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    Abstract
   Introduction
   Discussion
   Case Report
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Table of Contents
CASE REPORT  
Year : 2014  |  Volume : 17  |  Issue : 3  |  Page : 232-236
Coronary artery bypass grafting in a patient with protein S deficiency: Perioperative implications


1 Division of Cardiothoracic Surgery, Sultan Qaboos University Hospital, Muscat, Oman
2 Department of Anaesthesia, Sultan Qaboos University Hospital, Muscat, Oman

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Date of Submission28-Aug-2013
Date of Acceptance06-Apr-2014
Date of Web Publication3-Jul-2014
 

   Abstract 

Protein S (PS) along with activated protein C plays an important role in the down-regulation of in vivo thrombin generation. Its deficiency can cause abnormal and inappropriate clot formation within the circulation necessitating chronic anticoagulation therapy. The risk of developing thrombotic complications is heightened in the perioperative period in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Heparin resistance is very rare in these patients, especially when antithrombin levels are near normal. Management of CPB in this scenario is quite challenging. We report the perioperative management, particularly the CPB management, of a patient with type I PS deficiency and incidentally detected heparin resistance, who underwent coronary artery bypass grafting with CPB.

Keywords: Cardiopulmonary bypass; Coronary artery bypass grafting; Heparin resistance; Hypercoagulable states; Protein S deficiency

How to cite this article:
Balan B, Chengode S, Al Sabti H, Rao RN. Coronary artery bypass grafting in a patient with protein S deficiency: Perioperative implications. Ann Card Anaesth 2014;17:232-6

How to cite this URL:
Balan B, Chengode S, Al Sabti H, Rao RN. Coronary artery bypass grafting in a patient with protein S deficiency: Perioperative implications. Ann Card Anaesth [serial online] 2014 [cited 2019 Aug 19];17:232-6. Available from: http://www.annals.in/text.asp?2014/17/3/232/135875



   Introduction Top


Protein S (PS) is synthesized mainly in the liver, but vascular smooth muscle cells and endothelial cells also produce it. Plasma PS is measured as total PS antigen, free PS antigen and functional PS activity range. Currently followed classification of PS deficiency is recommended by the Scientific Standardization Committee of the International Society on Thrombosis and Hemostasis [Table 1]. PS is a vitamin K dependent plasma glycoprotein and functions as a cofactor of activated protein C (APC) in the inactivation of excess activated factor V and VIII, thus regulating in vivo thrombin generation. In addition, PS regulates fibrinolysis during early clot formation by inhibiting the initial thrombin formation and thereby decreasing the rate of thrombin activated fibrinolysis inhibitor activation. It is involved in the control of the extrinsic pathway of coagulation and also serves as a cofactor of tissue factor pathway inhibitor (TFPI) thus inhibiting tissue factor activity by promoting the interaction between TFPI and activated factor X. PS circulates in the plasma in two primary forms: Free and bound. The free form is the one which interacts with APC and prevents inappropriate in vivo coagulation. Deficient or abnormal free form of PS can result in abnormal clot formation within the venous circulation. The incidence of PS deficiency in the general population has been reported to be 0.16-0.21%. [1] The majority of these patients present with recurrent episodes of venous thromboembolism (VTE) like deep venous thrombosis (DVT) or pulmonary embolism (PE). The relative risk of VTE in patients with PS deficiency has been reported to be 5-11.5. [1],[2] PS deficiency can be acquired or inherited. The acquired form is usually due to hepatic disease, nephritic syndrome, disseminated intravascular coagulation, chronic infections such as HIV, pregnancy, vitamin K deficiency, vitamin K antagonist therapy, oral contraceptives, etc. [3] The inherited disorder is autosomal dominant. A heterozygous state has a slightly lower risk of developing thrombosis than a homozygous state. Homozygous PS deficiency is associated with greater risk of thrombosis from early life and survival is impossible unless detected early and treated appropriately. [1],[4],[5] Convincing evidence for increased incidence of arterial thrombosis in these patients is still debated. [6] A number of other inherited conditions can cause hypercoagulable states before, during and following CPB and include deficiencies of protein C, other natural anticoagulants, APC resistance secondary to factor V Leiden, prothrombin G20210A mutation, etc. Numerous acquired conditions such as thrombotic thrombocytopenic purpura, antithrombin III deficiency, heparin-induced thrombocytopenia, antiphospholipid antibody syndromes, myeloproliferative diseases, hyperhomocysteinemia, and oral contraceptive medications are associated with hypercoagulable state. [7] Perioperative thrombotic complications pose a unique challenge in patients with preexisting hypercoagulation who undergo cardiac surgery with cardiopulmonary bypass (CPB). [8] Incidental detection of heparin resistance in such patients, with a near normal preoperative antithrombin level, makes decision making on anticoagulation therapy even more challenging. We describe and discuss the perioperative management strategies adopted by us in a heterozygous protein S deficient patient undergoing cardiac surgery with CPB.
Table 1: Classification of protein S deficiency

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   Case Report Top


A 60-year-old male (weight 80 kg; height 170 cm) was scheduled for elective on pump coronary artery bypass grafting (CABG). His coronary angiogram showed double vessel disease and echocardiogram revealed an ejection fraction (EF) of 58% and no valvular pathology. He was a diagnosed case of inherited, heterozygous, type I PS deficiency and had a history of multiple episodes of DVT, and PE. He gave a family history of PE, DVT and unexplained sudden death of young individuals who were diagnosed to have PS deficiency. He was receiving oral warfarin. His protein S, C, and antithrombin levels before surgery are shown in [Table 2]. After admission, the anticoagulation was managed with low molecular weight heparin (LMWH) for 5 days before scheduled CABG surgery. LMWH was stopped 12 h before CABG.
Table 2: Laboratory result of different protein levels

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The patient was anesthetized and monitored as any other case undergoing CABG. Transesophageal echocardiography was also used. His preoperative activated clotting time (ACT) was 115 s and hematocrit was 37%; four units of fresh frozen plasma (FFP) were administered during prebypass period. The extracorporeal circuit consisted of a Sorin revolution centrifugal pump and Trillium coated circuit, Medtronic Affinity Oxygenator, 38 μm arterial filter, Myotherm (cardioplegia delivery system) and a hemofilter (Medtronic, Minneapolis, Minnesota, USA). A blood salvage and autotransfusion system (Autolog, Medtronic, Minneapolis, Minnesota, USA) was also employed during the surgery. The circuit was primed with 1000 ml of Plasmalyte solution (Plasmalyte RTI Inc., Franklin, USA), 500 ml of Voluven (Fresenius Kabi, Canada) and 10,000 units of unfractionated heparin (UFH) were added to the prime.

Initially, 25,000-units-UFH was administered to the patient to achieve an ACT of 480 s. The ACT achieved after three minutes was 400 s. Two more doses of 10,000 and 15,000 units of UHF were given after that the ACT increased to 497 s. Thereafter, the surgeon cannulated the aorta and the right atrium. The entire crystalloid prime in the CPB circuit was emptied through the arterial filter vent port by retrograde autologous arterial blood priming and autologous venous blood priming. A volume of 500 ml of FFP was added to the venous reservoir to maintain the adequate reservoir level and to flush the entire crystalloid prime before going on CPB. The measured ACT after five minutes of CPB was 452 s. Additional 10,000-units heparin was administered, which increased ACT to 509 s. On normothermic CPB and under antegrade warm blood cardioplegic myocardial protection, left internal mammary artery (LIMA) was grafted to left anterior descending artery and a reversed saphenous vein graft (SVG) was anastomosed to the obtuse marginal artery. A hematocrit of about 24% was achieved on CPB with the help of the hemofilter. A mean arterial pressure of 60-70 mmHg was maintained during CPB. The patient was weaned-off CPB successfully without any difficulty. After zero balance ultrafiltration, the hemoglobin after discontinuation of CPB was 9.7 g%. The urine output was 200 ml and ultrafiltrate was 2400 ml on CPB. The total CPB and aortic cross-clamp times were 58 and 18 min, respectively. After removal of the venous cannula, half of usual protamine dosing of 3 mg/kg was administered; thereafter, the ACT returned to 112 s. Before sternal closure, adequacy of flow through the SVG and LIMA conduits were confirmed using Medistim-VeriQ (Medistim, Oslo, Norway). Before tightening the sternal wires, topical tranexamic acid 2.5 g diluted in 50 ml of saline was instilled in the pericardial sac. The residual pump volume was ultrafiltered and about 800 ml of concentrated blood with a hematocrit of 32.5% and K + of 5 mmol was collected and later transfused. Through the blood salvage and auto-transfusion system, another 120 ml of washed red blood cells (RBCs), with a hematocrit of 58%, was transfused later. In the cardiac surgical intensive care unit, the ACT measured 188 s. Additional 50 mg of protamine was administered, the ACT decreased to 148 s. After observing chest tube drainage for 2 h, a bolus dose of 5000 units of UFH was administered which was followed by 500 units/h for 4 h, thereafter, its dosing was adjusted to 1000-1200 units/h to maintain an APTT of 50-60 s (APTT ratio of 1.5-2). The patient was restarted on oral aspirin, 81 mg, 6 h postoperatively and warfarin 5 mg on the 1 st postoperative day. Heparin infusion was discontinued 24 h after starting warfarin. Warfarin dose was adjusted to maintain an INR of 2-2.5. Total chest tube drain was 480 ml. The postoperative period was uneventful and the patient was discharged on the 7 th day after surgery.


   Discussion Top


Intravascular hemostasis is maintained by a fine balance between the pro- and antithrombotic factors present within the circulatory system. Patients with preexisting hypercoagulability may have an increased risk of thrombotic complications because of the hypercoagulable state induced with surgical trauma and stress but, theoretically during cardiac surgery, the anticoagulation and fibrinolytic state following inflammatory response to CPB counter this state. [9] CPB has a destructive effect on blood components, which affects the normal functioning of the coagulation system. [8] CPB triggered systemic inflammatory response can lead to consumption coagulopathy and microvascular thrombosis. This is exaggerated with impaired APC function usually seen with PS deficiency. [10],[11],[12] About 60% of the PS is bound to the complement regulatory protein, C4b-binding protein (C4bBP). The proportion of bound and unbound forms is regulated by the availability of C4bBP. Systemic inflammation can result in increased plasma levels of C4bBP as a consequence of acute phase reaction, which may lead to further reduction in the available free form of PS. [11],[12],[13] Therefore, we assumed that techniques of reducing systemic inflammation during CPB may have a beneficial effect on our patient's outcome. Utilization of heparin-coated circuits and techniques like retrograde and antegrade autologous priming, zero-balance ultrafiltration and intense blood conservation methods can reduce systemic inflammatory response to CPB and also conserve the available circulating PS. Unlike protein C and antithrombin, there is no purified form of PS available for clinical use. FFP is the only source of PS available to treat life-threatening thrombosis in PS deficiency and is being routinely used in sick, PS deficient, neonates. [14] We administered four units of FFP to the patient with an aim to augment the PS levels.

Cardiac surgical procedures result in several perioperative complications in PS deficient patients including graft occlusion, stroke, DVT, and pulmonary embolism. [15] Previous reports in patients with PS deficiency describe usual dose of heparin to achieve the recommended preCPB ACT. Schneider et al. [16] used heparin coated circuits and leukocyte filters to reduce heparin dose and also to minimize the inflammatory response. They managed the heparin and protamine dosing with the use of Hepcon/HMS device. In our patient, we used only kaolin and silica based ACT (Hemochron signature elite plus with Hemochron Jr. ACT + cartridges) for heparin monitoring. Our patient was not on UFH preoperatively and his preoperative antithrombin levels were almost normal. Even after the administration of four units of FFP for augmenting the PS levels, which is also a good source of antithrombin III, 3 mg/kg of heparin failed to achieve the recommended ACT value and we had to give double the usual dose of heparin to reach an ACT value of more than 480 s. Since FFP was administered before initial heparinization, we decided to try higher doses of heparin rather than heparin alternatives to achieve the required ACT value. We removed maximum possible crystalloid prime to avoid dilution of PS circulating in the patient before CPB. The 500 ml FFP added to the venous reservoir should also have augmented the circulating PS levels during bypass and would have helped to improve antithrombin III levels as well. We administered only half the calculated dose of protamine. This half neutralization of heparin was also used by Villacorta et al. [17] to avoid spontaneous venous graft thrombosis following CABG in a PS deficient patient. We do not know whether the heparin dosing and protamine reversal of heparin could have been managed better with a heparin dose response and heparin-protamine titration system like the Hepcon hemostasis management system as suggested by Schneider et al.

We could come across only one report of heparin resistance in patients with documented PS deficiency. Armando et al. [18] had reported extensive venous thrombosis, resistant to high dose of heparin, in a boy who developed autoimmune mediated PS deficiency following chicken pox infection. They had to treat this child with recombinant tissue plasminogen activator, in addition to very high dose of UFH infusion. The authors opined that adjunct therapy with PS or APC concentrates along with other anticoagulant therapy might be useful in heparin resistant thrombosis, especially in autoimmune PS deficiency. Even though our patient required higher doses of heparin for CPB and also in the postoperative period to maintain target levels of anticoagulation, he did not develop thromboembolic episodes. Administration of FFP, which is the only blood product rich in PS, and early initiation of coumarin anticoagulant could have benefitted our patient.

Thrombotic complications have been an unproven theoretical concern with intravenous (IV) tranexamic acid in cardiac surgery. [19] There are no reports of its IV use in PS deficient patients undergoing cardiac surgery. Vascular thrombosis or neurological complications have not been reported following topical instillation of tranexamic acid in the pericardial cavity, during sternal closure. It is our practice to instill topical tranexamic acid after all cardiac surgeries. This patient could have had a higher chance of venous graft thrombosis following IV tranexamic acid, but topical application of the same helped to reduce postoperative mediastinal blood loss without any adverse events.

We routinely transfuse the residual blood in the CPB circuit after centrifuging, washing and re-suspending the RBCs in saline, using the blood salvage system. In this case, we concentrated the whole blood with the ultrafiltration system in the CPB circuit itself and transfused it later. This was done with the intention of preserving the remaining clotting factors and PS, which would have been removed if the red cells were washed and resuspended. An extra 50 mg protamine was administered after transfusion of the concentrated pump blood. In this case of PS deficiency, we maintained the preoperative anticoagulation with LMWH, modified the preCPB, CPB, and postCPB management techniques and initiated early postoperative anticoagulation with appropriate monitoring, which resulted in an uncomplicated surgical outcome.

To summarize, protein S deficient patients pose a high risk for thrombotic complications in the perioperative period. Perioperative anticoagulation is a major concern in these patients which becomes a challenge if heparin resistance is detected incidentally before the institution of CPB. Management of perioperative anticoagulation and CPB techniques require a well-coordinated multidisciplinary approach during cardiac surgery with CPB.

 
   References Top

1.ten Kate MK, van der Meer J. Protein S deficiency: A clinical perspective. Haemophilia 2008;14:1222-8.  Back to cited text no. 1
    
2.Previtali E, Bucciarelli P, Passamonti SM, Martinelli I. Risk factors for venous and arterial thrombosis. Blood Transfus 2011;9:120-38.  Back to cited text no. 2
    
3.Joshi A, Jaiswal JP. Deep vein thrombosis in protein S deficiency. JNMA J Nepal Med Assoc 2010;49:56-8.  Back to cited text no. 3
    
4.Schwarz HP, Fischer M, Hopmeier P, Batard MA, Griffin JH. Plasma protein S deficiency in familial thrombotic disease. Blood 1984;64:1297-300.  Back to cited text no. 4
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6.Cho YP, Kwon TW, Ahn JH, Kang GH, Han MS, Kim YH, et al. Protein C and/or S deficiency presenting as peripheral arterial insufficiency. Br J Radiol 2005;78:601-5.  Back to cited text no. 6
    
7.Chan MY, Andreotti F, Becker RC. Hypercoagulable states in cardiovascular disease. Circulation 2008;118:2286-97.  Back to cited text no. 7
    
8.DeBois W, Liu J, Lee L, Girardi L, Ko W, Tortolani A, et al. Cardiopulmonary bypass in patients with pre-existing coagulopathy. J Extra Corpor Technol 2005;37:15-22.  Back to cited text no. 8
    
9.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.  Back to cited text no. 9
    
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11.Levi M. Coagulation. In: Cavaillon JM, Adrie C, editors. Sepsis and Non-Infectious Systemic Inflammation: From Biology to Critical Care. Wiley-VCH Verlag GmbH and Co.KGaA, Weinheim; 2009. p. 256-8.  Back to cited text no. 11
    
12.Levi M, Keller TT, van Gorp E, ten Cate H. Infection and inflammation and the coagulation system. Cardiovasc Res 2003;60:26-39.  Back to cited text no. 12
    
13.García de Frutos P, Alim RI, Härdig Y, Zöller B, Dahlbäck B. Differential regulation of alpha and beta chains of C4b-binding protein during acute-phase response resulting in stable plasma levels of free anticoagulant protein S. Blood 1994;84:815-22.  Back to cited text no. 13
    
14.Practical-Haemostasis.com. A Practical Guide to Laboratory Haemostasis. [updated 2012 April 29; cited 2014 Feb 10] Available from:   http://www.practical-haemostasis.com/Thrombophilia%20Tests/ps_assays.html. [Last accessed on 2014 Jun 25].  Back to cited text no. 14
    
15.Massoudy P, Thielmann M, Müller-Beissenhirtz H, Aleksic I, Marggraf G, Dietrich W, et al. Thrombophilia in cardiac surgery: Patients with protein S deficiency. Ann Thorac Surg 2006;82:2187-91.  Back to cited text no. 15
    
16.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.  Back to cited text no. 16
    
17.Villacorta J, Guidon C, Kerbaul F, Mesana T. An intraoperative coronary artery bypass graft thrombosis in a patient with protein S deficiency. J Cardiothorac Vasc Anesth 2001;15:805-6.  Back to cited text no. 17
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19.Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: Systematic review and cumulative meta-analysis. BMJ 2012;344:e3054.  Back to cited text no. 19
    

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Correspondence Address:
Baskaran Balan
Division of Cardiothoracic Surgery, Sultan Qaboos University Hospital, PO Box 35, Muscat
Oman
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-9784.135875

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    Tables

  [Table 1], [Table 2]

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