LRP1/CD91 is up-regulated in monocytes from patients with haemophilia A: a single-centre analysis.

The low-density lipoprotein receptor-related protein 1 (LRP1) is an ubiquitously expressed endocytic receptor that, among its several functions, is involved in the catabolism of coagulation factor VIII (FVIII) and in the regulation of its plasma concentrations. Although LRP1/CD91 polymorphisms have been associated with increased FVIII levels and a consequent thrombotic risk, no data are available on LRP1/CD91 expression in patients with inherited FVIII deficiency. With the aim of elucidating this issue, 45 consecutive patients with haemophilia A (HA) (18 severe, 5 moderate and 22 mild HA) were enrolled in this cross-sectional, single-centre survey. The LRP1/CD91 mean fluorescence intensity (MFI) in monocytes from HA patients was significantly higher than that detected in 90 healthy blood donors (105 vs. 67, P < 0.001). This over-expression was independent of hepatitis C virus infection status and varied according to the severity of the haemophilia, being higher in patients with more severe FVIII deficiency. In conclusion, our study documents for the first time that LRP1/CD91 is over-expressed on monocytes from HA patients, with the intensity of expression varying according to the severity of the FVIII deficiency. Further studies are needed to assess the clinical implications of these findings.

Major bleeding in patients undergoing PCI and triple or dual antithrombotic therapy: a parallel-cohort study.

The combination of oral anticoagulants with dual antiplatelet therapy (DAT) in patients undergoing percutaneous coronary intervention with stent implantation (PCI-stenting) is subject to controversy due to the high risk of bleeding. In this multicenter retrospective parallel-group study, we compared the rate of adverse events in chronically anticoagulated patients who underwent PCI-stenting and were discharged on aspirin, clopidogrel and warfarin (triple antithrombotic therapy [TT] group) and were followed in Italian anticoagulation centers, with a parallel cohort of patients who underwent PCI-stenting and were discharged on DAT group. The primary endpoint was the incidence of major bleeding while the patients were in TT and DAT. A secondary endpoint was the occurrence of major ischemic adverse events (MACEs). The final cohort consisted of 229 TT patients and 231 DAT patients followed up for 6 and 7 months, respectively. There were 11 (4.8%; 9.1% patient/years) major bleeding events in the TT group (1 was fatal) as compared to 1 (0.4%; 0.7% patient/years) event in the DAT group (p = 0.003). Of the 28 (6.1%) MACE recorded during the follow-up, 12 (5.2%) occurred in the TT group and 16 (6.9%) in the DAT group. In conclusion, despite close monitoring of anticoagulated patients in dedicated centers, the major bleeding incidence remains high among unselected patients undergoing PCI-stenting and treated with TT. Any efforts to minimize these events should be pursued.

Influence of recent immobilization and recent surgery on mortality in patients with pulmonary embolism.

BACKGROUND: The influence of recent immobilization or surgery on mortality in patients with pulmonary embolism (PE) is not well known. METHODS: We used the Registro Informatizado de Enfermedad TromboEmbólica (RIETE) data to compare the 3-month mortality rate in patients with PE, with patients categorized according to the presence of recent immobilization, recent surgery, or neither. RESULTS: Of 18,028 patients with PE, 4169 (23%) had recent immobilization, 2212 (12%) had recent surgery, and 11,647 (65%) had neither. The all-cause mortality was 10.0% (95% confidence interval [CI] 9.5-10.4), and the PE-related mortality was 2.6% (95% CI 2.4-2.9). One in every two patients who died from PE had recent immobilization (43%) or recent surgery (6.7%). Only 25% of patients with immobilization had received prophylaxis, as compared with 65% of the surgical patients. Fatal PE was more common in patients with recent immobilization (4.9%; 95% CI 4.3-5.6) than in those with surgery (1.4%; 95% CI 1.0-2.0) or those with neither (2.1%; 95% CI 1.8-2.3). On multivariate analysis, patients with immobilization were at increased risk for fatal PE (odds ratio 2.2; 95% CI 1.8-2.7), with no differences being seen between patients immobilized in hospital or in the community. CONCLUSIONS: Forty-three per cent of patients dying from PE had recent immobilization for ≥4 days. Many of these deaths could have been prevented.

Computer assisted anticoagulant therapy.

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.

Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance: a multicenter collaborative family study.

Deficiencies of antithrombin (AT), protein C (PC) or protein S (PS), and activated protein C resistance (APCR) are very well-established coagulation defects predisposing to venous thromboembolism (VTE). We performed a retrospective cohort family study to assess the risk for VTE in individuals with AT, PC, or PS deficiency, or APCR. Five hundred thirteen relatives from 9 Italian centers were selected from 233 families in which the proband had had at least 1 episode of VTE. We calculated the incidence of VTE in the whole cohort and in the subgroups after stratification by age, sex, and defect. The overall incidence of VTE (per 100 patient-years) in the group of relatives was 0.52. It was 1.07 for AT, 0.54 for PC, 0.50 for PS, 0.30 for APCR, and 0.67 in the group with a double defect. The incidence was associated with age, but not with sex. The mean age at onset was between 30 and 40 years for all the coagulation defects. Women had the peak of incidence in the age range of 21 to 40 years, earlier than men. The lifetime risk for VTE was 4.4 for AT versus APCR, 2.6 for AT versus PS, 2.2 for AT versus PC, 1.9 for PC versus APCR, and 1.6 for PS versus APCR. AT deficiency seems to have a higher risk for VTE than the other genetic defects. There is a relation between age and occurrence of thrombosis for both men and women. The latter had the peak of incidence earlier than the former.

Pre-operative plasma levels of soluble fibrin polymers correlate with the development of deep vein thrombosis after elective neurosurgery.

The role of blood tests in identifying patients at high risk for post-operative venous thromboembolism is undefined. The aim of this study was to evaluate the correlation between pre-operative plasma levels of soluble fibrin polymers (SFP), as determined by a recently developed enzyme-linked immunosorbent assay (ELISA) assay (TpP), and the incidence of deep vein thrombosis (DVT) after elective neurosurgery. Blood samples for SFP assay were withdrawn on the day before surgery from 157 consecutive patients undergoing elective neurosurgery for brain or spinal tumour. Patients were randomized to subcutaneous enoxaparin (40 mg once daily) or placebo given for at least 7 days. All patients wore compression stockings. DVT was assessed by bilateral venography, performed on day 8 +/- 1. Thirty-four patients (21.7%) were found to have a DVT, proximal in 11 (7%) and isolated distal in 23. Patients with and without DVT had a plasma pre-operative SFP levels of 6.2 +/- 4.6 and 1.9 +/- 1.5 mg/ml respectively (mean +/- SD) (P < 0.001). SFP levels in patients with proximal and isolated distal DVT were 7.6 +/- 5.1 and 5.5 +/- 4.4 microg/ml, respectively (P = 0.22). SFP cut-off levels categorized patients into three classes of DVT incidence. The incidence of DVT was 7.4% (6 of 81) for SFP levels < 2 microg/ml, 20.4% (11 of 54) for levels between 2 and 4.5 microg/ml, and 77.3% (17 of 22) for levels > 4.5 microg/ml (P= 0.001, Cochran-Mantel-Haenszel test). We conclude that pre-operative SFP levels correlate with post-operative DVT in elective neurosurgery patients. Further studies are required to define whether pre-operative SFP measurement could be useful in patient management.

Risk of venous thromboembolism and stroke associated with oral contraceptives. Role of congenital thrombophilias.

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; P < 0.001); 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; P < 0.01). A congenital thrombophilia involving the protein C anticoagulant system was documented in about 25% of young women developing venous thromboembolism while on OCs.

Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis.

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)

A comparative study on the quality of oral anticoagulant therapy (warfarin versus acenocoumarol).

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, p < 0.001). 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%, p < 0.05). 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.

Variation in hemostatic parameters after intra-arterial and intravenous administration of iodinated contrast media.

RATIONALE AND OBJECTIVES: A few case reports have suggested a possible thrombogenic effect of nonionic contrast media. In vitro investigations have lead to conflicting results. The authors performed three ex vivo studies to evaluate the influence of an ionic, ioxaglate, and a nonionic, iopamidol, low-osmolality contrast medium on a series of clotting and fibrinolytic parameters, after intravenous or intra-arterial administration, during routine diagnostic procedures. METHODS: In the first study, iopamidol was given to 20 consecutive patients through an arterial catheter for digital subtraction arteriography (DSA). In the second study, iopamidol was compared with ioxaglate. The media were randomly and blindly administered intravenously to 21 consecutive patients undergoing brain computed tomography (CT). Finally, ioxaglate was administered intra-arterially to 20 consecutive patients, in a situation comparable with that of the first study. RESULTS: In the first study, a weak anticoagulant effect and an activation of fibrinolysis were found, associated with indirect markers of thrombin generation, such as increased plasma levels of fibrinopeptide A (FpA) and thrombin-antithrombin III complexes (TAT). In the second study, no significant changes were seen with either contrast medium, for thrombin or fibrinolysis activation parameters. In the third study, the intra-arterially administered contrast medium elicited a marked increase of FpA and TAT, together with an anticoagulant effect. CONCLUSION: Both ionic and nonionic contrast media are able to interfere with the clotting/fibrinolytic system in the general circulation when they are administered to patients at the usual dosages. Ioxaglate shows more marked anticoagulant and thrombin-generating effects than iopamidol. The procedure (ie, arterial catheter versus intravenous infusion) seems to be more important than the category of contrast medium in conditioning the magnitude of these effects.

Duplex ultrasound diagnosis of symptomatic proximal deep vein thrombosis of lower limbs.

Real time ultrasound (US) was used to examine 165 consecutive inpatients with clinically suspected deep vein thrombosis of lower limbs. In order to evaluate accuracy, the results of non-invasive techniques were compared with ascending venography, performed in all patients. Assessment included only femoro-popliteal veins, because of difficulty in visualizing calf vein with US. Diagnosis of thrombosis was based on noncompressibility of the examined veins; pulsed Doppler provided further information by evaluating blood flow. In our series Duplex ultrasound was very accurate in detecting acute thrombosis of the proximal veins, sensitivity being 97% and specificity 98%. With US it is also possible to detect conditions that mimic deep vein thrombosis, such as muscular rupture, hematoma, popliteal cyst or compressive tumors. In conclusion US is considered a valid alternative to contrast venography in the diagnosis of proximal vein thrombosis of lower limbs.

Warfarin induced dermatitis and venous thrombosis in a patient with Protein S deficiency.

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.

Subcutaneous vs intravenous heparin in the treatment of deep venous thrombosis--a randomized clinical trial.

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.

[Ultrasonography in the diagnosis of deep venous thrombosis of the legs]. / Gli ultrasuoni nella diagnosi di trombosi venosa profonda dell'arto inferiore.

One hundred consecutive inpatients with clinically suspected deep venous thrombosis (DVT) were examined by US; the last 19 cases were studied also by means of color-Doppler US. In order to evaluate the method reliability, US results were compared with those obtained with contrast venography, which was performed on all patients. The studied region included the femoro-popliteal vein, while no attempt was made to image the calf veins, which are difficult to evaluate with US. In our series, venographic results were in substantial agreement with US findings, with 99% and 100% sensitivity and specificity, respectively. Diagnosis was based only on noncompressibility of the thrombotic vein, despite the absence of visible clots; pulsed Doppler information supported diagnosis by evaluating blood flow. Further diagnostic progress was provided by color-Doppler US, which allows flow lumen to be defined in color. US also allowed the detection of the conditions mimicking DVT, such as muscular ruptures, hematomas, popliteal cysts, or compressive tumors. In conclusion, US and color-Doppler US prove to be valid alternatives to contrast venography in the diagnosis of proximal DVT of the lower limbs.

Acenocoumarol and pentoxifylline in intermittent claudication. A controlled clinical study. The APIC Study Group.

The efficacy and safety of pentoxifylline (400 mg tid orally) and acenocoumarol, administered singly or in combination, in the treatment of intermittent 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 performance on the treadmill after one year of treatment. Benefit from active treatment was also apparent from the results of Doppler examinations performed after physical exercise. No significant differences were observed in comparing the effect of one active drug versus the other or versus the combined treatment. Five major hemorrhagic complications were registered in anticoagulated patients, two fatal cerebral hemorrhages and one gastrointestinal bleeding occurring 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 anticoagulant therapy are outweighed by the risk of serious bleeding, and (3) the risk of bleeding is probably increased by the combined treatment with pentoxifylline.

Thromboembolic manifestations and congenital factor V deficiency: a family study.

A case of congenital factor V deficiency is reported. Despite this defect in blood coagulation, the patient had experienced recurrent thrombophlebitis and was referred to us because of deep venous thrombosis of the lower limbs associated with pulmonary embolism. Both functional and immunological assays documented a deficiency of factor V (12 and less than 10%, respectively). The available family members were investigated and the same defect was found in 2 brothers of the propositus, who also suffered from thrombotic diseases (recurrent thrombophlebitis and myocardial infarction). The propositus has been treated with long-term oral anticoagulant therapy, no hemorrhagic complications or thrombotic recurrences being recorded in 2 years' time.