G.G. Sorano

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.

Fibrinogen and fibrinolytic activity in hyperthyroidism before and after antithyroid treatment

Plasma concentration of fibrinogen and Bβ 15–42, a specific product of fibrinogen metabolism induced by plasmin, were measured in a group of patients with untreated hyperthyroidism and in controls. Significantly increased plasma levels of both parameters were observed in hyperthyroid patients. The restoration of euthyroidism either by antithyroid drug or by radioiodine caused a significant decrease of fibrinogen and Bβ15–42. These data indicate that hyperthyroidism is another clinical condition associated with increased concentration of fibrinogen and Bβ 15–42.

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)

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.

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.

Subclinical activation of fibrinolysis in atherosclerotic disease detected by Bβ 15–42 assay

SummaryPlasma Bβ 15–42 and fibrinopeptide A (FPA) concentrations, which are respectively indicators of plasmin and thrombinin 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 Bβ 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 Bβ 15–42 were significantly elevated only in the former group when compared to controls (p<0.01). In the latter group we found significantly increased levels of FPA with respect to both controls (p<0.01) and patients with reversible and transient ischemic episodes (p<0.05). Moreover, the Bβ 15–42/FPA ratio was significantly lower in patients with irreversible ischemic episodes than in controls (p<0.01) and patients with transient ischemic episodes (p<0.01), while no difference was found between the latter group and controls, although FPA and Bβ 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.

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.

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.

“Falsely Increased” Bβ15–42 Levels in Diabetes

We read with interest the article by Small et al. (1), who found high levels of tissue plasminogen activator inhibitor in a group of diabetic patients. However, they did not find any relationship between the levels of tissue plasminogen inhibitor and the fibrinolytic activity, the latter being expressed by both the fibrin-plate lysis zone test and the levels of Bp15_42 antigen, which were found to be normal. We determined the Bp15_42 antigen, an early product of plasmin activity on fibrinogen/fibrin (2), by using a radioimmunoassay technique (IMCO, Stockholm). Two groups of diabetic patients were tested: insulin-dependent diabetes mellitus (IDDM; n = 29, 17 males, 12 females; mean age 23 yr, range 12-47 yr) and noninsulin-dependent diabetes mellitus (NIDDM; n = 50, 32 males, 18 females; mean age 57 yr, range 31-83 yr). The Mann-Whitney U test was used for statistical evaluation of the data. The results are expressed as medians and ranges. We found a significant increase in Bp15_42 values in both IDDM (12.7, 5.7-30.1 ng/ml; P < 0.001) and NIDDM (12.0, 5.4-26.4 ng/ml; P < 0.004) patients compared with 42 control subjects (10.1, 5.8-13.0 ng/ml). Moreover, we concomitantly measured fibrinopeptide A (FPA) by a radioimmunoassay method (Mallinckrodt, Paris, KY), a sensitive indicator of thrombin activity in vivo (3), which turned out to be significantly elevated in both groups (IDDM: 6.7, 1.4-40.1 ng/ml, P < 0.001; NIDDM: 6.6, 1.6-32.5 ng/ml, P < 0.001) compared with control subjects (2.3, 1.2-4.6 ng/ml). However, when we computed the ratio between Bp15_42 and FPA to obtain an index of relative plasmin to thrombin action on fibrinogen/fibrin, we found a significantly lower Bp15_42-FPA ratio in both groups of patients (IDDM: 1.85, 0.4-10.0 ng/ml, P < 0.001; NIDDM: 1.65, 0.3-8.2 ng/ml, P < 0.001) with respect to control subjects (3.85, 1.8-12.6 ng/ml). We feel that an imbalance between blood coagulation and fibrinolysis does exist in diabetes, and the increased fibrinolytic activity in vivo does not appear to sufficiently counterbalance the blood coagulation activity. This may be important because localized deposition of fibrin is dependent on an imbalance between its rate of formation and dissolution (4). The high plasminogen activator inhibitor activity found by Small et al. could have had a role in limiting the fibrinolytic activity that caused it to appear falsely normal. We therefore conclude that a correct evaluation of the fibrinolytic system in response to its inhibitors and the blood coagulation activity should take into account both the inhibitors of tissue plasminogen activators and the thrombin activity, measured by means of FPA.