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We report clinical findings, risk factors and neurological and cognitive long-term outcome in three Italian children aged 7, 8 and 5, respectively, who experienced cerebral venous sinus thrombosis (CVST). All children presented with headache, associated to nausea, vomiting and papilloedema. None suffered from epileptic seizures. In two of them a paresis of the sixth cranial nerve with diplopia was found. Diagnosis was confirmed by magnetic resonance imaging angiography (angio MRI) in all cases. In all patients plasma levels of protein C, protein S, antithrombin III (AT III), antiphospholipid antibodies (ApA) and homocysteine were detected. Furthermore, factor V Leiden mutation, prothrombin mutation G20210A and MTHFR mutation were searched for. A Protein C reduction was detected in all patients at onset; this finding, however, was not confirmed at follow-up in all of them. At one-year follow-up, neurological examination was normal in all children and neuropsychological assessment, aimed at excluding linguistic and non-linguistic cognitive deficits, revealed normal performances in two of them. In the third child, cognitive assessment confirmed a previously diagnosed developmental dyslexia.

To establish whether asymptomatic normotensive pregnant women with an abnormal uterine Doppler velocimetry, have haematological changes characteristic of congenital or acquired thrombophilia, and whether this information improve predict in pregnancy complications.A prospective study involved the enrolment of 30 healthy normotensive pregnant women between the 23rd and 27th week of gestation, subdivided into group A (normal uterine Doppler velocimetry) and group B (abnormal uterine Doppler velocimetry). Besides uterine velocimetry (resistence index and presence/absence of notch), at enrolment in the study the PI of the umbilical artery and of the middle cerebral artery were measured, in addition to the usual foetal biometric parameters (biparietal diameter and abdominal circumference). Contemporaneously, a 20 ml blood sample was taken for the dosage of protein C, protein S, antithrombin III, activated protein C resistance, antiphospholipid antibodies and platelet functionality. Subsequently, for all the remaining period of the pregnancy, data were collected relating to the onset of any materno-foetal complications and modality of delivery, as well as neonatal data up to the first 20 days of life.The incidence of adverse perinatal outcomes (pre-eclampsia, gestational hypertension, abruptio placentae, endouterine foetal death, preterm birth, caesarean section because of maternal or foetal problems, APGAR score lower than 7 at the 5th minute of life, small for gestational age) resulted as being 75% in group B versus 11% in group A (P0.001). The mean gestational age at delivery was 34 weeks (range 27-41) in group A versus 39 weeks (range 37-42) in group B (P0.001). No difference emerged as to either the mean activity in the plasma levels of the coagulation protein studied in patients with normal and abnormal uterine velocimetry. The same consideration is also true if the population is analysed in relation to the lesser or greater seriousness of the Doppler velocimetry abnormalities. Subdividing the patients in relation to the absence and to the presence of unfavourable perinatal outcomes, the thrombophilic indices appear to be substantially comparable.Uterine Doppler velocimetry, carried out between the 24th and the 26th week of pregnancy, proves its validity by identifying a population at high risk of adverse perinatal outcomes. In contrast, the investigations carried out on the haematological abnormalities characteristic of thrombophilia do not reveal any significant differences, either between patients with normal and those with abnormal velocimetry, or between patients with adverse perinatal outcomes and those without. It is thus unlikely that these preliminary data will lead to an improvement in the clinical reliability of uterine velocimetry.

This collaborative study, organized by the Hemostasis Subcommittee of C.I.S.M.E.L., evaluated the accuracy, precision, and comparability of the following six widely used fibrinogen assays: total clottable fibrinogen (Blombäck and Blombäck), clotting time (Von Clauss), turbidimetry (Ellis and Stransky), Chromotime System, prothrombin time (PT)-derived, and radial immunodiffusion (RID). The same frozen samples, with normal and high contents of fibrinogen, were examined in four laboratories. The methods were calibrated with an internal standard whose fibrinogen content was determined gravimetrically. Both the Von Clauss and the RID methods were reliable, accurate, and precise, if adequate calibration was used. The PT-derived method was highly reproducible, but had some problems with accuracy. We demonstrate that an adequate calibration procedure is indispensable for reliable fibrinogen measurements whatever method is used. Because neither the calibration procedures proposed by the manufacturers nor the use of lyophilized commercial plasmas is adequate for this purpose, we urge that an international standard for fibrinogen measurement be promptly established.

The constantly workload increase has led to the development of Computerised Decision Support Systems (CDSS) for a better management of patient care. Many clinical situations have been investigated to verify the utility of CDSS: few have demonstrated stable effects. One area where success has been reported is the field of oral anticoagulation management. CDSS system has demonstrated to be able to improve the treatment quality in comparison to manual method. In the future scenario of oral anticoagulant management CDSS will have a pivotal part, the constant increase of patients number and their pressure on thrombosis centres had led to the development of alternative models for delivery OAT: Primary care, General Practitioner, Patient self testing and self management and the use of CDSS has been central to the decentralisation process and may be useful in maintaining the efficacy and quality of anticoagulant control. GP with the aid of CDSS are able to deliver OAT as well as expert physician of Thrombosis Centre in terms of time spent by patient in therapeutic range.

We carried out a prospective, randomized trial to test whether a computer-based decision support system to initiate and maintain oral anticoagulant (OA) treatment can improve the laboratory quality of therapy.Two separate sets of patients on oral anticoagulants, in five Italian anticoagulant clinics, were studied: 335 patients in the first three months of treatment (stabilization phase), 916 patients (775 patient-years) beyond the third month of treatment (maintenance phase). Patients were randomized to a computerized system, which included algorithms able to suggest OA dosing and to schedule appointments (computer-aided dosing) or to an arm in which OA were prescribed by the same teams of expert physicians without such algorithms (control group). Primary outcomes were: A) the percentage of patients reaching a stable state of anticoagulation during each of the first three months of treatment; B) the percentage of time individuals spent within the aimed therapeutic range (maintenance phase).Patients in the computer-aided dosing group achieved a stable state significantly faster (p0.01) and they spent more time within the therapeutic range during maintenance (p0.001) than controls. The favorable effect of computer-aided dosing was mainly due to a reduction of the time spent below the therapeutic range and was associated with an increase of mean INR value, of anticoagulant drug dosage, and with a reduction of the number of appointments per patient (all changes significant: p0.001).The computer decision-aided support improves the laboratory quality of anticoagulant treatment, both during long-term maintenance and in the early, highly unstable phase of treatment, and it also significantly reduces the number of scheduled laboratory controls.

Cerebral venous and sinus thrombosis (CVST) is still considered a severe clinical problem that is difficult to diagnose and manage and is linked to a poor prognosis. Nonetheless, conventional cerebral angiography and magnetic resonance imaging (MRI), or more recently, MR angiography allow a more rapid and precise diagnosis, and prognosis has improved with the use of anticoagulant treatment. We report 23 cases of CVST consecutively admitted to the Institute of Neurology of the University of Parma during the period 1990-1997. In all cases diagnosis was confirmed by means of MRI or conventional angiography of brain vessels. Among the patients, 22 were female and 1 was male. In all patients, plasma levels of protein C, protein S, antithrombin III (ATIII) and antiphospholipid antibodies (APA) were evaluated. In 15 of 23 patients, the presence of factor V Leiden mutation was also determined, and found positive in 3 patients (20%). Of the 22 female patients, 15 (68%) were on low-oestrogen (containing less than 50 microg oestrogen) oral contraceptive (OC) treatment. This percentage of OC use by patients with CVST is much higher than that of the rest of the female Italian population. OC use was associated with the presence of factor V Leiden mutation in two cases, with a deficiency of protein C in 1 case and a deficiency of protein S in another.Whether low-oestrogen Ocs may induce cerebral thromboembolic events is an open matter. According to our data, it may be argued that Ocs, even if at low oestrogen content, represent a major risk factor for CVST. The use of Ocs, as is the case for systemic venous thromboembolic events, may further increase the risk of CVST in women carrying the factor V Leiden mutation or other inherited hyperthrombotic conditions.

The synthesis of a new compound, 2-amino-1,2-benzisothiazolin-3-one, is described and its antiplatelet activity was studied. A good platelet aggregation inhibitory activity of the tested drug was clearly demonstrated both in vitro and ex vivo, presumably through an effect on arachidonic acid cascade or directly on thromboxane A2 (TXA2) receptors. An early and long lasting effect on bleeding time has also been observed. The results suggest that 2-amino-1,2-benzisothiazolin-3-one could be a potential antithrombotic agent.

The paper reports on rate and type of thrombotic events occurring during the observational, prospective, inception-cohort, multicenter ISCOAT study. 2,745 unselected, daily practice patients, consecutively referring to 34 Italian anticoagulation clinics to monitor the oral anticoagulant treatment, were included in the study from beginning of their first anticoagulant course. During a total follow-up of 2,011 patient-years of treatment 70 thrombotic events (3.5 per 100 patient years) were recorded in 67 patients: 20 fatal (1%), 39 major (1.9%) and 11 minor (0.6%). 34/70 events occurred within the first 90 days of treatment (relative risk - at multivariate analysis - ofor =90 days vs.90 = 20.6, C.I. 12.7-33.5; p0.0001). The risk was higher in patients agedor =70 y (1.62, C.I. 1.0-2.61; p0.05), and when indication for anticoagulant treatment was peripheral/cerebral arterial disease (1.84, C.I. 1.01-3.36; p0.05). The frequency of thrombotic events was 17.5% when international normalised ratio (INR) levels were1.5, decreasing to 2.3% for INRs within the 2-2.99 category (relative risk of INRs2.0 vs.or =2 = 1.88, C.I. 1.16-3.07; p0.05). The recorded rate of thrombotic events was lower than that reported in the few available studies. A greater risk should be expected during the first 90 days of treatment, when anticoagulation levels are2.0 INR, in patients70 years and in those with cerebrovascular/peripheral arterial disease.

Bleeding is the most serious complication of the use of oral anticoagulation in the prevention and treatment of thromoboembolic complications. We studied the frequency of bleeding complications in outpatients treated routinely in anticoagulation clinics.In a prospective cohort from thirty-four Italian anticoagulation clinics, 2745 consecutive patients were studied from the start of their oral anticoagulation (warfarin in 64%, acenocourmarol in the rest). The target anticoagulation-intensity was low (international normalised ratio [INR]or = 2.8) in 71% of the patients and high (2.8) in the remainder. We recorded demographic details and the main indication for treatment and, every 3-4 months, INR and outcome events. Such events included all complications (bleeding, thrombosis, other), although only bleeding events are reported here, and deaths. We divided bleeding into major and minor categories.43% of the patients were women. Nearly three-fifths of the patients were aged 60-79; 8% were over 80. The main indication for treatment was venous thrombolism (33%), followed by non-ischaemic heart disease (17%). Mean follow-up was 267 days. Over 2011 patient-years of follow-up, 153 bleeding complications occurred (7.6 per 100 patient-years). 5 were fatal (all cerebral haemorrhages, 0.25 per 100 patient-years), 23 were major (1.1), and 125 were minor (6.2). The rate of events was similar between sexes, coumarin type, size of enrolling centre, and target INR. The rate was higher in older patients: 10.5 per 100 patient-years in those aged 70 or over, 6.0 in those aged under 70 (relative risk 1.75, 95% Cl 1.29-2.39, p0.001). The rate was also higher when the indication was peripheral and/or cerebrovascular disease than venous thromboembolism plus other indications (12.5 vs 6.0 per 100 patient-years) (1.80, 1.2-2.7, p0.01), and during the first 90 days of treatment compared with later (11.0 vs 6.3, 1.75, 1.27-2.44, p0.001). A fifth of the bleeding events occurred at low anticoagulation intensity (INR2, rate 7.7 per 100 patient-years of follow-up). The rates were 4.8, 9.5, 40.5, and 200 at INRs 2.0-2.9, 3-4.4, 4.5-6.9, and over 7, respectively (relative risks for INR4.5, 7.91, 5.44-11.5, p0.0001).We saw fewer bleeding events than those recorded in other observational and experimental studies. Oral anticoagulation has become safer in recent years, especially if monitored in anticoagulation clinics. Caution is required in elderly patients and anticoagulation intensity should be closely monitored to reduce periods of overdosing.

To assess the risk of thromboembolism in women using oral contraceptives (OCs), we identified through computer search in the hospitals of the province of Parma, Italy, all women aged 15-44 who were resident in the province and had a documented thromboembolic event in the years 1989-93. The number of users and nonusers of OCs was estimated by the drug sale data for the province and by the demographic statistics. In cases with venous thromboembolism (VT) the prevalence of concomitant deficiency of antithrombin III, protein C, protein S, and of factor V gene mutation Arg506GIn was evaluated. The incidence rate of VT was 37/59,603 woman-years in users (0.62 per 1000) and 13/303,954 woman-years in nonusers (0.042 per 1000), for a relative risk (RR) of 14.5 (95% confidence interval: 7.8-27.1; P0.001); the rate of stroke per 1000 woman-years was 0.17 in users and 0.036 in nonusers (RR = 4.6; 2.9-10.7; P0.01). A congenital thrombophilia involving the protein C anticoagulant system was documented in about 25% of young women developing venous thromboembolism while on OCs.

The International Sensitivity Index (ISI) of thromboplastins is determined by calibration using fresh plasmas from 60 patients stabilized on oral anticoagulants and 20 healthy subjects. This procedure is demanding, particularly for those who have no easy access to patients. The alternative use of a smaller number of lyophilized plasmas has already been considered, but one important issue, the number of repeated measurements to be carried out, has never been addressed. Two commercial rabbit thromboplastins, A and B, were calibrated in 3 laboratories against CRM 149R. On each of 10 working days, prothrombin times were measured for a different set of 8 fresh plasmas and for the same set of 8 lyophilized plasmas. The ISI values for both thromboplastins were estimated by orthogonal regression on fresh and lyophilized plasmas. The between- and within-laboratory CV values of the estimated ISI were taken as measures of precision of the calibration. In addition, ISI and CV were calculated daily on cumulative results obtained with lyophilized plasmas from day 1 to day 10. The ISI values for both thromboplastins calculated with lyophilized plasmas were not significantly different from those with fresh plasmas (mean of 3 laboratories: 1.42 vs 1.48 for A and 1.22 vs 1.20 for B). The between-laboratory precision of the calibration with lyophilized plasmas was not considerably different from that with fresh plasmas (CV for 3 labs: 5.2% vs 6.8% for A and 0.9% vs 2.2% for B). The ISI estimated with lyophilized plasmas on results of day 1 were not different from those of days 2 through 10. Good within-laboratory precision of the calibration (CV around 2%) was already achieved on day 3. In conclusion, this study shows that lyophilized plasmas pooled from normals and patients on oral anticoagulants can be used as substitutes for individual fresh plasmas to simplify the existing procedure for thromboplastin calibration.

To evaluate the role of low-molecular weight heparin (LMWH) as an alternative to oral anticoagulants in the prevention of recurrent venous thromboembolism, we compared in a randomized trial conventional warfarin treatment with a three-month course of enoxaparin 4000 anti-Xa units once a day subcutaneously. 187 patients with symptomatic deep-vein thrombosis (DVT), diagnosed by strain-gauge plethysmography plus D-dimer latex assay and confirmed by venography in most cases, were treated with full-dose subcutaneous heparin for ten days and then randomized to secondary prophylaxis. During the 3-month treatment period, 6 of the 93 patients who received LMWH (6%) and 4 of the 94 patients on warfarin (4%) had symptomatic recurrence of venous thromboembolism confirmed by objective testing (p = 0.5; 95% confidence interval [CI] for the difference, -3% to 7%). Four patients in the LMWH group had bleeding complications as compared with 12 in the warfarin group (p = 0.04; 95% CI for the difference, 4% to 14%). In the 9-month follow-up period, during which 34 patients on warfarin prolonged treatment for other 3 months and 14 up to one year, 10 patients in the enoxaparin group and 4 patients in the warfarin group suffered a documented recurrence of venous thromboembolism. Of these 14 late recurrences, just one occurred in patients with postoperative DVT. After one year there were 16 recurrences (17%) in the LMWH group and 8 (9%) in the warfarin group (p = 0.07; 95% CI for the difference, 1% to 16%).(ABSTRACT TRUNCATED AT 250 WORDS)

In our Center for the Surveillance of Anticoagulant Treatment, most of the 1700 patients followed-up are traditionally treated with acenocoumarol, while warfarin is administered nowadays to an increasing proportion of patients. To assess if the difference in the pharmacokinetics of these two drugs may determine a different laboratory quality of treatment, a retrospective study was performed on the computerized files of all 142 patients on treatment with warfarin for more than 100 days and on a control group of 142 patients treated with acenocoumarol, matched for age, sex, disease state and duration of oral anticoagulant therapy (OAT). The study considered 7071 assays for a total of 432 patient-years of treatment. The overall quality of treatment was significantly better in patients treated with warfarin (72% of controls within the therapeutic range versus 67% on acenocoumarol, p0.001). Also the individual quality of therapy, which was assessed as the percentage of patients with 75% or more assays in range, was in favour of warfarin (50.7% vs 34.5%, p0.05). Warfarin therapy was more stable and fewer assays were required for treatment monitoring. Confounding factors possibly influencing the treatment stability, such as interfering drugs, diagnostic or therapeutical procedures requiring withdrawal of anticoagulation, were evaluated and no significant difference between the two groups was found. The difference in the laboratory quality of OAT was marked in patients treated for prevention of arterial thromboembolism, while it was negligible in patients with venous thromboembolic disease, whose mean duration of OAT was considerably shorter. Since there is no evidence that acenocoumarol is more efficacious or safer than warfarin, the latter seems to be preferable for patients who are candidate to very prolonged OAT.

This collaborative study, organized by the Hemostasis Subcommittee of C.I.S.M.E.L., evaluated the accuracy, precision, and comparability of the following six widely used fibrinogen assays: total clottable fibrinogen (Blombäck and Blombäck), clotting time (Von Clauss), turbidimetry (Ellis and Stransky), Chromotime System, prothrombin time (PT)-derived, and radial immunodiffusion (RID). The same frozen samples, with normal and high contents of fibrinogen, were examined in four laboratories. The methods were calibrated with an internal standard whose fibrinogen content was determined gravimetrically. Both the Von Clauss and the RID methods were reliable, accurate, and precise, if adequate calibration was used. The PT-derived method was highly reproducible, but had some problems with accuracy. We demonstrate that an adequate calibration procedure is indispensable for reliable fibrinogen measurements whatever method is used. Because neither the calibration procedures proposed by the manufacturers nor the use of lyophilized commercial plasmas is adequate for this purpose, we urge that an international standard for fibrinogen measurement be promptly established.

A case of warfarin-induced dermatitis in a 79 year-old patient with Protein S deficiency is described. Both total Protein S antigen and free Protein S were moderately reduced (about 50%). The skin lesion did not progress to frank necrosis and it was associated with elevated creatin phosphokinase (CPK) levels in plasma and with thrombosis of the anterior tibial vein localized to the area of dermatitis (probably warfarin-induced deep venous thrombosis). After warfarin withdrawal and beginning of heparin therapy, serum CPK rapidly normalized and the skin lesion improved.

271 patients with acute symptomatic deep venous thrombosis of lower limbs, confirmed by strain-gauge plethysmography and/or venography, were randomly assigned to receive intermittent subcutaneous heparin calcium or heparin sodium by continuous intravenous infusion for 6-10 days. Heparin dosage was adjusted to maintain activated partial thromboplastin time values (Thrombofax reagent) at 1.3-1.9 times the basal ones. Strain-gauge plethysmography was repeated at the end of heparin treatment, and evaluation of therapy was performed by comparing the indexes of venous hemodynamics and by assessing the incidence of pulmonary embolism and of bleeding complications. In the intravenous group, Maximal Venous Outflow (MVO) increased from 20.8 +/- 12.8 to 28.4 +/- 17.5 ml/min per 100 ml of tissue and Venous Capacitance (VC) from 1.39 +/- 0.92 to 1.94 +/- 1.0 ml/100 ml of tissue (mean +/- SD). In the subcutaneous group, MVO increased from 21.0 +/- 12.7 to 27.5 +/- 18.1 and VC from 1.60 +/- 0.86 to 2.06 +/- 1.0. The median improvement of MVO and VC were 22% and 36% respectively in the IV group and 20% and 24% in the SC group. Clinical pulmonary embolism occurred in 2 patients in the intravenous group (1 fatal) and in 4 in the subcutaneous group (1 fatal). 9 major bleeding complications occurred in the intravenous group (1 fatal) and 5 in the subcutaneous group (1 fatal). The differences were not significant at the statistical analysis. The results suggest that subcutaneous intermittent heparin has a comparable efficacy to continuous intravenous heparin in the treatment of deep venous thrombosis. To the same conclusion points an overview of the seven randomized trials which compared these treatment modalities.

Heparin administration for operations with extracorporeal circulation (ECC) usually is performed following prefixed, standardized protocols. These regimens secure an adequate level of anticoagulation, hut they often involve prolonged periods of overheparinization associated with an undue risk of hemorrhage. The predictive value of preoperative studies on the anticoagulant effect of heparin was investigated in 10 patients. The study was performed both in vitro and in vivo using the Xa inhibitor assay as an index of the anticoagulation induced by heparin. Adding variable amounts of heparin in vitro to patient’s plasma resulted in straight (at least up to 7 U. per milliliter) and parallel, but not coincident, dose/response curves, so confirming a different individual sensitivity to heparin. Disappearance curves of the anticoagulant effect in plasma following intravenous administration of a single standard dose of heparin in the same patients showed an even greater patient-to-patient variability, with “half-life” times ranging from 30 to 150 minutes. No relationship was found between the two parameters (in vitro sensitivity to heparin and clearance rate from plasma in vivo). Moreover, neither of them could be correlated with the response to heparin, subsequently observed during ECC in the same patients. Preoperative investigations with the methods presently available are not adequate to choose individual heparin administration regimens for cardiac operations.

The efficacy and safety of pentoxifylline (400 mg tid orally) and aceno coumarol, administered singly or in combination, in the treatment of intermit tent claudication associated with chronic occlusive arterial disease were evaluated in a multi-center, randomized, factorial, blind clinical trial involving 146 patients. The response to treatment was assessed by measuring pain-free walking time on the treadmill and by Doppler ankle/arm systolic pressure ratio at rest and after treadmill. Both pentoxifylline and acenocoumarol were significantly more effective than placebo in increasing the proportion of patients who improved their per formance on the treadmill after one year of treatment. Benefit from active treatment was also apparent from the results of Doppler examinations per formed after physical exercise. No significant differences were observed in comparing the effect of one ac tive drug versus the other or versus the combined treatment. Five major hemorrhagic complications were registered in anticoagulated pa tients, two fatal cerebral hemorrhages and one gastrointestinal bleeding occur ring in the group treated with both active drugs. The investigators conclude that (1) pentoxifylline is effective and safe in the treatment of patients with intermittent claudication (2) the benefits of oral anti coagulant therapy are outweighed by the risk of serious bleeding, and (3) the risk of bleeding is probably increased by the combined treatment with pentox ifylline.

Heparin administration for operations with extracorporeal circulation (ECC) usually is performed following prefixed, standardized protocols. These regimens secure an adequate level of anticoagulation, but they often involve prolonged periods of overheparinization associated with an undue risk of hemorrhage. The predictive value of preoperative studies in the anticoagulant effect of heparin was investigated in 10 patients. The study was performed both in vitro and in vivo using the Xa inhibitor assay as an index of the anticoagulation induced by heparin. Adding variable amounts of heparin in vitro to patient's plasma resulted in straight (at least up to 7 U. per milliliter) and parallel, but not coincident, dose/response curves, so confirming a different individual sensitivity to heparin. Disappearance curves of the anticoagulant effect in plasma following intravenous administration of a single standard dose of heparin in the same patients showed an even greater patient-to-patient variability, with "half-life" times ranging from 30 to 150 minutes. No relationship was found between the parameters (in vitro sensitivity to heparin and clearance rate from plasma in vivo). Moreover, neither of them could be correlated with the response to heparin, subsequently observed during ECC in the same patients. Preoperative investigations with the methods presently available are not adequate to choose individual heparin administration regimens for cardiac operations.

Efficacy and safety of a low molecular weight heparin (Alfa LMWH) was compared with unfractionated heparin (UFH) in the prevention of post-operative venous thromboembolism after hip fractures. Forty-nine patients were randomized to treatment with Alfa LMWH 7500 anti-Xa coagulometric units twice daily or with UFH 5000 IU t.i.d. Screening for thrombosis was performed with 125-I-fibrinogen leg scanning and strain-gauge plethysmography. Positive results were confirmed by venography. Five patients in the Alfa LMWH group (20 per cent) developed venographycally proven deep vein thrombosis (DVT) versus seven (29 per cent) in the UFH group. One pulmonary embolism and two deaths occurred in the UFH group and none in the LMWH group. No differences in haemorrhagic complications and blood loss indices were observed. Alfa LMWH appears to be a promising drug for prevention of venous thromboembolism after orthopaedic surgery. A "flexible" schedule of administration is proposed on the basis of the results of plasma anti-Xa assays.

Deficiency of prostacyclin (PGI2) has been related to the pathogenesis of thrombotic thrombocytopenic purpura (TTP), and reduced PGI2 activity is thought to be secondary to a lack of plasma factor(s) which normally stimulates PGI2 production. We measured PGI2 production by means of the method of Moncada et al (Lancet 1:18, 1977), as platelet aggregation inhibitory activity released by venous specimen removed surgically in a 52 year-old woman with TTP in the acute phase of the disease. The patient was subsequently cured by plasma exchange.Platelet aggregation inhibitory activity released from venous tissues of the patient was normally detectable and comparable to that of a healthy control. Moreover, patient plasma was able to induce release of prostacyclin-like activity from exhausted veins (both from patient and normal control) as well as normal plasma. Hence release of PGI2 like activity from venous tissues and ability of plasma to stimulate prostacyclin synthesis in normal vascular tissues were not impaired in our patient with TTP in the acute phase of the disease.Our findings demonstrate that PGl2 deficiency is not implicated in the pathogenesis of all cases of TTP.

An inherited deficiency of antithrombin III (AT III), measured with four different, functional and immunological, methods, was found in 8 out of 11 examined members and in 3 out of 11 examined members of two Italian families (D.M. and A. families). Biological activity, measured with Abildgard’s clotting assay and with an amidolytic method, ranged between 17 and 75%. Cross immunoelectrophoresis, with or without heparin, performed in the two propositi and in 1; other relatives, showed a normal pattern of migration.A different behaviour of AT III after anticoagulation with acenocoumarin was seen in two long-term treated subjects. The proposita of the D.M. family, who had a history of recurrent thrombotic accidents, did not show any increase of AT III levels, measured in the first two weeks and after 6 and 12 months of therapy. A significant (about 50%) increase both with the functional and immunological methods was on the contrary observed in the propositus of A. family, who had undergone surgery because of mesenteric vein thrombosis. Until now both patients have been free of thrombotic recurrences.Our findings confirm previous reports of variable effects of oral anticoagulants on AT III levels in subjects with congenital deficiency.

2 cases of acute idiopathic thrombotic thrombocytopenic purpura are reported. Both of them were treated with plasma exchange, antiplatelet drugs and prednisolone and both completely recovered. Plasma exchange appeared to be the critical treatment. In 1 of these cases the prostacyclinlike activity released from venous tissues and the ability of plasma to stimulate synthesis of prostacyclinlike activity from venous tissues exhausted after repeated washings were investigated. Both activities were detectable and comparable to those of a healthy control. These findings do not support the hypothesis of a major role played by the prostacyclin system in the pathogenesis of thrombotic thrombocytopenic purpura.

F.VIII related activities (coagulant-VIII:C, antigen-VIIIR:AG, v.Willebrand factor- VIIIR.WF) before and after venous occlusion (VO) were investigated in pregnant women, in women on the pill, and in men with atherosclerosis obliterans. Mean basal values of atherosclerotic patients were not different from healthy male controls. A concordant rise in all the three activities was seen after VO in both groups without any change in the ratios between them. Basal values of women on long-term hormonal contraception were also comparable with those of a control group, while a group of third trimester pregnant women showed high values for all components, and very high ones for VIII R:AG, with striking increases in AG/C and AG/wF ratios. Following VO, strictly concordant variations in the three activities were observed in all cases, so that ratios remained always unchanged, at their different levels.The results are consistent with the hypothesis of a “complete” F.VIII released activity, induced by venous stasis in these conditions. Pregnancy has quite different effects on F.VIII in comparison with estro-progestinic treatment. No variations seem to be associate with occlusive arterial disease.

The effect of 1,4-bis-[3(3,4,,5-trimethoxybenzoyl-oxy)-propyl]-perhydro-1,4-diazepine (dilazep, Cormelian), a coronaroactive drug, was studied by various tests of hemostasis in vitro on human plasma. The antiplatelet action of the drug was clearly demonstrated: it inhibited, in appropriate concentrations, ADP, adrenaline and collagen induced aggregation platelet factor 3 (PF3) availability and clot retraction induced by ADP-reptilase. Conversely, coagulation tests as well as the lysis time of diluted whole blood were unaffected by the drug.

Three substances widely used as vasoactive drugs are known to have an inhibiting effect on platelet aggregation ‘in vitro’. We investigated the changes induced on thrombelastogram, routine clotting tests, euglobulin lysis time (ELT), platelet count, aggregation, and adhesiveness by i, v. administration of these drugs to man. The same indices were also studied ‘in vitro’ by adding comparable concentrations of the substances to human blood or plasma.Aminophilline did not produce any significant variation in ADP-or collagen-induced aggregation either ‘in vitro’ (50 to 200 μg/ml) or ‘in vivo’ (240 mg). A trend to disaggregation was seen only in a few cases. Shorter ELT were found 30 and 120 minutes after injection.A papaverine derivative (Metaverinum, 150 mg) showed a similar ‘in vivo’ pattern: minor changes in platelet function tests and a moderate activation of fibrinolysis were seen. The drug acted ‘in vitro’ as a powerful inhibitor of aggregation (from 30 µg/ml)while fibrinolysis was only activated at the highest concentration (120 µg/ml).Bencyclan, capable of inhibiting platelet function ‘in vitro’ at very low concentrations (0.25µM) did not show similar effects ‘in vivo’ (50 mg) apart from a reduced platelet adhesiveness to glass.