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Recombinant Human Coagulation Factor VIIa in Jehovah's Witness Patients Undergoing Liver Transplantation

Indisputably, liver transplantation is among the most technically challenging operations in current practice and is compounded by significant coagulopathy and portal hypertension. Recombinant human coagulation factor Vila (rFVIIa) is a new product that was initially described to treat bleeding in hemophilia patients. We present in this paper 10 liver transplants in Jehovah's Witness patients using this novel product at University of Southern California-University Hospital. The subject population included nine males and one female with an average age of 50 years. Six patients underwent cadaveric and four live donor liver transplantation. Surgeries were conducted following our established protocol for transfusion-free liver transplantation, which includes preoperative blood augmentation, intraoperative blood salvage, acute normovolemic hemodilution, and postoperative blood conservation. Factor rFVIIa was used at a dose of 80 g/kg intravenously just prior to the incision in all patients, and a second intraoperative dose was used in 3 patients. All living donor liver transplantation (LDLT) recipients did well and were discharged uneventfully with normal liver functions. Two of the six cadaveric recipients died. One patient died intraoperatively from acute primary graft nonfunction, and the other died 38 hours postoperatively from severe anemia. This report suggests factor rFVIIa might have a much broader application in surgery in the control of bleeding associated with coagulopathy.

THE JEHOVAH'S WITNESS POPULATION refuses blood products (PRBC, fresh frozen plasma, or platelets) for religious reasons. Because the liver is the principle site of synthesis and clearance of coagulation factors, coagulopathy is a hallmark of liver failure. Hemostatic abnormalities found in patients with liver failure include a prolonged prothrombin time, a reduced platelet count, and fibrinolysis. As a result of such considerations. Jehovah's Witness (JW) patients are a particularly challenging population for some major surgical procedures such as orthotopic liver transplantation (OLT).

Meticulous surgical techniques in combination with blood conservation techniques (such as acute normovolemic hemodilution [ANH], cell salvage, and the use of various prohemostatic agents such as aprotinin, aminocaproic acid) have been helpful in making it possible to conduct surgery without blood transfusions. In this paper, we document the use of a novel product (recombinant activated factor VIIa; rFVIIa) in the management of liver failure-related coagulopathy in 10 Jehovah's Witness patients undergoing liver transplantation.

Patients and Methods

This study was comprised of 10 patients, studied over a 2-year period from 2001 to 2003. The subject population was 9 males and 1 female, with an average age of 50 years. Six adults underwent cadaveric liver transplantation, whereas the remaining four received living donor liver transplantation (LDLT).

All patients were Jehovah's Witnesses with an advance directive refusing blood, fresh frozen plasma (FFP), and platelets even at the risk of their life. The same procedures and protocols were used for all patients to limit blood loss during the surgery. Such procedures included the use of preoperative blood augmentation with erythropoietin and iron. Intraoperative management included acute normovolemic hemodilution (ANH), cell savage, and the use of factor rFVIIa.

The protocol for ANH involved the removal of blood from the central line. The blood was removed via gravity flow to a citrate phosphate dextrose (CPDA) bag, which was stored at room temperature to preserve platelet function for up to 6 hours, while remaining in continuity with the patient. Intravascular euvolemia was maintained with 5 per cent albumin and crystalloids. Patient heart rates, blood pressure, pulmonary artery pressure, central venous pressure, and blood gases were monitored during ANH. All blood collected during this part of the procedure was reinfused after liver implantation, once blood loss was minimal. Cell salvage involved collecting all blood lost during surgery. The saved blood was washed and then reinfused.

Results

The clinical and biochemical profiles of the patients are presented in Tables 1 and 2. The indication for transplant was decompensating cirrhosis secondary to hepatitis C in 8 patients, alpha-1 antitrypsin deficiency in one patient, and cryptogenic cirrhosis in the last patient. The seventy of liver disease was measured by the Child Pugh score (mean [range] = 11 [9-14]) and the model of end stage liver disease (MELD) score (mean [range] = 21.9 [14-38]).

The mean preoperative hematocrit value was 37.9 (range, 26.9 to 47.3). The mean PT was 18.86 seconds (14.3-24.8) with a mean INR of 1.73. The platelet count ranged from 21 to 171, with a mean value of 69.9 10^sup 9^/L. The preoperative bilirubin measured from 1.3 to 33.1 with the mean of 8.45 mg/dL. The albumin level ranged from 1.9 to 4.0, with a mean of 2.88 gr/dL. Two patients were on dialysis preoperatively, one for hepatorenal syndrome and the second for end stage renal disease secondary to polycystic kidney disease. A third who was noted to have borderline kidney function was dialyzed intraoperatively to maintain euvolemia. A fourth patient with cirrhosis secondary to hepatitis C had associated hepatopulmonary syndrome, requiring 5 L of O2 via nasal cannula prior to transplantation.

TABLE 1. Clinical Data

The intraoperative data are presented in Table 3. Acute normovolemic hemodilution was used in 8 of the 10 patients. The average removal of blood was 3 units at the beginning of the surgery. In 2 patients, ANH was not performed due to the hemodynamic instability of the recipient. The cell saver was used in all patients. The mean operative time for both cadaveric and LDLT was 9 hours 17 min. The time taken for the live donors averaged 1 1 hours and was noted to be consistently longer because of the time coordination factor with the donor operation. The cadaveric transplantation mean time was 7 hours 47 minutes.

Recombinant factor VIIa was administered intravenously at 80 /kg body weight at the start of anesthesia. A second dose was administered 2 hours later (as deemed necessary by the operative surgeon) for persistent oozing suggestive of coagulopathy. A second dose was used in 2 of the 10 patients, and a third dose was used later during surgery in 1 patient. Recombinant factor VIIa was not used postoperatively in any of the patients.

Eight of the 10 patients tolerated the transplant well and were discharged in stable condition. One patient was readmitted 1 month after discharge with malaise, nausea, and vomiting. He was found to have a biloma and partial portal vein thrombosis. This particular patient had had a prior portacaval shunt, and the donor liver (right lobe) had two separate portal vein branches that were reconstructed on the back table using the patient's native internal jugular vein beyond the confluence of the facial vein. The patient was successfully treated with operative drainage of the biloma and an inferior mesenteric vein to a vena cava shunt.

One patient (no. 3) died intraoperatively from primary graft nonfunction of the transplanted liver. This patient also had significant azotemia secondary to hepatorenal syndrome, requiring preoperative and intraoperative dialysis. His starting hematocrit value was 26.9 per cent, and he had profound coagulopathy as reflected by a PT of 24.9 seconds and a platelet count of 34 10^sup 9^TL. The hepatectomy itself was performed with less than 100 cc of blood loss, but following reperfusion, the patient became fibrinolytic and severely coagulopathic. A second patient (no. 5) listed for a simultaneous liver and kidney transplant was also coagulopathic (PT 16.2 seconds) and severely thrombocytopenic with a platelet count of 21,000 at the time of transplant. She later died on the second postoperative day from severe anemia secondary to persistent raw surface ooze associated with the coagulopathy.

TABLE 2. Preoperative Laboratory Data

TABLE 3. Intraoperative Blood Management

Immunosuppression protocols were similar to those used for our non-JW patient population and were primarily a three-drug regimen consisting of tacrolimus, mycophenolate mofetil, and prednisone.

Discussion

Recombinant factor rFVIIa was originally developed to treat bleeding in hemophilia patients with inhibitors.1,2 This hemostatic product is a recombinant protein derived from transfected hamster kidney cells. The amino acid sequence and biological activity of rFVIIa are identical to human activated FVIIa.3 The in vitro effects and clinical applications of rFVIIa have been described in a variety of published reports.4-6 It has been used to correct coagulation disorders prior to invasive procedures in patients with bleeding diasthesis7 and in major surgery such as cardiac,8 pancreatic,9 and orthopedic,10 and in the settings of liver disease11,12 or trauma.13

Although the current study focuses on this small group of patients, it addresses the broader issue of reducing use of blood products in surgical patients. Although the concept of transfusion- free surgery has been primarily limited to JW patients, \more recently the risk of transmission of diseases such as hepatitis C, HIV, mad cow disease, and West Nile virus have stirred a general caution about liberal usage of blood products. An interest in the field of transfusion-free surgery has been slow to develop in the surgical discipline, despite the fact that more than 50 per cent of transfused blood is administered by surgeons. This report illustrates how careful decision making and the use of newly developed products in the area of coagulation might substantially decrease the amount of blood products transfused.

Based on the severity of coagulopathy and other comorbid conditions, most of the patients in this study would not have tolerated transfusion-free OLT. Furthermore, these patients would have been excluded from transfusion-free surgery based on published criteria.14 Factor rFVIIa was successful in controlling coagulopathy in 8 of the 10 patients, with no associated renal dysfunction. Two patients died in our group, one intraoperatively and one within the first 48 hours. These two patients had associated renal disease warranting preoperative dialysis. The coagulopathy in these two patients was relatively unresponsive to factor rFVIIa. We believe that the coagulopathy associated with uremia was complicated by a profound platelet dysfunction and deficiency in von Willebrand factor. In this situation, factor rFVIIa alone is insufficient for containing coagulopathy and needs to be supplemented with other products such as FFP or additional procoagulant agents.

Intraoperative blood loss is still a common problem in orthotopic liver transplantation, with a median transfusion requirements of 10 units of red blood cells.15,16 Consequences of end stage liver disease (ESLD) such as coagulopathy, thrombocytopenia, and venous congestion of the mesenteric venous system make the surgery more technically demanding and often requiring transfusion of blood and blood products.17 In addition, local conditions such as prior upper abdominal surgeries and/or portal vein thrombosis may lead to increased blood loss. Even with the recent progress in anesthetic and surgical care, severe hemorrhage is still a problem during liver transplantation.18 The issues surrounding the usage of blood and clotting factors during OLT is being accentuated in the face of organ shortage, more so because most cadaveric OLTs done today in the state of California are inpatients that are ICU bound (average MELD score of 33), have severe coagulopathy and frequently renal failure (higher MELD scores). The manipulation of the coagulation system is essential in decreasing blood transfusion during liver transplantation. Until recently, blood products such as FFP, platelets, and cryoprecipitate have formed the mainstay of therapy to treat coagulopathy. However, other methods have also been used in an attempt to decrease intraoperative blood loss. In one such clinical study, prophylactic use of tranexamic acid was associated with moderate decrease in intraoperative blood loss. It also reduced the requirements of fresh frozen plasma, platelets, and cryoprecipitate use in primary OLT.19 On a similar platform, other studies have used aprotinin during OLT in an attempt to decrease transfusion requirements, but with mixed results.20,21

The potential benefit of a procoagulant substance in surgery has to be balanced against the potential risk of thrombotic complications. The most common of these in OLT is hepatic artery thrombosis, which has been reported in one patient undergoing OLT while using rFVIIa.22 Fatal thrombosis has also been reported with the use of rFVIIa in patients undergoing extracorporeal membrane oxygenation.23 Also, one reported incidence of disseminated intravascular coagulation (DIC) occurred in a patient undergoing laparoscopic liver biopsy using rFVIIa.24 We did not have any hepatic artery thrombosis in our patients, but one patient developed portal vein thrombosis 1 month after transplantation. Given the technical issues and the length of time between the administration of the drug and the development of the complication (1 month later), it is unlikely that rFVIIa played a role in the thrombosis, as it has a half life of less than 2 hours. Based on its mechanism of action, rFVIIa should not promote coagulation in intact tissue. Friederich et al. have stated that the necessity of subendothelial tissue factor ensures a localized effect of rFVIIa, without systemic activation of coagulation.25 Hence with such a localized effect, diffuse intravascular coagulation or deep vein thrombosis was not expected, nor has it been observed.

In conclusion, despite the limitations of this study such as the lack of a control group and the lack of better monitoring of the intraoperative coagulopathy. the results suggest that rFVIIa, in addition to ANH and cell saver techniques, could be an effective adjunct in performing transfusion-free surgery in JW patients. This should not be limited to JW patients or to OLT. Coagulation therapy in surgery has not been well developed. Undoubtedly, this would have a significant role to play in fields of transplantation, trauma, and dysfunction related to massive blood transfusion. The complete merits of decreased blood transfusion have yet to be fully understood. The potential benefits go beyond surgical success and extend to hospital management and the cost benefits of lower usage of blood products.