Validating lactate dehydrogenase (LDH) as a component of the PLASMIC predictive tool (PLASMIC-LDH)

Background@#The PLASMIC score is a convenient tool for predicting ADAMTS13 activity of ＜10%.Lactate dehydrogenase (LDH) is widely used as a marker of haemolysis in thrombotic thrombocytopenic purpura (TTP) monitoring, and could be used as a replacement marker for lysis. We aimed to validate the PLASMIC score in a multi-centre Asia Pacific region, and to explore whether LDH could be used as a replacement marker for lysis. @*Methods@#Records of patients with thrombotic microangiopathy (TMA) were reviewed. Patients’ ADAMTS13 activity levels were obtained, along with clinical/laboratory findings relevant to the PLASMIC score. Both PLASMIC scores and PLASMIC-LDH scores, in which LDH replaced traditional lysis markers, were calculated. We generated a receiver operator characteristics (ROC) curve and compared the area under the curve values (AUC) to determine the predictive ability of each score. @*Results@#46 patients fulfilled the inclusion criteria, of which 34 had ADAMTS13 activity levels of ＜10%. When the patients were divided into intermediate-to-high risk (scores 5‒7) and low risk (scores 0‒4), the PLASMIC score showed a sensitivity of 97.1% and specificity of 58.3%, with a positive predictive value (PPV) of 86.8% and negative predictive value (NPV) of 87.5%. The PLASMIC-LDH score had a sensitivity of 97.1% and specificity of 33.3%, with a PPV of 80.5% and NPV of 80.0%. @*Conclusion@#Our study validated the utility of the PLASMIC score, and demonstrated PLASMIC-LDH as a reasonable alternative in the absence of traditional lysis markers, to help identify high-risk patients for treatment via plasma exchange.

Long-term follow-up results of cytarabine-containing chemotherapy for acute promyelocytic leukemia

Background/Aims@#We evaluated the feasibility and long-term efficacy of the combination of cytarabine, idarubicin, and all-trans retinoic acid (ATRA) for treating patients with newly diagnosed acute promyelocytic leukemia (APL). @*Methods@#We included 87 patients with newly diagnosed acute myeloid leukemia and a t(15;17) or promyelocytic leukemia/retinoic acid receptor alpha (PML-RARα) mutation. Patients received 12 mg/m2/day idarubicin intravenously for 3 days and 100 mg/m2/day cytarabine for 7 days, plus 45 mg/m2/day ATRA. Clinical outcomes included complete remission (CR), relapse-free survival (RFS), overall survival (OS), and the secondary malignancy incidence during a 20-year follow-up. @*Results@#The CR, 10-year RFS, and 10-year OS rates were 89.7%, 94.1%, and 73.8%, respectively, for all patients. The 10-year OS rate was 100% for patients that achieved CR. Subjects were classified according to the white blood cell (WBC) count in peripheral blood at diagnosis (low-risk, WBC < 10,000/mm3; high-risk, WBC ≥ 10,000/mm3). The low-risk group had significantly higher RFS and OS rates than the high-risk group, but the outcomes were not superior to the current standard treatment (arsenic trioxide plus ATRA). Toxicities were similar to those observed with anthracycline plus ATRA, and higher than those observed with arsenic trioxide plus ATRA. The secondary malignancy incidence after APL treatment was 2.7%, among the 75 patients that achieved CR, and 5.0% among the 40 patients that survived more than 5 years after the APL diagnosis. @*Conclusions@#Adding cytarabine to anthracycline plus ATRA was not inferior to anthracycline plus ATRA alone, but it was not comparable to arsenic trioxide plus ATRA. The probability of secondary malignancy was low.

Updated recommendations for the treatment of venous thromboembolism

Venous thromboembolism (VTE), which includes pulmonary embolism and deep vein thrombosis, is a condition characterized by abnormal blood clot formation in the pulmonary arteries and the deep venous vasculature. It is often serious and sometimes even fatal if not promptly and appropriately treated. Moreover, the later consequences of VTE may result in reduced quality of life. The treatment of VTE depends on various factors, including the type, cause, and patient comorbidities. Furthermore, bleeding may occur as a side effect of VTE treatment. Thus, it is necessary to carefully weigh the benefits versus the risks of VTE treatment and to actively monitor patients undergoing treatment. Asian populations are known to have lower VTE incidences than Western populations, but recent studies have shown an increase in the incidence of VTE in Asia. A variety of treatment options are currently available owing to the introduction of direct oral anticoagulants.The current VTE treatment recommendation is based on evidence from previous studies, but it should be applied with careful consideration of the racial, genetic, and social characteristics in the Korean population.

Atypical Hemolytic Uremic Syndrome Successfully Treated with Eculizumab / 대한내과학회지

Atypical hemolytic uremic syndrome (aHUS) is a rare syndrome characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal injury, which results from uncontrolled complement activation. Delayed diagnosis and treatment of aHUS may result in end-stage renal disease (ESRD) and an associated dependence on dialysis. In extreme cases, it may cause death due to multi-organ failure. Eculizumab, a humanized monoclonal antibody against C5, inhibits the formation of the terminal membrane attack complex and is used to treat aHUS. Here, we report a 46-year-old male patient who suffered from aHUS relapse, despite prior treatment with repeated plasma exchange and hemodialysis. Eculizumab therapy improved his hematologic findings without use of hemodialysis.

Prominent seasonal variation in pulmonary embolism than deep vein thrombosis incidence: a Korean venous thrombosis epidemiology study

Background/Aims@#Seasonal variation is an environmental factor proposed to affect the incidence of venous thromboembolism (VTE). However, VTE seasonal variation is not well studied in Asian populations, which have different genetic determinants of VTE compared to Westerners. The present study aimed at investigating seasonal variation of VTE occurrence and the effect of various demographic factors (i.e., age, sex, and co-morbidities) on variation. @*Methods@#VTE seasonal variation was evaluated in 59,626 index cases (from January 2009 to December 2013) in the Korean Health Insurance Review and Assessment Service database. We quantified and compared VTE occurrence across four seasons, and additionally assessed monthly through a chronobiological analysis. @*Results@#VTE incidence varied both seasonally and monthly, with new cases peaking in the winter (January and February) and the lowest incidence in the summer (August and September). After adjusting for sex, age, type of VTE, and combined cancer diagnosis, winter remained a significant independent factor driving VTE incidence. Additionally, seasonal variation was prominent in patients aged 60 years or older and in patients with pulmonary embolism, but not so prominent in patients of aged less than 60 years and patients with deep vein thrombosis. @*Conclusions@#Seasonal variation was a weak but independent contributor to VTE incidence in a Korean population diagnosed from 2009 to 2013, especially in those individuals with old age or suffering from a pulmonary embolism.

Consensus regarding diagnosis and management of atypical hemolytic uremic syndrome

Thrombotic microangiopathy (TMA) is defined by specific clinical characteristics, including microangiopathic hemolytic anemia, thrombocytopenia, and pathologic evidence of endothelial cell damage, as well as the resulting ischemic end-organ injuries. A variety of clinical scenarios have features of TMA, including infection, pregnancy, malignancy, autoimmune disease, and medications. These overlapping manifestations hamper differential diagnosis of the underlying pathogenesis, despite recent advances in understanding the mechanisms of several types of TMA syndrome. Atypical hemolytic uremic syndrome (aHUS) is caused by a genetic or acquired defect in regulation of the alternative complement pathway. It is important to consider the possibility of aHUS in all patients who exhibit TMA with triggering conditions because of the incomplete genetic penetrance of aHUS. Therapeutic strategies for aHUS are based on functional restoration of the complement system. Eculizumab, a monoclonal antibody against the terminal complement component 5 inhibitor, yields good outcomes that include prevention of organ damage and premature death. However, there remain unresolved challenges in terms of treatment duration, cost, and infectious complications. A consensus regarding diagnosis and management of TMA syndrome would enhance understanding of the disease and enable treatment decision-making.

Frequently Delayed Diagnosis and Misdiagnosis in MYH9-related Disorders: Data from Genetically Confirmed Cases of Korean Patients

MYH9-related disorders (MYH9RD) are autosomal-dominant disorders characterized by macrothrombocytopenia with or without leukocyte inclusion bodies or extra-hematological features, such as sensorineural deafness and renal impairment. MYH9RD can be misdiagnosed as an acquired form of thrombocytopenia including immune thrombocytopenic purpura (ITP). This leads to delayed diagnosis or administration of ineffective treatment. In the present study, we investigated the clinical and molecular characteristics of five unrelated Korean patients with MYH9RD and their family members, from four institutions. We reviewed clinical and laboratory data including extra-hematological manifestations. MYH9 pathogenic variants were detected by direct sequencing in all probands and the affected family members (N=10): two probands with c.5521G>A (p.Glu1841Lys) and one proband each with c.99G>T (p.Trp33Cys), c.287C>T (p.Ser96Leu), and c.3493C>T (p.Arg1165Cys). All patients had macrothrombocytopenia. Only the proband with Ser96Leu had extra-hematological manifestations. Past history revealed that two patients had been misdiagnosed with ITP and one of them had received a splenectomy. We validated the frequency of misdiagnosis (~20%) and genotype-phenotype correlations through a comprehensive review of previously reported cases of MYH9RD in Korea. It is important to suspect MYH9RD in patients with thrombocytopenia, and timely identification of macrothrombocytopenia and MYH9 pathogenic variants is required for early and accurate diagnosis of MYH9RD.

Prognostic utility of ADAMTS13 activity for the atypical hemolytic uremic syndrome (aHUS) and comparison of complement serology between aHUS and thrombotic thrombocytopenic purpura

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) involves dysregulation of the complement system, but whether this also occurs in thrombotic thrombocytopenic purpura (TTP) remains unclear. Although these conditions are difficult to differentiate clinically, TTP can be distinguished by low (<10%) ADAMTS13 activity. The aim was to identify the differences in complement activation products between TTP and aHUS and investigate ADAMTS13 activity as a prognostic factor in aHUS. METHODS: We analyzed patients with thrombotic microangiopathy diagnosed as TTP (N=48) or aHUS (N=50), selected from a Korean registry (N=551). Complement activation products in the plasma samples collected from the patients prior to treatment and in 40 healthy controls were measured by ELISA. RESULTS: The levels of generalized (C3a), alternate (factor Bb), and terminal (C5a and C5b-9) markers were significantly higher (all P<0.01) in the patients than in the healthy controls. Only the factor Bb levels significantly differed (P=0.008) between the two disease groups. In aHUS patients, high normal ADAMTS13 activity (≥77%) was associated with improved treatment response (OR, 6.769; 95% CI, 1.605–28.542; P=0.005), remission (OR, 6.000; 95% CI, 1.693–21.262; P=0.004), exacerbation (OR, 0.242; 95% CI, 0.064–0.916; P=0.031), and disease-associated mortality rates (OR, 0.155; 95% CI, 0.029–0.813; P=0.017). CONCLUSION: These data suggest that complement biomarkers, except factor Bb, are similarly activated in TTP and aHUS patients, and ADAMTS13 activity can predict the treatment response and outcome in aHUS patients.

Long-term rivaroxaban for the treatment of acute venous thromboembolism in patients with active cancer in a prospective multicenter trial

BACKGROUND/AIMS@#Limited data are available regarding the efficacy of rivaroxaban for the treatment of cancer-associated venous thromboembolism (VTE). The aim of this study was to evaluate the effectiveness and safety of rivaroxaban for the treatment of VTE in active cancer patients.@*METHODS@#In this prospective, multicenter, open-label trial (NCT01989845), we enrolled patients with active cancer and objectively diagnosed lower-extremity deep vein thrombosis, pulmonary embolism (PE), or both from November 2013 to June 2016. Active cancer was defined as a histologically confirmed malignancy, which was diagnosed or treated within the previous 6 months, or as a recurrent/metastatic cancer. Patients received oral rivaroxaban 15 mg twice daily for first 3 weeks, followed by 20 mg once daily for 6 months. The primary outcome was the symptomatic recurrent VTE and the secondary outcomes included any recurrent VTE, major or clinically relevant non-major (CRNM) bleeding events, and overall mortality. All study outcomes were validated by blinded central adjudication.@*RESULTS@#Of 124 patients enrolled, 110 (88.7%) had solid cancer, 93 (75.0%) had metastatic disease, and 110 (88.7%) were receiving chemotherapy or radiotherapy. During the 6-month study period, seven patients experienced symptomatic recurrent VTE (cumulative incidence, 5.9%), and two patients experienced incidental recurrent PE (cumulative incidence of any recurrent VTE, 7.6%). Major bleeding events occurred in six patients (cumulative incidence, 5.3%) and CRNM bleeding events in 11 patients (cumulative incidence, 10.2%). Twenty-eight patients (overall mortality, 24.0%) died.@*CONCLUSIONS@#Rivaroxaban is effective and safe for the treatment of VTE in patients with active cancer.

Association of MicroRNA Biogenesis Genes Polymorphisms with Ischemic Stroke Susceptibility and Post-Stroke Mortality / 대한뇌졸중학회지

BACKGROUND AND PURPOSE: MicroRNA (miRNA) expression has been examined in multiple conditions, including various cancers, neurological diseases, and cerebrovascular diseases, particularly stroke. Existing evidence indicates that miRNA biosynthesis and function play crucial roles in ischemic stroke physiology and pathology. In this study, we selected six known polymorphisms in miRNA-biogenesis genes; DICER rs13078A>T, rs3742330A>G; DROSHA rs10719T>C, rs6877842G>C; Ran GTPase (RAN) rs14035C>T; exportin 5 (XPO5) rs11077A>C. METHODS: We analyzed the associations between these polymorphisms and disease status and clinical factors in 585 ischemic stroke patients and 403 controls. Genotyping was performed with the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The DICER rs3742330A>G (AA vs. AG+GG: adjusted odds ratio [AOR], 1.360; 95% confidence interval [CI], 1.024 to 1.807; P=0.034) and DROSHA rs10719T>C polymorphisms (TT vs. CC: AOR, 2.038; 95% CI, 1.113 to 3.730; P=0.021) were associated with ischemic stroke prevalence. During a mean follow-up of 4.80±2.11 years, 99 (5.91%) of the stroke patients died. In multivariate Cox proportional hazard regression models, a significant association was found between RAN rs14035 and survival of large artery disease patients with ischemic stroke (CC vs. TT: adjusted hazard ratio, 5.978; P=0.015). CONCLUSIONS: An association was identified between the DICER and DROSHA polymorphisms and ischemic stroke. Specifically, polymorphisms (rs3742330 and rs10719) were more common in stroke patients, suggesting that they may be associated with an increased risk of ischemic stroke.

Efficacy and Safety of a New 10% Intravenous Immunoglobulin Product in Patients with Primary Immune Thrombocytopenia (ITP)

BACKGROUND: In the current study, we aimed to investigate the efficacy and safety of intravenous immunoglobulin (IVIg)-SN 10%, a new 10% IVIg formulation, in adult patients with severe primary immune thrombocytopenia (ITP; platelet count < 20 × 109/L). METHODS: Patients diagnosed as primary ITP, aged 19 years old or more, and had a platelet count of < 20 × 109/L by screening complete blood cell count performed within 2 weeks of study commencement were eligible. Patients received IVIg-SN 10% at a dose of 1 g/kg/day for two consecutive days. Response was defined as the achievement of a platelet count of ≥ 50 × 109/L at day 8. RESULTS: Out of 81 eligible patients, 31 patients were newly diagnosed, 7 patients had persistent ITP, and 43 patients had chronic ITP. In intent-to-treat analysis, 61.3 patients (75.7%) achieved response and satisfied the pre-defined non-inferiority condition. Median time to response was 2 days and mean duration of maintaining response after the completion of IVIg therapy was 9.13 ± 8.40 days. Response rates were not found to be dependent on the phase of ITP or previous treatment for ITP. The drug was well tolerated and the frequency of mucocutaneous bleeding decreased during the study period. CONCLUSION: In summary, IVIg-SN 10% formulation was found to be safe and effective in adult ITP patients (Trial registry at ClinicalTrials.gov, NCT02063789).

A case of atypical hemolytic uremic syndrome associated with the c.1273C>T mutation in the complement C3 gene

No abstract available.

Clinical Practice Guidelines for the Management of Atypical Hemolytic Uremic Syndrome in Korea

Atypical hemolytic uremic syndrome (aHUS) is a rare syndrome characterized by micro-angiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The major pathogenesis of aHUS involves dysregulation of the complement system. Eculizumab, which blocks complement C5 activation, has recently been proven as an effective agent. Delayed diagnosis and treatment of aHUS can cause death or end-stage renal disease. Therefore, a diagnosis that differentiates aHUS from other forms of thrombotic microangiopathy is very important for appropriate management. These guidelines aim to offer recommendations for the diagnosis and treatment of patients with aHUS in Korea. The guidelines have largely been adopted from the current guidelines due to the lack of evidence concerning the Korean population.

Reversible Heart Failure after Bortezomib Treatment in a Patient with Multiple Myeloma / 대한내과학회지

Bortezomib (Velcade(R)) came into the spotlight as a target therapy for multiple myeloma. It acts through reversible inhibition of intracellular proteasomes, which triggers apoptosis, with relative selectivity for malignant cells. It has been hypothesized that the accumulation of damaged proteins in myocytes impairs cardiac function. Cardiotoxicity is a rare side effect of bortezomib treatment. We report a case of reversible systolic heart failure that probably occurred after bortezomib treatment in a patient with multiple myeloma. Patients being treated with bortezomib who have previously had cardiac comorbidities should undergo routine cardiac monitoring.

A case of oxaliplatin-induced immune-mediated thrombocytopenia

Oxaliplatin is a platinum compound used in patients with gastrointestinal malignancies. It is known to evoke a drug-induced immune-mediated thrombocytopenia, which has not been reported in Korea. We describe a 53-year-old man who developed oxaliplatin-induced immune-mediated thrombocytopenia during chemotherapy for colon cancer. Oxaliplatin-dependent IgG platelet antibodies were detected in his serum on flow cytometry. He was treated with immunoglobulin and corticosteroids without any complications. Physicians should consider oxaliplatin-induced immune-mediated thrombocytopenia, when a sudden, isolated thrombocytopenia develops during chemotherapy with oxaliplatin.

Prevention of Venous Thromboembolism, 2nd Edition: Korean Society of Thrombosis and Hemostasis Evidence-Based Clinical Practice Guidelines

In 2010, we proposed the first Korean Guidelines for the Prevention of Venous Thromboembolism (VTE). It was applicable to Korean patients, by modifying the contents of the second edition of the Japanese guidelines for the prevention of VTE and the 8th edition of the American College of Chest Physicians (ACCP) evidence-based clinical practice guidelines. From 2007 to 2011, we conducted a nationwide study regarding the incidence of VTE after major surgery using the Health Insurance Review and Assessment Service (HIRA) database. In addition, we have considered the 9th edition of the ACCP Evidenced-Based Clinical Practice Guidelines, published in 2012. It emphasized the importance of clinically relevant events as opposed to asymptomatic outcomes with preferences for both thrombotic and bleeding outcomes. Thus, in the development of the new Korean guidelines, three major points were addressed: 1) the new guidelines stratify patients into 4 risk groups (very low, low, moderate, and high) according to the actual incidence of symptomatic VTE from the HIRA databases; 2) the recommended optimal VTE prophylaxis for each group was modified according to condition-specific thrombotic and bleeding risks; 3) guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and/or physician advice.

A Case of Primary Autoimmune Myelofibrosis / 대한내과학회지

Primary autoimmune myelofibrosis, the development of which is not preceded by a well-defined autoimmune disease, has recently been defined as a distinct clinicopathologic syndrome. We report herein a case of a 68-year-old woman who was diagnosed with primary autoimmune myelofibrosis and present a review of the literature. The patient manifested peripheral pancytopenia, was positive for autoantibodies, and developed myelofibrosis with no preceding autoimmune or hematologic disorders. Her condition was dramatically improved after administration of prednisolone.

Precursor B-Cell Acute Lymphoblastic Leukemia in Two Patients with a History of Cytotoxic Therapy / 대한내과학회지

Therapy-related myeloid neoplasms have been well characterized. However, precursor B-cell acute lymphoblastic leukemia in patients with prior malignancies is uncommon, and the effect of prior cytotoxic therapy on development of precursor B-cell acute lymphoblastic leukemia is controversial. Therapy-related precursor B-cell acute lymphoblastic leukemia has been reported occasionally. However, cytotoxic therapy-related precursor B-cell acute lymphoblastic leukemia has been reported in Korea only rarely. We herein describe two cases of therapy-related precursor B-cell acute lymphoblastic leukemia.

Two Cases of Hodgkin's Lymphoma after Allogeneic Hematopoietic Cell Transplantation / 대한내과학회지

Hematopoietic cell transplantation recipients have a high risk of subsequent malignant neoplasms. Among post-transplantation lymphoproliferative disorders (PTLDs) after hematopoietic cell transplantation, Hodgkin's lymphoma is rare and distinct from the majority of other PTLDs because of its later onset and relatively good prognosis. It is known to be associated with exposure to the Epstein-Barr virus, and the mixed cellularity subtype is the most common. We herein describe two cases of Hodgkin's lymphoma that developed after allogeneic hematopoietic cell transplantation.

Characterization of anti-factor VIII antibody in a patient with acquired hemophilia A

Acquired hemophilia A (AHA) is a bleeding disorder caused by the development of an auto-antibody against endogenous factor VIII (FVIII). In this study, the epitope of the autoantibody was identified in a 67-year-old female patient with AHA. A prolonged activated partial thromboplastin time (77.4 s) that failed to correct in an incubation mixing test (68.2 s), a decreased FVIII activity, and a high FVIII inhibitor (14.6 Bethesda units/mL) were observed. Enzyme-linked immunosorbent assay demonstrated that the antibody belonged to the immunoglobulin G4 subclass. An immunoblotting assay revealed the light chain (A3/C1/C2 domain) of FVIII as the binding region of the antibody. The bleeding experienced by our patient resulted from the interference of FVIII binding to both FIX by anti-A3 antibodies and phospholipids and von Willebrand factor by anti-C2 antibodies. To the best of our knowledge, this is the first study in Korea characterizing an autoantibody in the context of AHA.