Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis.

OBJECTIVE: To evaluate the coagulative/fibrinolytic cascade and the circulating markers of the endothelial injury in systemic sclerosis (SSc). METHOD: Plasma was obtained from 29 patients with SSc and tested for thrombin-antithrombin (TAT), fragments 1+2 (F1+2), dermatansulphate (DS), thrombomodulin (TM), lipoprotein (a) [Lp(a)], von Willebrand factor (vWF), tissue type plasminogen activator (tPA), plasminogen activator inhibitor (PAI), D-dimers, intercellular adhesion molecole-1 (ICAM-1), vascular cell adhesion molecule (VCAM), and E-selectin. The data were correlated with lung (forced vital capacity, diffusing lung capacity for carbon monoxide, vital capacity) and skin (skin score) involvement. RESULTS: Coagulation was significantly activated (increase in F1+2, P <.001; TAT, P <.01; and Lp(a), P <.05). TM was not significantly different from controls. vWF was significantly increased (P <.01), and its supranormal multimers increased in more than 50% of patients. DS was significantly increased in diffuse cutaneous SSc (P <.01). Fibrinolysis was impaired as shown by reduced D-dimers (P <.01) and decreased levels of PAI (P < 0.01). The markers of endothelial injury were also significantly elevated. DS correlated significantly with forced vital capacity (P <.01) and forced vital capacity ratio (P <.01). CONCLUSION: Injury to the endothelium reduces endothelial function, as suggested by impairment of fibrinolysis and activation of the coagulative pathway. The loss of the balance between fibrinolysis and coagulation contributes to vessel engulfment with fibrin and breakdown of vessel patency. The increase of circulating DS suggests that this factor may be a new marker of endothelial injury.

The management of oral anticoagulant therapy: the patient's point of view.

The aims of this study were to investigate on the general adhesion of the patients to oral anticoagulant therapy, and particularly on the quality of life of our patients, the doctor-patient relationship and the Centre-patient relationship. For this purpose we administered a questionnaire containing 17 main questions each with a maximum of 4 secondary questions. The questionnaire was administered to two groups of 127 and 137 oral anticoagulated patients (127 males and 137 females, mean age 55 +/- 19 years), followed at two Anticoagulation Clinics, in two Italian cities, Cagliari (Sardinia) and Padua (North East Italy). The cities differed in the number of patients monitored and the management modalities of anticoagulation. The results show that oral anticoagulant therapy does not limit the life-style of the patients. Only 11% of the patients complain of limitations to their daily life. Fifty-two percent believe their health has improved, and 87% are not afraid of negative consequences. The doctor-patient relationship is considered very important by 96% of patients. Seventy-eight percent refer to the Anticoagulation Clinic also for other health problems, 93% consider it important to be assessed by the doctor at the Anticoagulation Clinic, while 83% believe the doctor should always hand out the results personally. We conclude that in general oral anticoagulant therapy is accepted by the majority of patients, in spite of the need for periodic monitoring. The doctor-patient relationship should be taken into account, even in the case of a monitored, computer-assisted method of dose-adjustment.

Fibrinopeptide A, prothrombin fragment 1 + 2, thrombin-antithrombin complex and D dimer before and after injection of a nonionic contrast medium (iohexol).

The principal aim of this study was to evaluate, on biochemical grounds, whether injection of a low-osmolar nonionic contrast medium (iohexol) can induce a prothrombotic state and/or a change in fibrinolysis. Fifteen patients were submitted to urographic examination and the assays listed below were performed: before the injection (T0), 1 h after (T1), and 24 h after (T24) the injection of the contrast medium. The following assays were performed: fibrinopeptide A (FPA), prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT) and D dimer (D-D). The assays were carried out on 6 of the patients to whom a saline infusion was administered. Only a mild statistically significant increase was found in FPA levels at 1 h after injection of the contrast medium (mean and CI 95%: T0 4.4, 3.7-5.5; T1 6.0, 4.9-9.1; p = 0.003). F1+2, TAT and D-D did not show any significant change after the injection. These findings show that after injection of iohexol, only a mild, though statistically significant, increase in FPA levels was observed as an expression of increased thrombin activity. In the absence of any significant increases in TAT, F 1+2 and D-D, we have no evidence of a prethrombotic state.

Abnormalities of blood coagulation and fibrinolysis in psoriasis.

Contrasting data have been reported about cardiovascular diseases in psoriatic patients. The aim of this study was therefore to evaluate blood coagulation and fibrinolysis in psoriatic patients. For this purpose, in a first group of 48 patients, we measured blood coagulation and fibrinolysis inhibitors [antithrombin III (AT), protein C (PC) and alpha 2-antiplasmin (AP)], the products of thrombin and plasmin activity [fibrinopeptide A (FpA) and B beta(15-42) (B beta)], plasminogen (PLG) and fibrinogen (FBG). When all patients were considered we found a significant increase in B beta and FpA levels, while PC, PLG and AP values were significantly decreased when compared to controls. FBG and AT were not different from the controls. In order to understand whether the observed abnormalities of blood coagulation and fibrinolysis were related only to psoriasis we divided all the patients into two groups: (1) patients with cardiovascular disease or other risk factors (n = 28) and (2) patients affected only by psoriasis (n = 20). Since no difference was observed between groups 1 and 2, we conclude that these findings are related to psoriasis. Subsequently we considered a different group of psoriatic patients. In these patients we measured FpA and two new thrombin activation indicators, such as prothrombin fragment 1 + 2 and thrombin-antithrombin complex (TAT). In addition we evaluated the levels of D-dimer, the product of the dissolution of cross-linking fibrin by plasmin. In this second group FpA, prothrombin fragment 1 + 2 and D-dimer were significantly higher than controls. Only TAT was not statistically different from those of the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Controlled vitamin K content diet for improving the management of poorly controlled anticoagulated patients: a clinical practice proposal.

The aim of our study was to investigate the effect of a diet with a known vitamin K content on the monitor test for oral anticoagulant therapy. We studied 10 poorly controlled patients (7 women and 3 men, mean age 48 +/- 15 years) in therapy with acenocoumarol for at least 1 year. Another group of 10 poorly controlled patients was considered as a control group. After a baseline period, during which a free diet was allowed, patients were administered a diet with a controlled vitamin K content; in the same period, control subjects were not subjected to any dietary restriction. Thrombotest (Nyegaard, Oslo) was employed for monitoring oral anticoagulant therapy, with a therapeutic range between 2.3 and 4.8 INR. We found a significant difference by thrombotest between the percentages within the therapeutic range obtained before and during dietary treatment (p = 0.0001). The difference in percentages was -0.31 and the 95% CI, of the difference ranged from -0.45 to -0.17. No significant difference was shown in the control group in the same periods. Our data suggest that a diet with a controlled vitamin K content is effective in increasing the percentage of tests within the therapeutic range in patients with poorly controlled anticoagulation.

Activation of blood coagulation and fibrinolysis in Graves' disease.

We studied blood coagulation and fibrinolysis activities in hyperthyroidism before and after methimazole or 131I. Fibrinopeptide A and B beta 15-42, in vivo indicators of thrombin and plasmin activity, were measured by RIA, while fibrinogen by the Clauss method. We studied 50 patients, affected by toxic diffuse goiter. We evaluated 21 of them before and after treatment. Fibrinogen, fibrinopeptide A, and B beta 15-42 were higher in patients than in controls (p less than 0.0001). There was no difference in fibrinopeptide A nor in B beta 15-42 before or after treatment. In euthyroidism fibrinogen returned to normal values. Inflammation of the thyroid gland secondary to autoimmunity may activate blood coagulation by release of tissue factor. High fibrinogen before treatment may be explained as an aspecific response. Since it persists in euthyroidism, autoimmunity could account for high fibrinopeptide A and B beta 15-42 aftertreatment.

Bleeding time is prolonged during oral anticoagulant therapy.

We have performed the BT test in 55 patients undergoing oral anticoagulant therapy monitored by means of Thrombotest (TT). Patients in steady state of anticoagulation showed longer BT than normal controls; patients in overdose phase had longer BT values than either controls or patients in steady state. After recovery the overdose phase patients showed BT values not different from those of the controls. Moreover we were able to find in our patients a significant linear correlation between BT and TT. Impairment in primary haemostasis could be due either to a scarce fibrin deposition in the haemostatic plug or to deficiency of a possible vitamin K dependent vascular "bleeding factor".

Is the imbalance between thrombin and plasmin activity in diabetes related to the behaviour of antiplasmin activity?

The aim of this study was to evaluate the balance between thrombin and plasmin activity in a group of 79 diabetic patients (IDDM and NIDDM). For this purpose we determined fibrinopeptide A (FPA) and B beta 15-42, specific products of thrombin and plasmin activity. Moreover we investigated the behaviour of antithrombin III and alpha 2 antiplasmin, important inhibitors of blood coagulation and fibrinolysis. Results show an increase both in FPA and B beta 15-42 in IDDM and NIDDM patients when compared to healthy controls. However the ratio between B beta 15-42 and FPA was lower than in controls indicating an imbalance between thrombin and plasmin activity. Antithrombin III levels were not different from the controls and no correlation was found with Hb A1c. alpha 2 antiplasmin was found to be higher in IDDM when compared both with NIDDM and controls. A non linear correlation was found between Hb A1c and alpha 2 AP in both diabetic groups. We conclude that the imbalance between thrombin and plasmin activity may have a role in determining fibrin deposition. These subclinical abnormalities, unrelated to vascular complications and duration of the disease, may progressively contribute to the development of the vascular complications in diabetes.

[Activity of the coagulation and fibrinolysis in non-insulin-dependent diabetes mellitus. In vivo study]. / Attività della coagulazione e della fibrinolisi in corso di diabete mellito insulino indipendente. Uno studio in vivo.

In vivo study of blood coagulation and fibrinolysis activities in non insulin dependent diabetes mellitus. The aim of the study was to investigate in vivo blood coagulation and fibrinolysis activities in a group of diabetic patients NIDDM with and without vascular complications. For this purpose we determined two sensitive indicators in vivo of blood coagulation and fibrinolytic activities such as fibrinopeptide A and B beta 15-42 respectively. Moreover, we computed the ratio between B beta 15-42 and fibrinopeptide A in order to investigate a possible imbalance in vivo between blood coagulation and fibrinolysis. Control groups were 15 healthy subjects and 28 non diabetic patients affected by atherosclerotic disease. Fibrinopeptide A and B beta values were significantly higher in the diabetic patients than controls but there was no difference between the former group and the atherosclerotic patients. Also, no correlation was found for FPA, B beta, B beta/FPAr and HbAlc, fructosamine and blood glucose levels. There was no difference in B beta, FPA and B beta/FPAr values for patients treated with insulin and for those treated with either hypoglycemic agents or diet. Our data indicate that in diabetic patients fibrinolysis activity is increased, but it cannot counterbalance thrombin activity which appears much more enhanced. Finally, the lack of correlation for FPA, B beta, B beta/FPAr and HbAlc, fructosamine and blood glucose suggests that blood coagulation and fibronolysis abnormalities are not related to the degree of blood glucose control.

Subclinical activation of fibrinolysis in atherosclerotic disease detected by B beta 15-42 assay.

Plasma B beta 15-42 and fibrinopeptide A (FPA) concentrations, which are respectively indicators of plasmin and thrombin in vivo activity, were measured in 46 patients with ischemic arterial disease without signs of acute thrombosis. In the group as a whole, an increase in both B beta 15-42 and FPA was found. When the patients were divided in two groups on the basis of their reversible (transitory ischemic attacks and unstable angina) or irreversible (stroke and myocardial infarction) ischemic episodes, the levels of B beta 15-42 were significantly elevated only in the former group when compared to controls (p less than 0.01). In the latter group we found significantly increased levels of FPA with respect to both controls (p less than 0.01) and patients with reversible and transient ischemic episodes (p less than 0.05). Moreover, the B beta 15-42/FPA ratio was significantly lower in patients with irreversible ischemic episodes than in controls (p less than 0.01) and patients with transient ischemic episodes (p less than 0.01), while no difference was found between the latter group and controls, although FPA and B beta 15-42 were significantly higher. These results suggest that in patients with transient and reversible ischemic episodes fibrinolytic activity is able to counterbalance an increased thrombin activity, while this does not appear to occur in patients with irreversible ischemic episodes.

Thrombin activity and oral anticoagulant therapy: a preliminary study.

The aim of this work was to investigate whether the thrombin activity is related to the degree of anticoagulation induced by oral anticoagulants. Moreover, we tried to detect an optimal anticoagulation range at which the lowest possible thrombin activity can be reached. We investigated 28 patients (19 women and 9 men, mean age 54 +/- 9 years). Anticoagulation had been induced by acenocoumarol for at least 1 year before the beginning of this study. The degree of anticoagulation was monitored by the thrombotest coagulation method. The therapeutic range was 5-13%. The thrombin activity was measured by means of the fibrinopeptide A radioimmunological assay. In 15, 7, and 6 of the patients, thrombotest and fibrinopeptide A were carried out twice, once, and three times, respectively. Our results show first of all a significant positive relationship between thrombotest and fibrinopeptide A (p less than 0.001). Once this result was obtained, we tried to improve our identification of the behaviour of the thrombin activity in relation to the degree of anticoagulation assessed by thrombotest. For this purpose we employed a third-degree polynomial regression analysis which showed a better fit of the data. Since the curve became steeper from about 10% thrombotest levels, we divided the FPA values on the basis of thrombotest ranges. FPA values for the 14- to 25% thrombotest range were significantly different from those in the thrombotest range of 4-10%. Moreover, FPA levels in the 11 to 13% thrombotest range were significantly different from those in the thrombotest range of 4-10%. Our results suggest that a significant decrease in thrombin activity may be achieved only with a deep anticoagulation.

Evidence for a relationship between high fibrinogen levels and decreased thrombin activity in vivo in elderly subjects.

In order to investigate whether high fibrinogen levels were associated with elevated thrombin activity, we measured fibrinogen and fibrinopeptide A in 37 elderly healthy subjects ranging from 60 to 93 years. Fibrinogen levels (519.1 +/- 127.0 mg/dl) and fibrinopeptide A (5.9, 0.9-18.1 ng/ml) were significantly higher than in younger controls. A highly significant negative linear correlation was found between fibrinogen and fibrinopeptide A in the elderly subjects (p less than 0.01). However, a polynomial regression showed that this negative relationship was present at the fibrinogen levels ranging between 420 and 700 mg/dl. Our results suggest that high fibrinogen levels in elderly subjects do not necessarily mean that their thrombin activity is concomitantly increased.