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Interact CardioVasc Thorac Surg 2009;9:685-687. doi:10.1510/icvts.2009.208587 © 2009 European Association of Cardio-Thoracic Surgery
Acute mechanical prosthetic valve thrombosis after initiating oral anticoagulation therapy. Is bridging anticoagulation with heparin required?Department of Thoracic and Cardiovascular Surgery, AHEPA University Hospital, Thessaloniki, Greece Received 31 March 2009; received in revised form 25 June 2009; accepted 29 June 2009
*Corresponding author. Sakellaridi 25, 542 48 Thessaloniki, Greece. Tel.: +30 2310329729; fax: +30 2310329729.
Prosthetic valve thrombosis (PVT) represents a serious and potentially lethal complication. It can be attributed more frequently to inadequate anticoagulant therapy. We present a case of acute aortic mechanical valve thrombosis six months after implantation. The patient discontinued oral anticoagulation after being discharged following the primary operation. Two days after reinitiating warfarin as an outpatient, he developed acute valve thrombosis presenting with symptoms and signs of cardiac failure. He was managed with intravenous thrombolysis with a recombinant plasminogen activator which resulted in immediate resolution of thrombus and clinical improvement. A paradox procoagulant effect of warfarin is evident on the first one or two days after initiation of therapy. A ‘bridging’ protocol with unfractionated or low molecular weight heparin (LMWH) should be considered, according to recently published guidelines, until warfarin reaches therapeutic levels and exerts an antithrombotic effect.
Key Words: Aortic valve; Mechanical valve; Anticoagulation; Thrombosis; Embolism
Prosthetic valve thrombosis (PVT) remains a serious and potentially lethal complication. In the aortic and mitral position reported incidence varies widely from 0.5% to 6% per patient-year, and is highest in the mitral position [1]. The incidence can reach 13% in the first year in any valve position [2]. Inadequate anticoagulant therapy remains the main cause of this complication, while pitfalls in surgical technique and pannus formation can also act as contributing factors [3]. Thrombolysis has emerged as an alternative therapy in high-risk surgical patients, considering that surgical prosthetic valve replacement is related to significant operative morbidity and mortality rates [4]. We present a case of aortic mechanical valve thrombosis six months after implantation while initiating oral anticoagulant therapy on an outpatient basis in a patient who did not receive any anticoagulation during that period.
A 31-year-old man underwent an elective aortic valve replacement for symptomatic severe aortic regurgitation due to acute infective endocarditis. There was no past medical history of valvular disease or drug abuse. A mechanical 25 mm CarboMedics TopHat supra-annular aortic valve (CarboMedics Inc, Texas, USA) was implanted. The postoperative course was uneventful. Anticoagulation with a coumadin analog, acenocoumarol, started on the first postoperative day. No heparin was administered at that time in order to reduce the risk of early postoperative hemorrhage. The patient was discharged on the 7th postoperative day in excellent clinical condition. His medication consisted of digoxin and acenocoumarol. He was given specific instructions for international normalized ratio (INR) monitoring and was scheduled for a routine follow-up visit at the outpatients clinic four weeks after discharge. Unfortunately, the patient was lost from follow-up for a period of six months. He presented as an outpatient at this time asking for a new prescription for his medication. He explained that he had been completely asymptomatic during that period and refused to take his medication as prescribed. He was in sinus rhythm and NYHA I functional class without any clinical finding indicative of a valve-related complication. Transthoracic echocardiography revealed a well-seated mechanical aortic prosthesis without any paravalvular leak with a peak pressure gradient of 18.6 mmHg. Prothrombin time was within normal values. Considering his good clinical condition, he was treated as an outpatient on a starting dose of acenocoumarol of 4 mg for two days, when he was due to have the INR checked. No supplemental anticoagulant therapy, such as intravenous unfractionated heparin (UFH), which would require hospitalization, low molecular weight heparin (LMWH) or antiplatelet medication was administered at that time as ‘bridging’ therapy until INR reaches therapeutic values. Two days later he presented at the emergency department with acute onset of marked dyspnea and orthopnea NYHA III. Hemodynamics were stable. Clinical examination revealed muffled aortic prosthetic valve sounds. INR value was 2. Transthoracic echocardiography suggested restricted motion of the aortic prosthetic leaflets. Continuous-wave Doppler echocardiography confirmed severe obstruction with a peak pressure gradient of 100 mmHg. The left ventricle showed reduced contractility with an ejection fraction around 35%. The patient was admitted to the coronary care unit. Considering the patient's stable hemodynamic condition and the acute formation of thrombus, thrombolysis was elected as the treatment of choice. Intravenous therapy with a single dose of 6000 U of a recombinant fibrin-specific plasminogen activator, tenecteplase, was administered, according to the dosing regimen used for acute myocardial infarction. Fibrinogen levels were closely monitored. Subsequently, continuous infusion of UFH was initiated for a target partial thromboplastin time 50–70 s. Oral anticoagulation was administered on the following day. Another transthoracic echocardiogram performed 24 h after infusion revealed marked lysis of thrombus that resulted in a decreased peak pressure gradient of 32 mmHg. Left ventricular ejection fraction had increased to 50%. The patient's symptoms resolved over the next two days. Heparin infusion was discontinued when the INR reached a level of 3. The patient was discharged on his previous medication. One month later he presented at the outpatient clinic in sinus rhythm complaining of intermittent claudication type IIa affecting the left leg. Digital subtraction angiography revealed embolic obstruction of the left anterior and posterior tibial arteries that was attributed to the recent thrombolytic treatment. He was managed conservatively, after consulting the vascular surgeons, with subsequent improvement. During a six-year period of follow-up he remains asymptomatic in good clinical condition. Repeat serial echocardiographic examination performed annually revealed normal prosthetic valve function.
Implantation of a mechanical valve in contact with the bloodstream exposes the patient to a continual risk of valve thrombosis and embolism. This risk is increased, especially in the first three to six months after implantation [5]. This phenomenon is multifactorial. Inherent vascular disease may predispose to stasis and thrombus formation. Lack of endothelization of the raw valve surfaces promotes platelet aggregation. Additionally, inconsistencies in anticoagulation management during that period of increased thrombogenicity can contribute to early thromboembolism [6]. The optimal approach to early postoperative anticoagulation after mechanical valve replacement remains controversial. Guidelines in this area include the European Association for Cardio-thoracic Surgery (EACTS) guidelines [7] and the American Heart Association/American College of Cardiology (AHA/ACC) guidelines of 2008 [8], the European Society of Cardiology (ESC) valve guidelines of 2007 [9], the American College of Chest Physicians (ACCP) valve guidelines of 2008 [10], the British Society of Haematology guidelines [11], the Canadian Cardiovascular Society [12] and the Scottish Intercollegiate Guidelines Network (SIGN) guidelines [13]. Reports exist for long-living mechanical valves, especially in the aortic position, functioning properly without anticoagulation [14]. All these groups have focused on long-term anticoagulation after mechanical valve replacement, whereas there is little objective evidence supporting strategies for the management of anticoagulation in the early postoperative period [6]. The ACCP has formed the most recent and comprehensive guidelines on this area, published in 2008, and suggests administration of intravenous UFH or subcutaneous LMWH in patients immediately following mechanical valve replacement, as dictated by clinical concerns regarding postoperative bleeding, until the INR is at a therapeutic level for two consecutive days [10]. This is a grade 2C recommendation. The rationale supporting this strategy is based on the premise that initiating warfarin without simultaneous therapeutic heparin, could eventually promote thrombosis in situations of high thrombotic risk. The anticoagulant effect of warfarin is attained by blocking the activation of the intrinsic clotting factors VII, IX, X and II. However, warfarin exerts a paradox procoagulant effect, caused by blocking the activation of endogenous anticoagulants, protein C and protein S. Over time, treatment with warfarin results in reduced concentrations of all these factors in the circulation [15]. Proteins C and S have a short half-life of 8 and 30 h, respectively, whereas factor X and factor II have a half-life of 36 and 70 h, respectively. Therefore, proteins C and S are depleted shortly after the initiation of warfarin. This results in a transient hypercoagulable state in the first one or two days of warfarin therapy [16]. A rare serious manifestation of this phenomenon is described as warfarin-induced skin necrosis and involves thrombosis of small subcutaneous vessels manifesting clinically as cutaneous gangrene [17]. Moreover, recent evidence suggests that anticoagulant and antithrombotic effects of oral anticoagulants can be dissociated. Reduction in prothrombin (factor II) and factor X are more important than reductions in factors VII and IX for exerting an antithrombotic effect [18]. A rapid increase in INR observed during the first two days of warfarin therapy, reflects the reduction of factors VII and IX due to their short half-lifes. This forms the basis for overlapping treatment with heparin for at least two days of a therapeutic INR. Regarding the safety and efficacy of a combined anticoagulation strategy, a systematic review by Kulik published in 2006 suggests that the use of UFH in the early postoperative period, compared with the use of oral warfarin alone, yields a substantially higher risk of bleeding without reducing the risk of thromboembolism [6]. Few studies have evaluated the efficacy of LMWH in combination with oral warfarin [19, 20]. In a recent study, Steger and colleagues evaluated a low-dose scheme with 40 mg of enoxaparin twice daily administered subcutaneously for a mean of 6.7 days postoperatively combined with warfarin. They observed a 7% rate of minor bleeding and 0.7% of thrombosis [21]. Further prospective randomized studies are required to provide solid evidence for the best treatment option. Fibrinolytic therapy was chosen as a first treatment option considering the recent formation of thrombus and the stable clinical status at presentation [22]. Surgical management was reserved in case of failure of fibrinolytic treatment. Optimal management of PVT remains controversial. Lengyel and coworker consider thrombolysis as the first-line treatment for obstructive PVT, independent of NYHA class and thrombus size, if there are no contraindications [23]. On the other hand, in a recent series of 210 patients reported by Roudaut, surgical treatment was associated with significantly better long-term results in terms of recurrence and mortality and a lower incidence of embolic complications, which reached 15% in the fibrinolysis group [24]. In conclusion we consider that, in the presented clinical setting, ‘bridging’ anticoagulation therapy with either UFH or LMWH was indicated in order to provide a rapid anticoagulant effect until oral anticoagulation reached a therapeutic value. The major concern against applying this combined protocol is the risk of bleeding, which is significant during the early postoperative period. The paradoxical transient procoagulant effect of vitamin K antagonists should be kept under consideration when initiating oral anticoagulant therapy after mechanical valve replacement.
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Abstract
1. Introduction