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Ann Thorac Surg 2003;76:1593-1597
© 2003 The Society of Thoracic Surgeons

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Original article: cardiovascular

Coagulation monitoring and management of anticoagulation during cardiac assist device support

^a department of Anesthesia and Intensive Care Medicine, University of Innsbruck, Innsbruck, Austria
^b department of Pediatrics, University of Innsbruck, Innsbruck, Austria
^c department of Cardiac Surgery, University of Innsbruck, Innsbruck, Austria

Accepted for publication June 4, 2003.

^* Address reprint requests to Dr Fries, Department of Anaesthesia and Intensive Care Medicine, University of Innsbruck, Anichstr. 35, 6020 Innsbruck, Austria.
e-mail: dietmar.fries{at}uibk.ac.at

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
BACKGROUND: The incidence of clinically significant thromboembolic events due to the use of cardiac assist device systems remains high. Despite the considerable advances in cardiac assist device technology, the monitoring and management of the hypercoagulable coagulation status, resulting from foreign surfaces of the assist device system, altered rheologic conditions, and blood stasis in the recipient heart remain a challenge. Moreover septic complications and insufficient anticoagulation are responsible for thromboembolic events.

METHODS: In addition to standard coagulation analysis, functional coagulation tests were performed including the use of a thrombelastographic monitoring system (ROTEG) and a platelet function analyzer (PFA-100).

RESULTS: Severe biventricular ischemic heart failure developed in a 58-year-old man with acute myocardial infarction and he needed a biventricular assist device for a bridge to cardiac transplantation. Although the patient received acenocoumarol (Sintrom; Novartis Pharma, Vienna, Austria) and acetylsalicylic acid (Aspisol; Bayer AG, Leverkusen, Germany) as usual, ROTEG and the PFA-100 detected hypercoagulability while routine coagulation screening tests showed hypocoagulability. Moreover thrombus formation surrounding the canula of the left ventricular assist device was detected. Antithrombotic therapy with clopidogrel (Plavix) was initiated. Coagulation was closely monitored with modified thrombelastography and the PFA-100 to achieve sufficient but not overwhelming anticoagulation therapy. Three months after biventricular assist device implantation the patient underwent successful transplantation with no major blood loss.

CONCLUSIONS: Thrombelastography should be the standard form of monitoring in such patients to decrease the risk of thromboembolic events and prevent bleeding complications.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Cardiac transplantation has become an established therapy in the treatment of end-stage heart failure. Mechanical circulatory support has been introduced to bridge patients to cardiac transplantation. Despite considerable improvements in hemodynamic function, thromboembolism is still a feared complication during their use [1–3]. Because the mechanism of these thromboembolic events is poorly understood no definitive guidelines for anticoagulation therapy are available. Despite all efforts to achieve effective anticoagulation the risk of thromboembolic events is approximately 30% [4]. The main reasons are the contact between blood components and the foreign surfaces of the assist device system and altered rheologic conditions with different velocities of blood flow and blood stasis in the recipient heart [5]. Furthermore the native heart itself represents a source of thromboembolism. Clots may form in ventricles having poor contractile function, in the case of atrial fibrillation, and on artificial valves. Septic complications and insufficient anticoagulation are also responsible for thromboembolic events.

Embolism in these patients mainly affects the brain. Schmid and associates [6] pointed out that cerebral embolism was clinically evident in 47% of 36 observed patients over a mean period of 109 ± 88 days. In contrast to thromboembolic complications only a few reports exist about bleeding complications. McBride and associates [7] documented a 31% incidence of bleeding complications in 111 patients with biventricular assist device systems.

This report summarizes the divergence between a standard laboratory coagulation analysis used to predict hypocoagulable state and a thrombelastographic monitoring system (ROTEG) for detecting a hypercoagulable situation in a patient with a biventricular assist device. Adequate anticoagulation was achieved with the administration of clopidogrel (Plavix; Sanofi Pharma, Vienna, Austria). The patient underwent successful transplantation on this medication with no increased bleeding tendency.

	Material and methods

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Thrombelastography
Thrombelastography assesses coagulation not only by determining the time to initiation of clot formation and final clot formation but also by continuously analyzing clot firmness, which results from multiple interdependent processes: coagulation activation, thrombin formation, fibrin formation and polymerization, platelet activation and platelet-fibrin interaction [8]. An advantage of thrombelastography tests is that they show not only hypocoagulopathy but also hypercoagulopathic coagulation.

The ROTEG Coagulation Analyzer (Pentapharm, Munich, Germany) is a new instrument that operates on the principles of thrombelastography [9]. The detection system of the ROTEG, unlike that of the conventional thrombelastography, is guided by a ball-bearing that eliminates susceptibility to mechanical stress, movement, and vibration. An automatic pipetting system facilitates and standardizes test performance in the bedside setting. Furthermore activation of test samples accelerates measurement and appears to enhance reproducibility as compared with conventional thrombelastography analysis [10]. The measurements of ROTEG analysis are coagulation time corresponding to the reaction time in a conventional thrombelastography, clot formation time in accordance with the coagulation time, and maximum clot firmness, which is equivalent to the maximum amplitude.

The platelet function analyzer
The Platelet Function Analyzer-100 (PFA-100 [Dade/Behring, Marburg, Germany]) assays hemostatic function of whole blood under shear stress conditions. The instrument assesses platelet-dependent hemostasis in vitro by aspirating citrated blood through a capillary, similar to blood flow in a capillary in vivo. Coagulation is prompted on membranes coated with collagen/epinephrine (EPI) or collagen/adenosin diphosphate (ADP). The time needed for a clot to close a 150 µm aperture in the membrane is defined as the closure time. The range of normal values in our laboratory range is 85 to 165 seconds (EPI coagulation time) and 62 to 100 seconds (ADP coagulation time) [11]. The PFA-100 is able to detect deterioration of platelet adhesion caused by acetylsalicylic acid administration [12].

Laboratory measurements
Fibrinogen, hemoglobin value, and platelet cell count were determined by standard laboratory methods. Further analyzed were prothrombin time (PT, Thromborel S; Dade Behring, Marburg, Germany) and partial thromboplastin time (PTT, Pathrombin SL; Dade Behring) antithrombin (Antithrom Stago; Boehringer, Mannheim, Germany), factor VIII (turbidimetric test; Dade Behring, Marburg, Germany), factor XIII (Berichrom, PCS method; Dade Behring), Ristocetin-Co-Factor activity (Rist-CoF agglutination test; Dade Behring), von Willebrand factor (latex agglutination test; Roche Diagnostics, Mannheim, Germany), and D-dimer (LIA-latex agglutination; Roche Diagnostics).

	Results

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Case report
A 58-year-old man with previously recognized coronary artery disease and hypercholesterolemia sustained an acute coronary syndrome. Acute percutaneous transluminal coronary angioplasty with stenting of the left coronary artery was performed. Despite stenting, continuous application of dobutamin and noradrenalin, and insertion of an intraaortal balloon pump circulatory stabilization was not achieved. He was connected to an extracorporal membrane oxygenation system on the same day [13].

During the following 3 days myocardial function did not recover and a biventricular assist device (BIVAD [Thoratec Laboratories, Pleasanton, CA]) was implanted. Postoperative course was complicated by pulmonary and renal deterioration.

Initially the patient received anticoagulation therapy with unfractionated heparin (Heparin-Immuno; Baxter, Vienna, Austria). This treatment was followed by administration of acenocoumarol (Sintrom; Novartis Pharma, Vienna, Austria) 2 weeks after implantation of the BIVAD at a target international normalized ratio (INR) of 4.0 combined with 250 mg acetylsalicylic acid (Aspisol; Bayer AG, Leverkusen, Germany). Three weeks after BIVAD implantation partial thromboplastin time increased from initially 27 seconds to 73 seconds although heparin therapy had been discontinued 1 week before (Table 1). As the reason for this partial thromboplastin time increase was unclear, ROTEG analysis was performed. In contrast to our assumptions we detected an extremely hypercoagulable coagulation status. Clotting times (coagulation time and clot formation time) were short and maximum clot firmness was increased to about 80 mm (normal value 55 to 74 mm; Figs 1 and 2). In addition we used the PFA-100 to also analyze primary hemostasis: although the patient received acetylsalicylic acid, closure times were not prolonged (Fig 3). Clinically a large thrombus surrounding the canula of the left ventricular assist device was detected by transesophageal echocardiography.

View larger version (29K): [in this window] [in a new window]   Fig 1. Thrombelastographic monitoring system (ROTEG) analysis: maximum clot firmness (squares; in mm) and alpha angle (diamonds) from 23 days after biventricular assist device system implantation until 1 week after heart transplantation. After introducing therapy with clopidogrel, maximum clot firmness and alpha angle decreased to normal values. (TX = treatment.)

View larger version (35K): [in this window] [in a new window]   Fig 2. Results of platelet function analyzer examinations after biventricular assist device system implantation as well as after heart transplantation. Collagen/epinephrine coagulation time (CT) and adenosin diphosphate-CT were in the normal range despite aspirin therapy. Clotting times increased after introducing therapy with clopidogrel. Values normalized after heart transplantation was performed and clopidogrel therapy was terminated. (alp = alpha angle; CFT = clot formation time; EXTEG = thrombelastastographic analysis, activated with tissue thromboplastin; MCF = maximum clot firmness; roTEG = thrombelastic monitoring system.)

View larger version (31K): [in this window] [in a new window]   Fig 3. Demonstration of coagulation management over the whole period of treatment. (EPI-CT = collagen/epinephrine coagulation time [diamonds]; ADP-CT = coagulation time [squares].) (TX = treatment.)

Three months after BIVAD implantation, heart transplantation was successfully performed: 2,000 IE prothrombin complex (Beriplex; Aventis Behring, Marburg, Germany) was administered to compensate for oral anticoagulation (acenocoumarol [Sintrom]; Novartis Pharma, Vienna, Austria). In addition two therapeutic units of platelet concentrates and 15 µg desmopressin (Octostim; Ferring, Vienna, Austria) were needed to attain sufficient primary hemostasis preoperatively. Under these conditions PFA-100 ADP coagulation time dropped from 254 to 86 seconds (Fig 3). Coagulation management during surgery was monitored with ROTEG and the PFA-100. In total the patient received two further platelet concentrates, 15 U of fresh frozen plasma, 0.5 g tranexamic acid (Cyclocapron; Pharmacia Austria), and 1 g fibrinogen (Hemocompletan; Aventis Behring) during surgery. Coagulation monitoring and management were clinically efficient. Only 6 U of red cell concentrates were needed to maintain adequate hemoglobin concentrations.

After cardiac transplantation the patient was weaned uneventfully within a few days. The postoperative course was uncomplicated and the patient recovered very quickly. Control thrombelastography measurements 1 week after transplantation were within the normal range without any detectable signs of hypercoagulability while the patient received only 40 mg of low molecular weight heparin (enoxaparin [Lovenox]; Gerot, Pharmazeutika, Vienna, Austria) as thrombosis prophylaxis (Figs 1 and 2). The patient was transferred from the intensive care unit to the normal ward 6 days after transplantation (Fig 4).

View larger version (22K): [in this window] [in a new window]   Fig 4. Thrombelastographic monitoring system (ROTEG) tracing 23 days after biventricular assist device (BIVAD) implantation and 1 week after heart transplantation: detection of a hypercoagulable coagulation status by early onset and high amplitude on day 23 after BIVAD implantation; decrease in maximum clot firmness; and alpha angle back to normal values after heart transplantation. (ECMO = extracorporeal membrane oxygenation; LMW = low molecular weight; PFA = platelet function analyzer; TX = treatment.)

	Comment

Top Abstract Introduction Material and methods Results Comment References

Recently Schmid and associates [6] observed that standard coagulation monitoring fails to detect a hypercoagulable state in patients with cardiac assist device systems. They visualized microembolic signals using serial transcranial Doppler sonography and on days with clinically manifest embolism demonstrated that the number of microembolic signals was significantly increased. However the presence of elevated microembolic signals did not correlate with partial thromboplastin time and INR measurements [6]. Nabavi and associates [14] were also not able to identify a relationship between clinically manifest thromboembolic events and coagulation screening tests in patients with ventricular assist devices.

To achieve sufficient but not overwhelming anticoagulation, close and accurate but also practicable coagulation monitoring is essential. Most centers perform only standard coagulation screening tests (prothrombin time, partial thromboplastin time, serum fibrinogen, and platelet count) in patients treated with cardiac assist device systems. These tests were not suitable to detect the hypercoagulable state in our patient. The prothrombin time and partial thromboplastin time tests are in vitro tests developed to identify bleeding tendency. These tests provide no information on clot quality or hypercoagulability. Elevated serum fibrinogen levels are a well-known risk factor for occlusive arterial vessel diseases but in our patient fibrinogen was only moderately increased in the initial weeks after cardiac assist device implantation.

However the BIVAD support served as an acquired source of hypercoagulopathy and overshadowed all other known risk factors for developing thromboembolic complications. In this clinical situation the measurement of individual clotting factors including von Willebrand factor, factor VIII, antithrombin, and fibrinogen was of limited value. Antithrombin was constantly in the normal range while von Willebrand factor, factor VIII, and fibrinogen and also D-dimer were always seen to be elevated until transplantation was performed (Table 1). A product of plasmin-mediated proteolysis of fibrinogen, D-dimer is often used to exclude the diagnosis of venous thromboembolism. Elevated D-dimer levels are found under many clinical conditions including cardiac assist device support [15]. Therefore the specificity of the test is very low and may not be useful when monitoring anticoagulation therapy in a patient supported by a cardiac assist device system. Sensitive assays that detect thrombin action on fibrinogen are available for clinical use. These assays include prothrombin fragment 1+2. However these tests are not routinely available at our institution.

Platelet counts provide no information on platelet activation. Dewald and associates [16] scanned platelets by electron microscopy to detect alterations in morphology during the period of ventricular assist device support. The mean level of activated platelets increased significantly after 4 days and between day 14 and day 35 in that study.

In contrast to these standard measurements thrombelastography detects the velocity of clotting as well as the quality and firmness of the clot. It is therefore a reliable screening tool for detecting hypercoagulability [17]. Various authors have mentioned the advantages of thrombelastography monitoring in connection with the complex impact of ventricular assist device systems on the coagulation system [18].

While the plasmatic coagulation system was inhibited by acenocoumarol, increased activity of platelets may explain the hypercoagulability seen in our patient. Since acetylsalicylic acid failed to inhibit platelet activity as detected by the PFA-100 we decided to administer an effective platelet antagonist. The use of clopidogrel in patients with BIVAD has not been described in the literature to date. A major complication of clopidogrel is an increased tendency to bleed. In this case our patient sustained one episode of bleeding, which stopped without surgical intervention or discontinuation of anticoagulation treatment.

Bleeding tendency in the case of BIVAD explantation and cardiac transplantation is a life-threatening complication and a frequent problem. Three months after BIVAD implantation, heart transplantation was performed without any bleeding problems. To achieve a coagulation status sufficient for this major surgical procedure we performed ROTEG and PFA-100 analysis before, during, and after transplantation. The effect of clopidogrel was eliminated by transfusing platelet concentrates and administering desmopressin, while the effect of oral anticoagulation treatment was reversed by administering prothrombincomplex concentrates. As mentioned above our patient needed only 6 U of red blood cell concentrates. The blood loss during surgery was only about 50% to 60% of the calculated total blood volume, which was well within the expected range.

From our experience and a review of the literature [6, 14, 16] we can state that standard coagulation monitoring fails to detect hypercoagulability or to monitor appropriate anticoagulation treatment in patients with ventricular assist devices. Thrombelastographic monitoring is a sensitive technique for the detection of hypercoagulability and is easy to practice with the newly developed ROTEG system. We agree with other authors that thrombelastography should become the standard for monitoring in such patients in order to decrease the risk of thromboembolic events and prevent bleeding complications. ([19, 20])

Further clinical studies needed to demonstrate whether clopidogrel and other platelet antagonists such as GpIIb/IIIa antagonists are able to decrease the risk of thrombembolic events in patients with cardiac assist device systems.

	References

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