Amparo Santamaría

Risk of Ischemic Stroke Associated With Functional Thrombin-Activatable Fibrinolysis Inhibitor Plasma Levels

Background and Purpose— Recently, a novel procarboxypeptidase B–like proenzyme, called thrombin-activatable fibrinolysis inhibitor (TAFI), has been described. It plays an important role in the delicate balance between coagulation and fibrinolysis. TAFI leads to potent inhibition of tissue plasminogen activator–induced fibrinolysis. The relevance of TAFI in thromboembolic disease is unclear. We have investigated the risk of ischemic stroke (IS) in relation to plasma levels of functional TAFI. Methods— In a case-control study, we enrolled 264 individuals; 114 had IS, and 150 were recruited as controls who were age and sex matched and had no history of arterial disease. The individuals supplied information on their personal and family histories of cardiovascular diseases and conventional cardiovascular risk factors. Functional TAFI assays were performed by use of a method based on the activation of TAFI with thrombin-thrombomodulin and the measure of the TAFI activity generated. Other hemostatic parameters assayed were factor VIIIc, anti-phospholipid antibodies,fibrinogen, factor V Leiden, and the prothrombin gene G20210A mutations (PT20210A). Results— Functional TAFI levels were significantly higher in patients with IS (113.7±25%; range, 57% to 209%) than in controls (102.6±19%). The odds ratio for IS in patients with functional TAFI levels >120% was 5.7 (95% confidence interval, 2.3 to 14.1). Conclusions— We found that functional TAFI levels in plasma (>120%) increased the risk of IS ≈6-fold. Further studies should elucidate the physiological role of TAFI in arterial disease and possibly provide clues to therapeutic approaches.

Association after linkage analysis indicates that homozygosity for the 46C-->T polymorphism in the F12 gene is a genetic risk factor for venous thrombosis.

In a family-based study called GAIT (Genetic Analysis of Idiopathic Thrombophilia) that included a genome-wide scan we demonstrated that a polymorphism (46C-->T) in the F12 locus jointly influences variability of plasma (Factor XII) FXII levels and susceptibility to thrombotic disease. It then became germane to determine the prevalence of the 46C-->T polymorphism and its relative risk of thrombotic disease. We followed up evidence for genetic linkage with a case-control study, including 250 unrelated consecutive Spanish patients suffering from venous thrombotic disease and 250 Spanish subjects matched for sex and age as a controls. We measured FXII levels and genotyped the 46C-->T polymorphism, as well as a number of classical risk factors for thrombotic disease. We confirmed that individuals with different genotypes for this polymorphism showed significant differences in their FXII levels. Most importantly, the mutated T allele in the homozygous state (genotype T/T) was associated with an increased risk of thrombosis (adjusted OR of 4.82; 95% CI 1.5-15.6), suggesting that the polymorphism itself is an independent risk factor for venous thromboembolism. This study confirms that the 46C-->T polymorphism is a genetic risk factor for venous thrombosis in the Spanish population. In addition, our results confirm that a genome-wide scan coupled with a classical case-control association study is an extremely valuable approach to identify DNA variants that affect complex diseases.

Homozygosity of the T Allele of the 46 C→T Polymorphism in the F12 Gene Is a Risk Factor for Ischemic Stroke in the Spanish Population

Background and Purpose— Ischemic stroke (IS) is a complex disease that involves genetic and environmental factors. In a family-based study (the Genetic Analysis of Idiopathic Thrombophilia [GAIT] Project) that included a genome-wide scan, we demonstrated that a common polymorphism (46 C→T) in the exon 1 of the F12 gene jointly influences variability of plasma Factor XII levels and susceptibility to thrombotic disease. We have investigated the risk of IS related to this polymorphism in a case–control study. Methods— We studied 436 individuals: 205 diagnosed with IS and 231 age–gender–ethnic control subjects. We measured Factor VIIIc, fibrinogen, and Factor XIIc levels, and we genotyped the 46 C→T polymorphism in the F12 gene. Results— There were 91 women and 114 men in the IS group and 109 women and 122 men in the control group. We confirmed our previous observation that individuals with different genotypes for the 46 C→T polymorphism showed significant differences in Factor XIIc levels. Most importantly, the mutated T allele in the homozygous state (genotype T/T) was associated with an increased risk of IS with an adjusted odds ratio of 4.1 (95% CI, 1.1 to 15.9). Conclusions— This study suggests that the 46 C→T polymorphism is a genetic risk factor for IS in the Spanish population. In addition, our results confirm that the use of genetic linkage studies along with a case–control association study is an extremely valuable approach for identifying DNA variants that affect complex diseases.

Low-molecular-weight heparin as bridging therapy during interruption of oral anticoagulation in patients undergoing colonoscopy or gastroscopy.

Nowadays, most patients under oral anticoagulant therapy (OAT) require invasive procedures such as colonoscopy (CC) or gastroscopy (GC). The goals of the management of OAT are to minimise the risk of thromboembolism and bleeding. We have performed the first prospective, observational study to evaluate these parameters using fixed‐dose high‐risk thromboprophylactic therapy with sodic bemiparin (Hibor®) as bridging therapy. From January 2004 to January 2005, patients under OAT were included. Periprocedure prophylaxis consisted of: Acenocumarol patients: Day –3: withdrawal acenocumarol. Days −2,−1,0: Hibor ®3500 UI/d sc and days +1,+2,+3: Hibor® 3500 U/I + acenocumarol. And day +5: acenocumarol only. Warfarin patients: Days −5,−4: withdrawal warfarin, −3,−2,−1, 0; Hibor® 3500 UI/day sc, days +1,+2,+3,+4: Hibor® 3500 UI/day sc and warfarin and day +5; warfarin only. Thromboembolic complications and bleeding were recorded in a 3 month follow‐up. We included 100 consecutive patients in the intention‐to‐treat group. The remaining 98 patients were 50 women and 48 men. Mean age of women was 71.1 (range: 46–87) years and 70.7 (range: 39–86) years in men. Eighty‐three took acenocumarol, and 15 warfarin. Thirty‐two gastroscopies and 61 colonoscopies were performed and in five patients both were performed. No thromboembolic and bleeding complications related to bemiparin were observed in the 103 endoscopies. Two patients developed pruritus at the punction site. Fixed‐dose high‐risk thromboprophilactic therapy with bemiparin (Hibor®) is safe and effective as a bridging therapy in patients under OAT who require GC or CC.

Endothelial protein C receptor polymorphisms and risk of myocardial infarction

Haplotypes A1 and A3 in the endothelial protein C receptor gene are tagged by the 4678G/C and 4600A/G polymorphisms, respectively, and have been reported to influence the risk of venous thromboembolism. This study shows that A1 and A3 haplotype carriers have a reduced risk of myocardial infarction. Background Haplotypes A1 and A3 in the endothelial protein C receptor gene are tagged by the 4678G/C and 4600A/G polymorphisms, respectively, and have been reported to influence the risk of venous thromboembolism. We assessed whether these haplotypes modify the risk of premature myocardial infarction. Design and Methods We genotyped these polymorphisms in 689 patients with premature myocardial infarction and 697 control subjects. Activated protein C and soluble endothelial protein C receptor levels were also measured. Results After adjustment for other cardiovascular risk factors, A1 and A3 haplotypes protected against premature myocardial infarction (odds ratio 0.7, 95% CI 0.4–0.8, p=0.044 and 0.5, 0.3–0.6, p<0.001, respectively). Moreover, the protective role of these haplotypes seemed to be additive, as carriers of both the A1 and A3 haplotypes had adjusted odds ratios of 0.3 (0.2–0.5, p<0.001) and 0.4 (0.2–0.8, p=0.006) compared to those carrying only the A1 or A3 haplotype, respectively. The presence of the A1 haplotype was associated with increased levels of activated protein C whereas individuals carrying the A3 haplotype showed the highest soluble endothelial protein C receptor levels. Conclusions These results show that A1 haplotype carriers have a reduced risk of premature myocardial infarction via the association of this haplotype with increased activated protein C plasma levels. The study also shows that carriers of the A3 haplotype have a reduced risk of myocardial infarction, only in part due to increased soluble endothelial protein C levels.

Bacteremia by Gram-Negative Bacilli in Patients with Hematologic Malignancies

To compare the characteristics of bacteremic infections by different aerobic gram-negative bacilli (GNB) in patients with hematologic malignancies, we studied 54 consecutive monomicrobial bacteremias by Enterobacteriaceae (EB), 15 by Pseudomonas aeruginosa, 43 by other non-glucose-fermenting GNB (NGFGNB) and 11 by other GNB. Patients with EB and P. aeruginosa bacteremia usually developed the infection after intensive chemotherapy for leukemia or during a hematopoietic stem cell transplantation, while most infections in outpatients off therapy were due to NGFGNB. A significant proportion of bacteremias by EB (37%) and P. aeruginosa (40%) were accompanied by severe morbidity (septic shock, pneumonia or deep-seated organ infections) vs. only 7% of other NGFGNB (p < 0.01). Most infections by these latter bacteria were catheter-related bacteremias (80 vs. 2% of EB, p < 0.005), while most EB infections (61%) were uncomplicated bacteremias of unknown source (vs. 14% of other NGFGNB, p < 0.005). Appropriate antibiotics alone cured 98% of EB and 73% of P. aeruginosa bacteremias but only 26% of other NGFGNB (p < 0.005 for both differences), which were cured by catheter removal in 70%, usually after failure of antibiotic treatment. In conclusion, our results suggest that there are significant differences in the patient populations and clinical characteristics of bacteremic infections by the classic GNB (EB and P. aeruginosa) and the new NGFGNB in adults with hematologic malignancies.

Diagnostic yield of prothrombotic state studies in cryptogenic stroke

Around 30% of ischemic strokes are considered cryptogenic. We analyzed the diagnostic yield of prothrombotic state (PS) studies in patients with an initial cryptogenic stroke (CS).

Higher risk of ischaemic stroke associated with factor XI levels in dyslipidaemic patients

Background:  Ischaemic stroke (IS) is a complex disease that involves genetic and environmental factors. The role of factor XI (FXI) in arterial thrombosis is unclear. We have investigated the risk of IS related to FXI levels in a case–control study.

Reticulocyte recovery is faster in allogeneic and autologous peripheral blood stem cell transplantation than in bone marrow transplantation

To the Editor: Over recent years automated methods have allowed a more accurate quantitative measurement of the reticulocytes (RET) and, more importantly, a new parameter has emerged in the study of the biology of RET (1). Specifically, the automated flow cytometry RET counters subdivide the circulating RET into 3 maturational stages. The more immature fractions have a higher RNA content (1, 2), and their rise in the early stages of hematopoietic recovery following intensive chemotherapy or bone marrow transplantation (BMT) has been shown to be the earliest objective sign of marrow recovery (3-6). Since granulocytes and platelets recover earlier in peripheral blood stem cell transplant (PBSCT) than in BMT, we performed a prospective study to determine whether or not absolute and immature RET recover earlier following PBSCT than BMT (both allogeneic and autologous) and whether this rise preceds granulocytic recovery, as seen in BMT. Twenty-three consecutive patients undergoing autologous transplantation (13 BMT and 10 PBSCT) who successfully engrafted were prospectively studied (AUTO group). The allogeneic (ALLO) group included 19 consecutive patients who received an allogeneic graft (9 PBSCT and 10 BMT) from an HLA-identical sibling and who successfully engrafted. All autologous BMT recipients received granulocyte-colony-stimulating factor (G-CSF, 5 pg/kg sbc per day) from d+l and until stable neutrophil engraftment, but none of the other groups received any growth factor. Prophylaxis for graft-versus-host disease included cyclosporine A and a short course of methotrexate in all allogeneic grafts, without T-cell depletion of the graft in any case. The Sysmex R-2000 (TOA Company, Kobe, Japan) was used to quantify the absolute RET count and its maturation fractions. The high and medium fluorescence ratio RET fractions (HFR and MFR, respectively) have a high RNA content and include immature RET which are expressed as the percentage of total RET. Thus, the percentage of HFR and MFR is referred to as the immature RET fraction (IRF). Peripheral blood counts, absolute RET counts and IRF were closely monitored following the transplant. The following criteria were used to define the day of recovery of neutrophils, RET and I R F the first of at least 3 consecutive days with an absolute neutrophil count (ANC) >O.5x1O9/1 and the first of at least 3 consecutive da s with an absolute RET count of at least 0 . 0 2 ~ lo& (absolute RET recovery) and an IRF >lo% (expressed as the percentage of total circulating RET). The recovery kinetics of the IRF and the neutrophil recovery were compared in each group (ALLO and AUTO) between the PBSCT and BMT recipients. Statistical analyses were performed using Students t-test for paired and non-paired data for the comparison of the recovery of the ANC and IRF between groups. The results were expressed as the mean of the day of recovery and the 95% CI, using a p value <0.05 as the level of significance. Table 1 summarizes the results obtained in all the groups. In the AUTO group patients who received BMT recovered IRF on d 13.5 (95% CI, 11.2-20.2), absolute RET on d 26.9 (95% CI, 19.734.1) and the ANC on d 22.6 (95% CI, 16.6-30.4). Patients who received PBSCT recovered IRF on d 10.1 (95% CI, 8.7-12.7), absolute RET on d 15.8 (95% CI, 12.6-19) and the ANC on d 14.7 (95% CI, 11.7-18.2). There were no statistically significant differences in the recovery of IRF between autologous BMT and PBSCT, although a trend for a faster recovery in the PBSCT was observed (see Table 1). The absolute RET recovery was significantly faster in PBSCT than in BMT recipients. More importantly, the IRF recovered before the ANC in both subgroups; thus, an IRF >lo% was reached 9.1 d (95% CI, 4.6-13.5) before an ANC >O.5x1O9/1 in the PBSCT subgroup, while they recovered 4.6d (95% CI, 1.6-7.7) earlier in the BMT subgroup. Finally, as expected, the ANC

IgM anti-protein S antibodies as a risk factor for venous thrombosis.

Lupus anticoagulant (LA) and antiphospholipid antibodies (APA) are immunoglobulins directed at phospholipid-protein complexes that have been associated frequently with thrombophilia. Protein S (PS) is a protein with high affinity for phospholipids and can be a target for APA. It is a cofactor in the