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Ann Thorac Surg 2001;72:714-718
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

Warfarin therapy does not increase bleeding in patients undergoing heart transplantation

^a Division of Cardiothoracic Surgery, Joseph B. Whitehead Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
^b Department of Anesthesia, Emory University School of Medicine, Atlanta, Georgia, USA
^c Division of Cardiology, and Department of Internal Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
^d Departments of Anesthesiology, Pathology, and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA

Accepted for publication May 9, 2001.

Address reprint requests to Dr Vega, The Emory Clinic, 1365 Clifton Rd, Atlanta, GA 30322
e-mail: david_vega{at}emory.org

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Historically, warfarin has been discontinued or rapidly reversed with fresh frozen plasma in patients awaiting heart transplantation because of concerns regarding excessive bleeding. Because preoperative warfarin may have effects on bleeding after cardiac operations, we reviewed our experience to determine the risks in patients undergoing heart transplantation while maintained on warfarin.

Methods. The records of consecutive adult patients undergoing heart transplantation from January 1996 to December 1998 were reviewed. Preoperative and 24-hour postoperative data were obtained, including patient demographics; hematologic laboratory values; medication use; repeat or primary sternotomy data; allogeneic blood product administration; and chest tube drainage. Multivariate linear and logistic regression analyses were performed using these variables to determine risk factors for bleeding after heart transplantation.

Results. Ninety adult patients, mean age 50 years, underwent orthotopic heart transplantation during the 36-month period. No relationships existed between preoperative international normalized ratio (INR, mean = 1.83 ± 0.1, p = 0.84) or postoperative INR (mean = 2.2 ± 0.9, p = 0.63) and chest tube drainage (mean = 721 ± 63 mL). Relationships were observed between total blood product administration and preoperative INR (partial r = 0.30, p = 0.01) and postoperative INR (partial r = -0.37, p = 0.002); however, preoperative INR did not correlate (p = 0.29) when perioperative use of fresh frozen plasma was factored as a covariate. Inverse relationships were evident between postoperative INR and total blood product exposures, as well as transfusions of platelets (partial r = -0.26, p = 0.03), fresh frozen plasma (partial r = -0.28, p = 0.02), and red cells (partial r = -0.25, p = 0.04).

Conclusions. Although we noted no correlations between INR and chest tube output, inverse relationships were observed with transfusion requirements in the first 24 hours after transplantation. Preoperative warfarin may be safely continued in patients awaiting heart transplantation.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Warfarin therapy in patients awaiting heart transplantation (HT) reduces mortality and stroke rates. The incidence of thromboembolism in patients with left ventricular dysfunction due to cardiomyopathy is as high as 18% to 20% [1, 2]. Because of the potential for excessive bleeding, warfarin therapy in patients accepted for HT has historically been changed to heparin upon hospital admission [3, 4]. However, there is limited information about the influence of warfarin on bleeding during and after HT [5, 6].

Excessive bleeding is a persistent issue in HT due to multiple factors including platelet dysfunction caused by an intrinsic or extrinsic platelet defect [5, 7–9]. The administration of large doses of heparin has been shown to contribute to this platelet defect, as well as to the hyperfibrinolysis occurring during cardiopulmonary bypass (CPB) by an incomplete inhibition of thrombin [5, 8, 10]. Warfarin therapy appears to reduce CPB-induced coagulopathy by virtue of its ability to potentially provide more complete inhibition of thrombin [5, 7]. Preoperative heparin therapy has side effects or limitations including increased platelet reactivity, heparin resistance, and heparin-induced thrombocytopenia [3, 11–13]. On the basis of these concerns, our practice has been to maintain patients on warfarin therapy until HT regardless of United Network of Organ Sharing status with a target international normalized ratio (INR) of 2.0. Therefore, we reviewed our data from patients to evaluate the risks of bleeding and transfusion requirements in patients undergoing HT while maintained on warfarin.

	Material and methods

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The medical records of 90 consecutive adult patients undergoing orthotopic HT from January 1996 to December 1998 were reviewed. Immediately before transplantation, the next dose of warfarin was held if possible, and the patient was given 30 mg of vitamin K if the INR was more than 1.2. In most patients, preoperative heparin was omitted.

All patients underwent median sternotomy after standard anesthetic techniques were used, including fentanyl, pancuronium, and isoflurane when appropriate. Before skin incision, aprotinin or Epsilon Amino Caproic Acid (EACA) was started in most patients. After pericardiotomy, the patients were given heparin (400 U/kg) with bovine mucosal heparin to achieve an activated clotting time of more than 400 seconds, and the CPB circuit was primed with 10,000 U of heparin. Additional heparin, 100 U/kg, was administered every hour during CPB in aprotinin-treated patients, and kaolin activated clotting times were monitored. For orthotopic HT, standard aortic and bicaval cannulation were performed. The CPB was initiated, and the patient was cooled to 32°C. Implantation of the donor heart proceeded according to the technique described by Shumway and colleagues [14]. Rewarming was initiated during the pulmonary artery anastomosis. The aortic cross-clamp was removed, and lidocaine was administered. The usual air removal techniques were used. Isoproterenol was started, and the patient was weaned from CPB. Cannulas were removed, pacing wires were placed, and the patient was closed after reversal of heparin with protamine, normalization of activated clotting time, and achievement of hemostasis.

All patients received standard triple drug immunosuppressive therapy: cyclosporine, azathioprine, and steroids. Extubation occurred typically within 8 to 12 hours, and chest drains were removed when the output decreased to less than or equal to 150 mL/d. Blood product transfusion occurred based on variable clinical, hemodynamic, and laboratory findings.

The following preoperative and 24-hour postoperative data were recorded: warfarin, aspirin, ticlopidine, and heparin use; patient age, sex, and body surface area; INR; prothrombin time; platelet counts; blood product administration (including packed red blood cells, platelets, fresh frozen plasma [FFP], and cryoprecipitate); and chest tube output (CTO). The CPB times, aprotinin or EACA use, and primary or repeat sternotomy data were also recorded.

To determine whether warfarin had any relationship with postoperative bleeding and blood product administration, and to identify other factors potentially associated with these issues, univariate and multivariate linear regression analyses using a stepwise backward elimination process were performed using all recorded variables. A multivariate logistic regression analysis using a stepwise backward elimination process was used to determine variables significant for excessive postoperative bleeding, defined as more than 1,000 mL of blood loss within the first 24 hours after HT. Also, we compared EACA versus aprotinin usage, as well as primary versus repeat sternotomy with CTO and product administration in the first 24 hours postoperatively as end points, using the Student’s t test. p values less than 0.05 were termed significant, and results were expressed as mean ± standard error of the mean.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
A total of 90 adult patients underwent orthotopic HT during the 36-month period, January 1996 to December 1998, which included four heart/kidney transplants, and six repeat HTs. Thirty-four patients had repeat sternotomies. The age was 50 ± 1 years, with a range of 21 to 64 years. Seventy-four (82%) patients were taking warfarin, and the preoperative INR for all patients was 1.83 ± 0.1 with a range of 0.9 to 5.7. The mean postoperative INR for all patients was 2.2 ± 0.9. Eight (8.9%) patients were maintained on preoperative heparin, and three of these patients were also on warfarin at the time of operation.

The blood product administration for all patients at 24 hours included 3.0 ± 0.3 U of packed red blood cells, 0.68 ± 0.1 U of platelets, 2.2 ± 0.3 U of fresh frozen plasma, and 0.31 ± 0.1 U of cryoprecipitate. The mean total number of blood products at 24 hours was 6.2 ± 0.7 U (Fig 1). Seventeen (19%) patients did not receive any blood products within the first 24 hours. The mean initial 24 hour CTO (CTO/24 hours) was 721 ± 63 mL (Fig 2). Fifty-nine patients (66%) received aprotinin and 26 patients (29%) received EACA. Five (5.6%) patients received no hemostatic agents. Twenty-two (24%) patients were taking aspirin, and only 1 patient (1%) was taking ticlopidine preoperatively. Three (3.3%) patients required exploration for excessive bleeding. The mean CPB time was 139 ± 4 minutes.

View larger version (28K): [in this window] [in a new window]   Fig 1. The mean number of units of various blood products administered in the first 24 hours after heart transplantation; p < 0.05, Student’s t test. (ALL PTS = all 90 patients; CRYO = cryoprecipitate; FFP = fresh frozen plasma; PLTS = platelets; PRBC = packed red blood cells; TOTAL = total blood products.)

View larger version (28K): [in this window] [in a new window]   Fig 2. The mean chest tube output in the first 24 hours after heart transplantation in cubic centimeters. Patients with repeat (redo) sternotomies had greater chest drainage in the first 24 hours postoperatively than patients with primary sternotomies; p < 0.05, Student’s t test. (ALL PTS = all 90 patients; EACA = -aminocaproic acid.)

View larger version (17K): [in this window] [in a new window]   Fig 3. No relationship between postoperative international normalized ratio (INR) and amount of cumulative chest tube output in the first 24 hours (in milliliters) after heart transplantation by multivariate linear regression analysis (p = 0.49).

Inverse relationships were evident between postoperative INR and total product administration, as well as transfusions of platelets (partial r = -0.26, p = 0.03), FFP (partial r = -0.28, p = 0.02), and red cells (partial r = -0.25, p = 0.04). Variables associated with perioperative transfusion of red cells, FFP, or platelets are summarized in Table 1. The complete predictive model (r² = 0.69, p < 0.0001) for red cell transfusion yielded: . The complete predictive model (r² = 0.59, p < 0.0001) for FFP transfusion yielded: . The predictive model (r² = 0.69, p < 0.0001) for platelet transfusion yielded: .

Excessive bleeding (> 1,000 mL/first 24 hours) occurred in 15 (17%) patients. Table 2 summarizes the three variables associated with more than 1,000 mL blood loss in the first 24 hours (receiver operating characteristics area = 0.83): aspirin use and preoperative and postoperative platelet counts.

	Comment

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It is generally suggested that warfarin therapy in the preoperative setting is a risk factor for excessive bleeding, and that warfarin should be stopped 3 to 5 days before operation in favor of heparin [3–5]. However, this practice should be questioned for a number of reasons. First, many patients are awaiting their transplants while at home, and they arrive to the hospital only hours before transplantation. Second, some studies have suggested that preoperative heparin causes increased postoperative bleeding [8, 10], although this finding has not been universal [21]. One mechanism for increased bleeding with preoperative heparin therapy is increased fibrinolysis compared to preoperative warfarin [3, 5, 8, 10, 11]. Furthermore, Dietrich and colleagues [10] suggest that preoperative warfarin derivatives may preserve hemostatic systems, and that this may relate to better clinical outcomes. In a recent study, they compared patients undergoing cardiac operations receiving phenprocoumon (a warfarin analogue), intravenous heparin, and subcutaneous heparin. D-Dimer levels, as markers of fibrinolytic activity, were highest in the heparin-treated groups and lowest in the warfarin analogue-treated patients. The warfarin analogue-treated patients also demonstrated less hemostatic activation during CPB, and better platelet preservation [5, 10]. This study also revealed a trend toward reduced postoperative bleeding in patients who received the warfarin analogue. Our findings support these observations.

In addition, antithrombin III levels are abnormally low in patients being treated with long-term heparin [5, 7]. Lower antithrombin III levels cause heparin resistance or tachyphylaxis, as higher doses are required to achieve a desired level of anticoagulation [10]. In the study by Dietrich and colleagues [10], patients who received the preoperative warfarin analogue maintained significantly higher antithrombin III activity than did patients treated with preoperative heparin. The patients with lower antithrombin III activity before operation were more likely to exhibit increased heparin consumption, and they required higher doses of heparin. Consequently, higher doses of protamine were also needed for reversal [10].

Platelet dysfunction resulting from CPB is also a major factor for hemostatic dysfunction occurring after cardiac operation [8, 9, 15–17]. Heparin’s inability (ie, at lower levels consistent with activated clotting time-based dosing methods) to completely inhibit thrombin generation and activity and plasmin generation may contribute to the platelet dysfunction [11]. Other recent studies indicate that this limitation may be overcome by maintenance of higher, patient-specific heparin concentrations during CPB [22, 23]. Thrombin initiates fibrin formation, but it also activates tissue plasminogen activator, which generates plasmin release [5]. Plasmin, the enzyme responsible for initiating fibrinolysis, is a direct inhibitor of platelets [18]. Thrombin and plasmin both activate platelet release reactions, and plasmin inactivates platelet membrane receptors supporting a bleeding tendency [11, 18]. Greater reduction in thrombin (and presumably plasmin) formation occurred in patients treated with a warfarin derivative versus patients given heparin, and this may result in preserved platelet function after CPB [5].

In our patients, a higher postoperative INR was associated with less transfusion of blood products (Table 1). These data support the suggestions of Dietrich and associates that (1) an increased INR does not result in increased bleeding and transfusion and (2) that warfarin usage may actually reduce bleeding after cardiac operation by suppressing thrombin-mediated consumption of platelets and coagulation factors [5, 10].

Most of our patients also received either aprotinin or EACA. These agents decrease intraoperative and postoperative blood loss during cardiac operation and HT by preserving platelet membrane receptors, decreasing the accumulation of fibrin products, and blocking the action of kallikrein [5, 11, 17–20]. The use of these agents also contributes to decreased bleeding and blood product administration [18–20].

Our retrospective study demonstrates the safety of continuing warfarin anticoagulation in patients awaiting HT up until the hour of transplant, and further supports a previous report by Karck and Haverich [3]. The prolonged INR of these warfarin-treated patients had no impact on chest tube drainage or blood product administration [3]. In addition, our study demonstrates that not only does increased INR secondary to warfarin administration not result in increased postoperative bleeding and transfusion after HT, but that warfarin may reduce bleeding and blood product exposure based on preservation of blood coagulation proteins and platelets secondary to enhanced anticoagulation. In summary, based on our study, the historic practice of discontinuing preoperative warfarin treatment before HT is not warranted.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Kirk R. Kanter Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morris, C. D. Articles by Kanter, K. R. Search for Related Content PubMed PubMed Citation Articles by Morris, C. D. Articles by Kanter, K. R. Related Collections Transplantation - heart