Cardiac surgery requiring cardiopulmonary bypass (CPB) is associated with significant activation of hemostatic system leading to thrombi formation. Adequate anticoagulation is necessary to manage hemostatic and inflammatory response to CPB. ⁽¹⁾ Traditionally, systemic anticoagulation during CPB is best achieved by administering heparin 300-400 IU/kg to maintain ACT (Activated clotting time) >400 s. Heparin resistance is defined as an ACT of less than the target (400-480 seconds) after 600 to 800 units/kg of intravenous heparin. ⁽²⁾ The incidence of HR during CPB is about 4 to 26%. ⁽³⁾

There are various causes and management modalities of heparin resistance during CPB.We hereby report a case of a 40-year female who developed heparin resistance during CPB for mitral valve replacement.

A 40-year-old female presented with complaints of breathlessness which is gradually progressing (from NYHA grade II to III) associated with PND for past six months. She also had history of palpitation and easy fatiguability. She doesn’t have any other comorbid illness. On further examination, she has bilateral pitting pedal edema extending upto ankle with elevated JVP. Her vitals were pulse rate of 50- 65 beats/min which is irregularly irregular, blood pressure of 100/60 mmHg and respiratory rate of 16 breaths/min with saturation of 96% on room air. On auscultation she has mid-diastolic murmur in mitral area with normal S1 and S2.Other systemic examination was found to be normal.Inelectrocardiogram, the features of atrial fibrillation with controlled ventricular rate, left ventricular hypertrophy were present. 

On transthoracic echocardiogram, she was diagnosed with severe mitral stenosis, moderate pulmonary artery hypertension, right atrial pressure of 58 mm Hg, dilation of left atrium with clot and normal left ventricular systolic and diastolic function. Other laboratory investigations including coagulation parameters were found to be normal. She was started on LMWH single dose subcutaneously (0.6 ml), diltiazem 130 mg TDS and diuretics. Tablet Pantaprazole and tablet lorazepam was given as a premedication. Heparin was withheld on the day of surgery and other medications were continued.

In the operation theatre, large bore intravenous line and left radial arterial line were cannulated. Baseline five lead ECG, oxygen saturation and blood pressure were recorded. She was induced using standard hospital protocol for cardiac surgery and intubated with 7.5 size cuffed ETT. Right internal jugular vein was cannulaed with 7.5 Fr triple lumen catheter and right femoral artery was also cannulated. ECG, SpO2, IBP, CVP, CBG, temperature and urine output monitored throughout the procedure.  TEE was also inserted for continuous haemodynamic monitoring. Anaeshesia maintained with oxygen, air and sevoflurane. 

Following sternotomy, baseline ACT was recorded as 114s. Injection heparin was given at dose of 3mg/kg (150 mg) initially. Then ACT was recorded as 318s after 4 minutes. Again 100 mg of heparin was given and ACT was repeated and found as 340s. Heparin 75 mg was given after 3 mins. Despite administration of 325 mg of heparin, ACT values were less than 400s. Hence, we thought of heparin resistance (HR) and two units of fresh frozen plasma were given. Repeat ACT after FFP administration was 666s. CPB was instituted with moderate hypothermia. She was weaned from CPB and systemic heparinization was reversed with protamine dose of 275 mg and preoperative baseline ACT was achieved. Intraoperative and postoperative period was uneventful without any episodes of bleeding. She was electively ventilated for twenty-four hours and extubated the next day, as she was awake, able to take adequate spontaneous breath and hemodynamically stable with minimum supports and minimal drain.

HEPARIN:

Since its discovery by Dr. Jay McLean in 1915, heparin remains the primary anticoagulant during CPB.Heparin is a negatively charged glycosaminoglycan weighing 3000 to 30000 Daltons. ⁽⁴⁾ Heparin alone has no direct anticoagulant effect, but it potentiates the activity of antithrombin. Thepentasaccharide sequence in the heparin binds to antithrombin III (AT) and thrombin which allows AT to inhibit the procoagulant effect of thrombin by binding to the active-site serine resi­due of the thrombin molecule. ⁽⁵⁾ The inhibitory effect of AT is increased 1000-fold in the presence of heparin. As concentration increases, it inhibits factor Xa and factors IXa, XIa and XIIa. It also inhibits the thrombin induced activation of factors V and VIII. ⁽⁶⁾

Effects of CPB:

During cardiopulmonary bypass, exposure of blood to extracorporeal circuit leads to activation of inflammatory response, coagulation pathways, impairs platelet function and increases fibrinolytic activity. ⁽⁷⁾ All these changes lead to formation of micro vascular thrombi, haemorrhage and organ dysfunction. ⁽⁸⁾

ROLE OF HEPARIN:

Hattersley introduced the activated clotting time (ACT) in 1966 as a bioassay for monitoring heparin’s anticoagulant effect. After a baseline activated clot­ting time (ACT) is measured (the normal range is 80-120 seconds), a dose of 300 to 400 units/kg of heparin is given as an intravenous bolus. Subsequent heparin dosing for extracorporeal circu­lation (ECC) is targeted at maintaining ACT values longer than 400 to 480 seconds.

HEPARIN RESISTANCE:

Heparin resistance is defined as an ACT of less than the target (400-480 seconds) after 600 to 800 units/kg of intravenous heparin are administered. ⁽²⁾ There are no clear definitions for heparin resistance, basically it is the inability to achieve ACT > 400s even after unusually large doses of heparin.

Heparin resistance can be broadly classified as AT dependent and AT independent. The most common cause of heparin resistance is AT III deficiency which can be congenital or acquired. Normal AT III levels are 75-125%. The prevalence of deficiency in congenital AT is 1/3000; AT levels in these patients are 40% to 50% less than normal rates. (11) The acquired causes of AT III deficiency are DIC, cirrhosis, nephrotic syndrome, pregnancy, hemodialysis, ECMO, oral contraceptives, asparaginase therapy. It is further subdivided into two types. There will be reduced levels of antithrombin III in type I due to genetic mutation causing reduced synthesis. Type II defect is functionally defective antithrombin leading to reduced activity. Heparin itself can reduce antithrombin level by 30% due to its increased clearance. During CPB there is reduced levels of AT III and preoperative use of heparin and rise in acute phase reactants can further reduce levels of AT III leading to increased thrombotic risk and insensitivity to heparin. this can be detected by ACT levels along with ATIII levels and anti-factor Xa levels. Since our patient received heparin preoperatively, heparin itself may have reduced levels of AT III leading to heparin resistance. ⁽¹²⁾

AT independent causes for HR are increased heparin binding proteins (acute phase reactants), platelet activation, concomitant medications (eg. Nitroglycerin), increased heparin clearance, high levels of factor VIII and factitious heparin resistance.

Predictors of heparin resistance are AT levels less than or equal to 60%, preoperative heparin therapy, platelets> 300000/mm³, age >65 years, increased factor VIII and fibrinogen levels.

MANAGEMENT OF HEPARIN RESISTANCE:

Heparin resistance can be managed by administering antithrombin concentrates, FFP and alternate anticoagulants like direct thrombin inhibitors (bivalirudin, lepirudin), GP IIb/IIIa antagonists (tirofiban), factor X a inhibitor(danaproid). ⁽¹³⁾

AT concentrates are available in two forms: recombinant AT concentratewhich is DNA engineeredproduct made from goat's milk and the other is a purified human plasma harvest derivative.

The administration of FFP(10 ml/kg) prolongs ACT as it contains AT III (1 U AT for each ml of FFP) but it is associated with many disadvantages like transfusion related complication like viral infections,volume overload( 500 ml required),allergic reactions,transfusion related acute lung injury,thrombocytopenia.Spiess et al¹ did a comprehensive review comparing efficacy of FFP and AT for treatment of HR and he concluded that AT is a much safer option compared to FFP  for HR due to minimal side effects although it is expensive.

Danaparoid can be used in patients with increased risk of HR but their use is assosciated with increased risk of bleeding due to longer half life and lack of reversal agent. It is the only FDA approved class of drugs to be used as anticoagulation during CPB other than heparin.

In our patient, we suspected heparin resistance maybe due to the preoperative administration of LMWH which may have led to reduced antithrombin levels intraoperatively. Preoperative heparin therapy exhausts AT levels intraoperatively which was substantiated by the study done by Onur et al¹⁴.

There is increased incidence of heparin resistance during CPB as patients are started on anticoagulants prophylactically. Hence there is need for knowledge and awareness among anaesthesiologists about predictors, causes, management and other alternative agents for heparin resistance during CPB.

Conflict of Interest: No

Funding: No funding sources

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