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The gain-of-function variation p.I1157T in C3 was previously identified in 8 patients with atypical hemolytic uremic syndrome (aHUS) at Mie University Hospital. In the present study, we identified another 11 patients with aHUS with this variation, including 10 pediatric patients (onset age: 1-16 years). The variation seems to be geographically concentrated around Mie Prefecture in Japan. Fifteen of the 19 patients with aHUS experienced infection as probable triggering events. All 19 patients had renal dysfunction. Seven patients, including 2 from the previous study and 5 from the present study, were treated with eculizumab, with all showing a good response with hematological normalization. Among the 5 eculizumab-treated patients in the present study, 3 had an ambiguous diagnosis of aHUS due to low-grade hemolysis even with elevated levels of lactate dehydrogenase and bilirubin. In those cases, in-house targeted DNA sequencing identified the C3 p.I1157T variation carriers, which enabled the early initiation of treatment with eculizumab. The present study supports the early introduction of eculizumab in patients with aHUS, especially pediatric patients.

The usefulness of the waveform of activated partial thromboplastin time (APTT) in various diseases has been evaluated in recent years. The APTT waveform was examined in patients with hemophilia and patients positive for lupus anticoagulant (LA). The correlation with the FVIII activity was highest for the height of acceleration peak. The peak time of acceleration, velocity, and ½ fibrin formation, and the width of acceleration and velocity were significantly long and the height of acceleration was significantly low in patients with hemophilia. The height of velocity was significantly low in patients with hemophilia with inhibitor. There were no significant differences in the APTT waveform between patients with hemophilia and patients with LA, but the peak of acceleration and ½ fibrin formation were significantly longer and the height of acceleration and velocity were significantly lower in patients with hemophilia with inhibitor than in the patients with LA. Wave changes in the APTT were observed in all 22 patients positive for LA, while a biphasic waveform was observed in patients with hemophilia with FVIII activity <10.0%. The APTT waveform is useful for the analysis of hemostatic abnormalities in patients with hemophilia.

The activated partial thromboplastin time (APTT) waveform includes several parameters that are related to various underlying diseases. The APTT waveform was examined in various diseases. Regarding the pattern of APTT waveform, a biphasic pattern of the first or second derivative curve (DC) was observed in patients with hemophilia and patients positive for antiphospholipid (aPL) antibodies or coagulation factor VIII (FVIII) inhibitors. The time of the first and second DC and fibrin formation at 1/2 height were prolonged in patients with hemophilia, patients with inhibitors, patients positive for aPL, patients treated with anti-Xa agents, and patients with disseminated intravascular coagulation (DIC). These values all tended to decrease in pregnant women (at 28-36 weeks' gestation). The height of the second derivative peak 1 was significantly lower in patients with hemophilia, patients with FVIII inhibitors, patients positive for aPL, patients treated with anti-Xa agents, and patients with DIC; these values tended to be significantly higher in pregnant women. The height of the first DC was significantly lower in patients who were positive for FVIII inhibitors and was significantly higher in patients treated with anti-Xa agents and pregnant women. The height of the first and second DC was useful for the analysis of hemophilia, FVIII inhibitor, and aPL.

Thrombotic thrombocytopenic purpura (TTP) frequently develops in patients with connective tissue diseases (CTDs). ADAMTS13 and von Willebrand factor (VWF) are closely related to the onset of TTP. We investigated the roles of ADAMTS13 and VWF in thrombotic events of patients with CTD. ADAMTS13 activity and VWF and VWF propeptide (VWFpp) levels in CTD, primary antiphospholipid antibody syndrome (pAPS), and controls were measured to examine their relationship with thrombosis. ADAMTS13 activity levels were significantly low in the patients with CTD but not in the patients with pAPS. No significant difference in the ADAMTS13 activity levels among the various CTD subgroups was found. The levels of VWF and VWFpp were significantly elevated in the patients with pAPS and CTD compared with that of control groups. Eleven patients with CTD developed TTP, and their ADAMTS13 activity levels were significantly lower than patients having CTD without TTP. However, the ADAMTS13 activity levels showed no difference between the patients having CTD with and without thrombotic events. The VWF antigen levels were significantly high in the patients having CTD with TTP. There were no significant differences in the VWF levels of the patients having CTD with TTP and thrombosis. The VWFpp levels were significantly high in the patients having CTD with TTP and thrombosis. The VWF and VWFpp levels were significantly high in the patients with pAPS. Decreased ADAMTS13 activity and elevated VWF and VWFpp levels were observed in patients with CTD. These abnormalities in patients with CTD may represent the increased risk of thrombosis in CTD.

We analyzed a cohort of 36 females with pregnancy loss. In addition to 11 patients with antiphospholipid antibody syndrome and 2 patients with congenital antithrombin (AT) or protein C deficiency, we identified 5 patients with low fibrinogen levels (median 110 mg/dL) prior to 10 weeks of gestation. Four of these 5 patients underwent a fibrinogen gene analysis, and all 4 were found to be heterozygotes for the α-fibrinogen (FGA) Thr321Ala polymorphism. One female without hypofibrinogenemia with a history of 8 pregnancy losses was found to be homozygous for the same polymorphism, and she also showed hypercoagulability without thrombosis. In conclusion, there was a relatively high frequency of pregnancy loss in the setting of hypofibrinogenemia and/or the FGA Thr312Ala polymorphism, and this may be an important risk factor for pregnancy loss and a hypercoagulable state in later pregnancy., (© The Author(s) 2015.)

Thrombotic microangiopathy (TMA) or thrombotic thrombocytopenic purpura (TTP) is a life-threatening syndrome characterized by increased number of fragmented red cells (FRCs) and thrombocytopenia. FRCs can be measured using the recently developed automated hematology analyzer XE-2100. The normal range for FRCs is 0% to 0.205%, as determined by the automated hematology analyzer XE-2100. The FRC count is significantly elevated in patients with TMA associated with liver transplantation, bone marrow transplantation, or TTP. In patients with TMA after liver transplantation, the FRC count is significantly higher than in those without TMA. In receiver operating characteristic analysis for the diagnosis of TMA, the area under the curve is 0.986, suggesting that FRC is a useful marker for the diagnosis of TMA. When the cutoff value of FRC for TMA is 1.2%, the sensitivity is 90% and the specificity is 96%, indicating that FRC is the most useful screening test for the diagnosis of TMA.