Rotation thromboelastometry and the hypercoagulable state in Cushing's syndrome.

INTRODUCTION: Rotation thromboelastometry (ROTEM®) can be used for hypercoagulability evaluation. Cushing's syndrome (CS) is associated with hypercoagulability; however, ROTEM® has never been evaluated in this setting. OBJECTIVE: To evaluate hypercoagulability in CS using ROTEM® and to correlate these parameters with coagulation markers and with the presence of deep vein thrombosis. DESIGN AND METHODS: Thirty patients with active CS (26 women) and 30 controls matched for age, sex, body mass index, diabetes mellitus, arterial hypertension, ABO blood group and smoking were included. We measured levels of activated partial thromboplastin time (aPTT), platelets, fibrinogen, D-dimer, factor VIII (FVIII), von Willebrand factor (vWF) and C-reactive protein. ROTEM® was used to evaluate the intrinsic (INTEM), extrinsic (EXTEM) and fibrinogen (FIBTEM) pathways. Doppler ultrasonography was performed to search for lower limbs deep vein thrombosis. RESULTS: INTEM clotting time using ROTEM® was shorter in patients than in controls (P = 0·04). Other ROTEM® parameters were not different. Mean aPTT was shorter in patients than in controls (P = 0·001). The FVIII, vWF and D-dimer levels were higher in patients than in controls (P = 0·001, 0·001 and 0·02, respectively). Obese CS patients presented higher levels of platelets and alterations in maximum clot formation (MCF), alpha angle and maximum speed of clot formation of INTEM (P = 0·03, 0·02 and 0·02, respectively) and an increase in the MCF of FIBTEM (P = 0·02). No deep vein thrombosis was found. CONCLUSIONS: Although FVIII and vWF were abnormal in CS patients, only the initiation clot formation was different in the ROTEM® methodology and no deep vein thrombosis was found.

Plasminogen activator inhibitor-1 4G/5G promoter polymorphism and PAI-1 plasma levels in young patients with ischemic stroke.

The 4G/5G polymorphism in the plasminogen activator inhibitor-1 (PAI-1) gene, has been associated with arterial disease. In this study, we investigated the association of IS in young patients with CRP and PAI-1 levels and frequency of insertion-deletion polymorphism of PAI-1 gene. The plasma levels of PAI-1 and CRP and the frequency of 4G/5G polymorphism were analyzed in 127 Brazilian young patients that presented IS and in 201 healthy and unrelated control subjects. The levels of CRP (P < 0.001) and PAI-1 (P < 0.001) were significantly higher in patients when compared with control group. Only PAI-1 plasma levels were independently associated with risk of IS (OR 3.40; 95% CI 1.49-7.74; P = 0.001) after adjustments for lifestyles covariates. The 4G/4G genotype was significantly more frequent among control subjects as compared to patients (OR 0.41; 95% CI 0.24-0.68; P < 0.001). Although increased PAI-1 plasma levels are associated with development of IS in Brazilian young patients, they are not influenced by the 4G/5G PAI-1 polymorphism.

Arterial thrombosis and acute myocardial infarction with angiographically normal coronary arteries in a woman heterozygous for both factor V Leiden and prothrombin mutation.

Thirteen years after her last thrombotic event, anticoagulation was discontinued in a patient with combined thrombophilia involving mutation in factor V and G20210A polymorphism of the prothrombin gene. The only history was of arterial thrombosis. Three months later she presented a transmural myocardial infarction caused by coronary thrombosis.

JAK2V617F mutation in patients with splanchnic vein thrombosis.

BACKGROUND: Splanchnic vein thrombosis can be the presenting manifestation of myeloproliferative neoplasms. However, the diagnosis of a myeloproliferative neoplasm in these patients is often problematic, and more objective criteria are needed. AIM: To determine the frequency of the mutation JAK2V617F in patients with splanchnic vein thromboses. METHODS: A consecutive series of 108 adult patients with portal vein thrombosis (n = 77) and Budd-Chiari syndrome (n = 31) referred for hemostasis evaluation was retrospectively studied, with a median follow-up of 51 months (1-104). RESULTS: One or more prothrombotic risk factors were present in 63% of the patients. Twenty-four (22%) out of the 108 patients presented the JAK2V617F, including 2 cirrhotic patients. Most had a low mutated allele burden (median 16.5%). JAK2V617F was present in all four patients with a previous diagnosis of a myeloproliferative neoplasm. In nine JAK2V617F-positive patients, the diagnosis of a myeloproliferative neoplasm was made at the thrombosis work-up, during follow-up or after JAK2V617F detection. Among the other 11 patients carrying the mutation, 2 patients have died, 4 had no evidence suggesting a myeloproliferative neoplasm, 1 had a normal bone marrow biopsy, and the other 4 could not be persuaded to undergo a biopsy. Among the patients without an overt myeloproliferative neoplasm, 15 out of 99 (15%) presented the JAK2V617F mutation. None of the JAK2V617F-negative patients have developed signs of a myeloproliferative neoplasm during follow-up. CONCLUSIONS: Our findings suggest that JAK2V617F occurs in a high proportion of patients with splanchnic vein thrombosis, and reinforces the diagnostic utility of JAK2V617F testing in this setting.

Gene Variants Associated With Venous Thrombosis: A Replication Study in a Brazilian Multicentre Study.

Single nucleotide polymorphisms (SNP) associated with Venous Thromboembolism (VTE) risk have been identified in European and American populations. Replicate SNPs associated with VTE in a Brazilian multicenter case-control study of the Southeast region. Patients with previous VTE assisted at the Outpatient Clinics of 3 centers of the Southeast Brazilian region were compared to normal controls of the same geographic region. We evaluated 29 SNPs associated with VTE risk in other populations, and 90 SNPs for stratification analysis of the population. Due to high admixture of Brazilian population and lack of previous studies, the calculation of the sample power was performed after genotyping. Sample size, allelic frequency and Hardy-Weinberg equilibrium were estimated. The association and odds ratio analyses were estimated by logistic regression and the results were adjusted for multiple tests using Bonferroni correction. The evaluation of the genetic structure similarity in the cases and controls was performed by AMOVA. 436 cases and 430 controls were included. It was demonstrated that this sample has a statistical power to detect a genetic association of 79.4%. AMOVA showed that the genetic variability between groups was 0.0% and 100% within each group. None of the SNPs showed association with VTE in our population. A Brazilian multicenter case-control study with adequate sample power, high genetic variability though no stratification between groups, showed no replication of SNPs associated with VTE. The high admixture of Brazilian population may be responsible for these results, emphasizing the influence of the population genetic structure in association studies.

807C/T polymorphism in the platelet glycoprotein Ia gene in young patients with ischemic stroke of undetermined etiology.

Platelet membrane glycoprotein receptors mediate key reactions in arterial thrombosis. The relationship between glycoprotein Ia polymorphisms and the risk of ischemic stroke, however, remains controversial. A matched case-control study was conducted to evaluate this question in young patients. Seventy patients with ischemic stroke of undetermined etiology, with ages ranging from 15 to 50 years, and 70 healthy control individuals, matched by age, gender and ethnicity, were tested for the 807C/T genotypes. Patients were excluded if they had systemic diseases known to predispose to thrombosis or any defined etiology of ischemic stroke. The frequencies of the 807T glycoprotein Ia variant and of conventional risk factors for arterial thrombosis (hypertension, smoking, diabetes mellitus, use of oral contraceptives, levels of serum cholesterol and body mass index) were compared in stroke patients and control individuals. The 807T allele was found in 61% of patients and 53% of control individuals (matched-pair odds ratio, 1.38; 95% confidence interval, 0.69-2.74; P = 0.42). Arterial hypertension and smoking were more frequent in patients than control individuals (matched-pair odds ratio, 2.83; 95% confidence interval, 1.05-8.02; P = 0.04; and odds ratio, 3.20; 95% confidence interval, 1.10-9.97, P = 0.03, respectively). In conclusion, our results do not support an independent association between the 807C/T polymorphism and stroke of undetermined etiology. The interplay of this polymorphism with arterial hypertension in the causation of ischemic stroke requires further evaluation.

Thrombophilic mutations and risk of retinal vein occlusion.

PURPOSE: The association of retinal vein occlusion and hereditary thrombophilia abnormalities is not established, with controversial results in the literature. This study investigates the association between retinal vein occlusion and three thrombophilic mutations: factor V 1691A (factor V Leiden), prothrombin 20210A (PT 20210A) and homozygous methylenetetrahydrofolate reductase 677T (MTHFR 677TT). METHODS: 55 consecutive retinal vein occlusion patients and 55 controls matched by age, gender and race, were tested for the presence of the following mutations: factor V Leiden, PT 20210A and MTHFR 677TT. The frequencies of the three mutations in cases and controls were compared. RESULTS: Factor V Leiden was found in 3.6% of patients and in 0% of controls; PT 20210A was found in 1.8% of patients and 3.6% of controls, (matched-pair odds ratio, 0.5; 95% confidence interval, 0.04 to 5.51); MTHFR 677TT was found in 9% of patients and 9% of controls (matched-pair odds ratio, 1; 95% confidence interval, 0.92 to 3.45). Arterial hypertension was more frequent in patients than controls (matched-pair odds ratio, 3.4; 95% confidence interval, 1.25 to 9.21). CONCLUSIONS: This study suggests that thrombophilic mutations are not risk factors for RVO. Routine investigation of hereditary thrombophilia in these patients is not justified.

Sex differences in patients receiving anticoagulant therapy for venous thromboembolism.

In patients with venous thromboembolism (VTE), the outcome during the course of anticoagulant therapy may differ according to the patient's sex. We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) database to compare the rate of VTE recurrences, major bleeding, and mortality due to these events according to sex.As of August 2013, 47,499 patients were enrolled in RIETE, of whom 24,280 (51%) were women. Women were older, more likely presented with pulmonary embolism (PE), and were more likely to have recent immobilization but less likely to have cancer than men. During the course of anticoagulation (mean duration: 253 d), 659 patients developed recurrent deep vein thrombosis (DVT), 576 recurrent PE, 1368 bled, and 4506 died. Compared with men, women had a lower rate of DVT recurrences (hazard ratio [HR]: 0.78; 95% confidence interval [CI]: 0.67-0.91), a similar rate of PE recurrences (HR: 0.98; 95% CI: 0.83-1.15), a higher rate of major bleeding (HR: 1.21; 95% CI: 1.09-1.35), and higher mortality due to PE (HR: 1.24; 95% CI: 1.04-1.47). On multivariable analysis, any influence of sex on the risk for recurrent DVT (HR: 0.88; 95% CI: 0.75-1.03), major bleeding (HR: 1.10; 95% CI: 0.98-1.24), or fatal PE (HR: 1.01; 95% CI: 0.84-1.22) was no longer statistically significant.In conclusion, women had fewer DVT recurrences and more bleeds than men during the course of anticoagulation. These differences were not due to sex, but very likely to other patient characteristics more common in female patients and differences in treatment choice.

Influence of recent immobilization or surgery on mortality in cancer patients with venous thromboembolism.

BACKGROUND: The influence of recent immobilization or surgery on mortality in cancer patients with venous thromboembolism (VTE) has not been thoroughly studied. METHODS: We used the RIETE Registry data to compare the 3-month mortality rate in cancer patients with VTE, with patients categorized according to the presence of recent immobilization, surgery or neither. The major outcomes were fatal pulmonary embolism (PE) and fatal bleeding within the first 3 months. RESULTS: Of 6,746 patients with active cancer and acute VTE, 1,224 (18%) had recent immobilization, 1,055 (16%) recent surgery, and 4,467 (66%) had neither. The all-cause mortality was 23.4% (95% CI: 22.4-24.5), and the PE-related mortality: 2.5% (95% CI: 2.1-2.9). Four in every ten patients dying of PE had recent immobilization (37%) or surgery (5.4%). Only 28% of patients with immobilization had received prophylaxis, as compared with 67% of the surgical. Fatal PE was more common in patients with recent immobilization (5.0%; 95% CI: 3.9-6.3) than in those with surgery (0.8%; 95% CI: 0.4-1.6) or neither (2.2%; 95% CI: 1.8-2.6). On multivariate analysis, patients with immobilization were at an increased risk for fatal PE (odds ratio: 1.8; 95% CI: 1.2-2.5). CONCLUSIONS: One in every three cancer patients dying of PE had recent immobilization for ≥ 4 days. Many of these deaths could have been prevented with adequate thromboprophylaxis.

Clinical characteristics of patients with factor V Leiden or prothrombin G20210A and a first episode of venous thromboembolism. Findings from the RIETE Registry.

BACKGROUND: The clinical characteristics of patients with factor V Leiden or prothrombin G20210A presenting with a first episode of venous thromboembolism (VTE) have not been thoroughly studied. METHODS: RIETE is an ongoing registry of consecutive patients with acute VTE. We compared the clinical characteristics of patients with factor V Leiden, prothrombin G20210A, or no thrombophilia, at presentation with a first episode of VTE. RESULTS: As of May 2009, 22428 patients had been enrolled with a first episode of VTE. Of these, 345 had factor V Leiden, 261 had prothrombin G20210A, and 2399 tested negative. Sixty-two percent of the VTE episodes in women with factor V Leiden or prothrombin G20210A (40% in men) were associated with an acquired risk factor. Among women, pregnancy or contraceptive use accounted for 63% and 67% of such risk factors. Patients with factor V Leiden presented with pulmonary embolism (PE) less likely than those with prothrombin G20210A (31% vs. 51%; p<0.001) or with negative testing (31% vs. 45%, p<0.001). In addition, PE patients with Factor V Leiden presented with hypoxaemia (Sat O(2) levels<90%) less likely than those with prothrombin G20210A (4.5% vs. 17%; p<0.001) or with no thrombophilia (4.5% vs. 20%; p<0.001). CONCLUSIONS: Most VTE episodes in women (not men) with factor V Leiden or prothrombin G20210A were associated with an acquired risk factor (mostly pregnancy or contraceptive use). Only 4.5% of patients with factor V Leiden presenting with acute PE had hypoxaemia.

Normal plasma antithrombin activity in patients with relapsing-remitting and secondary progressive multiple sclerosis.

OBJECTIVE: Multiple sclerosis (MS) is an inflammatory disease characterized by multifocal areas of central nervous system (CNS) demyelination. Activation of coagulation factors and fibrin deposition are observed around CNS blood vessels in experimental autoimmune encephalomyelitis, an animal model of MS. Antithrombin (AT) is a potent anticoagulant with remarkable anti-inflammatory properties, and its inhibitory effects on coagulation and inflammation may play a role in the pathogenesis and clinical course of MS. We studied the association between plasma AT activity and clinical forms of MS. PATIENTS AND METHODS: A total of 69 patients, 37 with relapsing-remitting and 32 with secondary progressive MS, were included in the study. A control group (CG) of 34 normal subjects was also studied. Plasma AT activity (Stachrom ATIII) was quantified using a chromogenic activity assay with normal reference values ranging from 70% to 120% of AT activity. RESULTS: We found no difference between plasma AT levels in patients and those in CG. We also found no association of AT levels with activity of disease, duration of disease progression, level of neurological disability, and treatment. CONCLUSION: We found no association between plasma AT activity and RRMS or SPMS. It remains to be studied whether exists or not an association between abnormal plasma AT activity and other MS forms.

O uso do ácido epsilon amino caproico intra-alveolar para o controle do sangramento pós-exodontia em pacientes anticoagulados / The use of epsilon amino caproic acid intraalveolar to control bleeding after extraction in anticoagulated patients

Quando pacientes em uso de anticoagulantes são submetidos a exodontias, há risco de sangramento pós-operatório. A manutenção da terapia anticoagulante tem sido indicada desde que o INR esteja dentro dos níveis terapêuticos. Recursos adicionais para o controle do sangramento, como o uso de ácido épsilon amino capróico (EACA), podem ser adotados. O objetivo deste estudo foi relatar uma série de casos de exodontias seguidas de uso intra-alveolar de EACA, em pacientes em uso de anticoagulantes com INR & # 8804; 3.0. De 25 exodontias, apenas um paciente precisou de intervenção profissional para controlar o sangramento pós-operatório. Os resultados sugerem que o uso de EACA intra-alveolar, associado aos cuidados pós-cirúrgicos de rotina, pode contribuir para a hemostasia em pacientes em uso de anticoagulantes.

When patients on anticoagulants are submitted to dental extractions, there is risk of postoperative bleeding. The maintenance of anticoagulant therapy has been indicate donce the INR is within the therapeutic levels. Additional resources for bleeding control like the use of epsilon amino caproic acid (EACA) may be adopted. The objective of this study was to report a series of cases of tooth extractions followed by the intra-alveolar use of EACA, in patients using anticoagulants with INR ≤ 3.0. From 25 tooth extractions, only one patient needed professional intervention to control postoperative bleeding. The results suggest that the use of intra-alveolar EACA, associated with routine post-surgical care, may contribute to hemostasis in patients using anticoagulants.

Prothrombin 20210A and oral contraceptive use as risk factors for cerebral venous thrombosis.

BACKGROUND: This study investigates the association between cerebral vein thrombosis (CVT) and the mutations FV 1691A (factor V Leiden), PT 20210A and MTHFR 677TT and acquired factors including oral contraceptive (OC) use. METHODS: 26 patients (21 females) and 217 healthy controls (134 females) were studied. Multiple regression analysis was performed. RESULTS: The frequency of the three mutations in cases and controls were: PT 20210A, 23 versus 1%, odds ratio (OR) 21.40 (95% CI 4.29-118.75), p < 0.001; FV 1691A, 8 versus 1%, OR 5.94 (95% CI 0.66-46.9); MTHFR 677TT, 4 versus 7%, OR 0.54 (95% CI 0.03-4.08). OC use was more frequent in female patients over 14 years old than in controls (84 vs. 40%, OR 8.15, 95% CI 2.09-37.13, p < 0.001). The model that best explained the thrombotic risk included PT 20210A and OC use. CONCLUSIONS: PT 20210A and OC use are the main thrombophilic risk factors predisposing to CVT and should be routinely investigated in patients with this disease.

Thrombophilic mutations and risk of retinal vein occlusion

PURPOSE: The association of retinal vein occlusion and hereditary thrombophilia abnormalities is not established, with controversial results in the literature. This study investigates the association between retinal vein occlusion and three thrombophilic mutations: factor V 1691A (factor V Leiden), prothrombin 20210A (PT 20210A) and homozygous methylenetetrahydrofolate reductase 677T (MTHFR 677TT). METHODS: 55 consecutive retinal vein occlusion patients and 55 controls matched by age, gender and race, were tested for the presence of the following mutations: factor V Leiden, PT 20210A and MTHFR 677TT. The frequencies of the three mutations in cases and controls were compared. RESULTS: Factor V Leiden was found in 3.6 percent of patients and in 0 percent of controls; PT 20210A was found in 1.8 percent of patients and 3.6 percent of controls, (matched-pair odds ratio, 0.5; 95 percent confidence interval, 0.04 to 5.51); MTHFR 677TT was found in 9 percent of patients and 9 percent of controls (matched-pair odds ratio, 1; 95 percent confidence interval, 0.92 to 3.45). Arterial hypertension was more frequent in patients than controls (matched-pair odds ratio, 3.4; 95 percent confidence interval, 1.25 to 9.21). CONCLUSIONS: This study suggests that thrombophilic mutations are not risk factors for RVO. Routine investigation of hereditary thrombophilia in these patients is not justified.

OBJETIVOS: A associação entre oclusão venosa retiniana e trombofilias hereditárias não está estabelecida, com resultados controversos na literatura. O presente estudo investiga a associação entre a oclusão venosa retiniana e três mutações trombofílicas: fator V 1691A (fator V Leiden), protrombina 20210A (PT 20210A) e mutação C677T do gene da metileno-tetra-hidro-folato redutase (MTHFR 677TT). MÉTODOS: Cinquenta e cinco pacientes portadores de oclusão venosa retiniana e 55 controles pareados por idade, sexo e raça foram testados para a presença das seguintes mutações: fator V Leiden, PT 20210A e MTHFR 677TT. As freqüências das três mutações em casos e controles foram comparadas. RESULTADOS: Fator V Leiden foi encontrado em 3,6 por cento dos pacientes e em 0 por cento dos controles; PT 20210A foi encontrada em 1.8 por cento dos pacientes e em 3,6 por cento dos controles, (odds ratio, 0,5; 95 por cento IC, 0,04 to 5,51); MTHFR 677TT foi encontrada em 9 por cento dos pacientes e em 9 por cento dos controles (odds ratio, 1; 95 por cento IC, 0,92 to 3,45). Hipertensão arterial foi encontrada mais freqüentemente em pacientes do que em controles (odds ratio, 3,4; 95 por cento IC, 1,25 to 9,21). CONCLUSÕES: O presente estudo sugere que mutações trombofílicas não são fatores de risco para oclusão venosa retiniana. A investigação rotineira para trombofilias hereditárias neste grupo de pacientes não é indicada.

Deficiência de inibidores naturais: diagnóstico laboratorial / Deficiency of natural inhibitor: laboratory diagnosis

Neste relato são apresentados aspectos clínicos e a importância da deficiência dos inibidores da coagulação, antitrombina, proteina C e proteína S, ressaltando-se o diagnóstico laboratorial desta anomalia.

The clinical aspects and the importance of the deflciency of the three coagulation inhibitors, antithrombin, protein C and protein S, are discussed in this report.