Effectiveness of recombinant activated factor VII in haemorragic cancer-related disseminated intravascular coagulation: a case report

Introduction

Bleeding in disseminated intravascular coagulation (DIC) associated with advanced or metastatic tumours is often difficult to control by conventional therapies, such as transfusion of red blood cells, fresh-frozen plasma, cryoprecipitate, and platelet concentrates¹. Furthermore, this support and replacement therapy is associated with an increased risk of morbidity and mortality².

We present the case of a woman, without a known history of cancer, who presented with pyramidal syndrome of sudden onset due to an intracranial bleed. She had DIC and was successfully treated with recombinant activated factor VII (rFVIIa).

Case Report

A 76-year old woman was admitted to our Department because of a sudden headache, blurred speech and right hemiparesis. On physical examination, she was slightly confused and her Glasgow Coma Scale score was 12. Computed tomography (CT) of the brain revealed a subdural haematoma with a diameter of 14 mm, cerebral oedema causing a mild mass effect with right midline shift and a tentorial cerebellar haemorrhage (Figure 1).

Figure 1.

CT scan of the brain at the time of the patient’s admission to hospital.

Laboratory findings on admission indicated the presence of acute DIC: fibrinogen 98 mg/dL (n.v. 150–400 mg/dL), prothrombin time 19 sec, activated partial prothrombin time 42.3 sec, D-dimer 48,055 ng/mL (n.v. 0–243 ng/mL), platelet count 48x10⁹/L, and antithrombin 58%.

Suspecting an acute myeloid leukaemia, bone marrow aspiration and biopsy were performed and showed metastases of an adenocarcinoma of uncertain origin.

Four units of fresh-frozen plasma, six units of platelets, four units of packed red blood cells and an intravenous bolus of 10 mg vitamin K were administered, without correction of the haemostatic parameters.

Approximately 6 hours after admission to hospital the patient’s neurological status worsened considerably (Glasgow Coma Scale score 3) and another CT scan demonstrated substantial expansion of the intracranial haematoma with a left hemispheric subdural haematoma of 18 mm in diameter, a midline shift of 17 mm, with evidence of uncal trans-tentorial herniation and a posterior parafalcine haematoma (Figure 2).

Figure 2.

CT scan of the brain 6 hours after admission to hospital.

The patient’s critical condition with a life-threatening, expanding intracranial mass and the long distance between our hospital and the nearest Neurosurgery Unit led us to use rFVIIa therapy; a single dose of 90 μg/kg was administered to limit the patient’s bleeding and to bridge the time to a neurosurgical intervention. The patient arrived alive at the Neurosurgery Unit. The haematoma was evacuated successfully and the bleeding stopped definitively; no thromboembolic complications were observed following rVIIa administration. Seven days later the patient was discharged from the Neurosurgery Unit and received chemotherapy for the newly diagnosed, disseminated adenocarcinoma of unknown origin. Her neurological symptoms resolved completely and a CT scan of the brain performed 10 days later showed complete resolution of the haemorrhagic mass and no recurrent bleeding (Figure 3). The patient is still alive after 9 months of follow-up.

Figure 3.

CT scan of the brain 10 days after surgery.

Discussion

rFVIIa is a potent, synthetic haemostatic agent; its mechanism of action is dependent on forming a complex with tissue factor and generating sufficient thrombin at the site of the injured vessel wall. The haemostatic effect of rFVIIa is related to two different mechanisms of action: (i) binding of rFVIIa to tissue factor starts the coagulation pathway by activating factor X and factor IX³; (ii) rFVIIa binds to the surface of activated platelets, causing activation of factor X and generation of thrombin⁴.

This drug has been effectively used in different bleeding disorders: patients with haemophilia and inhibitors^5,6, Glanzmann’s thromboasthenia⁷, post-surgical and post-partum bleeding and in critically injured patients⁸. Many cases and case-series of treatment of bleeding episodes in patients with advanced underlying malignancy have also been reported^1,9.

DIC is characterised by an uncontrolled activation of coagulation and fibrinolytic pathways with an excessive release of thrombin and fibrin, resulting in consumption of coagulation factors and platelets and diffuse deposition of fibrin in the vasculature of organs. Bleeding, blood clotting and organ failure are the clinical consequences of this process¹⁰. Because DIC is a secondary phenomenon, no specific therapy is applicable to all cases.

The usual therapeutic approach in patients with cancer and DIC is based on two principles: replacement of deficient blood components and treatment of the underlying cancer. In 2004 Sallah et al. reported a series of 18 patients with advanced cancer and bleeding disorders related to DIC who were successfully (15/18) treated with serial doses of rFVIIa (90 μg/kg) in addition to replacement therapy and, in three cases, chemotherapy¹. These authors concluded that concomitant occurrence of DIC is not an absolute contraindication to rFVIIa administration. In our case a single dose of rFVIIa was able to avoid a potentially fatal evolution of an intracranial haemorrhage and to allow a life-saving surgical procedure.

In conclusion, our case suggests that the use of rFVIIa can be effective and safe in cancer patients with life-threatening bleeding related to DIC. Thus, rFVIIa is a possible therapeutic option for haemorrhagic DIC in cancer patients in whom conventional management fails.