Increased Risk for Thromboembolism Associated with High Coagulation Factor VIII (F VIII) Levels in Patients with Malignant Lymphoma.

An increased annual incidence of thromboembolic events (TE) of up to 11% has been observed in patients with solid tumors, whereas there exists little data on TE in hematologic malignancies. A previous study found a 6,6% incidence of TE in patients with high grade Non Hodgkin’s lymphoma (HG-NHL) mostly occuring during the first three months of therapy. Little is known about pathogenesis and risk factors in this patient group. We retrospectively evaluated the medical records of all patients with malignant lymphoma treated at our institution between 1991 and 2004. In a seperate effort laboratory analysis for detection of acquired and hereditary thrombophilia was performed at diagnosis and during treatment in 44 patients with various hematologic malignancies: HG-NHL (n = 22), Low grade- NHL (LG-NHL) (n = 7), Hodgkin’s disease (HD) (n = 6), CNS-lymphoma (n = 1) and acute myeloid leukemia (AML) (n = 8). A total of 96 TE occurred in 80 of 1048 patients (7,6%) with malignant lymphoma: DVT (n = 51), pulmonary embolism (n = 19), central venous catheter thrombosis (n = 11), upper extremity thrombosis due to tumor compression (n = 9), central nervous system thrombosis (n = 3), arterial thrombosis (n = 2) and portal vein thrombosis (n = 1). 69 TE (72%) occurred during treatment, whereas 27 (28%) were diagnosed prior to (n = 16) (17%) or after completion of therapy (n = 11) (11%). 9 patients (9%) had comorbid solid tumors. In 12 patients (15%) results of thrombophilia screening were available and FVIII levels were high (> 150%) in 7 (58%). In the prospectively analyzed patient cohort 30 (68%) had high FVIII levels, 22 (50%) showing very high levels (> 180%). High FVIII was associated with high von Willebrand factor (vWF) and increased collagen binding activity, but not with elevated IL 6 or TNF-a. 4 patients (9%) had heterozygous factor V Leiden mutation, one had the G20210A mutation of the prothrombin gene. Fibrinolysis was normal in all patients as were protein C, S and AT-III. No anticardiolipin antibodies or lupus anticoagulants were detected. However only 2 patients (4,4%) in this cohort developed TE, one of whom also had heterozygous protein C resistance. Patients with malignant lymphoma are at substantial risk for TE, especially during treatment, thus prophylactic anticoagulation seems warranted. Our study shows sustained strikingly high factor VIII levels in patients with malignant lymphoma even months or years after a TE as well as in a prospectively analyzed, yet mostly asymptomatic cohort with lymphoma and acute leukemia. Infection as a cause of secondary F VIII elevation in these patients was ruled out by absence of fever and normal IL 6 and TNF-a. Increased FVIII activity (> 150%) has been recognized as an independent risk factor for TE, however the pathogenesis is unclear so far and high FVIII and vWF levels have previously also been found in Multiple Myeloma patients. Ongoing investigations will focus on the implication of these findings in the pathophysiology of hematologic disease.