Thromboembolic Disease – Critical Evaluation of Laboratory Investigation

Abstract

SummaryPrevious studies of patients with thromboembolic disease have revealed an association either with hereditary anticoagulant protein deficiencies or with defects in the fibrinolytic system. To obtain a more comprehensive picture and to investigate which analyses are useful in the evaluation of such patients, we have performed an extensive laboratory investigation in 439 individuals with thromboembolic disease. Anticoagulant protein deficiencies were found in 24 patients. Deficiencies of protein C (n = 10) and protein S (n = 9) were most common followed by deficiencies of antithrombin III (n = 3) and plasminogen (n = 2). Six of the nine protein S deficient patients demonstrated a selective deficiency of free protein S with normal total protein S concentrations. To diagnose protein C and S deficiencies among the 201 patients receiving oral vitamin K antagonists, the concentrations of protein C and S were compared with the mean concentration of several other vitamin K-dependent proteins. One protein C and three protein S deficiencies were identified among the treated patients. The number of protein C deficiencies found in this group was significantly lower than the number found among untreated patients. Although fewer protein S deficiencies were also identified among the treated patients, than in the untreated group, the difference was not statistically significant. The results suggest that protein C deficiencies went undetected in the treated group and that oral anticoagulant therapy should be discontinued before efforts to diagnose protein C deficiency are made. We found no cases with heparin cofactor II deficiency. Lupus anticoagulant was present in 10 patients. Evaluation of the fibrinolytic system revealed that the patient group had slightly lower mean euglobulin fibrinolytic activity (EFA) after venous occlusion than controls and a subgroup (approximately 15%) of patients with EFA below the level of the 5th percentile of controls, could be distinguished. Repeated analysis demonstrated a substantial individual day-to-day variation in both patients and controls and the combined EFA results did not clearly distinguish patients from controls. There was a significant negative correlation between EFA and plasminogen activator inhibitor (PAI) levels in both patients and controls and the patient group had significantly higher levels of PAI than the control group. In contrast, there was no difference between controls and patients in tissue plasminogen activator (tPA) release after venous occlusion and no correlation between EFA and tPA was observed. These results suggest that although a statistically significant difference between patients and controls in values of fibrinolytic parameters was found, an extensive laboratory evaluation of the fibrinolytic system in individual patients may not be warranted. The association between patients with thrombosis and deficiencies of anticoagulant proteins suggests that the investigation of individual patients should focus on these components.

The factor VR506Q mutation causing APC resistance is highly prevalent amongst unselected outpatients with clinically suspected deep venous thrombosis

“…Our study demonstrated the FV : R506Q mutation to be an important risk factor in outpatients with DVT. This is in marked contrast to other congenital prothrombotic disorders, which are only rarely found in thrombosis patients [19][20][21][22][23][24]. More than a quarter of the outpatients with venous thrombosis verified by phlebography were found to be carriers of the FV : R506Q mutation, a strikingly high proportion, even larger than figures reported for selected series of thrombosis patients from other countries [2,4,9,12].…”

Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C.

“…Immunological assays were then designed and used to investigate individuals with thromboembolic disease, as deficiencies of these proteins would hypothetically lead to a thrombotic tendency. The association between thromboembolic disease and deficiency of proteins C or S is now well established (1,3,4). The now hypothesized cofactor to APC is the first anticoagulant factor to be proposed on the basis of observations made in an individual patient with thromboembolic disease.…”

“…However, heterozygous deficiencies of anticoagulant proteins can only be found in a minority of cases (4). This suggests that there are genetic defects predisposing for thrombosis yet to be identified.…”

“…Analytical Methods. Blood sampling and routine coagulation methods were performed as described (4). The plasma concentrations of protein S and protein C were determined with immunochemical methods (4) and with commercially available functional assays: Coatest protein C (Chromogenix, Molndal, Sweden) and Staclot protein S (Stago, Asnieres, France).…”

Activated protein C resistance and anticoagulant proteins in young adults with central retinal vein occlusion

“…The prevalence of protein S deficiency is not quite clear, but is considered to be that of protein C, 1:200. Earlier investigations on the prevalence of deficiencies in the anticoagulant proteins in patients with thrombotic disease, have shown that 4-6% of the patients show such deficiencies (Taberno et al 1991;Malm et al 1992). In our investigation, 11% of the patients showed deficiencies in the anticoagulant proteins.…”