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.
Atypical Hemolytic Uremic Syndrome ; Biomarkers ; Complement Activation ; Complement System Proteins ; Enzyme-Linked Immunosorbent Assay ; Humans ; Mortality ; Plasma ; Purpura, Thrombotic Thrombocytopenic ; Thrombotic Microangiopathies

BACKGROUND: Thrombotic microangiopathy (TMA) with non-deficient ADAMTS-13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13) outcome is unknown hence the survival analysis correlating with ADAMTS-13 activity is conducted in Malaysia. METHODS: This was a retrospective epidemiological study involving all cases of TMA from 2012–2016. RESULTS: We evaluated 243 patients with a median age of 34.2 years; 57.6% were female. Majority of the patients were Malay (62.5%), followed by Chinese (23.5%) and Indian (8.6%). The proportion of patients with thrombotic thrombocytopenic purpura (TTP) was 20.9%, 72.2% of which were acquired while 27.8% were congenital. Patients with ADAMTS-13 activity ≥5% had a four-fold higher odds of mortality compared to those with ADAMTS-13 activity <5% (odds ratio: 4.133, P=0.0425). The mortality rate was 22.6% (N=55). Most cases had secondary etiologies (42.5%), followed by acquired TTP (16.6%), atypical hemolytic uremic syndrome (HUS) or HUS (12.8%) and congenital TTP (6.4%). Patients with secondary TMA had inferior overall survival (P=0.0387). The secondary causes comprised systemic lupus erythematosus (30%), infection (29%), pregnancy (10%), transplant (8%), malignancy (6%), and drugs (3%). Transplant-associated TMA had the worst OS (P=0.0016) among the secondary causes. Plasma exchange, methylprednisolone and intravenous immunoglobulin were recorded as first-line treatments in 162 patients, while rituximab, bortezomib, vincristine, azathioprine, cyclophosphamide, cyclosporine, and tacrolimus were described in 78 patients as second-line treatment. CONCLUSION: This study showed that TMA without ADAMTS-13 deficiency yielded inferior outcomes compared to TMA with severeADAMTS-13 deficiency, although this difference was not statistically significant.
Asian Continental Ancestry Group ; Atypical Hemolytic Uremic Syndrome ; Azathioprine ; Bortezomib ; Cyclophosphamide ; Cyclosporine ; Epidemiologic Studies ; Female ; Humans ; Immunoglobulins ; Lupus Erythematosus, Systemic ; Malaysia* ; Methylprednisolone ; Mortality ; Plasma Exchange ; Pregnancy ; Purpura, Thrombotic Thrombocytopenic ; Retrospective Studies ; Rituximab ; Tacrolimus ; Thrombospondins ; Thrombotic Microangiopathies* ; Vincristine

China ; Consensus ; Humans ; Purpura, Thrombotic Thrombocytopenic ; Thrombotic Microangiopathies/therapy*

Thromobotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS), characterized by microangiopathic hemolytic anemia, thrombocytopenia, fever, central nervous system abnormalities, and renal dysfunction, is severe multisystem disorder. TTP-HUS occurs predominantly in the reproductive aged-women, associated with poor prognosis. Although the morbidity and mortality have been significantly decreased by using plasma exchange therapy, refractory TTP-HUS remains a tremendous problem. It is crucial to differentiate other microangiopathic hemolytic anemia disease with a confusing presentation and to perform the immediate plasmapheresis. We have experienced three cases, which were initially diagnosed as HELLP syndrome or immune thrombocytopenic purpura. Despite of aggressive plasmapheresis, two women died. We present these cases with a review of the literature on pregnancy-associated thrombotic microangiopathy, including ADAMTS-13 activity assay as a new diagnostic test.
Anemia, Hemolytic ; Central Nervous System ; Diagnostic Tests, Routine ; Female ; Fever ; HELLP Syndrome ; Humans ; Plasma Exchange ; Plasmapheresis ; Pre-Eclampsia ; Pregnancy ; Pregnancy Complications ; Prognosis ; Purpura, Thrombocytopenic, Idiopathic ; Purpura, Thrombotic Thrombocytopenic ; Thrombocytopenia ; Thrombotic Microangiopathies

Thrombotic microangiopathy (TMA) is a group of highly heterogeneous, acute and severe clinicopathological syndromes, characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and ischemic injury of end organs. TMA has the characteristics of dangerous condition, multiple organ involvement and high mortality. Patients with severe TMA need to be admitted to intensive care unit (ICU) for organ function support therapy. Early and rapid evaluation, differential diagnosis, and timely and effective treatment are the key to improve the prognosis of TMA patients. Here, we review the pathophysiological changes, diagnosis differential diagnosis, and treatment of the severe TMA in adult.
Adult ; Humans ; Thrombotic Microangiopathies/therapy* ; Purpura, Thrombotic Thrombocytopenic/therapy* ; Anemia, Hemolytic/therapy* ; Treatment Outcome ; Diagnosis, Differential

Thrombotic thrombocytopenic purpura(TTP) is a clinical syndrome of unknown etiology and characterized by microangiopathic hemolytic anemia, thrombocytopenia, fluctuating neurological status, renal dysfunction and fever. Systemic lupus erythromatosus(SLE) is also multisystemic disease that some of clinical features may mimic TTP. Therefore both diseases have led to diagnostic confusion. We experienced two cases with SLE who subsequently or initially developed TTP. In case 1, a 44-year old woman had 1-year previous history of SLE and presented with dyspnea. After diagnosis of thrombotic microangiopathy by renal biopsy, she was managed with steroid, cyclophosphamide pulse therapy, fresh frozen plasma infusion and plasmapheresis. She was treated by aggressive treatment; nevertheless, she died on 15th admission day. In case 2, a 22-year old man was admitted because of nausea and vomiting. SLE with TTP was diagnosed by ARA criteria and the finding of microangiopathic hemolytic anemia. He was treated with plasmapheresis, fresh frozen plasma infusion and steroid therapy. He showed clinical response to the therapy, and has shown no recurrence of disease until now on. In conclusion, we suggest that early diagnosis and prompt therapy such as plasmapheresis and plasma infusion are very important in SLE with TTP.
Adult ; Anemia, Hemolytic ; Biopsy ; Cyclophosphamide ; Diagnosis ; Dyspnea ; Early Diagnosis ; Female ; Fever ; Humans ; Nausea ; Plasma ; Plasmapheresis ; Purpura, Thrombocytopenic* ; Purpura, Thrombotic Thrombocytopenic ; Recurrence ; Thrombocytopenia ; Thrombotic Microangiopathies ; Vomiting ; Young Adult

Diagnosis of thrombotic microangiopathy (TMA) is challenging due to its close association with other forms of microangiopathic hemolytic anemia, such as malignant hypertension and disseminated intravascular coagulation, and because other manifestations including cytopenia and acute kidney injury are manifestations of other medical comorbidities. Further challenges for accurate diagnosis include distinguishing between primary and secondary TMA, as well as between hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). TTP is typically differentiated from HUS by the presence of more severe thrombocytopenia, along with a higher frequency of altered mental status with relatively preserved renal function. However, the clinical course can vary among patients, requiring polymerase chain reaction testing of patient stools for enterohemorrhagic Escherichia coli and a disintegrin and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS13) assay. To reduce the mortality rate, prompt initiation of plasmapheresis is important in cases where TPP cannot be excluded. Future advances enabling more rapid testing for ADAMTS13 levels will reduce the need for unnecessary plasmapheresis, so that treatment strategy can be more optimized.
Acute Kidney Injury ; Anemia, Hemolytic ; Comorbidity ; Diagnosis ; Diagnosis, Differential ; Disseminated Intravascular Coagulation ; Enterohemorrhagic Escherichia coli ; Hemolytic-Uremic Syndrome ; Humans ; Hypertension, Malignant ; Mortality ; Plasma Exchange ; Plasmapheresis ; Polymerase Chain Reaction ; Purpura, Thrombotic Thrombocytopenic ; Thrombocytopenia ; Thrombospondins ; Thrombotic Microangiopathies

We report the case of a 14-year-old girl, diagnosed with atypical thrombotic microangiopathy (TMA). The patient presented with persistent fever, nausea, and newly developed peripheral edema. Her laboratory findings indicated chronic anemia with no evidence of hemolysis, thrombocytopenia, or elevated serum creatinine level. A few days after hospitalization, acute renal failure and fever worsened, and proteinuria developed. On day 40 of hospitalization, she experienced a generalized tonic seizure for 5 min, accompanied by renal hypertension. Brain magnetic resonance imaging revealed posterior reversible leukoencephalopathy syndrome. After steroid pulse therapy, a renal biopsy was performed because of delayed recovery from thrombocytopenia. The biopsy findings showed features of thrombotic microangiopathic hemolysis with fibrinoid change restricted. Current diagnostic criteria for TMA have focused on thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, and diagnosis is based on the clinical presentation and etiology, with the consequence that idiopathic and atypical forms of TMA can be overlooked. Developing effective tools to diagnose TMA, such as studying levels of ADAMTS13 or testing for abnormalities in the complement system, will be the first step to improving patient outcomes.
Acute Kidney Injury ; Adolescent ; Anemia ; Biopsy ; Brain ; Complement System Proteins ; Creatinine ; Diagnosis ; Edema ; Female ; Fever ; Hemolysis ; Hemolytic-Uremic Syndrome ; Hospitalization ; Humans ; Hypertension, Renal ; Leukoencephalopathies ; Magnetic Resonance Imaging ; Nausea ; Proteinuria ; Purpura, Thrombotic Thrombocytopenic ; Resin Cements ; Seizures ; Thrombocytopenia ; Thrombotic Microangiopathies*

We report the case of a 14-year-old girl, diagnosed with atypical thrombotic microangiopathy (TMA). The patient presented with persistent fever, nausea, and newly developed peripheral edema. Her laboratory findings indicated chronic anemia with no evidence of hemolysis, thrombocytopenia, or elevated serum creatinine level. A few days after hospitalization, acute renal failure and fever worsened, and proteinuria developed. On day 40 of hospitalization, she experienced a generalized tonic seizure for 5 min, accompanied by renal hypertension. Brain magnetic resonance imaging revealed posterior reversible leukoencephalopathy syndrome. After steroid pulse therapy, a renal biopsy was performed because of delayed recovery from thrombocytopenia. The biopsy findings showed features of thrombotic microangiopathic hemolysis with fibrinoid change restricted. Current diagnostic criteria for TMA have focused on thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, and diagnosis is based on the clinical presentation and etiology, with the consequence that idiopathic and atypical forms of TMA can be overlooked. Developing effective tools to diagnose TMA, such as studying levels of ADAMTS13 or testing for abnormalities in the complement system, will be the first step to improving patient outcomes.
Acute Kidney Injury ; Adolescent ; Anemia ; Biopsy ; Brain ; Complement System Proteins ; Creatinine ; Diagnosis ; Edema ; Female ; Fever ; Hemolysis ; Hemolytic-Uremic Syndrome ; Hospitalization ; Humans ; Hypertension, Renal ; Leukoencephalopathies ; Magnetic Resonance Imaging ; Nausea ; Proteinuria ; Purpura, Thrombotic Thrombocytopenic ; Resin Cements ; Seizures ; Thrombocytopenia ; Thrombotic Microangiopathies*

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy characterized by endothelial cell damage, resulting in microangiopathic hemolytic anemia, thrombocytopenia, and various degrees of neurological and renal impairment caused by microvascular thrombi. It is rare in children and frequently follows a fatal course. TTP is divided into 2 types: one is inherited and associated with ADAMTS-13 gene mutations and the other is acquired and associated with anti-ADAMTS-13 autoantibodies. The measurement of ADAMTS-13 activity in plasma, identification of ADAMTS-13 circulating inhibitor, anti-ADAMTS-13 IgG, and ADAMTS-13 gene sequencing are crucial to the diagnosis of TTP. Plasma exchanges are the first-line treatment for acquired TTP, combined with steroids and immunosuppressive drugs. Here, we describe the case of an adolescent patient with TTP, confirmed by decreased level of ADAMTS-13 activity and an increased level of ADAMTS-13 inhibitor, who was successfully treated by plasma exchanges.
Adolescent ; Anemia, Hemolytic ; Autoantibodies ; Child ; Endothelial Cells ; Humans ; Immunoglobulin G ; Plasma ; Plasma Exchange ; Purpura ; Purpura, Thrombotic Thrombocytopenic ; Steroids ; Thrombocytopenia ; Thrombotic Microangiopathies ; Thymine Nucleotides