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Transfusion of cold-stored platelet concentrates (CS-PCs) appears effective in massively bleeding patients. However, few studies have evaluated their in vivo hemostatic function in severe thrombocytopenia.The in vivo function of plasma-depleted human PCs was evaluated in rabbits with a blocked reticuloendothelial system and busulfan-induced thrombocytopenia. On day 1, a human apheresis PC was processed in a platelet additive solution (PAS-PC) and split evenly for cold or room temperature storage (RTS). On days 3, 6, or 9, RTS- or CS-PAS-PCs were transfused (4.0 × 10The mean pre-transfusion rabbit platelet count was 8.6 ± 5.2 × 10CS-PAS-PCs might achieve similar hemostasis as RTS-PAS-PCs in thrombocytopenic patients with mild bleeding. Hemostatic efficacy could be improved by transfusing more CS-PAS-PCs.

There is a global concern about the safety of COVID-19 vaccines associated with platelet function. However, their long-term effects on overall platelet activity remain poorly understood. Here we address this problem by image-based single-cell profiling and temporal monitoring of circulating platelet aggregates in the blood of healthy human subjects, before and after they received multiple Pfizer-BioNTech (BNT162b2) vaccine doses over a time span of nearly 1 year. Results show no significant or persisting platelet aggregation trends following the vaccine doses, indicating that any effects of vaccinations on platelet turnover, platelet activation, platelet aggregation, and platelet-leukocyte interaction was insignificant.

The production of red blood cells in vitro, which is useful for basic or clinical research, has been improved. Further optimization of culture protocols may facilitate erythroid differentiation from hematopoietic stem cells to red blood cells. However, the details of erythropoiesis, particularly regarding the behaviors of differentiation-related proteins, remain unclear. Here, we performed erythroid differentiation using two independent bone marrow- or cord blood-derived CD34+ cell sources and identified proteins showing reproducible differential expression in all groups. Notably, most of the proteins expressed at the early stage were downregulated during erythroid differentiation. However, seven proteins showed upregulated expression in both bone marrow cells and cord blood cells. These proteins included alpha-synuclein and selenium-binding protein 1, the roles of which have not been clarified in erythropoiesis. There is a possibility that these factors contribute to erythroid differentiation as they maintained a high expression level. These findings provide a foundation for further mechanistic studies on erythropoiesis.

We aimed to determine the association between acute platelet reactivity and clinical outcome in acute ischemic stroke (AIS) or transient ischemic attack (TIA) with large-artery atherosclerosis (LAA).In this prospective, 16-multicenter study, we enrolled AIS/TIA patients with LAA receiving clopidogrel. We assessed the association of P2Y12 reaction units (PRU) 24 hours after initiation of antiplatelets with the CYP2C19 genotype and recurrent ischemic stroke within 90 days, and the difference between acute (≤ 7 days) and subacute (8-90 days) phases.Among the 230 AIS/TIA patients enrolled, 225 with complete outcome data and 194 with genetic results were analyzed. A higher PRU was significantly associated with recurrent ischemic stroke within 90 days (frequency, 16%), and within 7 days (10%). Twenty-nine patients (15%) belonged to a CYP2C19 poor metabolizer group (CYP2C19Acute PRU evaluation possesses predictive value for recurrent ischemic stroke, especially within 7 days in AIS/TIA with LAA.

Japan is an island country, and the Japanese people have had minimal genetic exchange with other ethnolinguistic groups. Consequently, the population is highly uniform and has limited HLA diversity relative to people from other countries. However, Japan has three ethnolinguistic groups, and HLA distributions differ depending on geographic region. To collect an HLA-rich variety of bone marrow bank donor registrants, it is essential to know the precise distribution of HLA in Japan. We analyzed HLA alleles and haplotypes based on HLA information of 177 041 bone marrow donor registrants. Registrants were grouped depending on the prefecture and region (a group of prefectures) as commonly used in Japan. The prefectures did not show the same distributions, but the tendency was similar for each region. We found that Okinawa Prefecture and the mainland can be clearly divided as haplotypes: [A*24:02-C*01:02-B*54:01-DRB1*04:05] and [A*24:02-C*01:02-B*59:01-DRB1*04:05] were typically found in Okinawa (P = .02, P < .001). Moreover, these types were found almost exclusively in Japan and Korea. Donor registration centers of the Japan Marrow Donor Program are currently located in all prefectures. It is essential to deploy registration centers to collect registrants with a large variety of HLA types covering all of Japan.

Background Our previous study showed that ultraviolet C (UVC) from xenon (Xe) flash without any photoreactive compounds inactivated bacteria in platelet concentrates (PCs) with less damage to platelets (PLTs) as compared with Xe flash containing ultraviolet A, ultraviolet B, and visible light. Here, we report a UVC irradiation system for PCs under flow conditions consisting of a flow path-irradiation sheet, a peristaltic pump, and a collection bag. Study design and methods Platelet concentrates containing Ringer's solution (R-PCs) inoculated with bacteria were injected into a flow path sheet using a peristaltic pump, being irradiated with UVC from Xe flash. The quality of the irradiated PCs containing platelet additive solution (PAS-PCs) was assessed based on PC variables, PLT surface markers, and aggregation ability. Results Streptococcus dysgalactiae (12 tests) and Escherichia coli (11) were all negative on bacterial culture, while Staphylococcus aureus (12) and Klebsiella pneumoniae (14) grew in one and two R-PCs, respectively. Bacillus cereus spores were inactivated in 7 of 12 R-PCs. PC variables became significantly different between irradiated and nonirradiated PAS-PCs. P-selectin, first procaspase-activating compound (PAC-1) binding, and phosphatidylserine increased by irradiation. Aggregability stimulated by adenosine diphosphate, collagen, or thromboxane A2 increased in the irradiated PAS-PCs, while that by thrombin became smaller compared with nonirradiated controls. Conclusion This newly developed system inactivated bacteria including spores in R-PCs. PAS-PCs irradiated by this system retained acceptable in vitro quality and aggregability. Usage of a peristaltic pump instead of agitator during irradiation may enable this system to be directly combined with an apheresis blood cell separator.

HLA sequence-based DNA typing (SBT) by long-range PCR amplification (LR PCR) and next-generation sequencing (NGS) is a high-throughput DNA sequencing method (LR-NGS-SBT) for the efficient and sensitive detection of novel and null HLA alleles to the field-4 level of allelic resolution without phase ambiguity. However, the accuracy and reliability of the HLA typing results using buccal cells (BCs) and saliva as genetic source materials for the LR-NGS-SBT method are dependent largely on the quality of the extracted genomic DNA (gDNA) because a large degree of gDNA fragmentation can result in insufficient PCR amplification with the incorrect assignment of HLA alleles because of allele dropouts. In this study, we developed a new cost-efficient swab storage gel (SSG) for wet swab collection of BCs (BC-SSG) and evaluated its usefulness by performing different DNA analytical parameters including LR-NGS-SBT to compare the quality and quantity of gDNA extracted from BCs (in SSG or air dried), blood and saliva of 30 subjects. The BC-SSG samples after 5 days of storage revealed qualitative and quantitative DNA values equivalent to that of blood and/or saliva and better than swabs that were only air-dried (BC-nSSG). Moreover, all the gDNA extracted from blood, saliva and BC-SSG samples were HLA-typed successfully to an equivalent total of 408 alleles for each sample type. Therefore, the application of BC-SSG collection media for LR-NGS-SBT has benefits over BC dried samples (dry swabs) such as reducing retesting and the number of untestable BC samples because of insufficient DNA amplification.

Gastrointestinal bleeding (GIB) is among the major complications affecting implantable continuous-flow left ventricular assist device (iLVAD) recipients and is the major cause of re-hospitalization. GIB in iLVAD recipients is sometimes critical, and controlling bleeding using conventional approaches is difficult. A 35-year-old woman developed refractory GIB from multiple gastric polyps and de novo angiodysplasia after Jarvik2000® iLVAD implantation. Discontinuation of anticoagulation and antiplatelet therapies had little effect on GIB; thus, multiple endoscopic hemostatic therapies were performed. However, bleeding recurred several times, and red blood cell (RBC) transfusion in large volumes was required for progressive anemia. Furthermore, the von Willebrand factor (VWF) multimer analysis revealed loss of the high-molecular weight multimer, which may have resulted from the high-speed rotation of the axial-flow LVAD pump. To supplement VWF, cryoprecipitate was administered, but it was effective for only several days. Finally, the patient was treated with octreotide, a somatostatin analog, on post-operative day 58. After starting octreotide, tarry stool gradually decreased, and progression of anemia slowed down within the first 14 days of treatment; thus, the total RBC transfusion volume was reduced without additional hemostatic interventions, including cryoprecipitate administration. The patient developed mediastinitis on post-operative day 68 and died of sepsis on post-operative day 72. There was no adverse effect associated with octreotide use. Although the observation period was short, octreotide appears to be useful for resolving recurrent GIB after iLVAD implantation and reducing blood transfusions.

Background CYP2C19variants are associated with the antiplatelet effects of clopidogrel against recurrent cardiovascular events. However, it remains unknown whether the elapsed time from stroke onset affects the relationship between the genetic variants and such events. To address this, we conducted a prospective cohort study to determine the effect ofCYP2C19variants on clinical outcomes in the chronic phase.Methods and Results:In total, 518 Japanese non-acute stroke patients treated with clopidogrel were registered at 14 institutions. Patients were classified into 3 clopidogrel-metabolizing groups according toCYP2C19genotype: extensive metabolizer (EM:*1/*1), intermediate metabolizer (IM:*1/*2or*1/*3), and poor metabolizer (PM:*2/*2,*2/*3, or*3/*3). Antiplatelet effects of clopidogrel were assessed by adenosine diphosphate (ADP)-induced platelet aggregation and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. The endpoint was composite cerebrocardiovascular events (CVEs). In 501 successfully followed-up patients, the median time from index stroke to enrollment was 181 days. There were 28 cardiovascular and 2 major bleeding events. There were no significant differences in the rates of cardiovascular events among the groups. Conclusions Despite associations betweenCYP2C19variants and on-clopidogrel platelet reactivity, there was no significant difference in rates of CVEs in the chronic stroke phase among the 3 clopidogrel-metabolizing groups ofCYP2C19variants.

Objectives:The present study aimed to examine the association between tranexamic acid use and adverse effects (seizures, thromboembolism, and renal dysfunction) in a pediatric trauma population using a national inpatient database in Japan. We also assessed the association between tranexamic acid use

A characteristic clinical feature of COVID-19 is the frequent incidence of microvascular thrombosis. In fact, COVID-19 autopsy reports have shown widespread thrombotic microangiopathy characterized by extensive diffuse microthrombi within peripheral capillaries and arterioles in lungs, hearts, and other organs, resulting in multiorgan failure. However, the underlying process of COVID-19-associated microvascular thrombosis remains elusive due to the lack of tools to statistically examine platelet aggregation (i.e., the initiation of microthrombus formation) in detail. Here we present a method for massive image-based profiling, temporal monitoring, and big data analysis of circulating platelets and platelet aggregates in the blood of COVID-19 patients at single-cell resolution, to provide previously unattainable insights into the disease. In fact, our analysis of the image data from 110 hospitalized patients shows the anomalous presence of excessive platelet aggregates in nearly 90% of all COVID-19 patients. Furthermore, results indicate strong links between the concentration of platelet aggregates and the severity, mortality, and respiratory condition of patients with COVID-19. Finally, high-dimensional analysis based on deep learning shows that the disease behaves as systemic thrombosis.

Background We previously reported a flow path-ultraviolet C (UVC) irradiation system for platelet concentrates (PCs) with platelet additive solution (PAS) to minimize contamination by bacteria. Here, we investigated functionalities of irradiated platelets (PLTs) in in vitro thrombus formation and in vivo hemostasis. Study design and methods PAS-PCs were irradiated with flash UVC using the flow path system. Their variables (PLT count, mean platelet volume, pH, glucose, lactate, glycoprotein [GP] Ib, and activated integrin αIIbβ3) were evaluated. Static adhesion to collagen or fibrinogen was analyzed using fluorescent microscopy. Thrombus formation under flow conditions was assessed using a collagen-coated bead column. Adenosine diphosphate (ADP)-induced Akt phosphorylation was determined by western blot. In vivo hemostasis and circulatory survival of PLTs were assessed with a rabbit bleeding model. Results All variables, except for GPIb expression, were slightly, but significantly, impaired after flash UVC irradiation throughout the 6-day storage period. No difference was observed in static adhesion to either collagen or fibrinogen between irradiated and nonirradiated PAS-PCs. In vitro thrombus formation of flash UVC-irradiated PAS-PCs was significantly greater than that of nonirradiated PAS-PCs. ADP-induced Akt phosphorylation was enhanced in irradiated PAS-PCs. In vivo hemostatic efficacy was comparable between the groups on Day 1. The efficacy declined in nonirradiated PAS-PCs on Day 5, while it was retained in flash UVC-irradiated PAS-PCs. Circulatory survival of PLTs was lower in irradiated PAS-PCs. Conclusions PAS-PCs irradiated with UVC from xenon flash have favorable properties to achieve hemostasis compared with nonirradiated PAS-PCs.

Background Japan has now become a super-aged society. Notably, as the Japanese society ages, the prevalence of falls, which represent an aging-related problem, has increased. Locomotive syndrome (LS) is a condition of decreased mobility due to locomotive organ disorder. The loco-check is simple tool to detect early-stage LS. The loco-check comprises seven items relating to daily activities. Higher numbers of affirmative answers in the loco-check are negatively associated with physical functions. The purpose of this study was to examine the potential correlation between the number of affirmative answers given on the “loco-check” survey and the likelihood of experiencing at least one fall during the following one-year period. Methods This prospective study included 154 cases (35 men, 119 women), all aged 65 years or older, answered the loco-check at baseline. As part of their normal treatment process, the participants made monthly visits to the out-patient department; thus, at each of these visits for the following 12 months a medical doctor interviewed each patient to determine whether they had experienced a fall during the previous month. Results The mean age of the sample was 77.3 years, and the median number of affirmative answers given was 2.0. The number of affirmative answers significantly correlated with the cases which had a fall event within the follow-up period. Specifically, an increase in one “yes” answer on the loco-check increased the relative risk of fall (odds ratio: 1.32; 95% Confidence interval (CI): 1.03–1.70). In addition, the risk of fall was high in cases which showed the number of affirmative answers given on the loco-check ≥4 (odds ratio: 9.26; 95% CI: 1.05–81.7). Conclusion The number of affirmative answers given on the loco-check is positively correlated with a fall event within the following year.

We identified a probable new null HLA-C allele, C*03:23N, which originated from C*03:04:01:02, but does not react with Cw3 antibodies. This allele was identified by sequence analysis, which indicated that a single G-to-A substitution at position 406 in exon 3 created a null allele under a new mechanism: the mutation changes the position of the intron 2-exon 3 splice site to be further into exon 3, leading to a frameshift and a premature stop codon. Sequence analysis of cDNA confirmed the existence of the causative alternative acceptor splice site and the resultant deletion of 64 nucleotides in exon 3. Analysis of 220 blood or bone marrow donors in Japan with C*03:23N demonstrated that Japanese HLA-C*03:23N is on the haplotype A*26:01∼C*03:23N∼B*40:02∼DRB1*09:01.

A 45-year-old man, who was implanted with an inferior vena cava (IVC) filter in his infrarenal IVC, had a complication of deep vein thrombosis (DVT) propagation from the IVC, beyond the IVC filter, to the right calf and left external iliac veins. The entire IVC filter was covered with a massive thrombus. We first decided to retrieve the IVC filter itself, which was suspected of causing metallic allergy. The thrombotic IVC filter was successfully retrieved using multi-step catheter intervention. To our knowledge, this is the first case report to describe successful multi-step catheter intervention for retrieval of an IVC filter covered with a massive thrombus.

CYP2C19variants are associated with the antiplatelet effects of clopidogrel against recurrent cardiovascular events. However, it remains unknown whether the elapsed time from stroke onset affects the relationship between the genetic variants and such events. To address this, we conducted a prospective cohort study to determine the effect ofCYP2C19variants on clinical outcomes in the chronic phase.Methods and Results:In total, 518 Japanese non-acute stroke patients treated with clopidogrel were registered at 14 institutions. Patients were classified into 3 clopidogrel-metabolizing groups according toCYP2C19genotype: extensive metabolizer (EM:*1/*1), intermediate metabolizer (IM:*1/*2or*1/*3), and poor metabolizer (PM:*2/*2,*2/*3, or*3/*3). Antiplatelet effects of clopidogrel were assessed by adenosine diphosphate (ADP)-induced platelet aggregation and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. The endpoint was composite cerebrocardiovascular events (CVEs). In 501 successfully followed-up patients, the median time from index stroke to enrollment was 181 days. There were 28 cardiovascular and 2 major bleeding events. There were no significant differences in the rates of cardiovascular events among the groups.Despite associations betweenCYP2C19variants and on-clopidogrel platelet reactivity, there was no significant difference in rates of CVEs in the chronic stroke phase among the 3 clopidogrel-metabolizing groups ofCYP2C19variants.

Gastrointestinal bleeding (GIB) is among the major complications affecting implantable continuous-flow left ventricular assist device (iLVAD) recipients and is the major cause of re-hospitalization. GIB in iLVAD recipients is sometimes critical, and controlling bleeding using conventional approaches is difficult. A 35-year-old woman developed refractory GIB from multiple gastric polyps and de novo angiodysplasia after Jarvik2000

Treating a patient with heparin-induced thrombocytopenia can be challenging particularly when the patient requires urgent cardiac surgery that uses heparin for anticoagulation. We herein report a case of a 61-year-old man with idiopathic dilated cardiomyopathy associated with heparin-induced thrombocytopenia and who underwent plasma exchange to remove heparin-induced thrombocytopenia antibodies before undergoing left ventricular assist device implantation. The surgery was performed using cardiopulmonary bypass and unfractionated heparin.

Objectives To investigate whether administering fibrinogen concentrate or cryoprecipitate is associated with increased postoperative thromboembolic events and improved mortality in patients undergoing thoracic aortic surgery. Design Multicenter retrospective cohort study using propensity-score analyses and multivariate logistic regression analysis to control for confounders. Setting Four hospitals (1 national cardiovascular center and 3 university hospitals). Participants Patients undergoing thoracic aortic surgery with cardiopulmonary bypass between January 2010 and October 2012 (n = 1,047). Interventions Outcomes in patients treated with fibrinogen concentrate or cryoprecipitate (fibrinogen group) were compared with those who did not receive these products (no fibrinogen group) based on propensity-score matching. Multivariate logistic regression analysis then was performed to confirm the results. Measurements and Main Results Among 1,047 patients enrolled in this study, 247 patients received fibrinogen concentrate or cryoprecipitate. The median amount of administered fibrinogen was 3 g (interquartile range 2-4 g). Eighty-seven patients were excluded from the propensity-score matching because of missing data. Propensity-score–matched analysis showed no significant difference in the incidence of thromboembolic events or 30-day mortality rate between the groups. Multivariate analysis revealed that the fibrinogen group showed no significant difference in thromboembolic events (odds ratio 1.22; 95% confidence interval 0.76-1.95; p = 0.408) or mortality rate (odds ratio 0.44; 95% confidence interval 0.18-1.12; p = 0.081) compared with those in the no fibrinogen group. Conclusions Administering fibrinogen concentrate or cryoprecipitate was associated with neither thromboembolic events nor 30-day mortality in patients undergoing thoracic aortic surgery. Administering fibrinogen concentrate or cryoprecipitate is safe and does not appear to increase thromboembolic events and mortality in thoracic aortic surgery patients.

Objective.To compare the incidence of venous thromboembolism (VTE) following total knee arthroplasty (TKA) between patients with rheumatoid arthritis (RA) and those with osteoarthritis (OA).Methods.The subjects were composed of 1084 Japanese patients with OA and 204 with RA. Primary effectiveness outcomes were any deep vein thrombosis (DVT) as detected by bilateral ultrasonography up to postoperative Day 10 (POD10) and pulmonary embolism (PE) up to POD28. The main safety outcomes were bleeding and death from any cause up to POD28. Plasma D-dimer levels were measured before and at POD10 after TKA.Results.The study cohort was composed of 1288 patients from 34 hospitals. There was no death up to POD28. PE occurred in 2 patients with OA and in no patients with RA. The incidence of primary effectiveness outcome was 24.3% and 24.0% in patients with OA and RA, respectively. The incidence of major bleeding up to POD28 was 1.3% and 0.5% in patients with OA and RA, respectively. No differences in the incidence of VTE (symptomatic/asymptomatic DVT plus PE) or bleeding were noted between patients with RA and OA. D-dimer levels on POD10 were significantly higher in patients with OA compared with those with RA. Also, D-dimer levels on POD10 were significantly lower in patients receiving fondaparinux than in patients without pharmacological prophylaxis.Conclusion.Despite some differences in demographic data, patients with RA and OA have equivalent risks of VTE and bleeding following TKA.

The authors stopped using tranexamic acid (TXA) in April 2013. The present study aimed to examine the impact of a "no-TXA-use" policy by comparing the adverse effects of TXA and clinical outcomes before and after the policy change in patients undergoing cardiovascular surgery.A single center retrospective cohort study.A single cardiovascular center.Patients undergoing cardiovascular surgery between January 2008 and July 2015 (n = 3,535).Patients' outcomes before and after the policy change were compared to evaluate the effects of the change.The seizure rate decreased significantly after the policy change (6.9% v 2.7%, p0.001). However, transfusion volumes and blood loss volumes increased significantly after the policy change (1,840 mL v 2,030 mL, p = 0.001; 1,250 mL v 1,372 mL, p0.001, respectively). Thirty-day mortality was not statistically different (1.6% v 1.4%, p = 0.82), nor were any of the other outcomes. Propensity-matched analysis and segmented regression analysis showed similar results.The mortality rate remained the same even though the seizure rate decreased after the policy change. Blood loss volume and transfusion volume both increased after the policy change. TXA use provides an advantageous benefit by reducing the need for blood transfusion.

In pregnant women, activated partial thromboplastin time (APTT) does not precisely reflect the anticoagulant effect of a therapeutic dose of heparin. However, the measurement of anti-Xa activity can be used to monitor the anticoagulant effect of heparin, since the plasma concentrations of coagulation factors increase in pregnant women. We evaluated the in vitro effects of increased concentrations of fibrinogen and other coagulation factors (FVII, FVIII, and FIX) on the results of assays of APTT and anti-Xa activity in plasma samples with various therapeutic concentrations of unfractionated heparin (UFH). In the presence of UFH, APTT was shortened by increased concentrations of fibrinogen, FVII, or FVIII, and this effect was much stronger when the FVIII concentration was increased. In the plasma samples containing 0.5 or 0.7 U/mL of UFH, the APTT was shortened by approximately half or one-third, respectively, when 6 U FVIII/mL was added to the sample. The anti-Xa activity was not influenced by increased concentrations of the coagulation factors. In the present study, we also evaluated the sensitivities to UHF of four APTT reagents, and found a 1.65-fold difference in the sensitivity to UFH among APTT reagents. Our results demonstrate that increased FVIII concentration shortens APTT under therapeutic doses of UFH, and that APTT thus underestimates the anticoagulant effect of UFH in pregnant women, mainly due to the increased FVIII concentration.

Heparin-induced thrombocytopenia (HIT) is a pro-thrombotic side effect of heparin therapy caused by HIT antibodies with platelet-activating properties. Recent advances in understanding of spontaneous HIT syndrome, which can occur even without any heparin exposure despite its clinical and serological characteristics being similar to those of HIT, reveal the following HIT clinical features atypical for an immune-mediated disease. Heparin-naïve patients can develop IgG antibodies as early as day 4, as in a secondary immune response. Evidence for an anamnestic response upon heparin re-exposure is lacking. In addition, HIT antibodies are relatively short-lived, unlike those in a secondary immune response. Antigen immunoassays are commonly used worldwide for serological diagnosis of HIT. However, such assays do not indicate whether HIT antibodies have platelet-activating properties, leading to low diagnostic specificity for HIT. The detection of platelet-activating antibodies using a washed platelet activation assay is crucial for making a HIT diagnosis. These atypical clinical and serological features should be carefully considered while appropriately diagnosing HIT, which leads to appropriate therapy such as immediate administration of an alternative anticoagulant for preventing thromboembolic events and re-administration of heparin during surgery involving cardiopulmonary bypass when HIT antibodies are no longer detectable.

Objectives The present study aimed to examine the association between tranexamic acid (TXA) use and adverse effects (seizures, thromboembolism, and renal dysfunction) in a pediatric cardiac surgery population using a national inpatient database in Japan. The authors also assessed the association between TXA use and other clinical outcomes (length of hospital stay and in-hospital mortality). Design A nationwide, retrospective cohort study using propensity score analyses. Setting Japanese Diagnosis Procedure Combination inpatient database. Participants Pediatric patients who underwent cardiac surgery using cardiopulmonary bypass between July 2010 and March 2014 (N = 11,275). Interventions None. Measurements and Main Results Propensity-score matching created 3,739 pairs of patients with and without TXA administration. Propensity-matched analysis showed that the proportion of seizures was significantly higher in the TXA group than in the non-TXA group (1.6% v 0.2%, difference, 1.4%; 95% confidence interval, 1.0-1.9; p Conclusions TXA use is associated with a significantly increased risk of seizures. However, there is no difference in any other outcomes between the TXA and non-TXA groups.

SummaryTo diagnose heparin-induced thrombocytopenia (HIT), detection of platelet-activating antibodies (HIT antibodies) is crucial. However, serum platelet activation profiles vary across patients and depend on test conditions. We evaluated the association between clinical outcomes and platelet-activating profiles assessed by a platelet microparticle assay (PMA), which detects activation of washed platelets induced by HIT antibodies, in 401 consecutive patients clinically suspected of having HIT. We made modifications to the assay, such as donor selection for washed platelets that increased sensitivity. Serum that activated platelets at a therapeutic (but not high) heparin concentration was defined as positive. Of these, serum that activated platelets within 30 minutes or in the absence of heparin was defined as strongly positive. The remaining samples were considered weakly positive. As a result, 97 % and 93 % of patients who tested strongly and weakly positive had clinical profiles consistent with HIT, respectively. The incidence of thromboembolic events (TEEs) after heparin exposure in patients who tested strongly positive, weakly positive, and negative was 61 %, 40 %, and 29 %, respectively. Among patients who did not experience a TEE on the day HIT was suspected, there was no significant difference in the cumulative incidence of subsequent TEEs between patients who tested strongly and weakly positive when argatroban was initiated on the same day (19.0 % vs 7.1 %, p=0.313), but there was a significant difference when argatroban therapy was delayed by one or more days (61.1 % vs 17.6 %, p=0.007). The modified PMA is effective in diagnosing HIT and identifying patients at high risk for HIT-associated TEEs.Supplementary Material to this article is available online at www.thrombosis-online.com.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic side effect of heparin therapy caused by HIT antibodies, i.e., anti-platelet factor 4 (PF4)/heparin IgG with platelet-activating properties. For serological diagnosis, antigen immunoassays are commonly used worldwide. However, such assays do not indicate their platelet-activating properties, leading to low specificity for the HIT diagnosis. Therefore, over-diagnosis is currently the most serious problem associated with HIT. The detection of platelet-activating antibodies using a washed platelet activation assay is crucial for appropriate HIT diagnosis. Recent advances in our understanding of the pathogenesis of HIT include it having several clinical features atypical for an immune-mediated disease. Heparin-naïve patients can develop IgG antibodies as early as day 4, as in a secondary immune response. Evidence for an anamnestic response on heparin re-exposure is lacking. In addition, HIT antibodies are relatively short-lived, unlike those in a secondary immune response. These lines of evidence suggest that the mechanisms underlying HIT antibody formation may be compatible with a non-T cell-dependent immune reaction. These atypical clinical and serological features should be carefully considered while endeavoring to accurately diagnose HIT, which leads to appropriate therapies such as immediate administration of an alternative anticoagulant to prevent thromboembolic events and re-administration of heparin during surgery involving cardiopulmonary bypass when HIT antibodies are no longer detectable.

Platelet-activating antibodies, which recognize platelet factor 4 (PF4)/heparin complexes, induce spontaneous heparin-induced thrombocytopenia (HIT) syndrome or fondaparinux-associated HIT without exposure to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). This condition mostly occurs after major orthopedic surgery, implying that surgery itself could trigger this immune response, although the mechanism is unclear. To investigate how surgery may do so, we performed a multicenter, prospective study of 2069 patients who underwent total knee arthroplasty (TKA) or hip arthroplasty. Approximately half of the patients received postoperative thromboprophylaxis with UFH, LMWH, or fondaparinux. The other half received only mechanical thromboprophylaxis, including dynamic (intermittent plantar or pneumatic compression device), static (graduated compression stockings [GCSs]), or both. We measured anti-PF4/heparin immunoglobulins G, A, and M before and 10 days after surgery using an immunoassay. Multivariate analysis revealed that dynamic mechanical thromboprophylaxis (DMT) was an independent risk factor for seroconversion (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.34-3.02; P = .001), which was confirmed with propensity-score matching (OR, 1.99; 95% CI, 1.17-3.37; P = .018). For TKA, the seroconversion rates in patients treated with DMT but no anticoagulation and in patients treated with UFH or LMWH without DMT were similar, but significantly higher than in patients treated with only GCSs. The proportion of patients with ≥1.4 optical density units appeared to be higher among those treated with any anticoagulant plus DMT than among those not treated with DMT. Our study suggests that DMT increases risk of an anti-PF4/heparin immune response, even without heparin exposure. This trial was registered to www.umin.ac.jp/ctr as #UMIN000001366.

SummaryBackground and purposeThere have been no large-scale studies on the impact of diabetes mellitus (DM) on outcomes in Japanese patients undergoing coronary artery bypass grafting (CABG).Methods and subjectsA multi-institutional retrospective cohort study was conducted in 14 Japanese centers. All adult patients who underwent isolated CABG from 2007 to 2008 were included (n=1522, mean age: 68.5years). The definitions of DM were all patients admitted with diagnosis of DM and preoperative glycated hemoglobin (Hb) A1c≥6.5%. Univariate and multivariate analyses were performed to identify the risk of morbidity and mortality.ResultsThere were 849 DM and 572 non-DM patients. Preoperative mean HbA1c were 7.1% in the DM group and 5.7% in the non-DM group (p

A 33-year-old woman developed deep venous thrombosis at 7 gestational weeks (GW). Heparin-induced thrombocytopenia was evident at 9 GW during unfractionated heparin infusion. Immediately, anticoagulation therapies together with antithrombin (AT) infusion were commenced with the use of argatroban from 9 GW, and fondaparinux was substituted for argatroban after 24 GW. The patient had hereditary AT deficiency type I determined by laboratory findings and results of genomic DNA analysis. The pregnancy ended in full-term vaginal delivery of a healthy male without adverse effects of the anticoagulation therapies. This was the first report of a pregnant woman who developed heparin-induced thrombocytopenia caused by heparin therapy for deep venous thrombosis due to AT deficiency.