The Society of Thoracic Surgeons, The Society of Cardiovascular Anesthesiologists, and The American Society of ExtraCorporeal Technology

Clinical Practice Guidelines—Anticoagulation During Cardiopulmonary Bypass

Linda Shore-Lesserson, MD; Robert A. Baker, PhD, CCP; Victor A. Ferraris, MD, PhD; Philip E. Greilich, MD; David Fitzgerald, MPH, CCP; Philip Roman, MD, MPH; John W. Hammon, MD


Anesth Analg. 2018;126(2):413-424. 

In This Article

Heparin Contraindications and Heparin Alternatives

Class IIa Recommendations

  • Clinical scoring estimates that use a fall in platelet count greater than 50% or a thrombotic event between 5 and 14 days after a heparin exposure can be used to determine whether a heparin–platelet antibody test should be performed to diagnose heparin-induced thrombocytopenia (HIT). (Level of Evidence B)

  • Serum tests that include functional testing with serotonin release assay (SRA) or heparin-induced platelet activation (HIPA) can be beneficial in identifying patients with HIT who have a history of thrombocytopenia, and elevated clinical HIT risk scores, when platelet factor 4 (PF4)–heparin antibody testing is inconclusive (weakly positive) for HIT. (Level of Evidence C)

  • For patients who are seropositive for heparin-platelet antibodies or have a recent history of HIT, it is reasonable to delay elective cardiac operations requiring CPB until a patient's functional test or antigenic (antibody) assay are negative, with the expectation that heparin anticoagulation therapy for CPB is likely to be safe and effective. (Level of Evidence C)

  • For patients with a diagnosis of HIT and in need of an urgent operation requiring CPB, anticoagulation with bivalirudin is a reasonable option. (Level of Evidence B)

Class IIb Recommendation

  • In patients with significant renal dysfunction who are seropositive for HIT and require urgent operation requiring CPB, use of plasmapheresis, argatroban, or heparin with antiplatelet agents (such as tirofiban, ilioprost) may be considered, understanding that there are increased risks of bleeding with these interventions. (Level of Evidence C)

The chief contraindications to the use of heparin for CPB are a history of HIT and known hypersensitivity to heparin. Whereas HIT is characterized by the development of immunoglobulin G antibodies recognizing PF4-heparin complexes,[33,34] hypersensitivity reactions to heparin can be type I, II, or IV.[35,36] Heparin-induced thrombocytopenia with or without thrombosis occurs in patients who form PF4-heparin immune complexes capable of activating platelets.[37,38] These anti–PF4-heparin antibodies form the basis for the clinical antigenic assay (enzyme-linked immunosorbent assay [ELISA]) for HIT.[37] Although PF4-heparin complexes after heparin exposure can be quite high (greater than 30% among surgical patients), the incidence of HIT is much lower (1% to 2%).[39–43] Patients who test positive (antigen assay) for anti–PF4-heparin antibodies preoperatively appear to have a higher overall risk for complications and increased mortality after cardiac surgery.[44–46] Given the 60- to 90-day amnestic period for HIT antibodies, postponing elective cardiac surgery in patients with elevated PF4-heparin antibodies could potentially mitigate this avoidable risk.[47–50] Platelet count monitoring is currently recommended for patients with heparin exposure before cardiac surgery (eg, cardiac catheterization or deep vein thrombosis prophylaxis) to determine whether further testing is indicated.[43]

Detection of PF4-heparin antibodies that activate platelets and trigger serotonin release requires a highly specific and sensitive functional test for HIT.[51] Functional testing with SRA or HIPA detect only those immunoglobulin G antibodies capable of activating platelets.[43] Thrombocytopenia or thrombosis are much more likely when platelet activation occurs. Specific tests of platelet serotonin release can be particularly helpful when low levels of positivity are detected using HIT antibody (antigen) assays, which are sensitive but not specific to platelet activation.[37,51]

Heparin-induced thrombocytopenia is a clinicopathologic diagnosis.[52] The spectrum ranges from formation of anti–PF4-heparin antibodies to increasing degrees of thrombocytopenia due to platelet activation, and in its most severe form, diffuse deposition of platelet-related thrombi into microcirculation and extreme depletion of circulating platelets. In a single-center observational study of 1,722 patients undergoing cardiac surgery, HIT was suspected in 63 (3.6%) and confirmed in 24 (1.4%).[53] Validated clinical scoring systems can guide initial decision-making and laboratory testing.[37,53–57] These scoring methods take into consideration the characteristic temporal relationship of the onset of thrombocytopenia (with or without thrombotic event) to heparin exposure (5 to 14 days),[58] the percent decrease in platelet count (greater than 30% to 50%), and absolute level of platelets (20 to 100,000/uL), in addition to duration of CPB and other potential contributory causes of thrombocytopenia.[55,57] The negative predictive value (for HIT) for patients with a low clinical scores is 98% (range, 97% to 100%).[56,57] Therefore, additional serologic testing and delays in heparin anticoagulation or complications associated with heparin alternatives in these patients can be avoided.

The positive predictive value of the anti–PF4-heparin assay (ELISA) for HIT is very low (2% to 15%).[59,60] As such, this assay should be limited to patients with higher pretest probabilities (for HIT) found in those with intermediate (positive predictive value 10% to 20%) or high (positive predictive value 40% to 80%) clinical scores. That usually occurs when the fall in platelet count exceeds 50% or a thrombotic event occurs between postoperative days 5 and 14. Patients with low antibody titers (optical density less than 0.4) would be candidates for heparin anticoagulation without further intervention given the high sensitivity (90% to 98%) of this clinical assay.[43,51] Postoperatively, close monitoring of platelet counts are recommended and screening for HIT antibodies considered if clinical scores indicate further serologic testing is warranted.

Patients with mild elevations in anti–heparin-PF4 titers (optical density 0.4 to 1.0) should have further serologic testing using a functional assay especially if their clinical scores are in the intermediate or high ranges.[37] The high sensitivity (90% to 98%) and specificity (80% to 97%) of the functional assays (SRA, HIPA) make them the gold standard for diagnosing HIT.[61] Negative SRA and HIPA frequently occurs in patients with elevated antibody titers using the clinical antigen assays (ELISA) owing to PF4-heparin antibodies that do not activate platelets or cause thrombocytopenia or thrombosis.[33] Patients with high clinical scores and high antibody titers (optical density greater than 1.0) are candidates for heparin alternatives when urgent operations preclude the use a functional assay (SRA, HIPA).

True hypersensitivity to heparin is rare, yet can occur in patients allergic to heparin or the sources of heparin (eg, porcine or bovine sources of heparin).[35,36,62–64] Patients clinically suspected of having hypersensitivity to heparin should undergo testing to confirm the diagnosis as soon as possible, given the often urgent need for heparin anticoagulation in a variety of clinical settings.[35]

The decision to utilize an alternative anticoagulant agent during CPB is based on the urgency of the cardiac procedure and on heparin antibodies capable of activating platelets. The American College of Chest Physicians recommends delaying nonurgent cardiac procedures until heparin antibodies are no longer detectable.[43] The single most cumbersome aspect of heparin alternatives is inability to rapidly reverse anticoagulation after weaning from CPB. For nearly all heparin alternatives, there is no reversal agent equivalent to protamine. Other negative side effects include prolonged operative times and the risk of increased blood loss and transfusion. Although several agents have been used as alternates to heparin,[45,52] there is only sufficient data on bivalirudin to make recommendations in this clinical setting.