BESIDES a variety of optional measures to compensate for blood loss, thrombocytes and coagulation factors can be administered to treat coagulopathy resulting from specific deficiencies in cases of severe bleeding. Recently recombinant blood coagulation factor VIIa (rFVIIa, NovoSeven®) became available to treat patients with hemophilia with inhibitors of coagulation factors IX or X. rFVIIa has also been used to treat other causes of severe bleeding; for instance, in cirrhotic patients scheduled for orthotopic liver transplantation, 1–4for thrombocytopenic patients, 5,6or for patients suffering from Glanzmann thrombasthenia. 7The authors describe the use of rFVIIa for treating a patient with liver cirrhosis and hypersplenism requiring total hip arthroplasty (THA).
A 59-yr-old woman came to our hospital for a preoperative interview 3 weeks before THA. The patient had a history of hip fracture, which was treated in 1998 using reposition osteosynthesis. During the removal of the osteosynthesis material in 1999, the patient showed an increased bleeding tendency with a severe postoperative bleed. Subsequently, the patient developed pseudoarthrosis, thereby requiring the planned THA.
The patient indicated that she still developed hematomas relatively easily. Even smaller injuries continued bleeding up to 20 min. A year before the preoperative interview, the patient was refused THA in another hospital because of the bleeding incident in 1999 and the persistent prolonged bleeding time and existing thrombocytopenia.
The patient had developed alcoholic liver cirrhosis, portal hypertension, and hypersplenism. Alcohol consumption was stopped by the patient after determination of the internal defects. Physical investigation of the patient revealed the following parameters: length 162 cm, weight 60 kg, blood pressure 140/80 mmHg, heart rate 72 beats/min. No icterus, no erythema palmare, and no spider naevi could be determined. In the patient's abdomen, neither the liver nor spleen were palpable. Laboratory investigation showed an increased prothrombin time (PT), a slightly increased bleeding time, and a clearly lowered amount of thrombocytes. Laboratory data are shown in table 1.
The patient was administered spinal anesthesia, using intrathecal 0.1 mg morphine dissolved in 4 ml bupivacaïne 0.5%, 8and a cemented total hip prosthesis was placed. The duration of surgery was 80 min, with a perioperative blood loss of 1,890 ml. The blood was collected and treated (filtration and washing) by a cell saver (Hemonetics 5 plus, Hemonetics, Braintree, MA). After processing the collected blood, 560 ml (hemoglobin 20.16 g/dl) was infused into the patient.
The cell saver remained connected to the patient postoperatively for further collection and processing of the lost blood. During the first 6 h after surgery, the total blood loss was 1,850 ml (fig. 1). These 1,850 ml were also treated by the cell saver, and the processed red cells, 560 ml (hemoglobin 20.5 g/dl) in total, was reinfused to the patient. The patient's coagulation status deteriorated even further, with a decrease of platelets from 55*109/l to 44*109/l, and an increase of the PT to 20 s. Therefore, rFVIIa 100 μg/Kg (NovoSeven®, Novo Nordisk A/S, Copenhagen, Denmark) was administered intravenously without the addition of thrombocytes. After rFVIIa administration, the total amount of blood lost via the drain was 670 ml during the subsequent 11 h (fig. 1). Postoperative bleeding completely ceased 18 h postoperatively, requiring no further intervention.
Recombinant factor VIIa forms a complex with tissue factor (TF) that is present in the wound bed, and thereby acts as a catalyst of local blood coagulation. This explains the excellent efficacy of rFVIIa in patients with hemophilia A or B suffering from inhibitors against FVIII or FIX, respectively. TF is a membrane-bound glycoprotein that is expressed on cells in the subendothelium. Tissue injury disrupts the endothelial cell barrier that normally separates TF-expressing cells from the circulating blood, thereby directly exposing TF to circulating blood, resulting in the high affinity binding of RFVIIa. The TF/RFVIIa complex activates FX to Fxa, leading to the generation of thrombin (FIIa) and subsequent fibrin formation. In healthy nonhemophiliacs this thrombin generation leads to the activation of cofactors V and VIII, as well as to the accumulation of activated thrombocytes at the site of injury.
Administering rFVIIa to patients with liver cirrhosis, thrombocytopenia, or reduced thrombocyte function may result in additional thrombin generation on the phospholipid surface of activated thrombocytes. Since thrombin generation is one of the most powerful existing activators of thrombocytes, the additional rFVIIa-induced thrombin generation might compensate for the reduced amount of thrombocytes available and the associated decreased thrombin generation. 5,6,9,10Furthermore, a bolus injection of rFVIIa generates a local burst of thrombin, which subsequently results in the activation of thrombin-activatable fibrinolysis inhibitor (TAFI). TAFI is activated by high concentrations of thrombin. 11Activated TAFI down-regulates fibrinolysis by cleaving C-terminal lysine and arginine residues from partially degraded fibrin 12These lysine and arginine residues are essential cofactors in tissue-type plasminogen activator (t-PA) mediated fibrinolysis.
Recombinant FVIIa is not antigenic and does not carry the potential for transmission of disease. However, the current cost of rFVIIa, in a dose of 100 μg/kg, is approximately 3,000–3,800 ($2,668–$3,430) per patient. The risks of allogenic blood transfusions are associated with incremental hospital costs. In a recently published study these additional costs were estimated to be $1,000–$1,500 per unit of blood transfused. 13