Robert B. Francis

Elevated Fibrin D-Dimer Fragment in Sickle Cell Anemia: Evidence for Activation of Coagulation during the Steady State as well as in Painful Crisis

The fibrin D-dimer degradation fragment is produced by plasmin degradation of cross-linked fibrin. Elevated plasma D-dimer levels indicate increased plasmin degradation of cross-linked fibrin, and are therefore an indirect indication of increased thrombin activity and fibrin formation. With an ELISA assay sensitive to plasma D-dimer levels of less than 50 ng/ml, elevated levels of D-dimer were found in 23 of 25 subjects with sickle cell disease tested during the steady state, and in all 21 subjects tested serially while hospitalized for painful crisis (total of 40 samples). Mean D-dimer was 79 +/- (SD) 25 ng/ml in 35 normal subjects, 566 +/- 739 ng/ml in sickle cell disease subjects in the steady state, and 1,038 +/- 1,010 ng/ml in sickle cell subjects during painful crisis; these differences were highly significant (p less than 0.001). No correlation was observed between levels of D-dimer in the steady state and the time since the last painful crisis; D-dimer was elevated in all 7 patients tested more than 6 months after their last painful crisis. Most steady-state patients did not have other microvascular occlusive manifestations, such as active leg ulcers or aseptic necrosis of bone, which could explain the increased D-dimer levels observed. It is concluded that increased thrombin activity and fibrin formation are features of steady-state sickle cell disease, and that they further increase during painful crisis. Possible causes and implications of increased thrombin activity and fibrin formation in subjects with sickle cell disease are discussed.

Clinical Significance of Accelerated Fibrinolysis in Liver Disease

We compared site and severity of bleeding in 46 patients with cirrhosis of the liver and accelerated fibrinolysis (defined as a dilute whole-blood clot lysis time less than 2 h) to 44 patients with cirrhosis of the liver and normal fibrinolysis (dilute whole-blood clot lysis time greater than 4 h). Patients with accelerated fibrinolysis had a significantly higher incidence of severe soft-tissue bleeding after trauma and a trend toward increased intracranial bleeding. Mucosal, postoperative, and gastrointestinal bleeding were equally frequent in the two groups. The median partial thromboplastin time was significantly longer, and the median bilirubin and fibrin/fibrinogen degradation product levels were significantly higher in the group with accelerated fibrinolysis, but median prothrombin time, platelet count, and levels of fibrinogen and serum albumin were comparable. The fibrinolytic inhibitor epsilon-aminocaproic acid successfully controlled bleeding in 4 of 6 cases used. Accelerated fibrinolysis may predispose patients with cirrhosis to soft-tissue and intracranial bleeding.

Evidence that smoking alters prostacyclin formation and platelet aggregation in women who use oral contraceptives.

Smoking markedly intensifies the risk of cardiovascular disease in women who use oral contraceptives. The mechanism of this effect is not known, but evidence in vitro and in male smokers suggests that nicotine and cigarette smoke can alter prostaglandin formation and platelet function. However, these effects had not been studied with regard to women. We evaluated the effects of smoking on prostacyclin formation and platelet aggregation in 38 women who were matched according to age and weight. These included 24 women who used oral contraceptives (15 smokers, 9 nonsmokers) and 7 smokers who did not use oral contraceptives. In addition, a control group comprised seven healthy, nonsmoking women who did not take oral contraceptives. Prostacyclin formation, reflected by the excretion rate of its stable metabolite 6-keto-prostaglandin F1 alpha, was measured by means of radioimmunoassay in 4-hour urine specimens obtained during a smoking-free period and after participants had inhaled smoke from four high-nicotine cigarettes. In addition, ex vivo platelet aggregation in response to adenosine diphosphate and the stable thromboxane/endoperoxide analog U 46619 was evaluated before and after the inhalation of cigarette smoke. Oral contraceptive users who smoked greater than or equal to 5 years had a lower basal 6-keto-prostaglandin F1 alpha level than nonsmokers or those with a smoking history of less than 5 years (84 +/- 11 versus 159 +/- 28 versus 171 +/- 18 ng/gm of creatinine, p less than 0.01). Inhalation of smoke from four high-nicotine cigarettes did not alter 6-keto-prostaglandin F1 alpha in the smokers who did not use oral contraceptives. However, excretion of 6-keto-prostaglandin F1 alpha was further reduced in the smokers who used oral contraceptives (133 +/- 20 to 86 +/- 9 ng/gm of creatinine, p less than 0.05). Platelet aggregation did not change after inhalation of cigarette smoke in the women who did not take oral contraceptives, but aggregation increased in participants who used oral contraceptives. These results suggest that prostacyclin inhibition may be an important mechanism for the increased cardiovascular risk in women smokers who take oral contraceptives.

Hemostasis Findings in Headache and Psychosocial Stress Associated with Cerebral Ischemia

We assessed the prevalence of headache and psychosocial stress in a group of patients with cerebral ischemia and evaluated hemostatic function in these patients. Headache and preceding psychosocial stress were present in one-third and one-half, respectively, of patients capable of providing an adequate history and answering a standardized psychosocial questionnaire. There were no significant differences in hematocrit, white blood cell count and differential, fibrinogen, and platelet activation peptide ß-thromboglobulin, between patients with and without headache and between high- and low-stress patients. Fibrin D-dimer (a fragment of cross-linked fibrin) was significantly lower in high-stress compared to low-stress patients. There was no association between headache and stress level. These findings make unlikely the hypothesis that headache associated with cerebral ischemia is platelet-mediated and suggest that psychosocial stress on a chronic basis is not associated with procoagulant tendencies in this population.

Use of Noninvasive Laboratory Testing in the Prediction of Thrombosis in the Nephrotic Syndrome

A noninvasive method for diagnosing thrombosis in the nephrotic syndrome could be useful clinically. We measured hematocrit, fibrinogen, creatinine, antithrombin III, plasminogen, and alpha-2-plasmin inhibitor levels in 20 patients with nephrotic syndrome objectively studied for the presence of thrombosis, and found that by using combinations of three or more of these variables good discrimination could be obtained between those patients with and without thrombosis. We conclude that it is possible to predict risk of thrombosis in nephrotic syndrome using relatively simple noninvasive laboratory tests.