Coagulation Monitoring

Activated Coagulation Time

The ACT was first introduced by Hattersley in 1966 and is still the most widely used monitor of heparin effect during cardiac surgical procedures. Whole blood is added to a test tube containing an activator, either diatomaceous earth (Celite) or kaolin. The presence of activator augments the contact activation phase of coagulation, which stimulates the intrinsic coagulation pathway. The ACT can be performed manually, whereby the operator measures the time interval from when blood is injected into the test tube to when clot is seen along the sides of the tube. More commonly, the ACT is automated, as it is in the Hemochron (International Technidyne Corp., Edison, NJ) and ACT Plus (Medtronic Perfusion Services, Minneapolis, MN) systems. In the automated systems, the test tube is placed in a device that warms the sample to 37°C. The Hemochron device rotates the test tube, which contains Celite activator and a small iron cylinder, to which 2 mL of whole blood is added. Before clot forms, the cylinder rolls along the bottom of the rotating test tube. When clot forms, the cylinder is pulled away from a magnetic detector, interrupts a magnetic field, and signals the end of the clotting time. Normal ACT values range from 80 to 120 seconds. The Hemochron ACT also can be performed using kaolin as the activator in a similar manner.

The ACT Plus (formerly Hemotec [Hepcon] ACT) device is a cartridge with two chambers that contain kaolin activator and are housed in a heat block. Blood (0.4 mL) is placed into each chamber, and a daisy-shaped plunger is raised and passively falls into the chamber. The formation of clot slows the rate of descent of the plunger. This decrease in velocity of the plunger is detected by a photo-optical system that signals the end of the ACT test. The Hemochron and Hemotec ACT tests have been compared in several investigations and have been found to differ significantly at low heparin concentrations. However, differences in heparin concentration, activator concentration, and the measurement technique make comparison of these tests difficult and have led to the realization that the results of the Hemochron and Hemotec ACT tests are not interchangeable. In adult patients given 300 IU/kg of heparin for cardiopulmonary bypass (CPB), the Hemochron and Hemotec ACTs were both therapeutic at all time points, although the Hemochron ACT was statistically longer at two time points.

The ACT test can be modified by the addition of heparinase. With this modification, the coagulation status of the patient can be monitored during CPB while the anticoagulant effects of heparin are eliminated. Because this test is a side-by-side comparison of the untreated ACT with the heparinase ACT, it also has the advantage of being a rapid test for assessment of a circulating heparin-like substance or for residual heparinization after CPB.

With the introduction of ACT monitoring into cardiac surgical practice, clinicians have been able to titrate heparin and protamine dosages more accurately. As a result, many investigators report reductions in blood loss and transfusion requirements, although many of these studies used retrospective analyses. The improvements in postoperative hemostasis documented with ACT monitoring are potentially attributable to better intraoperative suppression of microvascular coagulation and improved monitoring of heparin reversal with protamine.

ACT monitoring of heparinization is not without pitfalls, and its use has been criticized because of the extreme variability of the ACT and the absence of a correlation with plasma heparin levels ( Fig. 13.1 ). Many factors have been suggested to alter the ACT, and these factors are prevalent during cardiac surgical procedures. When the extracorporeal circuit prime is added to the patient's blood volume, hemodilution occurs and may theoretically increase the ACT. Evidence suggests that this degree of hemodilution alone is not enough to alter the ACT. Hypothermia increases the ACT in a “dose-related” fashion. Although hemodilution and hypothermia significantly increase the ACT of a heparinized blood sample, similar increases do not occur in the absence of added heparin. The effects of platelet alterations are more problematic. At mild-to-moderate degrees of thrombocytopenia, the baseline and heparinized ACTs are not affected. It is not until platelet counts are reduced to less than 30,000 to 50,000/µL that the ACT may be prolonged. Patients treated with platelet inhibitors such as prostacyclin, aspirin, or platelet membrane receptor antagonists have a prolonged heparinized ACT compared with patients not treated with platelet inhibitors. This ACT prolongation is not related exclusively to decreased levels of platelet factor 4 (PF4; PF4 is a heparin-neutralizing substance) because it also occurs when blood is anticoagulated with substances that are not neutralized by PF4. Platelet lysis, however, significantly shortens the ACT because of the release of PF4 and other platelet membrane components, which may have heparin-neutralizing activities. Anesthesia and operation decrease the ACT and create a hypercoagulable state, possibly by creating a thromboplastic response or through activation of platelets.

During CPB, heparin decay varies substantially, and its measurement is problematic because hemodilution and hypothermia alter the metabolism of heparin. In a CPB study, the consumption of heparin varied from 0.01 to 3.86 IU/kg/min, and no correlation was noted between the initial sensitivity to heparin and the rate of heparin decay.

Heparin Resistance

Heparin resistance is documented by an inability to increase the ACT of blood to expected levels despite an adequate dose and plasma concentration of heparin. In many clinical situations, especially when heparin desensitization or a heparin inhibitor is suspected, heparin resistance can be treated by administering increased doses of heparin in a competitive fashion. If an adequately prolonged clotting time is ultimately achieved using greater-than-expected doses of heparin, a better term than heparin resistance would be “altered heparin responsiveness.” During cardiac surgical procedures, the belief that a safe minimum ACT value of 300 to 400 seconds is required for CPB is based on a few clinical studies and a relative paucity of scientific data. However, an inability to attain this degree of anticoagulation in the heparin-resistant patient engenders the fear among cardiac surgical providers that the patient will experience microvascular consumptive coagulopathy or that clots will form in the extracorporeal circuit.

Many clinical conditions are associated with heparin resistance. Sepsis, liver disease, and pharmacologic agents represent just a few. Many investigators have documented decreased levels of antithrombin III (AT III) secondary to heparin pretreatment. Patients receiving preoperative heparin therapy traditionally require larger heparin doses to achieve a given level of anticoagulation when that anticoagulation is measured by the ACT. Presumably, this “heparin resistance” is the result of deficiencies in the level or activity of AT III. Other possible causes include enhanced factor VIII activity and platelet dysfunction leading to a decrease in ACT response to heparin. In vitro addition of AT III enhances the ACT response to heparin. AT III concentrate is available as a heat-treated human product or in recombinant form, and its use is a reasonable method of treating patients with documented AT III deficiency ( Box 13.1 ).

Box 13.1

Heparin Resistance

• It is primarily caused by antithrombin III deficiency in pediatric patients.

• It is multifactorial in adult cardiac surgical patients.

• The critical activated coagulation time value necessary in patients who demonstrate acquired heparin resistance is not yet determined.

• Heparin resistance also can be a sign of heparin-induced thrombocytopenia.

Measurement of Heparin Sensitivity

Even in the absence of heparin resistance, patients' responses to an intravenous bolus of heparin are extremely variable. The variability stems from different concentrations of various endogenous heparin-binding proteins such as vitronectin and PF4. This variability exists whether measuring heparin concentration or the ACT; however, variability seems to be greater when measuring the ACT. Because of the large interpatient variation in heparin responsiveness and the potential for heparin resistance, it is critical that a functional monitor of heparin anticoagulation (with or without a measure of heparin concentration) be used in the cardiac surgical patient. Bull documented a threefold range of ACT response to a 200 IU/kg heparin dose and similar discrepancy in heparin decay rates and thus recommended the use of individual patient dose-response curves to determine the optimal heparin dose. This is the concept on which POC individual heparin dose-response (HDR) tests are based.

An HDR curve can be generated manually by using the baseline ACT and the ACT response to an in vivo or in vitro dose of heparin. Extrapolation to the desired ACT provides the additional heparin dose required for that ACT. Once the actual ACT response to the heparin dose is plotted, further dose-response calculations are made based on the average of the target ACT and the actual ACT ( Fig. 13.2 ). This method was first described by Bull and forms the scientific basis for the automated dose-response systems in the proprietary Hemochron and Hemotec devices. The Hemochron RxDx (International Technidyne Corp., Edison, NJ) system uses the heparin-response test, which is an ACT with a known quantity of in vitro heparin (3 IU/mL). A dose-response curve is generated that enables calculation of the heparin dose required to attain the target ACT by using an algorithm that incorporates the patient's baseline ACT, estimated blood volume, and heparin-response test. The patient's heparin sensitivity can be calculated in seconds per international units per milliliter (s/IU/mL) by dividing the heparin-response test by 3 IU/mL.

The Hemochron RxDx system also provides an individualized protamine dose based on the protamine-response test (PRT). This is an ACT with one of two specific quantities of protamine, depending on the amount of circulating heparin suspected (2 or 3 IU/mL). The protamine dose needed to return the ACT to baseline can be calculated on the basis of a protamine-response curve using the patient's heparinized ACT, the PRT, and an estimate of the patient's blood volume.

Heparin Concentration

Proponents of ACT measurement to guide anticoagulation for CPB argue that a functional assessment of the anticoagulant effect of heparin is mandatory and that the variability in ACT represents a true variability in the coagulation status of the patient. Opponents argue that during CPB, the sensitivity of the ACT to heparin is altered, and ACT does not correlate with heparin concentration or with anti–factor Xa activity measurement. Heparin concentration can be measured using the Hepcon HMS system, which uses an automated protamine titration technique. With a cartridge with four or six chambers containing tissue thromboplastin and a series of known protamine concentrations, 0.2 mL of whole blood is automatically dispensed into the chambers. The first channel to clot is the channel in which the protamine concentration most accurately neutralizes the heparin without a heparin or a protamine excess. Because protamine neutralizes heparin in the ratio of 1 mg protamine per 100 IU heparin, the concentration of heparin in the blood sample can be calculated. A cartridge that monitors heparin concentration over a wide range can be used first, followed by another cartridge that can measure heparin concentrations within a more narrow range. The maintenance of a stable heparin concentration rather than a specific ACT level usually results in administration of larger doses of heparin because the hemodilution and hypothermia during CPB increase the sensitivity of the ACT to heparin.

Protamine Effects on Coagulation Monitoring

Reversal of heparin-induced anticoagulation is most frequently performed with protamine. Different successful dosing plans have been proposed. The recommended dose of protamine for heparin reversal is 1 to 1.3 mg protamine per 100 IU heparin; however, this dose often results in a protamine excess.