HaemophiliaVolume 23, Issue 4 p. e391-e393 Letter to the Editor Top-level sport in athletes with severe haemophilia A J. R. Gonzalez-Porras, Corresponding Author J. R. Gonzalez-Porras jrgp@usal.es orcid.org/0000-0003-3266-7996 Department of Haematology, Hospital Universitario de Salamanca-IBSAL-USAL, Salamanca, Spain Correspondence Jose Ramon Gonzalez-Porras, Unidad de Hemostasia y Trombosis, Servicio de Hematología, Hospital Universitario de Salamanca-IBSAL-USAL, Salamanca, Spain. Email: jrgp@usal.esSearch for more papers by this authorF. Lopez-Cadenas, F. Lopez-Cadenas Department of Haematology, Hospital Universitario de Salamanca-IBSAL-USAL, Salamanca, SpainSearch for more papers by this authorI. Alberca, I. Alberca Department of Haematology, Hospital Universitario de Salamanca-IBSAL-USAL, Salamanca, SpainSearch for more papers by this authorJ. M. Bastida, J. M. Bastida orcid.org/0000-0002-8007-3909 Department of Haematology, Hospital Universitario de Salamanca-IBSAL-USAL, Salamanca, SpainSearch for more papers by this author J. R. Gonzalez-Porras, Corresponding Author J. R. Gonzalez-Porras jrgp@usal.es orcid.org/0000-0003-3266-7996 Department of Haematology, Hospital Universitario de Salamanca-IBSAL-USAL, Salamanca, Spain Correspondence Jose Ramon Gonzalez-Porras, Unidad de Hemostasia y Trombosis, Servicio de Hematología, Hospital Universitario de Salamanca-IBSAL-USAL, Salamanca, Spain. Email: jrgp@usal.esSearch for more papers by this authorF. Lopez-Cadenas, F. Lopez-Cadenas Department of Haematology, Hospital Universitario de Salamanca-IBSAL-USAL, Salamanca, SpainSearch for more papers by this authorI. Alberca, I. Alberca Department of Haematology, Hospital Universitario de Salamanca-IBSAL-USAL, Salamanca, SpainSearch for more papers by this authorJ. M. Bastida, J. M. Bastida orcid.org/0000-0002-8007-3909 Department of Haematology, Hospital Universitario de Salamanca-IBSAL-USAL, Salamanca, SpainSearch for more papers by this author First published: 02 June 2017 https://doi.org/10.1111/hae.13283Citations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume23, Issue4July 2017Pages e391-e393 RelatedInformation

Aim Few studies specifically focus on elderly splenectomized immune thrombocytopenia (ITP) patients. Older patients with ITP and excellent health are often excluded from surgery splenectomy. We aimed to compare the safety and efficacy of splenectomy in elderly and non-elderly ITP patients and to examine the effect of age on therapeutic response.Material and methods We carried out a retrospective analysis of a series of 218 patients who had undergone splenectomy for ITP. We compared the data from the elderly group (65yrs, 57 patients) with the young group (<65yrs, 162 patients).Results Surgical technique (laparoscopy or open laparotomy splenectomy) was comparable between the two age groups. The adjusted risk of major bleeding following splenectomy for elderly patients was three times that for young patients (OR 3.05, 95% CI: 1.44-6.52). The median duration of postoperative hospital stay was longer for elderly than for young patients (8d vs. 4d, P<0.001). However, we identified a subgroup of elderly ITP patients, those aged between 65 and 70yrs who had undergone laparoscopic splenectomy, with a low risk of postoperative complications. Of the 218 patients, 89% achieved a favorable response to splenectomy. A favorable response was significantly less common in elderly than in young people (79% vs. 92%, P=0.005). However, we observed an acceptable long-term control of ITP in the elderly group, in which the probability of maintaining response for 14yrs after splenectomy was 56%.Conclusions Patients aged 65yrs experienced negative effects on safety and efficacy outcomes of splenectomy for ITP, but further studies are needed to identify predictors of postsplenectomy outcomes in this group.

Background Few studies have evaluated the risk of pregnancy-related adverse events in asymptomatic relatives of probands for VTE and factor V Leiden or the G20210A variant. The antepartum management of this population ranges from antepartum anticoagulation therapy to clinical surveillance. Objective To evaluate the risk of placenta-mediated pregnancy complications and pregnancy-related VTE in VTE-asymptomatic families of probands with VTE and who are heterozygous carriers of either factor V Leiden or PT-G20210A mutation. Methods One hundred and fifty-eight relatives, who had 415 pregnancies, were retrospectively evaluated. Odds ratios and 95% confidence intervals were calculated to compare pregnancy outcomes between women with and without thrombophilia. Results In the factor V Leiden group, 22 placenta-mediated pregnancy events of 152 pregnancies (14.4%) were reported, compared with 25 adverse events of 172 pregnancies in the G20210A prothrombin group (14.5%) and 13 adverse events of 91 pregnancies in the non-carrier group (14.2%). Carriers of factor V Leiden or G20210A prothrombin were not associated with a higher risk of pregnancy-adverse outcomes compared with non-carriers: OR 1.02 (95% CI, 0.402.25) and 1.25 (95% CI, 0.483.24), respectively. Four episodes of pregnancy-associated VTE of 415 pregnancies (0.96%) were recorded. Two episodes of VTE in the G20210A group, one in the factor V Leiden group, and one episode in the non-carrier group were noted. Conclusions In VTE-asymptomatic relatives of probands with VTE, the presence of factor V Leiden or the G20210A prothrombin mutation in heterozygosis should not lead to a decision to instigate antepartum prophylaxis.

Allogeneic hematopoietic stem cell transplantation recipients have an increasing risk of both hemorrhagic and thrombotic complications. However, the competing risks of two of these life-threatening complications in these complex patients have still not been well defined. We retrospectively analyzed data from 431 allogeneic transplantation recipients to identify the incidence, risk factors and mortality due to thrombosis and bleeding. Significant clinical bleeding was more frequent than symptomatic thrombosis. The cumulative incidence of a bleeding episode was 30.2% at 14 years. The cumulative incidence of a venous or arterial thrombosis at 14 years was 11.8% and 4.1%, respectively. The analysis of competing factors for venous thrombosis revealed extensive chronic graft-versus-host disease to be the only independent prognostic risk factor. By contrast, six factors were associated with an increased risk of bleeding; advanced disease, ablative conditioning regimen, umbilical cord blood transplantation, anticoagulation, acute III-IV graft-versus-host disease, and transplant-associated microangiopathy. The development of thrombosis did not significantly affect overall survival (P=0.856). However, significant clinical bleeding was associated with inferior survival (P<0.001). In allogeneic hematopoietic stem cell transplantation, significant clinical bleeding is more common than thrombotic complications and affects survival.

There are no data on characteristics and molecular basis of the hereditary protein C (PC) deficiency in Spain. We analyzed a panel of probands with PC deficiency from symptomatic Spanish families.

Abstract 1955 Background and aims: Transplantation-associated thrombotic microangiopathy (TA-TMA) is a significant complication of allogeneic stem cell transplantation (HSCT). Although endothelial injury represents the final common pathway of disease, the exact pathophysiology of TA-TMA remains unclear. A variety of potential risk factors have been proposed such as different conditioning regimens, the development of acute graft versus host disease (GVHD), concomitant infection, or the use of calcineurin inhibitor (cyclosporine, tacrolimus) and sirolimus. The recent use of both tacrolimus and sirolimus for GVHD prophylaxis suggest increasing the risk of TA-TMA, especially in patients receiving busulfan and cyclophosphamide. However, there are little studies in which tacrolimus/sirolimus GVHD prophylaxis was compared with other tacrolimus-based regimens in order to determine the really increased incidence of TA-TMA. The purpose of this study was to determine the incidence and risk factors of TA-TMA in 86 allogeneic-HSCT recipients who received tacrolimus-based regimens (with sirolimus or with methotrexate) for GVHD prophylaxis. Patients and Methods: We conducted a retrospective cohort study of 86 consecutive allogeneic-HSCT recipients (aged over 18 years) transplanted in our unit between September 2007 and July 2012; GVHD prophylaxis consisted on tacrolimus and methotrexate (N = 19) or tacrolimus and sirolimus (N= 64); 3 patients received tacrolimus and sirolimus for acute GVHD treatment. Median age was 51 years (range 20–68) and 59.3% male. 40.7% of patients were diagnosed of acute leukemia, 23.3% myelodisplastic syndrome, 23.2% lymphoproliferative disorders, 7% multiple myeloma, 5.9% other hematological malignancies. The EBMT status at the moment of HSCT was intermediate/advanced in 63% of patients. The source of stem cells was peripheral blood in 87.2% and bone marrow in 12.8%. 57% of patients receiving an unrelated donor transplant. Nineteen patients (22.1%) received a HLA-mismatch graft. Reduced intensity conditioning was administered in 74.4%. 67.4% developed acute GVHD, 58.1% grade II-IV acute GVHD. Median follow-up was 248 days (range 16–1357). The diagnosis of TA-TMA was considered according to probable TMA criteria as defined by validation study by Cho et al. Results: TA-TMA occurred in 9/86 patients (10,5%): 2/19 patients in the tacrolimus-methotrexate regimen group (10.5%) and 7/67 in the tacrolimus/sirolimus regimen group (10.4%). Median time until diagnosis of TA-TMA was 67 days (range, 37 – 405 days), and 8/9 patients were diagnosed before the day +110 post-HSCT; none of them developed chronic GVHD previously to the diagnosed of TA-TMA. Several variables have been analyzed but only acute GVHD (p=0.026) and acute gut GVHD (p=0.007) were significantly associated with TA-TMA in the univariate analysis. Of note, in the tacrolimus/sirolimus group, only acute gut GVHD (p=0.04) but not acute GVHD, was associated with TA-TMA. In the multivariate analysis, only grade ≥2 acute gut GVHD retained their association with TA-TMA development (OR = 13.33, 95% CI = 1.51 – 117.38). Conclusions: In contrast to previously published evidence, these data support that the use of tacrolimus/sirolimus GVHD prophylaxis does not increase the risk of TA-TMA compared to tacrolimus/methotrexate regimen. However, none of the patients included in our study have received busulfan-cyclophosphamide conditioning. On the other hand, the most important risk factor for TA-TMA in allogeneic-HSCT recipients who received tacrolimus-based GVHD prophylaxis regimens was grade ≥2 acute gut GVHD. Consequently we propose especially close monitoring for TA-TMA in these patients. Disclosures: No relevant conflicts of interest to declare.

Dear Sir, Activated platelets play a crucial role in the pathogenesis of acute coronary syndrome (ACS) (1), and platelet size can be a determinant of platelet function. Thus, large platelets are metabolically more active than small platelets and have greater pro-thrombotic potential (2). However, the clinical influence of platelet size, measured as mean platelet volume (MPV), is controversial (3–6). An alternative to MPV measurement is the analysis of immature platelet fraction (IPF). Newly formed platelets can be distinguished from mature platelets that are poor in RNA by flow cytometric quantification using fluorescent dyes that bind RNA (7). However, this method produces high intra-assay reproducibility coefficients of variation (8) and requires specialist personnel to perform it. A new, rapid and fully automated method for the measurement of reticulated platelets, expressed as the immature platelet fraction (IPF), using the Sysmex XE-2100 blood cell counter has been under development. Recently, Grove et al showed that measurements of IPF made with the Sysmex XE-2100 were significantly higher in patients with ACS than in healthy subjects (9), although further studies were required. Therefore, the aim of this study is to examine the relationship between IPF and ACS in a case-control study. A total of 404 individuals were enrolled in the study. A total of 202 patients with a documented first episode of ACS were prospectively recruited upon admission to the Coronary Unit. The diagnosis of ACS included ST segment elevation myocardial infarction (STEMI, n = 129) and non-ST segment elevation ACS (NST ACS, n = 73). The latter group included non-ST segment elevation myocardial infarction (NSTEMI) and unstable angina (UA) patients. Diagnosis of STEMI, NSTEMI and UA was made according to the new ESC/ACC consensus definition (10). The control group for our study included 202 unrelated healthy persons without a history of vascular or thromboembolic disease and a normal electrocardiogram. All subjects gave their informed consent to enter the study. Blood was collected from the antecubital vein at 08:00 a.m. on day 1 or 2 after admission. IPF was calculated as the ratio of immature platelets to the total number of platelets in a fully automated haematology analysis system (Sysmex XE-2100; Sysmex,

Background aimsImmune thrombocytopenic purpura (ITP) is a bleeding disorder characterized by an accelerated destruction of platelets as a result of the presence of autoreactive antibodies. Patients with ITP also display activated platelet-autoreactive T cells. Mesenchymal stem cells (MSC) inhibit both T- and B-cell activation and may have functional impairments in autoimmune disorders.MethodsWe analyzed the potential role of MSC in the pathogenesis of ITP.ResultsMSC from ITP showed an impaired proliferative capacity and a lower capability of inhibiting activated T- cell proliferation compared with healthy donors. While MSC from controls showed a decreased expression of p27 after stimulation with platelet-derived growth factor, this effect was not observed in MSC from patients. Furthermore, MSC from healthy donors down-regulated p16 upon exposure to platelet-released supernatant, while this effect was not observed for ITP. Interestingly, caspase 9 expression was higher in MSC from ITP.ConclusionsThese abnormalities suggest a role of MSC malfunction in the physiopathology of the disease and may have therapeutic implications.

BACKGROUND:Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by a deficient expression of glycosylphosphatidylinositol-anchored proteins (GPI-APs), due to somatic mutations of the phosphatidylinositolglycan complementation Class A (PIG-A) gene.STUDY DESIGN AND METHODS:In this study, the expression of a high number of GPI-APs on different subsets of peripheral blood (PB) cells from 14 PNH patients and their potential association with underlying genetic abnormalities has been analyzed.RESULTS:This study confirms the existence of variable patterns of expression of different GPI-APs on both major and minor PB-cell subsets from PNH patients. The size of the PNH clone within PB neutrophils and monocytes was systematically higher than that of other cell populations. Genetic changes were detected in the PIG-A gene in 5 of 13 cases analyzed. Interestingly, the reactivity for many GPI-APs was significantly higher on different subsets of normal PB cells from PNH patients than those observed on healthy volunteers.CONCLUSION:The best combination of markers for the diagnostic screening of PNH would include evaluation of CD14 on monocytes and of CD16 on neutrophils, although further analysis of CD55 and CD59 expression may contain additional clinically useful information. Clear association between the genetic changes detected in the PIG-A gene in 5 of 13 cases analyzed, and the phenotypic profile of PNH cells has not been found. Additionally, an abnormally higher expression of several GPI-APs among normal residual cells from PNH patients in comparison to healthy donors was observed, suggesting that factors other than the PIG-A mutation could determine the phenotypic profile of PB cells in PNH.

Background Routine analyses for thrombophilia include determination of the presence of factor V Leiden and prothrombin 20210A polymorphisms. However, the usefulness of these determinations is controversial and the clinical benefit remains questioned because of the moderate risk of associated thrombosis in carriers. In the search for clusters of thrombotic risk factors to estimate individual risk better, we studied the effect of AB0 blood group, a highly prevalent factor with mild prothrombotic features, on the risk and severity of venous and arterial thromboses in carriers of these polymorphisms.Design and Methods We genotyped the AB0 blood group in 981 carriers of factor V Leiden or prothrombin 20210A polymorphisms. In order to avoid the over-representation of a particular genotype and to suppress confounding factors, we included only non-related heterozygous carriers without additional genetic risk factors. We studied 609 patients with venous thromboembolism (287 with factor V Leiden, and 322 with prothrombin 20210A), 174 patients with myocardial infarction (78 with factor V Leiden, and 96 with prothrombin 20210A), and 198 controls (96 with factor V Leiden, and 102 with prothrombin 20210A).Results Non-OO blood group did not increase the risk of myocardial infarction in carriers of factor V Leiden or prothrombin 20210A. However, non-OO blood group contributed significantly to the expression of venous thrombosis associated with both factor V Leiden (OR: 1.76; 95%CI: 1.06–2.91) and prothrombin 20210A (OR: 2.17; 95%CI: 1.33–3.53). Exclusion of A2A2 and A2O from the non-00 blood group (because factor VIII-von Willebrand factor levels are similar in these and the 00 blood group) increased the thrombotic risk. Finally, non-OO blood group was associated with an earlier onset in symptomatic carriers of these polymorphisms.Conclusions Our study suggests that non-OO blood group increases the risk and severity of venous thrombosis in carriers of prothrombotic polymorphisms. Thus, AB0 phenotyping or genotyping analyses may be valuable components in assessing future thrombophilic risk profiles and might have implications for the policy of thrombosis prophylaxis and treatment.

Antithrombin, the most potent anticoagulant in vivo, displays a significant conformational flexibility. The native five-stranded anticoagulant form transforms under different conditions or mutations to inactive six-stranded conformations: latent or polymer. However, the function, potential deleterious effects, and clearance of these forms are not completely known. The dimerization of latent antithrombin with a native molecule has been suggested to have thrombotic potential. We have assessed the potential thrombogenicity of high amounts of latent and polymeric antithrombin by experiments performed in mice and human plasma. Moreover, we have analyzed the clearance of 125I-labeled native, latent, polymer, and thrombin-complexed antithrombins in rat, as well as the clearance of latent antithrombin from plasma of patients treated with commercial concentrates. Our results show that high plasma levels of latent or polymeric antithrombin do not interfere with the anticoagulant function of native antithrombin. Moreover, we confirm that all monomeric forms of antithrombin have similar turnover. Finally, we show that polymers have the longest half-life of all conformers, being in circulation for prolonged periods of time. In conclusion, our data support that latent and polymeric antithrombin would not likely have a thrombotic effect, thus dispelling doubts about the potential harmful effect of latent antithrombin present in commercial concentrates for therapeutic use. Moreover, the suggested antiangiogenic role of latent antithrombin, together with its stability in plasma and its negligible thrombogenicity raises the possibility of its use as a new antiangiogenic drug.

The antithrombin A384S mutation has a relatively high frequency in the British population but has not been identified in other populations. This variant has been associated with cases of thrombotic disease, but its clinical relevance in venous thrombosis remained unclear. We have conducted a secondary analysis of the prevalence of the mutation in a large case-control study, including 1018 consecutive Spanish patients with venous thromboembolism. In addition, we evaluated its functional consequences in 20 carriers (4 homozygous). This mutation, even in the homozygous state, did not affect anti-Xa activity or antigen levels, and it only slightly impaired anti-IIa activity. Thus, routine clinical methods cannot detect this anomaly, and, accordingly, this alteration could have been underestimated. We identified this mutation in 0.2% of Spanish controls. Among patients, this variant represented the first cause of antithrombin anomalies. Indeed, 1.7% patients carried the A384S mutation, but 0.6% had any other antithrombin deficiency. The mutated allele was associated with an increased risk of venous thrombosis with an adjusted OR of 9.75 (95% CI, 2.2-42.5). This is the first study supporting that antithrombin A384S mutation is a prevalent genetic risk factor for venous thrombosis and is the most frequent cause of antithrombin deficiency in white populations.

Background: Despite the well-known pro-thrombotic and pro-inflammatory plasma homocysteine effects, it remains uncertain whether these effects can be associated with an adverse cardiac outcome in young patients admitted with acute coronary syndromes.Methods: Homocysteine levels were determined within 24 h after admission in 244 consecutive patients aged less than 56 years who presented with an acute coronary syndrome. We evaluated the relationship between homocysteine and both short-term (death, myocardial [re] infarction), and long-term prognosis (death, recurrent acute coronary syndrome and/or ischemic stroke), after 3.4 +/- 1.7 years of follow-up.Results: Hornocysteine levels were similar in patients both with and without in-hospital event: 8.65 (5.36-10.48) vs. 8.98 (7.38-11.13) mu mol/l, p=NS. However, patients who presented with the combined event during follow-up had higher homocysteine levels than those free of the event: 10.54 (7.90-11.76) mu mol/l vs. 8.52 (7.11-10.23) mu mol/l, p=0.001. Patients who either died (13.78 vs. 8.87 mu mol/l, p=0.012) or had a myocardial infarction (10.75 vs. 8.76 mu mol/l, p=0.006) or unstable angina (10.46 vs. 8.76, p=0.006) during follow-up had higher homocysteine levels. According to the Cox regression analysis: age [hazard ratio 1.05, CI 95%, 0.99-1.10], left ventricular ejection fraction <= 40% [hazard ratio 1.93, CI 95%, 0.98-3.79], and homocysteine tertile 3 [hazard ratio 2.05, Cl 95%, 1.13-3.71] were the significant determinants of the combined adverse event during follow-up. Although 41 (18%) of patients presented the TT genotype of the methylen-tetrahydrofolate-reductase thermolabile variant mutation, its occurrence had a neutral effect on inorbid-mortality.Conclusions: High homocysteine levels at admission strongly predict late cardiac events in young patients with acute coronary syndromes. (C) 2006 Elsevier Ireland Ltd. All rights reserved.

The Consensus Document on Alternatives to Allogenic Blood Transfusion (AABT) has been drawn up by a panel of experts from 5 scientific societies. The Spanish Societies of Anesthesiology (SEDAR), Critical Care Medicine and Coronary Units (SEMICYUC), Hematology and Hemotherapy (AEHH), Blood Transfusion (SETS) and Thrombosis and Hemostasis (SETH) have sponsored and participated in this Consensus Document. Alternatives to blood transfusion have been divided into pharmacological and non-pharmacological, with 4 modules and 12 topics. The main objective variable was the reduction of allogenic blood transfusions and/or the number of transfused patients. The extent to which this objective was achieved by each AABT was evaluated using the Delphi method, which classifies the grade of recommendation from A (supported by controlled studies) to E (non-controlled studies and expert opinion). The experts concluded that most of the indications for AABT were based on middle or low grades of recommendation, "C", "D", or "E", thus indicating the need for further controlled studies.

Intravenous immunoglobulin (IVIG) products are considered a useful treatment in patients with chronic idiopathic/immune thrombocytopenic purpura (ITP) to prevent bleeding or prior to surgery, when platelet counts have to be rapidly increased. IGIV3I Grifols is a highly purified, unmodified human IgG product whose manufacturing process follows the same basic principles of Flebogamma® (another IVIG manufactured by Grifols in clinical use since 1992). The main differences between both processes are how purification steps are sequentially arranged, and the introduction of two specific steps to inactivate/remove any potential contaminating pathogen (solvent-detergent treatment and sequential nanofiltration through 35 and 20 nm pore size filters), as additional viral elimination steps to pasteurization, already present in Flebogamma®. An open prospective study was planned to investigate the efficacy and safety of IGIV3I Grifols in 20 adult patients with chronic ITP (at least 6 months after diagnosis). Twenty adult subjects were enrolled and 19 patients with chronic ITP in acute phase (platelet counts <20x109/l) were treated. Patients received 0.4 g/kg body weight for 5 consecutive days. Efficacy endpoints were the proportion of patients who reached a platelet count ≥50x109/l, the time taken for the platelet count to reach the target level and the duration of response. Regression of haemorrhages was documented during the first 14 days of follow-up. Safety parameters including adverse events (AEs), laboratory determinations and vital signs were regularly monitored. The follow-up of patients ended 3 months after first dose of IGIV3I Grifols to determine any change in viral markers for HIV, HCV, HBV and HAV. Results from intention to treat (ITT) population (n=20) and per protocol (PP) population (n=19) are presented. A patient was withdrawn from the study because she did not present an immune idiopathic thrombocytopenic purpura. A total of 14 patients (ITT = 70%; PP = 74%) responded to the study drug. The median time to platelet response was ≥2.5 days and the median number of days in which the platelet count remained ≥50x109/l was ≥7.0 days. For 17 patients (ITT = 85%; PP = 89%) a regression of the bleeding episodes was reported on day 14. Eight out of 20 patients presented 21 AEs potentially related to the study drug (16 mild and 5 moderate). Headache and fever (6 cases each), hypertension (2), decreased blood pressure (2) or hypotension (1), blood pressure fluctuation (1), thrombocythaemia (1), bradycardia (1) and asthenia (1) were AEs potentially related to study drug. No patients experienced clinically significant abnormalities in the laboratory values (haematology and renal and hepatic functions) and no patients changed their virological markers during the follow-up of the study. The results show that IGIV3I Grifols is safe and adequate to achieve a safe platelet count in patients with refractory chronic ITP.

The protein Z-dependent protease inhibitor (ZPI) is a hemostatic serpin with anticoagulant activity. As for antithrombin, deficiency of ZPI could have relevant thrombotic consequences. We have studied 6 genetic modifications affecting the ZPI gene, identifying 5 haplotypes. Haplotype H5 is featured by a stop codon at position 67. The relevance of these genetic modifications and haplotypes in venous thrombosis was evaluated in a case-control study including 1018 patients and 1018 age- and sex-matched controls. Surprisingly, the H5 haplotype was found in 0.9% of controls, supporting that the Arg67Stop change is a low frequency nonsense polymorphism. The prevalence of this haplotype increased significantly in patients (3.0%), one of whom was in a homozygous state. Multivariate analysis confirms that carriers have a 3.3-fold risk of developing venous thrombosis (P = .002; 95% CI: 1.5-7.1). Moreover, we observed a significant association of this polymorphism with familial history of thrombosis (P < .001). Our study supports that the ZPI Arg67Stop nonsense polymorphism might be an independent genetic risk factor for venous thrombosis. This polymorphism has slightly lower prevalence but similar thrombotic risk than the FV Leiden or prothrombin 20210A. Although further studies are required, all available data support that the ZPI is a candidate to play a significant role in thrombosis and should be evaluated in thrombophilic studies.

The Consensus Document on Alternatives to Allogenic Blood Transfusion (AABT) has been drawn up by a panel of experts from 5 scientific societies. The Spanish Societies of Anesthesiology (SEDAR), Critical Care Medicine and Coronary Units (SEMICYUC), Hematology and Hemotherapy (AEHH), Blood Transfusion (SETS) and Thrombosis and Hemostasis (SETH) have sponsored and participated in this Consensus Document. Alternatives to blood transfusion have been divided into pharmacological and non-pharmacological, with 4 modules and 12 topics. The main objective variable was the reduction of allogenic blood transfusions and/or the number of transfused patients. The extent to which this objective was achieved by each AABT was evaluated using the Delphi method, which classifies the grade of recommendation from A (supported by controlled studies) to E (non-controlled studies and expert opinion). The experts concluded that most of the indications for AABT were based on middle or low grades of recommendation, "C", "D", or "E", thus indicating the need for further controlled studies.

Much of the variability in the sensitivity to warfarin in anticoagulated patients is associated with the c.-1639G > A polymorphism of the vitamin K-epoxide reductase (VKORC1) gene. However, its association with the acenocoumarol dose in patients under anticoagulant therapy has not been studied. The c.-1639G > A genotype of VKORC1 was determined in 113 patients on stable anticoagulation requiring low (n = 42), medium (n = 42) or high (n = 21) acenocoumarol doses. To evaluate the association between acenocoumarol requirements and the c.-1639G > A variant, multivariate logistic regression models were fitted, adjusting for age, gender, and the c.430C > T and c.1075A > C variants of cytochrome P450 2C9 (CYP2C9). A total of 90.5% of the patients in the low acenocoumarol dose group carried the A allele of VKORC1:c.-1639G > A. The A allele independently increased the odds of requiring a low acenocoumarol dose [odds ratio (OR) 9.4; 95% confidence interval (CI) 1.9-46.4; P = 0.006], especially when the homozygous form was present (OR 44.2; 95% CI 5.5-354.6; P < 0.001). The A allele was less frequent in the high dose group showing an inverse association with the requirement for high doses (OR 0.04; 95% CI 0.01-0.22; P < 0.001). The A allele of the c.-1639G > A polymorphism of VKORC1 is therefore associated with a low-dose requirement for acenocoumarol in patients receiving anticoagulant therapy.