Cardiopulmonary Bypass: Anticoagulation and Antagonism

Heparin: Mechanism, Dosing, and Monitoring

• Anticoagulation is imperative in any cardiac case involving CPB to prevent clot formation in the extracorporeal circuit. Unfractionated heparin is the most common anticoagulant used for these cases due to its reversibility and ability to be monitored.

Mechanism of Action

• Heparin binds to AT III and inhibits the coagulation cascade by inactivating several clotting factors, mainly thrombin (factor IIa) and factor Xa. This prevents fibrinogen from converting to fibrin and prevents stable clot formation.

Dosing

• Heparin is typically administered as a bolus prior to initiating CPB, and its dosing is usually weight-based. Dose response is variable for individual patients and should be monitored as discussed below.
  • A weight-based dose of 300-400 units/kg is widely accepted for the initiation of CPB.^1,2
  • Total body weight is traditionally used for weight-based dosing; however, pharmacokinetic and pharmacodynamic models have been used for individualized dosing.^1,3

Monitoring

ACT

• ACT is considered the current gold standard for measuring anticoagulation status during CPB. The test is a functional measure of whole blood’s ability to form a clot. ACT levels should be assessed prior to initiating anticoagulation and at regular intervals during CPB.^1,4
  • Typical ACT values acceptable for initiating CBP are 400-480 seconds.¹
  • ACT may be compromised in settings of hypothermia, platelet dysfunction, and hemodilution (Table 1); thus, tests measuring heparin concentration (anti-Xa assays) may be useful as supplementation to ACT.
  • Compared to tests using a single activator, “Maximally activated” or “ACT Plus” ACTs limit variability, are less susceptible to hypothermia, are more sensitive, and correlate more closely with factor Xa activity.¹

Heparinase Assays

• Heparinase assays are often used in conjunction with ACT to distinguish heparin-induced anticoagulation from other anticoagulant effects. Using this heparin-specific measurement, along with ACT, can help with protamine reversal and avoid residual heparin.

Heparin Resistance and AT III

• Heparin resistance is often defined as failure to reach the target ACT level of 400-480 seconds after administering high doses of unfractionated heparin (>500-600 units/kg).⁴
• Congenital (1 in 3000 individuals) and acquired AT III deficiencies are thought to be the main cause of heparin resistance. Acquired AT deficiencies are associated with liver disease, nephrotic syndrome, and chronic heparin therapy.⁴
• Please see the OA summary on Heparin Resistance for more details. Link

Treatment for Heparin Resistance

• Give additional heparin if a standard dose was used initially
• Consider administering AT concentrate or fresh frozen plasma if AT concentrate is unavailable
• If the patient remains subtherapeutic, consider alternative anticoagulants to heparin

ATIII-Independent Heparin Resistance

• Although AT is the primary treatment, AT-independent mechanisms can contribute to heparin resistance. Several heparin-binding proteins may reduce the biologic availability of heparin.⁴ Increased factor VIII activity is associated with the propagation phase of clotting and may contribute to heparin resistance in some instances.⁴

Heparin Alternatives

• Although heparin is the routinely used anticoagulant in cardiac cases with CPB, there are instances in which alternative agents are selected.

Contraindications to Heparin in CPB

• Acute heparin-induced thrombocytopenia (HIT)
• Known hypersensitivity/anaphylaxis to heparin

HIT

• Heparin binds to platelet factor 4 (PF4), which can generate an immune response through immunoglobulin G (IgG). These IgG-PF4-heparin complexes bind to FcγRIIa receptors on platelets and cause platelet activation and aggregation.⁵ Increased thrombin is generated from this process, which leads to a hypercoagulable state and platelet consumption.⁵
• Please see the OA summary on HIT for more details. Link

Diagnosis of HIT

• The “4 T score” is an easy-to-use clinical scoring system often used to exclude the diagnosis of HIT. A higher score will trigger further testing.
  • Points are allotted for each of the 4 components listed below:
    • Acute Thrombocytopenia (drop in platelet count below baseline)
    • Timing of onset compared to last heparin exposure
    • Presence of Thrombosis
    • Other causes of Thrombocytopenia
• An enzyme-linked immunosorbent assay is used to detect heparin antibody levels; however, this test is sensitive but not specific and cannot make a definitive diagnosis. The positive antibody test result can be present without active HIT.^1,6
• The serotonin release assay is the gold standard for diagnosing HIT and measures immune complex function; however, it may be a send-out test and typically takes several days to obtain results.⁶

Alternatives to Heparin

• In the setting of acute HIT and need for urgent cardiac surgery,1 an alternative to heparin may be required during CPB.
• Bivalirudin is a direct thrombin inhibitor and the most commonly used alternative to heparin during CPB.^1,5 The use of bivalirudin increases the risk of prolonged bleeding since there is not currently a reversal agent.
  • Ecarin clotting time is more accurate than ACT monitoring; however, it is not available as a point-of-care test, and thus ACT is typically used as a replacement to monitor anticoagulation status.¹
  • Hypothermia both prolongs bivalirudin’s anticoagulant effect through slowed metabolism and impairs endogenous thrombin generation, synergistically increasing the risk of bleeding during and after cardiac surgery.¹
• Plasmapheresis has limited evidence for use during CPB but has been used to eliminate PF4-heparin antibodies prior to cardiac surgery. Heparin is then used for anticoagulation during CPB.^1,6,7
• Iloprost has been used to inhibit platelet activation with the use of heparin in patients with HIT.⁷
• Argatroban is also a direct thrombin inhibitor and is commonly used in vascular cases without CPB. The medication is typically reserved for patients with severe renal dysfunction since it is associated with more significant postoperative bleeding compared to bivalirudin.^6,7

Antagonism

Protamine is a strongly positive molecule that binds to negatively charged heparin, forming an inactive neutral salt. The drug is administered slowly by intravenous injection to avoid adverse reactions described below.

Dosing

• Traditional dosing for heparin reversal is 1 mg of protamine per 100 units of heparin used (1:1 ratio). However, titrating lower doses of protamine based on heparin measurements may reduce the risk of bleeding.⁸
  • Excess protamine impairs platelet function and aggregation; thus, one should not exceed 2.6 mg of protamine per 100 units of heparin.^1,8
  • Heparin rebound is possible after protamine administration and is more pronounced with high-dose heparin. Low-dose protamine infusions (25 mg/h for 6 hours) have been used to abolish the heparin rebound after CPB.^1,8

Protamine Reactions

Please see the OA summary on protamine reactions for more details. Link

• Type I: transient hypotension from mast cell histamine release. This is the most common protamine reaction.
• Type II: true allergic/anaphylactic and immune-related reactions. Symptoms include urticaria, bronchospasm, and cardiovascular collapse.
• Type III: severe pulmonary hypertension and right heart failure from heparin-protamine complexes in the pulmonary circulation.

Patients at Increased Risk for Protamine Allergy

• Prior vasectomy
• Prior protamine exposure (cardiac surgery or through neutral protamine hagedorn insulin)
• Fish allergy