Activated-Protein-C Resistance in Cancer Patients

Abstract

Background: Resistance to activated protein C (aPC) is usually linked to factor V Leiden, but may occur in other disorders associated with hypercoagulability. In this study, we investigated the frequency of resistance to aPC in patients with advanced cancer and examined the relationship of aPC resistance to other markers of coagulation activation. Methods: Patients (n = 39) had an established diagnosis of advanced cancer; controls (n = 20) were healthy persons. aPC resistance was measured as the ratio of activated partial thromboplastin times with and without aPC (aPC-sensitivity ratio, aPC-SR). The factor V Leiden mutation was detected by a polymerase-chain-reaction based technique. Other assays were performed by standard laboratory methods. Data were analyzed using t tests and the Pearson correlation. Results: aPC-SR was below 2 SD for 5 of the cancer patients (13%), but none of the controls; only 1 of the 5 had the factor V Leiden mutation. aPC-SR was inversely correlated (p < 0.01) with factor VIII and fibrinogen in patients and with prothrombin activation fragment 1.2 (F1.2) in controls. Patient factor VIII, von Willebrand factor, (vWF), fibrinogen, F1.2 and D dimer were all significantly increased (p < 0.01); antithrombin III, protein C and proteins were similar to controls. Factor VIII correlated with vWF (p < 0.001) and F1.2 with d-dimer (p < 0.001). Other associations (p < 0.05) were observed between factor V and protein C, fibrinogen and protein C, factor V and antithrombin III and protein C and antithrombin III. Four cancer patients had a history of thromboembolism; their aPC-SR was similar to that of patients without thrombosis. Of the several coagulation measures examined, only vWF was higher in the patients with thrombosis (p = 0.01). Interpretation: Cancer patients have evidence of intravascular coagulation and increases in procoagulants and may have aPC resistance. The aPC resistance is not due to factor V Leiden, but is rather associated with elevated levels of factor VIII and fibrinogen, and in itself does not predict thrombosis.

Thrombin generation and activated protein C resistance in patients with essential thrombocythemia and polycythemia vera

“…41,42,49 However, in malignant conditions other than ET and PV, the appearance of APC-resistant phenotype has been determined by increased levels of plasma FV and factor VIII (FVIII), instead of decreased PS levels. 40,41,50,51 In conclusion, we have shown that plasma from ET and especially PV patients is APC-resistant, which may account for the increased thrombotic risk associated with these disorders. This study provides a new insight in the pathogenesis of the thrombophilic state in patients with ET and PV by linking together the appearance of acquired APC resistance (a condition that is associated with an increased thrombotic risk), the occurrence of reduced levels of specific coagulation factors and neutrophil activation, and JAK2 V617F mutational status.…”

Correlation of Coagulation Markers With Axillary Lymph Node Metastasis in Carcinoma Breast

“…Levels of factor VIII and D-dimer are reported to be considerably high in cancer patients compared to healthy control subjects. 7 Procoagulant activity has been shown to be associated with stage of the disease. 8 Possible causes of increased procoagulants seem to be endothelial cell damage, endothelial synthesis (accelerated with the induction of tumour during angiogenesis), endothelial proliferation or an acute phase reaction due to vascular abnormalities, in addition to activation of the coagulation system as a result of increased tissue factor.…”

Joint effects of cancer and variants in the factor 5 gene on the risk of venous thromboembolism

“…19 Previous studies have also found an increased prevalence of acquired APC resistance in patients with cancer. [46][47][48] It is licit to assume that two sources of APC resistance (i.e. acquired and inherited) in cancer patients would greatly increase the risk of a VTE, similarly to the synergistic effect of oral contraceptive use in individuals with FVL, as both result in a poor response to APC.…”