Daniel Dias Ribeiro

Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study

In thrombophilic families, protein S deficiency is clearly associated with venous thrombosis. We aimed to determine whether the same holds true in a population-based case-control study (n = 5317). Subjects were regarded protein S deficient when protein S levels were < 2.5th percentile of the controls. Free and total protein S deficiency was not associated with venous thrombosis: free protein S < 53 U/dL, odds ratio [OR] 0.82 (95% confidence interval [CI], 0.56-1.21) and total protein S < 68 U/dL, OR 0.90 (95% CI, 0.62-1.31). When lower cutoff values were applied, it appeared that subjects at risk of venous thrombosis could be identified at levels < 0.10th percentile of free protein S (< 33 U/dL, OR 5.4; 95% CI, 0.61-48.8). In contrast, even extremely low total protein S levels were not associated with venous thrombosis. PROS1 was sequenced in 48 subjects with free protein S level < 1st percentile (< 4 6 U/dL), and copy number variations were investigated in 2718 subjects, including all subjects with protein S (free or total) < 2.5th percentile. Mutations in PROS1 were detected in 5 patients and 5 controls reinforcing the observation that inherited protein S deficiency is rare in the general population. Protein S testing and PROS1 testing should not be considered in unselected patients with venous thrombosis.

Factor V Leiden and increased risk for arterial thrombotic disease in young Brazilian patients.

The contribution of mutations in the prothrombin (FII G20210A), methylenetetrahydrofolate reductase (C677T) genes and factor V Leiden (FVL) to the pathogenesis of arterial thrombosis remains controversial. In this study, these polymorphisms were investigated by polymerase chain reaction–restriction fragment length polymorphism in a group of 53 patients that presented arterial thrombosis other than myocardial infarction as a first thrombotic event and 275 control subjects living in the state of Minas Gerais, Brazil. Odds ratio (OR) and χ2 tests were applied for statistical comparisons. Similar frequencies were detected among patients and control subjects for the C677T mutation. The 20210A mutation was present in 3.6% of the control subjects but was not detected among ischemic stroke patients. Significant differences were detected only for factor V Leiden (odds ratio 7.11; 95% confidence interval 1.55–32.73). Our data indicate that, among these genetic factors, factor V Leiden was identified as an important risk factor for arterial thrombosis in this group of patients. In addition, our results indicate regional differences in the incidence of these genetic factors in Brazil, as compared to the incidences reported in other studies.

Portal Vein Thrombosis and Budd–Chiari Syndrome

Venous thrombosis results from the convergence of vessel wall injury and/or venous stasis, known as local triggering factors, and the occurrence of acquired and/or inherited thrombophilia, also known as systemic prothrombotic risk factors. Portal vein thrombosis (PVT) and Budd-Chiari syndrome (BCS) are caused by thrombosis and/or obstruction of the extrahepatic portal veins and the hepatic venous outflow tract, respectively. Several divergent prothrombotic disorders may underlie these distinct forms of large vessel thrombosis. While cirrhotic PVT is relatively common, especially in advanced liver disease, noncirrhotic and nontumoral PVT is rare and BCS is of intermediate incidence. In this article, we review pathogenic mechanisms and current concepts of patient management.

Permissive Hypotension and Desmopressin Enhance Clot Formation

BACKGROUND Experimental studies of uncontrolled hemorrhage demonstrated that permissive hypotension (PH) reduces blood loss, but its effect on clot formation remains unexplored. Desmopressin (DDAVP) enhances platelet adhesion promoting stronger clots. We hypothesized PH and DDAVP have additive effects and reduce bleeding in uncontrolled hemorrhage. METHODS Rabbits (n = 42) randomized as follows: sham; normal blood pressure (NBP) resuscitation; PH resuscitation-60% baseline mean arterial pressure; NBP plus DDAVP 1 hour before (DDAVP NBP) or 15 minutes after beginning of shock (DDAVP T1 NBP); and PH plus DDAVP 1 hour before (DDAVP PH) or 15 minutes after beginning of shock (DDAVP T1 PH). Fluid resuscitation started 15 minutes after aortic injury and ended at 85 minutes. Intraabdominal blood loss was calculated, aortic clot sent for electron microscopy. Activated partial thromboplastin time, platelet count, thromboelastometry, arterial blood gases, and complete blood count were performed at baseline and 85 minutes. Analysis of variance was used for comparison. RESULTS NBP received more fluid volume and had greater intraabdominal blood loss. DDAVP, when administered preshock, significantly reduced blood loss in NBP and fluid requirement when given postshock. Platelets, arterial blood gas, complete blood count, and activated partial thromboplastin time were similar at 85 minutes. NBP delayed clot formation and worsened thrombodynamic potential on thromboelastometry, whereas PH and DDAVP improved. Electron microscopy showed lack of fibrin on NBP clots, whereas DDAVP and PH clots displayed exuberant fibrin/platelet aggregates. DDAVP NBP presented intermediate clots. CONCLUSION PH reduced bleeding and improved hemostasis compared with normotensive resuscitation. DDAVP given preshock exerted similar effects with normotensive resuscitation.

Low prevalence of the JAK2V617F in patients with ischemic stroke or cerebral venous thrombosis.

Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder associated with increased risks for bleeding and the expression and storage of urokinase plasminogen activator (u-PA) in platelets, despite normal u-PA in plasma (reviewed in [1]). In the recent article on QPD published in this journal [1], QPD was proposed to result from defective u-PA regulation by megakaryocytes. However, the levels of u-PA in other QPD cells and urine have not been reported. Individuals with QPD are at increased risk of experiencing bleeding following hemostatic challenges, and approximately 50% experience episodic, spontaneous hematuria, which is associated with higher levels of platelet u-PA [2]. As urine normally contains significant amounts of u-PA (40–80 mg/ml) [3], we investigated whether individuals with QPD have an increased urinary u-PA as a potential contributor to their urinary tract bleeding.

Pneumonia and risk of venous thrombosis: results from the MEGA study

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Association of the C3435T polymorphism of the MDR1 gene and therapeutic doses of warfarin in thrombophilic patients.

V. C . DE OL I VE IR A A LME IDA , * A. C . DE SOUZA FER RE IRA , D. D . R IBE I RO , K . B . GO MES BO RGES , § A . P . SALLES MOURA FER NANDES§ and A . L . BRUNIALT I GODARD* *Laboratório de Genética Animal e Humana, Departamento de Biologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais; Departamento de Genética Molecular, Hermes Pardini; Ambulatório de Hematologia, Hospital das Clı́nicas, Universidade Federal de Minas Gerais; and §Departamento de Análises Clı́nicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Minas Gerais, Brazil

ApoB/ApoA-I ratio in young patients with ischemic cerebral stroke or peripheral arterial disease.

Although smoking and hypertension are classic risk factors for atherothrombotic diseases, the relationship of dyslipidemia and vascular diseases, other than myocardial infarction, is less clearly established, especially in young subjects. In the current study, a detailed analysis of the lipid and apolipoprotein profiles was conducted in young patients of ischemic cerebral stroke (IS) and peripheral arterial disease (PAD). Plasma levels of C-reactive protein (hs-CRP), total cholesterol (TC), high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), triglycerides (TG), and apolipoproteins A-I (ApoA-I) and apolipoproteins B (ApoB), which include the ApoB/ApoA-I ratio, were analyzed in a group of 81 patients who presented with IS (n = 46) or PAD (n = 35) as well as in 167 control subjects. Significant differences were observed for hs-CRP, TC, HDLc, LDLc, TG, ApoA-I, and ApoB levels, as well as for the ApoB/ApoA-I ratio, between the control and the IS or PAD groups. However, after adjustment for sex, age, smoking, hypertension, hs-CRP, and dyslipidemia (LDLc, TC, HDLc, TG, ApoA, ApoB, and ApoB/ApoA-I ratio), hs-CRP, ApoB, and the ApoB/ApoA-I ratio were independently associated with increased risks of IS or PAD. Increased ApoB/ApoA-I ratio and hs-CRP levels are independently associated with occurrence of IS and PAD in young patients and are significant markers of alterations on lipid and apolipoproteic profiles and inflammatory responses, respectively, in these patients.

Seasonal variation of venous thrombosis: a consecutive case series within studies from Leiden, Milan and Tromsø

D. D . R I BE I RO, * P . BUCCIARELL I , S . K . BR AEKKAN,§– W. M. L I J FER ING ,* S . M. PASSAMONTI , E . E . BR ODIN ,§– F . R . ROSENDAAL ,* I . MART INELL I and J . -B . HA NSEN §– *Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; Hematology, University Hospital, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Medicine and Medical Specialties, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico and University of Milan, Milan, Italy; §Hematological research group (HERG), Department of Clinical Medicine, University of Tromsø, Tromsø; and –Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway

Warfarin drug interactions: a comparative evaluation of the lists provided by five information sources

PurposeDetecting potential drug interactions can lead to early interventions that protect patients from serious drug-related problems. The aim of this study was to evaluate the agreement among the lists of warfarin interactions provided by five information sources.MethodsThe lists of warfarin interactions and the corresponding severity ratings and documentation levels presented by the three compendia and by the World Health Organization (WHO) Model Formulary were all compared, and each list was compared to that provided on the package insert of Marevan, a brand of warfarin. The compendia used were: Drug Interaction Facts, Drug Interactions: Analysis and Management and DRUG–REAX. A kappa coefficient was used to calculate the agreement among the sources.ResultsA total of 537 interactions were listed. Only 13 (2.4%) were common to the five sources. The global Fleiss’ kappa coefficient was −0.0080, which indicated poor agreement. Eleven warfarin interactions appeared only in the Marevan package insert. Importantly, 243 interactions (45.3% of the total) were deemed significant in at least one compendium. Only two warfarin interactions were reported as critical by all three compendia and by WHO. The most critical interactions cited by the compendia were missing from the package insert.ConclusionsPoor agreement was found among five sources listing warfarin interactions. Potentially severe clinical consequences might occur due to these discrepant recommendations. Finally, the lack of standard terminology and clinical guidance, as well as the possible inaccuracy of severity ratings and documentation might contribute to heterogeneous procedures in clinical practice.