Abstract
Heparin resistance can be dangerous when using cardiopulmonary bypass. Screening of the AT III level is recommended preoperatively. In the case of HIT type II, surgery should be delayed if possible. To avoid reaction after protamine administration, the protamine should be given slowly over about 10 minutes.
Keywords
AT III, heparin, HIT, protamine, tirofiban
Case Synopsis
An 81-year-old woman with dyspnea at rest due to aortic stenosis (valve area 0.4 cm 2 , mean gradient 50 mm Hg) presents for aortic valve replacement. Past medical history is significant for a recent pulmonary embolism, for which she received intravenous heparin therapy. At the time of operation, antithrombin III (AT-III) levels are low and the activated partial thromboplastin time is elevated. After heparinization (375 U/kg), the activated clotting time (ACT) increases to 325 seconds. An additional 125 U/kg heparin and 2000 units of AT-III concentrate are given. Thereafter the ACT increases to 866 seconds, and cardiopulmonary bypass (CPB) is commenced without further complications.
Problem Analysis
Definition
Unfractionated heparin is a heterogeneous mixture of sulfated oligosaccharides with molecular weights ranging from 5000 to 50,000 daltons. The anticoagulant activity of heparin is initiated via binding to AT-III, which results in a conformational change that increases its inactivation of thrombin and factors Xa and IXa. Thus in the setting of low AT-III activity, the clinical effect of heparin is reduced.
Recognition, Risk Assessment, and Implications
There is wide individual variability in the clinical anticoagulant response to a single dose of heparin. This necessitates evaluation with on-site or laboratory coagulation testing. Owing to the extreme importance of ensuring sufficient anticoagulation before initiating CPB, on-site testing is preferred. A number of options are available to clinically assess heparin-induced anticoagulation.
The activated partial thromboplastin time is sensitive to low plasma heparin concentrations (0.1–1.0 U/mL). However, with the high doses of heparin required for the initiation of CPB, values exceed this method’s detection limit.
The ACT assesses the clinical anticoagulation effect of the large doses of heparin (200–400 U/kg) required for the initiation of CPB. In their historical study from 1975 Bull and colleagues found out that an ACT of 300 seconds was enough in 50 patients. The authors added a 60% safety margin (180 seconds), which gives the number of 480 seconds. Since then, for 40 years ACT values above 480 seconds have been considered safe worldwide for anticoagulation during routine CPB. Even so, ACT values may be misleading because they can be prolonged by factors other than heparin, such as hypothermia, hemodilution, and thrombocytopenia. Further, clinical investigations have shown that ACT values correlate poorly with plasma heparin concentrations in patients during mild hypothermic CPB. However, methods using the heparin concentration as “gold standard” instead of ACT measurements have not been shown to be superior, while being much more complicated and expensive. The problem with false high values using celite activated ACT tubes in the presence of aprotinin is—after withdrawal of the drug (aprotinin) from the market—no longer of importance.
Heparin resistance results in an unanticipated small increase in ACT values after initial and subsequent heparin dosing. Approximately 1 in 2000 patients has a heterozygotic deficiency (40%–70% activity) of AT-III and is thus predisposed to developing deep vein thrombosis and pulmonary embolism. Significant reductions in AT-III levels may also occur secondary to AT-III consumption during heparin therapy. Other causes of heparin resistance include left ventricular clot, use of oral contraceptives, and thrombocytosis. These entities may be due to reduced plasma concentrations of heparin caused by its increased binding to plasma proteins and endothelium.
Heparin may cause thrombocytopenia via immune-mediated and non–immune-mediated mechanisms. There are two types of heparin-induced thrombocytopenia (HIT) that can result from heparin use. Type I is non–immune mediated, and type II is immune mediated. For standardization, the term non–heparin immune-associated thrombocytopenia is recommended for type I HIT. This is a benign condition, with no heparin-dependent antibodies present. The term heparin-induced thrombocytopenia is recommended for type II HIT, in which heparin-dependent antibodies are detectable and produce thrombocytopenia.
Management
Three different aspects of anticoagulation during cardiac surgery with CPB are discussed: routine management using anticoagulation with heparin and neutralization with protamine, management of AT-III deficiency (as in the case synopsis), and HIT.
For the initiation of CPB, the heparin dose is based on body weight (300–400 U/kg). It is essential to obtain an ACT of at least 480 seconds before initiating CPB. Determining the ACT before initiating CPB allows one to detect inadequate heparin dosing or AT-III deficiency. It is also recommended that the heparin injection be given via a central venous line after aspirating blood to ensure vascular delivery. Subsequent heparin can be dosed empirically during CPB (e.g., 5000–10,000 U/h, one-third the initial dose every hour). It is, however, strongly recommended to measure the ACT every 30 minutes when on bypass. If the ACT is less than 480 seconds, an additional dose (see earlier discussion) should be given. Hypothermia and hemodilution prolong ACT values independent of heparin concentration. Thus basing subsequent heparin doses on ACT values may lead to inadequate inhibition of thrombin activity and subclinical thrombosis, fibrinolysis, and depletion of coagulation factors and platelets. Maintenance of patient-specific heparin concentrations during CPB may result in more accurate heparin dosing, more complete thrombin inhibition, and reduced postoperative bleeding and blood product use.
With suspected heparin resistance, one must first confirm that the heparin was indeed given intravenously, followed by the administration of additional heparin from another vial or lot to exclude lot-specific reduced heparin activity. If the ACT values still remain below those expected, despite large doses of heparin, AT-III concentrates should be given, with an initial dose of at least 2000 U. Because of the danger of AT-III deficiency (thrombosis during CPB), the routine clinical practice in most centers is to confirm adequate AT-III levels in patients before any operation is performed requiring extracorporeal circulation.
Non–heparin immune-associated thrombocytopenia (type I HIT) implies absent heparin-dependent antibodies. This entity is probably caused by direct nonimmune platelet activation by heparin. Type I HIT is usually associated with larger doses of heparin. In contrast, type II HIT can occur with any heparin dose. Further, type I HIT occurs earlier in the clinical treatment course (usually within 4 days) in 30% of patients receiving intravenous heparin therapy. The induced platelet abnormality is usually mild and reversible, even with continued heparin administration. Type I HIT is self-limited and usually causes no important complications (e.g., thrombosis). Heparin therapy is continued despite low platelet counts. The clinical importance of type I HIT lies in the necessity to differentiate it from the more serious type II HIT.
Type II HIT (or heparin-induced thrombocytopenia with thrombosis [HITT] syndrome) is an immune-mediated reaction to heparin that is often underdiagnosed and may lead to venous and arterial thrombosis. Type II HIT exists as three distinct entities: (1) latent (antibodies without thrombocytopenia), (2) HIT (antibodies with thrombocytopenia), and (3) HITT (antibodies with thrombocytopenia and thrombosis).
Type II HIT is potentially more dangerous than type I HIT because it can be associated with thromboembolic complications (absent in type I). About 0.5% to 3% of patients given heparin develop type II HIT and moderate thrombocytopenia. In some, this leads to venous or arterial thrombosis. Thrombosis frequently leads to disastrous clinical sequelae, including loss of limbs and even death. The basis for this severe adverse drug reaction is production of an immunoglobulin G antibody that reacts with heparin and platelet factor 4 antigenic complexes. The diagnosis of type II HIT is made with the “four T’ s”—thrombocytopenia, timing of platelet count fall, thrombosis or other sequelae, and other causes for thrombocytopenia ( Table 36.1 ). This score is not only a laboratory diagnosis but uses clinical patient factors. In up to 20% of the patients there are antibodies to immobilized heparin–platelet factor 4 antigenic complexes detectable. This does not alone lead to the diagnosis HIT. The heparin-induced platelet aggregation test (HIPA) assay is the gold standard to make the diagnosis.
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