Lupus Anticoagulant and Cardiopulmonary Bypass

Patients with lupus anticoagulant (LA), with or without antiphospholipid syndrome (APS) requiring cardiopulmonary bypass (CPB), present a unique set of clinical challenges. These include LA interference with unfractionated heparin (UFH) monitoring by the activated clotting time (ACT) as well as the risk of both circuit and systemic thrombosis. LA is one of the heterogeneous group of antiphospholipid antibodies.[1] Although LA causes prolongation of activated partial thromboplastin time (aPTT) and ACT in vitro assays, persistently positive LA is associated with increased risk of thrombosis.[1] The ACT is a point-of-care test used to assess the adequacy of heparinization and is monitored every 30 to 40 minutes during bypass by the anesthetic team. It is known that the ACT poorly correlates with the plasma heparin level and does not accurately predict the protamine sulfate dose needed for reversal of UFH following termination of CPB.[2] Previously we have demonstrated that patients without LA undergoing CPB have a poor correlation between ACT and heparin anti-Xa levels.[3] Although monitoring the inhibition of factor Xa by heparin is the gold standard for measuring the anticoagulant effect of UFH, it is not widely available in many hospital laboratories and providing heparin anti-Xa levels to assess the heparin levels in a timely manner for patients undergoing CPB is not always practical. Therefore, the ACT remains the main measure for monitoring the anticoagulant effect of UFH during CPB. Inaccurate assessment of anticoagulant effect of UFH with ACT[3] is further complicated by the presence of LA that may independently prolong the ACT and may be present in up to 5% of otherwise healthy patients.[4]

We present our 5 years' experience of patients with positive LA with or without APS requiring CPB, from a tertiary cardiac surgery referral center in London, United Kingdom. The study was approved by the Research Ethics Committee and the local Research and Development Office (reference number: 19/NW/0474). The need for individual informed consent was waived for retrospective analysis of data collected prospectively for routine care, with no breach of privacy or anonymity.

A total of 19 patients with LA had CPB during the study period (Jan 2016–2020). Median age was 62 (range: 42–78) years and 54% were female. Of these only 16% (3) of patients had APS and, in the remainder, LA was detected during preoperative assessment by a prolonged aPTT using SynthASil (HemosIL, Werfen, Warrington, Cheshire, United Kingdom). The median aPTT was 46 (range: 37–85) (reference range: 26–36) seconds at baseline and all 19 patients had confirmed LA with screen and confirm tests using Dilute Russell's viper venom time. All patients had a repeat test 12 weeks later confirming the persistently positive LA prior to or after the surgery. In our routine clinical practice, UFH 300 to 400 U/kg is administered aiming for an ACT more than 480 seconds prior to the CPB.[3] In the presence of an LA, heparin anti-Xa level (using a chromogenic liquid anti-Xa assay [Werfen, Warrington, Cheshire, United Kingdom]) was used to quantitate UFH, and ACT was recorded in parallel for comparison. UFH 300 to 400IU/kg was administered intravenously to each patient initially and further doses were given if the heparin anti-Xa level was less than 4.0 U/mL to maintain heparin anti-Xa more than 4.0U/mL³. A standard dose of UFH 10,000 units was administered to all patients at the priming of the CPB followed by a median dose of 30,000 units (range: 15,000–42,000 units) of UFH during the CPB. At CPB termination, protamine sulfate was administrated intravenously in keeping with 1 mg of protamine sulfate for 100 units of UFH administered (a median dose of 400 mg [range: 300–550 mg])

Median ACT prior to administration of UFH was 220 (range: 180–260) seconds (locally established reference range of 70–120 seconds (Haemochron Signature Elite, Werfen, United Kingdom). Median heparin anti-Xa level and ACT prior to administration of protamine sulfate were 4.5U/mL (range: 4.0–6.2) and 630 seconds (540–910 seconds), respectively. Correlation between anti-Xa level and ACT was poor (r = 0.16, p = 0.46) ([Fig. 1]). None of the patients developed circuit thrombosis or significant bleeding requiring transfusion. Postoperatively, all patients received standard thromboprophylaxis (at least 6–8 hours postsurgery provided adequate hemostasis was achieved) or therapeutic anticoagulation if the patients had a confirmed diagnosis of APS prior to surgery. Despite standard thromboprophylaxis, one patient (5%) with LA with no confirmed APS developed postoperative thrombosis with pulmonary embolism and right upper limb deep vein thrombosis. Notably this patient had additional cardiovascular risk factors for thrombosis including congenital heart disease. None of the patients died during immediate postoperative period or at 1 year follow-up.

Fig. 1 Correlation between heparin anti-Xa level and ACT in 19 patients with lupus anticoagulant who had cardiopulmonary bypass. ACT, activated clotting time; CI, confidence interval.

These favorable outcomes are in contrast to previous adverse case reports of APS patients undergoing cardiac surgery. A retrospective study with five patients with APS undergoing cardiac surgery had a perioperative mortality rate of 60% with a 1-year mortality rate of 80%.[5] Another study with 19 patients with APS undergoing cardiovascular surgery, 84% (16/19) had major postoperative complications, including coronary graft thrombosis, myocardial infarction, stroke, pulmonary embolus, and major bleeding events.[6]

Several strategies have been used to monitor anticoagulation in patients with LA undergoing cardiac surgery such as no change to standard ACT goals for CPB (usually 400–480s),[3] keeping an ACT level that is twice the normal range, creating a patient-specific ACT titration curve or using heparin anti-Xa level. Use of latter method as in our patient cohort is most likely to provide an accurate measure of anticoagulation during the procedure and prediction of protamine sulfate required for heparin reversal. However, the heparin anti-Xa assay has to be performed in the laboratory and obtaining the results in timely manner can be challenging. The anti-Xa level required for CPB (>4.0U/mL) is higher than that used for therapeutic heparin (0.3–0.7U/mL) and the assay becomes nonlinear at more than 2U/mL, so serial dilution of the sample is required. We performed heparin anti-Xa level postprotamine sulfate to make sure complete reversal of heparin was achieved. Although ACT was performed as the comparison, ACT levels remained elevated in patients with LA similar to their preheparin values.

In conclusion, there was no circuit thrombosis or significant bleeding in our cohort. Although current guidelines advocate against routine coagulation screens prior to surgical interventions, it remains common practice. Coagulation testing is not required to predict bleeding risk in patients undergoing CPB but detection of LA may be valuable to avoid erroneous heparin monitoring by ACT. This raises the question whether aPTT should be performed in patients undergoing CPB to detect LA to provide better anticoagulant management during CPB. Additionally, many laboratories use aPTT reagents that are not sensitive to LA which will miss this effect, but ACT will still be affected leading to suboptimal anticoagulant management during CPB. When LA is detected in patients undergoing CPB, the use of a heparin anti-Xa assay is preferable to ACT for the measurement of heparin effect to avoid circuit thrombosis and to judge correct protamine dose for reversal.

Note

Any additional information can be provided by the corresponding author upon reasonable request. The material in this manuscript was presented at British Society for Haematology Annual Scientific meeting 2022 as an oral abstract form.

Authors' Contributions

D.J.A. was responsible for design of the study, acquiring data, statistical analysis, interpretation of the data, and writing the manuscript. C.C.T. collected the data. M.L. interpreted the data and reviewed the manuscript. All authors reviewed and approved the final version of the manuscript.

Publication History

Article published online:
26 July 2022

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