Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy: The SCARLET Randomized Clinical Trial.

Importance: Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy. Objective: To determine the effect of human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy. Design, Setting, and Participants: The SCARLET trial was a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study conducted in intensive care units at 159 sites in 26 countries. All adult patients admitted to one of the participating intensive care units between October 2012 and March 2018 with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure, defined as an international normalized ratio greater than 1.40 without other known etiology and a platelet count in the range of 30 to 150 × 109/L or a greater than 30% decrease in platelet count within 24 hours, were considered for inclusion. The final date of follow-up was February 28, 2019. Interventions: Patients with sepsis-associated coagulopathy were randomized and treated with an intravenous bolus or a 15-minute infusion of thrombomodulin (0.06 mg/kg/d [maximum, 6 mg/d]; n = 395) or matching placebo (n = 405) once daily for 6 days. Main Outcome and Measures: The primary end point was 28-day all-cause mortality. Results: Among 816 randomized patients, 800 (mean age, 60.7 years; 437 [54.6%] men) completed the study and were included in the full analysis set. In these patients, the 28-day all-cause mortality rate was not statistically significantly different between the thrombomodulin group and the placebo group (106 of 395 patients [26.8%] vs 119 of 405 patients [29.4%], respectively; P = .32). The absolute risk difference was 2.55% (95% CI, -3.68% to 8.77%). The incidence of serious major bleeding adverse events (defined as any intracranial hemorrhage; life-threatening bleeding; or bleeding event classified as serious by the investigator, with administration of at least 1440 mL [typically 6 units] of packed red blood cells over 2 consecutive days) was 23 of 396 patients (5.8%) in the thrombomodulin group and 16 of 404 (4.0%) in the placebo group. Conclusions and Relevance: Among patients with sepsis-associated coagulopathy, administration of a human recombinant thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT01598831.

ACTN1 mutations cause congenital macrothrombocytopenia.

Congenital macrothrombocytopenia (CMTP) is a heterogeneous group of rare platelet disorders characterized by a congenital reduction of platelet counts and abnormally large platelets, for which CMTP-causing mutations are only found in approximately half the cases. We herein performed whole-exome sequencing and targeted Sanger sequencing to identify mutations that cause CMTP, in which a dominant mode of transmission had been suspected but for which no known responsible mutations have been documented. In 13 Japanese CMTP-affected pedigrees, we identified six (46%) affected by ACTN1 variants cosegregating with CMTP. In the entire cohort, ACNT1 variants accounted for 5.5% of the dominant forms of CMTP cases and represented the fourth most common cause in Japanese individuals. Individuals with ACTN1 variants presented with moderate macrothrombocytopenia with anisocytosis but were either asymptomatic or had only a modest bleeding tendency. ACTN1 encodes α-actinin-1, a member of the actin-crosslinking protein superfamily that participates in the organization of the cytoskeleton. In vitro transfection experiments in Chinese hamster ovary cells demonstrated that altered α-actinin-1 disrupted the normal actin-based cytoskeletal structure. Moreover, transduction of mouse fetal liver-derived megakaryocytes with disease-associated ACTN1 variants caused a disorganized actin-based cytoskeleton in megakaryocytes, resulting in the production of abnormally large proplatelet tips, which were reduced in number. Our findings provide an insight into the pathogenesis of CMTP.

Thrombosis from a prothrombin mutation conveying antithrombin resistance.

We identified a novel mechanism of hereditary thrombosis associated with antithrombin resistance, with a substitution of arginine for leucine at position 596 (p.Arg596Leu) in the gene encoding prothrombin (called prothrombin Yukuhashi). The mutant prothrombin had moderately lower activity than wild-type prothrombin in clotting assays, but the formation of thrombin-antithrombin complex was substantially impaired. A thrombin-generation assay revealed that the peak activity of the mutant prothrombin was fairly low, but its inactivation was extremely slow in reconstituted plasma. The Leu596 substitution caused a gain-of-function mutation in the prothrombin gene, resulting in resistance to antithrombin and susceptibility to thrombosis.

Recombinant human soluble thrombomodulin (thrombomodulin alfa) to treat disseminated intravascular coagulation in solid tumors: results of a one-arm prospective trial.

BACKGROUND: Disseminated intravascular coagulation (DIC) associated with solid tumors (DIC-ST) is often encountered in clinical practice. Patients with DIC-ST are usually in poor condition and have bleeding diathesis due to advanced or metastatic diseases. Although some affected patients are treated with heparin, this strategy has not been prospectively studied. Recombinant human soluble thrombomodulin (thrombomodulin alfa, TM-α) is a new anticoagulant developed in Japan. We conducted a prospective study that evaluated the efficacy and safety of TM-α in patients with DIC-ST. METHODS: A prospective one-arm study with TM-α was conducted for DIC-ST. TM-α (380 U/kg) was given for 30 min intravenously once daily for 6-14 days. The primary efficacy endpoint was the DIC resolution rate. Change in DIC scores and improvement in bleeding symptoms and outcomes were also evaluated. Safety endpoints included the incidence of bleeding-related adverse events. RESULTS: A total of 101 patients were treated with TM-α. The three main underlying malignant diseases were lung, stomach, and breast cancer, which accounted for 60 % of all patients. The DIC resolution rate was 34.0 % at the end of TM-α treatment. Improvement in DIC scores was seen in 55.2 % of patients, while only 22.9 % of patients had worsening of DIC scores. The overall survival rate was 55.4 % on day 28. The incidence of hemorrhage related to TM-α was 12.9 % until day 28. Cases of severe hemorrhage related to TM-α did not occur. CONCLUSIONS: TM-α is effective and safe for DIC-ST. This agent is the treatment of choice for the management of DIC-ST.

Plasminogen activator inhibitor-1 in aging.

Plasminogen activator inhibitor-1 (PAI-1), a principal inhibitor of fibrinolysis, is induced in thrombotic, fibrotic, and cardiovascular diseases, which in turn primarily afflict the older population. This induction of PAI-1 may play an important role in the pathology of these diseases as PAI-1 can regulate the dissolution of fibrin and also inhibit the degradation of the extracellular matrix by reducing plasmin generation. PAI-1 expression is elevated in aged individuals and is significantly upregulated in a variety of pathologies associated with the process of aging, including myocardial and cerebral infarction, vascular (athero) sclerosis, cardiac and lung fibrosis, metabolic syndromes (e.g., hypertension, hyperlipidemia, and insulin resistance), cancer, and inflammatory/stress responses. Thus, PAI-1 may play a critical role in the development of aging-associated pathological changes. In addition, PAI-1 is recognized as a marker of senescence and a key member of a group of proteins collectively known as the senescence-messaging secretome. In this review, we highlight the role of PAI-1 in the pathophysiology of aging and aging-associated disorders.

TUBB1 mutation disrupting microtubule assembly impairs proplatelet formation and results in congenital macrothrombocytopenia.

This report describes a family with TUBB1-associated macrothrombocytopenia diagnosed based on abnormal platelet ß1-tubulin distribution. A circumferential marginal microtubule band was undetectable, whereas microtubules were frayed and disorganized in every platelet from the affected individuals. Patients were heterozygous for novel TUBB1 p.F260S that locates at the α- and ß-tubulin intradimer interface. Mutant ß1-tubulin was not incorporated into microtubules with endogenous α-tubulin, and α-tubulin expression was decreased in transfected Chinese hamster ovary cells. Transduction of mutant ß1-tubulin into mouse fetal liver-derived megakaryocytes demonstrated no incorporation of mutant ß1-tubulin into microtubules with endogenous α-tubulin and diminished proplatelet formation, leading to the production of fewer, but larger, proplatelet tips. Furthermore, mutant ß1-tubulin was not associated with endogenous α-tubulin in the proplatelets. Deficient functional microtubules might lead to defective proplatelet formation and abnormal protrusion-like platelet release, resulting in congenital macrothrombocytopenia.

Ribavirin-induced intracellular GTP depletion activates transcription elongation in coagulation factor VII gene expression.

Coagulation FVII (Factor VII) is a vitamin K-dependent glycoprotein synthesized in hepatocytes. It was reported previously that FVII gene (F7) expression was up-regulated by ribavirin treatment in hepatitis C virus-infected haemophilia patients; however, its precise mechanism is still unknown. In the present study, we investigated the molecular mechanism of ribavirin-induced up-regulation of F7 expression in HepG2 (human hepatoma cell line). We found that intracellular GTP depletion by ribavirin as well as other IMPDH (inosine-5'-monophosphate dehydrogenase) inhibitors, such as mycophenolic acid and 6-mercaptopurine, up-regulated F7 expression. FVII mRNA transcription was mainly enhanced by accelerated transcription elongation, which was mediated by the P-TEFb (positive-transcription elongation factor b) complex, rather than by promoter activation. Ribavirin unregulated ELL (eleven-nineteen lysine-rich leukaemia) 3 mRNA expression before F7 up-regulation. We observed that ribavirin enhanced ELL3 recruitment to F7, whereas knockdown of ELL3 diminished ribavirin-induced FVII mRNA up-regulation. Ribavirin also enhanced recruitment of CDK9 (cyclin-dependent kinase 9) and AFF4 to F7. These data suggest that ribavirin-induced intracellular GTP depletion recruits a super elongation complex containing P-TEFb, AFF4 and ELL3, to F7, and modulates FVII mRNA transcription elongation. Collectively, we have elucidated a basal mechanism for ribavirin-induced FVII mRNA up-regulation by acceleration of transcription elongation, which may be crucial in understanding its pleiotropic functions in vivo.

Combined medialis pedis and medial plantar fasciocutaneous flaps for coverage of soft tissue defects of multiple adjacent fingers.

Soft tissue defects of adjacent multiple fingers covered by a single large flap require secondary separation of the flap into each finger. Such covering obstructs independent motion of injured fingers until the single large flap is separated. This report describes the technique of combined medialis pedis and medial plantar fasciocutaneous flaps for reconstructing soft tissue defects of multiple adjacent fingers. Three male patients (age range, 18-33 years) underwent soft tissue reconstructions of multiple adjacent fingers with combined flaps. Injuries involved three adjacent palmar fingers, two adjacent palmar fingers, and two adjacent dorsal fingers. Average sizes of the combined flaps were 4.2 × 4.0 cm for the medialis pedis flap and 3.0 × 1.8 cm for the medial plantar fasciocutaneous flap. All flaps survived without vascular complications, and donor sites healed uneventfully. All patients experienced excellent recovery of range of motion for the reconstructed fingers. In conclusion, combined flaps may offer an alternative for coverage of soft tissue defects that involve multiple adjacent fingers.

Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbß3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia.

Congenital macrothrombocytopenia is a genetically heterogeneous group of rare disorders. αIIbß3 has not been implicated in these conditions. We identified a novel, conserved heterozygous ITGA2B R995W mutation in 4 unrelated families. The surface expression of platelet αIIbß3 was decreased to 50% to 70% of control. There was spontaneous PAC-1 and fibrinogen binding to resting platelets without CD62p expression. The activation state of αIIbß3 in 293T cells was higher for αIIb-W995 than for ß3-H723 but was weaker than for ß3-N562. FAK was spontaneously phosphorylated in αIIb-W995/ß3-transfected 293T cells. These results indicate that αIIb-W995/ß3 has a constitutive, activated conformation but does not induce platelet activation. αIIb-W995/ß3-transfected CHO cells developed membrane ruffling and abnormal cytoplasmic protrusions. The increased size and decreased number of proplatelet tips in αIIb-W995/ß3-transduced mouse fetal liver-derived megakaryocytes indicate defective pro-platelet formation. We propose that activating mutations in ITGA2B and ITGB3 represent the etiology of a subset of congenital macrothrombocytopenias.

Bernard-Soulier syndrome caused by a hemizygous GPIbß mutation and 22q11.2 deletion.

BACKGROUND: Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder characterized by giant platelets, thrombocytopenia, and a prolonged bleeding time, which is caused by homozygous mutations in the GPIbα, GPIbß, or GPIX genes. The 22q11.2 deletion syndrome (22q11.2DS) is caused by a microdeletion on chromosome 22, which includes the GPIbß gene, and is characterized by abnormal development of the pharyngeal apparatus and heart. Thus, patients with 22q11.2DS are obligate carriers for BSS. METHODS: We evaluated two infants with BSS and performed the genetic analysis of the GPIbα, GPIbß, or GPIX genes, and investigated the segregation of the mutation within the families. The status of the 22q11.2 deletion was examined by fluorescence in situ hybridization and single-nucleotide polymorphism array copy number analysis. RESULTS: DNA sequencing analysis revealed that the infants were compound heterozygous for a hemizygous mutation in the GPIbß gene (p.Trp148X and p.Leu97Phe, respectively) and 22q11.2 deletion in the other chromosome. Both infants had the common 3Mb 22q11.2 deletion but did not show major phenotypic features of 22q11.2DS, such as developmental delay, cardiac defects, dysmorphic facial features, palatal anomalies, hypocalcemia, and immune deficiency. The 22q11.2DS would not have become clear if detailed molecular genetic analyses of BSS had not been performed. CONCLUSIONS: Our cases illustrate that a suspicion of 22q11.2 deletion is warranted in pediatric BSS patients with a mutation in the GPIbß gene, even without remarkable symptoms.

Down-regulation of PROS1 gene expression by 17beta-estradiol via estrogen receptor alpha (ERalpha)-Sp1 interaction recruiting receptor-interacting protein 140 and the corepressor-HDAC3 complex.

Pregnant women show a low level of protein S (PS) in plasma, which is known to be a risk for deep venous thrombosis. 17Beta-estradiol (E(2)), an estrogen that increases in concentration in the late stages of pregnancy, regulates the expression of various genes via the estrogen receptor (ER). Here, we investigated the molecular mechanisms behind the reduction in PS levels caused by E(2) in HepG2-ERalpha cells, which stably express ERalpha, and also the genomic ER signaling pathway, which modulates the ligand-dependent repression of the PSalpha gene (PROS1). We observed that E(2) repressed the production of mRNA and antigen of PS. A luciferase reporter assay revealed that E(2) down-regulated PROS1 promoter activity and that this E(2)-dependent repression disappeared upon the deletion or mutation of two adjacent GC-rich motifs in the promoter. An electrophoretic mobility shift assay and DNA pulldown assay revealed that the GC-rich motifs were associated with Sp1, Sp3, and ERalpha. In a chromatin immunoprecipitation assay, we found ERalpha-Sp protein-promoter interaction involved in the E(2)-dependent repression of PROS1 transcription. Furthermore, we demonstrated that E(2) treatment recruited RIP140 and the NCoR-SMRT-HDAC3 complex to the PROS1 promoter, which hypoacetylated chromatin. Taken together, this suggested that E(2) might repress PROS1 transcription depending upon ERalpha-Sp1 recruiting transcriptional repressors in HepG2-ERalpha cells and, consequently, that high levels of E(2) leading to reduced levels of plasma PS would be a risk for deep venous thrombosis in pregnant women.

Mutation of the beta1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule assembly.

Congenital macrothrombocytopenia is a genetically heterogeneous group of rare disorders. We identified the first TUBB1 mutation, R318W, in a patient with congenital macrothrombocytopenia. The patient was heterozygous for Q43P, but this single-nucleotide polymorphism (SNP) did not relate to macrothrombocytopenia. Although no abnormal platelet beta1-tubulin localization/marginal band organization was observed, the level of beta1-tubulin was decreased by approximately 50% compared with healthy controls. Large and irregular bleb protrusions observed in megakaryocytes derived from the patient's peripheral blood CD34(+) cells suggested impaired megakaryocyte fragmentation and release of large platelets. In vitro transfection experiments in Chinese hamster ovary (CHO) cells demonstrated no incorporation of mutant beta1-tubulin into microtubules, but the formation of punctuated insoluble aggregates. These results suggested that mutant protein is prone to aggregation but is unstable within megakaryocytes/platelets. Alternatively, mutant beta1-tubulin may not be transported from the megakaryocytes into platelets. W318 beta1-tubulin may interfere with normal platelet production, resulting in macrothrombocytopenia.

Divergent fracture-dislocation of the hamatometacarpal joint: case report.

Hamatometacarpal fracture-dislocation is a rare injury that consists of a fourth metacarpal fracture and a fifth carpometacarpal joint injury. We present the case of a 21-year-old man with a divergent hamatometacarpal fracture-dislocation that consisted of a combination of dorsal intra-articular fracture-dislocation of the fourth carpometacarpal joint, palmar dislocation of the fifth carpometacarpal joint, and fracture of the hook of the hamate. The mechanism of palmar dislocation of the fifth metacarpal base and fracture of the hook of the hamate involved extension of the fifth metacarpal and ulnopalmar load transmission.

Advances in the understanding of MYH9 disorders.

PURPOSE OF REVIEW: MYH9 disorders are autosomal dominant macrothrombocytopenias with leukocyte inclusion bodies caused by mutations in MYH9, the gene for the nonmuscle myosin heavy chain IIA. May-Hegglin anomaly and Sebastian, Fechtner, and Epstein syndromes belong to MYH9 disorders. The present review summarizes the recent advances in genetic diagnosis and our understanding of the pathogenetic mechanisms of MYH9 mutations and the development of nonhematological complications. RECENT FINDINGS: A genotype-phenotype cohort study showed that patients with an MYH9 mutation in the motor head domain of myosin IIA have severe macrothrombocytopenia and are at a high risk for the development of glomerulonephritis and deafness. Among these, Arg702 mutations are associated with the most severe phenotype. In-vitro studies on cultured megakaryocytes elucidated that myosin IIA inhibits proplatelet formation. The loss of myosin IIA function owing to MYH9 mutations promotes proplatelet formation and may trigger precocious and premature platelet release, resulting in macrothrombocytopenia. Giant platelets only residually express mutant myosin IIA that has a loss of function and cannot participate in the reorganization of cytoskeletal contractile structures. Renal histopathological and immunochemical studies have suggested that glomerulonephritis in MYH9 disorders is caused by podocyte malfunction owing to defects in the myosin IIA structure and MYH9 expression. SUMMARY: MYH9 disorders are not merely benign hematological abnormalities, but serious syndromic disorders affecting the kidney, inner ear, and lens. A genetic diagnosis is mandatory for an accurate prognosis of nonhematological complications and management or possibly prophylactic treatment.

Unrecognized blood clotting factors.

Most clotting factors were initially discovered as agents functionally deficient in the plasmas of rare patients with hereditary coagulation disorders. During 1940s to 1960s, many factors were named by different investigators after the name of the patient who lacked a new factor. Consequently, there were the same factors with different names. To avoid confusion, the International Committee on the nomenclature of clotting factors was founded and discussed the identity or non-identity of clotting factors by specialists. There remain, however, several factors that were not officially authorized. We attempt to review some of these factors that seem to be not identical with any known clotting factors.

Myh9 R702C is associated with erythroid abnormality with splenomegaly in mice.

MYH9 disorders are characterized by giant platelets, thrombocytopenia, and Döhle body-like cytoplasmic inclusion bodies in granulocytes. However, whether these disorders cause any changes in erythroid cells has yet to be determined. This study analyzed the influence of Myh9 R702C, as one of the most commonly detected MYH9 disorders, on erythroid cells in a mouse model. Knock-in mice expressing Myh9 R702C mutation either systemically or specific to hematological cells (R702C and R702C vav1 mice, respectively) were used in this study. Both displayed lower hemoglobin and higher erythropoietin levels than wild-type (WT) mice, along with significant splenomegaly. Flow cytometric analysis revealed erythroblasts present at a higher rate than WT mice in the spleen. However, no obvious abnormalities were seen in erythroid differentiation from megakaryocyte/erythroid progenitor to erythrocyte. Cell culture assay by fetal liver and colony assay also showed normal progression of erythroid differentiation from erythroid burst-forming unit to red blood cell. In conclusion, R702C and R702C vav1 mice displayed erythroid abnormality with splenomegaly. However, erythroid differentiation showed no obvious abnormality. Further research is required to elucidate the underlying mechanisms.

Patients with Epstein-Fechtner syndromes owing to MYH9 R702 mutations develop progressive proteinuric renal disease.

Recent linkage analyses of nondiabetic African-American patients with focal segmental glomerulosclerosis (FSGS) have identified MYH9, encoding nonmuscle myosin heavy chain IIA (NMMHC-IIA), as a gene having a critical role in this disease. Abnormalities of the MYH9 locus also underlie rare autosomal dominant diseases such as May-Hegglin anomaly, and Sebastian, Epstein (EPS), and Fechtner (FTNS) syndromes that are characterized by macrothrombocytopenia and cytoplasmic inclusion bodies in granulocytes. Among these diseases, patients with EPS or FTNS develop progressive nephritis and hearing disability. We analyzed clinical features and pathophysiological findings of nine EPS-FTNS patients with MYH9 mutations at the R702 codon hot spot. Most developed proteinuria and/or hematuria in early infancy and had a rapid progression of renal impairment during adolescence. Renal histopathological findings in one patient showed changes compatible with FSGS. The intensity of immunostaining for NMMHC-IIA in podocytes was decreased in this patient compared with control patients. Thus, MYH9 R702 mutations display a strict genotype-phenotype correlation, and lead to the rapid deterioration of podocyte structure. Our results highlight the critical role of NMMHC-IIA in the development of FSGS.

FLNA p.V528M substitution is neither associated with bilateral periventricular nodular heterotopia nor with macrothrombocytopenia.

Filamin A is encoded by the FLNA gene on chromosome Xq28 and functions in cross-linking actin filaments into orthogonal networks in the cortical cytoplasm. FLNA p.V528M was initially detected in a female autopsy case of X-linked bilateral periventricular nodular heterotopia (BPNH), a neuronal migration disorder characterized by subependymal nodules of gray matter. During our mutation analysis of FLNA in a boy with apparent X-linked thrombocytopenia, we detected the p.V528M variant. The patient, mother and sister, who were heterozygous for the substitution, did not have BPNH. We observed an allele frequency of 4.8% in healthy control Japanese, but did not observe the variant in Caucasian subjects. Hemizygous controls had a normal platelet count and size. We suggest that p.V528M is neither associated with BPNH nor with thrombocytopenia and giant platelets, and represents a functional polymorphism.

Effects of thrombomodulin alfa on hemostatic parameters in disseminated intravascular coagulation: Post hoc analysis of a phase 3 randomized controlled trial.

BACKGROUND: The efficacy and safety of thrombomodulin alfa (TM-α), a cofactor protein promoting thrombin-mediated protein C activation, have been examined in a phase 3 randomized, double-blinded, parallel-group trial in Japan. We have previously reported that TM-α is noninferior to heparin for the resolution of disseminated intravascular coagulation (DIC). OBJECTIVE: To investigate the basis for the efficacy of TM-α in the phase 3 clinical trial in Japan through post hoc analysis of coagulation and fibrinolysis parameters. PATIENTS/METHODS: The 227 patients of the full analysis set population described in the original phase 3 trial in Japan were included in this analysis. Changes in parameters between before and after TM-α or heparin administration in each of the two patient groups, with underlying diseases of either hematologic malignancy or infection, were studied separately and results were compared between TM-α and heparin treatment groups in a post hoc manner. RESULTS: TM-α administration did not prolong activated partial thromboplastin time but significantly decreased thrombin-antithrombin complex levels compared with heparin treatment. TM-α administration reduced consumption of endogenous anticoagulants such as antithrombin and protein C by DIC, compared with the heparin group. DIC scores were decreased in both TM-α and heparin groups during the 6-day treatment. CONCLUSION: TM-α can alleviate intravascular coagulation and consumption of anticoagulants without extending coagulation times. This may be associated with the relatively low risk of bleeding during TM-α treatment.

Incidence and risk factors of early bacterial infections after unrelated cord blood transplantation.

Incidence and characteristics of early bacterial infection within 100 days after unrelated cord blood transplantation (UCBT) were assessed for 664 pediatric and 1208 adult recipients in Japan. Cumulative incidence of early bacterial infection at day 100 post-UCBT was 11% (95% confidence interval [CI], 8%-13%) for children and 21% (CI, 19%-24%) for adults (P < .0001). Early bacterial infection in adults had a significant impact on mortality (hazard ratio [HR] = 2.1, CI, 1.7-2.6; P < .0001), although no significant risk factors were identified. Multivariate analysis identified older age group (6-10, and 11-15 years versus 0-5 years of age) at transplant (HR = 2.0 and 2.7, CI, 1.1-3.5 and 1.4-4.9; P = .020 and .002, respectively) as an independent risk factor of early bacterial infection for children. Early bacterial infection in children did not have a significant impact on mortality when adjusted. Of 315 bacteremia, 74% were caused by Gram-positive microorganisms. Pneumonia occurred in 39 patients including 13 cases of Stenotrophomonas maltophilia pneumonia. Early bacterial infection had a negative effect on survival for adults and the median day of development was 10 days after transplant, suggesting that the prevention of bacterial infection in the very early post-UCBT phase is important.