G. Mameli

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.

α2antiplasmin and disseminated intravascular coagulation in liver cirrhosis

Subnormal concentrations of alpha 2 Antiplasmin (alpha 2 AP) in liver cirrhosis may be due to an impaired hepatic synthesis and/or to a fibrinolysis activation in disseminated intravascular coagulation (DIC). In order to clarify this problem, in 26 cirrhotic patients (15 compensated and 11 decompensated) alpha 2 AP plasma activity and plasma Fibrinopeptide A (FPA) were measured. Serum albumin, p-Cholinesterase (p-CHE), Fibrinogen and Fibrinogen Degradation Products (FDP) were also carried out. Our data show that alpha 2 AP and FPA were equally abnormal in compensated and decompensated cirrhosis. The significant negative correlation obtained between alpha 2 AP and FPA as well as the lack of correlation between alpha 2 AP and albumin, alpha 2 AP and p-CHE in both groups suggests that, in our patients, alpha 2 AP decrease may be due to a fibrinolysis activation induced by a DIC which appears chronic since Fibrinogen and FDP were normal. These findings are in agreement with the results obtained in the four subgroups a posteriori selected on the basis of FPA levels: alpha 2 AP in subgroups with high FPA was significantly different from controls while it did not differ in subgroups with normal FPA.

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.

Apathetic Graves’ disease and acquired hemophilia due to factor VIIIc antibody

Acquired hemophilia due to autoantibody to Factor VIII coagulant (Factor VIIIc) is a rare event which may be observed in patients with different autoimmune diseases. To our knowledge, this association has been reported only once in patients with autoimmune thyroid disease. Here we describe a patient presenting with a severe hemorrhagic disorder due to Factor VIIIc antibody in whom biochemical screening for thyroid diseases led to a diagnosis of hyperthyroid Graves’ disease not associated to overt clinical features. This case underlines the importance of carrying out a complete screening for autoimmunity, including thyroid autoimmune disease, in all patients with apparently isolated serum Factor VIIIc inhibitors.

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.

Fibrinopeptide A and Bβ 15–42 in Liver Cirrhosis

In order to detect even minimal fibrinolysis activation in liver cirrhosis, we measured fibrinopeptide Bβ 15–42 (Bβ 15–42), an indicator of plasmin activity in vivo and α2-antiplasmin (α2-AP) in a group of cirrhotic patients. The second goal of this study was to investigate whether an increased fibrinolytic activity is related to a chronic disseminated intravascular coagulation. For this purpose we concomitantly measured fibrinopeptide A (FPA), marker of thrombin activity in vivo. Results show significantly higher levels of Bβ 15–42 in cirrhotic patients than in control (p 2-AP was lower in patients with high FPA levels than in patients with normal FPA (p 2-AP only in patients with high FPA (p 2-AP when all patients were considered. These findings confirm that in liver cirrhosis fibrinolysis activation may occur. The primary pathogenetic role of DIC may be important in this respect. However the lack of correlation between FPA and Bβ 15–42 suggests that other pathogenetic factors may be involved in determining fibrinolysis activation.

Dynamic NMR of low-sensitivity fast-relaxing nuclei: 17O NMR and DFT study of acetoxysilanes

17O NMR is not routinely used for structure characterization, and kinetic studies of fluxional organic compounds are seldom undertaken because poor sensitivity and fast quadrupole relaxation are frequently regarded as intractable issues. This work shows how, nowadays, quantitative 17O dynamic NMR studies on small organic molecules are feasible without enrichment being needed. It reports on acetoxysilanes, a class of fluxional compounds whose structure and dynamics were to be clarified. Natural abundance 17O NMR spectra were recorded over a wide range of temperatures using standard instrumentation. The analysis relies on simple linewidth measurements and directly provides the activation parameters. The activation enthalpy is found to decrease with increasing number of acetoxy groups bound to silicon. Density functional theory calculations properly predict this trend and show that a single oxygen atom of the acetoxy group is bound to silicon, excluding chelation as binding mode, and that the dynamic process involves the shift of the silicon atom between the two oxygen atoms of the acetoxy group. Copyright

Inhibition of blood coagulation activation and oral anticoagulants in patients with mechanical heart valve prostheses

Oral anticoagulants are widely used for preventing thromboembolic events in many pathological conditions, such as mechanical or biological heart valve prosthesis, atrial fibrillation, deep vein thrombosis and post-myocardial infarction (1). Particularly, the intensity of anticoagulation to be induced in patients with mechanical heart prosthesis is not well established. In fact, the Dutch Thrombosis Policy recommends deep anticoagulation (3.6-4.8 INR) irrespective of whether the prosthesis is aortal or mitral (2). In contrast the Consensus Committee for antithrombotic therapy in patients with mechanical prosthetic valves, with North American thromboplastins, suggests a therapeutic range between 2.2 and 3.3 INR for both ball and tilt disk prosthesis (3). Again, the guidelines on oral anticoagulation published on behalf of the British Society for Hematology recommend a target of between 3 and 4.5 for mechanical heart valves (1). But is deeper anticoagulation more effective in the biochemical inhibition of the coagulation cascade ? Is there any difference between aortal and mitral prosthesis considering that a higher thromboembolic risk may be present in the latter due to hypercoagulability secondary to atrial fibrillation and blood stagnation ? For this purpose we chose to measure prothrombin F 1+2 peptide that is cleaved by factor Xa from the prothrombin molecule, since it has recently been shown that F 1+2 is reduced during oral anticoagulants (4).

Are prothrombin fragment 1+2 and thrombin-antithrombin complexes useful in the management of oral anticoagulant therapy?

We investigated the behavior of prothrombin fragment F1+2 and thrombin-antithrombin complexes in 70 patients treated with chronic anticoagulant therapy. Moreover, in a longitudinal study 37 patients were evaluated twice and 16 patients three times. Twenty-eight age-and sex-matched healthy subjects were also studied as a control group. Prothrombin fragment F1+2 and thrombinantithrombin complexes were significantly higher in controls than in patients on anticoagulants. There were no differences in prothrombin fragment F1+2 or thrombinantithrombin values among patients with different International Normalized Ratios, nor in the same patients studied two or three times. Our results confirm that oral anticoagulant treatment can effectively reduce thrombin activity. However, strong anticoagulation does not induce a further significant decrease in fragment F1+2 values. Therefore, we feel measurement of fragment F1+2 might be less useful than thought in optimizing oral anticoagulant therapy.