Increased Clot Formation in the Absence of Increased Thrombin Generation in Patients with Peripheral Arterial Disease: A Case–Control Study

Lower extremity peripheral arterial disease (PAD) most frequently presents with pain during ambulation, which is known as "intermittent claudication". Some relief of symptoms is possible with exercise, pharmacotherapy, and cessation of smoking. The risk of limb-loss is overshadowed by the risk of mortality from coexistent coronary artery and cerebrovascular atherosclerosis. Primary therapy should be directed at treating the generalised atherosclerotic process, managing lipids, blood sugar, and blood pressure. By contrast, the risk of limb-loss becomes substantial when there is pain at rest, ischaemic ulceration, or gangrene. Interventions such as balloon angioplasty, stenting, and surgical revascularisation should be considered in these patients with so-called "critical limb ischaemia". The choice of the intervention is dependent on the anatomy of the stenotic or occlusive lesion; percutaneous interventions are appropriate when the lesion is focal and short but longer lesions must be treated with surgical revascularisation to achieve acceptable long-term outcome.

The WHO/Rose Questionnaire on intermittent claudication was developed in 1962 for use in epidemiological surveys, and has been widely used. Several population studies have shown, however, that it is only moderately sensitive (60-68%), although highly specific (90-100%). In this study, reasons for the poor sensitivity and good specificity were determined following its application to 586 claudicants and to 61 subjects with other causes of leg pain. The results showed two important findings: firstly, that over half of the false negatives were produced by one question alone; and secondly that only three questions were required to maintain the specificity of the questionnaire. This knowledge, in conjunction with the pre-testing of additional questions, enabled a new questionnaire to be constructed: the "Edinburgh Claudication Questionnaire". This questionnaire was tested on 300 subjects aged over 55 years attending their general practitioner, and found to be 91.3% (95% CI 88.1-94.5%) sensitive and 99.3% (95% CI 98.9-100%) specific in comparison to the diagnosis of intermittent claudication made by a physician. The repeatability of the questionnaire after 6 months was excellent (kappa = 0.76, p < 0.001). These results suggest that this revised version of the WHO/Rose Questionnaire should be adopted for use in future epidemiological surveys of peripheral vascular disease.

The binding of fibrinogen and fibrin to platelets is important in normal hemostasis. The extent of platelet-fibrin interaction can be measured as the viscoelastic strength of clot by rotational thromboelastometry (ROTEM). In this study, we investigated the effect of fibrinogen concentration and its relative contribution to overall clot strength using ROTEM. Blood samples were collected from healthy volunteers. The effects of platelet count on clot strength, determined by maximum clot elasticity (MCE), were evaluated on ROTEM using platelet-rich plasma (PRP) adjusted with autologous plasma to generate a range of platelet counts. PRPs were adjusted to 10 x 10(3) mm(-3), 50 x 10(3) mm(-3), and 100 x 10(3) mm(-3) and spiked with fibrinogen concentrates at 550 and 780 mg/dL. The effect of fibrin polymerization on clot strength, independent of platelet attachment, was analyzed by the cytochalasin D-modified thromboelastometry (FIBTEM) method. Additional retrospective analysis of clot strength (MCE) in two groups of thrombocytopenic patients was conducted. Clot strength (MCE) decreased at a platelet count below 100 x 10(3) mm(-3), whereas increases in MCE peaked and reached a plateau at platelet counts from 400 x 10(3) mm(-3). Increasing fibrinogen concentrations in PRP increased clot strength in a concentration-dependent manner, even at low platelet counts (10 x 10(3) mm(-3)). The positive correlation between clot strength and plasma fibrinogen level was also confirmed in the analysis of the data obtained from 904 thrombocytopenic patients. These in vitro and clinical data indicate that the clot strength increases in a fibrinogen concentration-dependent manner independent of platelet count, when analyzed by ROTEM. The maintenance of fibrinogen concentration is critical in the presence of thrombocytopenia. EXTEM (extrinsic activation) and FIBTEM may be useful in guiding fibrinogen repletion therapy.