation when large doses of heparin are used as required for cardiac surgical procedures. However, certain limitations are associated with this method of monitoring. The ACT is relatively insensitive to low concentrations of heparin, and ACT measurements are not particularly reproducible.^[823] These deficiencies are especially important when ACT monitoring is used to verify heparin neutralization with protamine. ACT monitoring may also be influenced by

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The heparin management test (HMT) (Pharmanetics, Morrisville, NC) offers promise as a solution to several problems associated with ACT monitoring during cardiac surgery. This method exploits recent advances in dry reagent chemistry for analysis of coagulation. The HMT uses a microprocessor-controlled analyzer and disposable test cards to provide a rapid, reproducible measure of functional anticoagulation in heparin-containing whole blood. A reaction chamber within each test card contains paramagnetic iron oxide beads and the dry chemical reagents necessary to activate coagulation in the blood sample.^[827] After a drop of blood is added to the card, capillary action draws a small portion of this blood sample into the reaction chamber. An oscillating magnetic field is applied to the solution of blood, chemical reactants, and beads. A light beam passes through the test chamber and detects oscillations in the amplitude of transmitted light coincident with bead movement. As clot formation occurs, the beads become enmeshed within the clot, thereby reducing the amplitude of light oscillations to trigger the end time for the HMT measurement. The minute sample of blood drawn into the test chamber and the sensitivity of the clot detection method used in this system minimize confounding effects from hypothermia and hemodilution. Preliminary evaluation of this monitor during cardiac surgery suggests that the HMT may provide a more accurate and more reproducible measure of heparin activity than the ACT does.^{[828] [829]} Recently, the HMT has been incorporated into an array of tests performed on a single analyzer platform, the Rapidpoint Coag (Bayer Diagnostics, Tarrytown, NY). The HMT is performed in series with the heparin titration test (HTT) and the protamine response time (PRT) to acquire patient-specific recommendations for subsequent dosing of heparin and protamine, respectively. In addition, the Rapidpoint Coag analyzer has been used in concert with the ecarin clotting time (ECT) to monitor dosing of the specific thrombin inhibitor bivalirudin.^[830]

A third measure of heparin anticoagulation, also used primarily during cardiac surgery, is the high-dose thrombin time (HiTT) (International Technidyne, Edison, NJ). The HiTT assay contains high reagent concentrations of thrombin to cleave fibrinogen directly and generate a fibrin clot. In the presence of these excess thrombin concentrations, clot formation occurs independently of plasma coagulation factors other than fibrinogen. As a result, the HiTT is prolonged by heparin (or other thrombin inhibitors), extreme degrees of hypofibrinogenemia or dysfibrinogenemia, and high concentrations of fibrin split products.^{[831] [832]} During most surgical procedures requiring heparin administration, HiTT prolongation will correlate with the heparin anticoagulant effect. The major limitation to more widespread use of the HiTT assay has been the limited shelf life of the thrombin reagent, which must be mixed just before performing the test.

Preoperative laboratory-based coagulation testing remains common practice in patients with a preexisting coagulopathy and those scheduled to undergo surgical procedures commonly associated with postoperative coagulopathy, such as cardiac or hepatic surgery. Most often, the prothrombin time (PT) and activated partial thromboplastin time (aPTT) are measured to provide baseline reference values for the patient, although the dose-response curves for these assays limit their usefulness when high-dose heparin anticoagulation is used. As point-of-care coagulation monitors that measure PT and aPTT become increasingly available, it is important to recognize that the test results from these monitors will not necessarily mirror the results reported by the hospital-based laboratory. Results from point-of-care coagulation monitoring may differ from laboratory testing because reagent sensitivities vary considerably from manufacturer to manufacturer and from one lot of reagent to another. In addition, laboratory-based testing relies on plasma samples, as opposed to whole blood samples commonly used in point-of-care testing.^[833] Indeed, some of the delay inherent in laboratory-based testing results from the time required to process the plasma sample from the patient's whole blood. Because values obtained with point-of-care monitors are unlikely to agree with laboratory-based testing, their successful use in clinical practice will often require that baseline reference values be determined for each individual patient.