Patients undergoing coronary artery bypass graft (CABG) surgery are commonly at risk for hemorrhagic and thrombotic complications due to either patient-related factors (e.g., congenital or acquired coagulopathies) or more commonly procedure-related factors (iatrogenic trauma and the effects of cardiopulmonary bypass [CPB] circuit).1 Thus, maintaining a proper balance of pro- and anticoagulant proteins is desirable to optimize postoperative outcomes.
As a vitamin K-dependent coactivator for protein C, protein S facilitates the inactivation of factor Va and factor VIIIa to prevent excessive hemostatic system activation. Hereditary protein S deficiency is an autosomal dominant hypercoagulable disease associated with venous thromboembolism, and the estimated prevalence of inherited protein S deficiency in the general population ranges from 0.03% to 0.21%.2 Previous case reports showed that CABG patients with protein S deficiency had an increased risk for graft occlusion and venous thromboembolism.3–6 In this report, per IRB approval by Washington University School of Medicine, we describe a novel perioperative management of 2 patients with preoperative diagnosis of protein S deficiency scheduled for CABG without prophylactic use of an antifibrinolytic drug and postoperative hemostatic blood products.
A 67-year-old man with coronary artery disease (CAD) was admitted with progressive dyspnea. The family history was only significant for a brother with protein S deficiency and recurrent deep vein thrombosis, and the patient was reported to have protein S deficiency without venous thromboembolism.
Cardiac catheterization revealed an 80% stenosis at the mid-left main coronary artery, 90% stenosis at mid-circumflex, 70% stenosis at the posterolateral branch, and 100% stenosis at the distal right coronary artery. On admission, his platelet count was 249 × 106/μL, prothrombin time was 13.9 seconds (reference range: 11–15 seconds), and activated partial thromboplastin time was 32.7 seconds (reference range: 21–36.5 seconds). Due to the positive family history of protein S deficiency, preprocedure levels of protein S, protein C, and antithrombin III were measured. Preoperative hypercoagulability assessment showed a largely reduced free protein S level of 30% (reference range: 64%–158%), while protein C activity was 114% (reference range: 80%–160%) and the antithrombin III activity was 95% (reference range: 80%–140%).
During an uncomplicated elective 3-vessel CABG surgery, the patient indirectly received 7 units (1.75 L) of intraoperative fresh frozen plasma (FFP) as the priming fluid of the CPB circuitry. Intraoperatively, the blood was anticoagulated with unfractionated heparin (bolus and infusion) to maintain an activated coagulation time >480 seconds, and a stable heparin concentration was maintained (i.e., using an infusion of one-third of the initial dose per hour) while on CPB per our institutional routine. No prophylactic or need-based intraoperative antifibrinolytic drugs were administered. Protamine was given based on the measurement of the whole blood heparin level at the end of CPB (duration: 171 minutes). At the termination of CPB, serum-free protein S activity was 41%, which approximates the projected level of 47.1% based on the usage of 1.75 L FFP and the preoperative free protein S level.
The patient remained in stable postoperative condition, and a heparin infusion started on day 2 was only interrupted temporarily for the chest tube and pacing wires removal on postoperative day 3. Collective chest tube drainage was 402 mL for a 24-hour period. The patient did not require postoperative blood products and was subsequently discharged on postoperative day 7. Neither bleeding nor thrombotic complications occurred during the 1-week postoperative period (Table 1).
A 63-year-old wheelchair-bound man with significant CAD was admitted for unstable angina. His medical history was significant for several thrombotic events (e.g., deep vein thrombosis, pulmonary emboli, myocardial infarction, and cerebrovascular accident) that were treated with warfarin. In 2006, the patient had 39% of protein S activity but 88% of protein C activity, with a mildly elevated International Normalized Ratio (INR) of 1.57 which suggested a subtherapeutic warfarin effect.
Cardiac work-up confirmed persistent CAD with 50% stenosis at the left main coronary artery, 50% stenosis at the distal circumflex artery, and 70% stenosis at the mid-circumflex artery. On admission, his platelet count was 118 × 106/μL, prothrombin time was 26.3 seconds (INR of 2.38), and activated partial thromboplastin time was 27.7 seconds. Although the diagnosis of protein S deficiency could not be confirmed while receiving warfarin treatment, the substantial difference between the patient’s protein S and protein C levels strongly suggested protein S deficiency. The warfarin effect was allowed to dissipate without vitamin K administration after starting a heparin infusion. On the fifth day before CABG surgery, his INR was 1.67, free protein S, and C activity were 43% and 90%, respectively. On the day of surgery, the patient had functional antithrombin III activity of 83%.
Elective 3-vessel CABG was performed on day 9 of hospitalization. The patient indirectly received 1.8 L FFP as the priming fluid for the CPB circuitry. Intraoperatively, his blood was anticoagulated with unfractionated heparin (bolus and infusion) to maintain an activated coagulation time >480 seconds, and a stable heparin concentration was maintained using a heparin infusion (i.e., one-third the initial dose per hour) while on CPB (duration: 141 minutes). Prophylactic administration of antifibrinolytic drugs was avoided based on the risk-benefit analysis for bleeding versus thrombosis. At the end of CPB, heparin-neutralizing protamine was administered based on the terminal whole blood heparin concentration, and the patient had uneventful perioperative and postoperative courses.
His total chest tube drainage was 250 mL per 24-hour period, and subcutaneous heparin was started at postoperative day 3. Other than the FFP in the CPB circuit, no other blood components were given in the intra- and postoperative periods. Due to the patient’s history of thrombotic events, warfarin was also restarted postoperatively to achieve an INR of 2 to 3, and the patient was discharged on postoperative day 15 in stable condition with an INR of 2.32. Neither apparent postoperative graft occlusions nor other thrombotic complications occurred during the 2-week postoperative observation period (Table 1).
CPB can disrupt hemostasis through hemodilution (i.e., as related to CPB prime and cardioplegia administration) as well as through contact (i.e., blood interface with the surface of the CPB circuit) and tissue factor/factor VIIa-mediated activation/consumption.7 A recent study showed that exposure to CPB could significantly change thrombin activity persisting to the postoperative period by impairing the generation of activated protein C.8 Increasing the protein C level by administrating protein C zymogen concentrate was shown to be important in moderating inflammation and sepsis-associated organ failure after cardiac surgery.9 Thus, cardiac surgery involving CPB could be a platform for aggressive consumptive coagulopathy in patients even without inherited or acquired coagulopathies.
Protein S, protein C, and thrombomodulin down-regulate the activation of factors Va and VIIIa. While 60% of the total protein S remains bound to the C4b-binding protein, only the free protein S has full anticoagulant activity. Given the long half-life of free protein S (96 hours) and a prior report of a postoperative thrombotic event associated with protein S deficiency,10 normalization of protein S should be considered to minimize the potential risk for perioperative thrombotic complications, especially in high-risk surgical settings. In our review of the literature, there were 9 case reports/series describing protein S-deficient patients undergoing cardiothoracic operations. Only 4 of those reports described potential associations with anticoagulation/antifibrinolytic interventions, which consisted of a mixture of prophylactic FFP administration, warfarin usage, and aprotinin usage.3,4,6,11 In contrast to these studies, we added a novel approach that allows larger volume supplementation of protein S by prophylactic priming of the CPB circuit with nearly twice the previously reported volume of FFP (7–9 units). Similar to therapeutic plasma exchange procedures, the use of a plasma-based CPB prime will not result in volume overload in these patients since any excess volume in the CPB circuit can be removed with hemoconcentration. In addition to increasing protein S level, this method of using the large extracorporeal space in the CPB circuit could, in theory, correct deficiencies of other anticoagulants (e.g., protein C or antithrombin III) or procoagulant coagulation factors.
Prophylactic administration of antifibrinolytic drugs (and previously the serine protease inhibitor aprotinin) is used to attenuate the risk of perioperative bleeding, especially in high-risk patients. Patients at risk for thrombotic complications include those who have: (1) hereditary or acquired deficiencies of the normal anticoagulants (e.g., protein C or S, antithrombin III), (2) other hereditary (e.g., Factor V Leiden, prothrombin mutation, hyperhomocysteinemia) or acquired (e.g., antiphospholipid, cardiolipin antibodies, heparin-induced thrombocytopenia) hemostatic system abnormalities, or (3) upregulated hemostatic systems (e.g., generalized hypoperfusion, end-stage cardiomyopathies, sepsis, or any other disease states that lead to disseminated intravascular coagulopathy). However, data evaluating empiric antifibrinolytic use to reduce bleeding or transfusion with hereditary or acquired hypercoagulability defects are poorly understood although patients may bleed less.12
Both patients described in this report underwent uneventful CABG procedures without hematologic or hemostatic complications despite the avoidance of antifibrinolytic (e.g., epsilon aminocaproic or tranexamic acid) or serine protease inhibitors (e.g., aprotinin).4 Neither patient received prophylactic warfarin for protein S deficiency, because a large prospective study5 using continuous anticoagulation did not effectively prevent thrombotic events in protein S-deficient patients. Although the repletion of protein S level in protein S-deficient surgical patients is desired, the clinically relevant threshold of protein S level in these patients that could prevent spontaneous thrombotic complications needs to be investigated.
1. Kucuk O, Kwaan HC, Frederickson J, Wade L, Green D. Increased fibrinolytic activity in patients undergoing cardiopulmonary bypass operation. Am J Hematol. 1986;23:223–9
2. ten Kate MK, van der Meer J. Protein S deficiency: a clinical perspective. Haemophilia. 2008;14:1222–8
3. Köner O, Tekin S, Soybir N, Gülcan F, Karaoğlu K. Cardiac operation in a patient with combined homozygous protein C and protein S deficiency. J Cardiothorac Vasc Anesth. 2000;14:188–90
4. Massoudy P, Thielmann M, Müller-Beissenhirtz H, Aleksic I, Marggraf G, Dietrich W, Jakob H. Thrombophilia in cardiac surgery–patients with protein S deficiency. Ann Thorac Surg. 2006;82:2187–91
5. Grocott HP, Clements F, Landolfo K. Coronary artery bypass graft surgery in a patient with hereditary protein S deficiency. J Cardiothorac Vasc Anesth. 1996;10:915–7
6. Schneider S, Sakert T, Lucke J, McKeown P, Sharma A. Cardiopulmonary bypass for a coronary artery bypass graft patient with heterozygous protein C deficiency and protein S deficiency. Perfusion. 2006;21:117–20
7. Despotis GJ, Gravlee G, Filos K, Levy J. Anticoagulation monitoring during cardiac surgery: a review of current and emerging techniques. Anesthesiology. 1999;91:1122–51
8. Taneja R, Liaw PL, Al Ghazaly S, Priestap F, Murkin JM, Martin CM. Effect of cardiopulmonary bypass on thrombin generation and protein C pathway. J Cardiothorac Vasc Anesth. 2013;27:35–40
9. Crivellari M, Della Valle P, Landoni G, Pappalardo F, Gerli C, Bignami E, Marino G, Zangrillo A, D’Angelo A. Human protein C zymogen concentrate in patients with severe sepsis and multiple organ failure after adult cardiac surgery. Intensive Care Med. 2009;35:1959–63
10. De Paulis R, Bognolo G, Tomai F, Bassano C, Tracey M, Chiariello L. Early coronary artery bypass graft thrombosis in a patient with protein S deficiency. Eur J Cardiothorac Surg. 1996;10:470–2
11. Spanier TB, Chen JM, Mancini DM, Smith CR, Edwards NM. Cardiac transplantation in a patient with protein S deficiency. Ann Thorac Surg. 1999;68:1078–80
12. Donahue BS, Gailani D, Higgins MS, Drinkwater DC, George AL Jr. Factor V Leiden protects against blood loss and transfusion after cardiac surgery. Circulation. 2003;107:1003–8