INTRODUCTION — The initial evaluation of a patient with suspected thrombotic thrombocytopenic purpura (TTP) or another primary thrombotic microangiopathy (TMA) syndrome must focus on distinguishing these primary syndromes from other systemic disorders that can present with microangiopathic hemolytic anemia (MAHA) and thrombocytopenia.
This topic review describes our initial approach to the child or adult with MAHA and thrombocytopenia for whom the etiology is uncertain. Details of the evaluation and management of specific, defined primary TMA syndromes including TTP are presented in separate topic reviews on these syndromes. (See 'Overview of primary TMA syndromes' below.)
TERMINOLOGY — The following terminology is used in this topic review:
Microangiopathic hemolytic anemia (MAHA) — MAHA is a descriptive term for non-immune hemolysis (ie, Coombs-negative hemolysis) resulting from intravascular red blood cell fragmentation that produces schistocytes on the peripheral blood smear (picture 1) . Abnormalities in the microvasculature, including small arterioles and capillaries, are frequently involved. Intravascular devices such as a prosthetic heart valve or assist devices may also cause MAHA. Characteristic laboratory data are a negative direct antiglobulin (Coombs) test (DAT), an increased lactate dehydrogenase (LDH), increased indirect bilirubin, and low haptoglobin.
Thrombotic microangiopathy (TMA) — Not all episodes of MAHA are caused by a TMA, and not all TMA will present with MAHA and thrombocytopenia. For example, some syndromes present with TMA limited to the kidney.
TMA describes a specific pathologic lesion in which abnormalities in the vessel wall of arterioles and capillaries lead to microvascular thrombosis . TMA is a pathologic diagnosis made by tissue biopsy, typically a kidney biopsy. It is commonly inferred from the observation of MAHA and thrombocytopenia in the appropriate clinical setting.
●The primary TMA syndromes include TTP (hereditary or immune), Shiga toxin-mediated hemolytic uremic syndrome (ST-HUS), drug-induced TMA (DITMA) syndromes, complement-mediated TMA (CM-TMA; hereditary or acquired), and rare hereditary disorders of vitamin B12 metabolism or factors involved in hemostasis. These syndromes require urgent, targeted treatment directed at the TMA pathophysiology. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)".)
With the exception of TTP (TMA resulting from severe ADAMTS13 deficiency) and hemolytic uremic syndrome (HUS; Shiga toxin-mediated TMA), we use names that indicate the underlying cause. The nomenclature will evolve further as pathophysiologic mechanisms are better understood.
We do not use the term "atypical hemolytic uremic syndrome (aHUS)," because this term has no specificity. aHUS was used historically to describe children with MAHA, thrombocytopenia, and kidney failure not associated with diarrhea. Unfortunately, the term is often used to describe any patient with a TMA who does not have severe ADAMTS13 deficiency or a documented Shiga toxin, therefore it has little clinical usefulness.
We also do not use the term "idiopathic" to describe any of the primary TMA syndromes. This term was used historically to imply ADAMTS13 deficiency in patients who did not have other recognized conditions that may cause TMA. The term "idiopathic" also has no specificity and should be avoided.
●Other systemic disorders that can present with MAHA and thrombocytopenia include pregnancy-associated syndromes (eg, preeclampsia with severe features and HELLP syndrome), severe hypertension, systemic infections and malignancies, autoimmune disorders such as systemic lupus erythematosus, and complications of hematopoietic stem cell or solid organ transplantation. Unlike the primary TMA syndromes, these systemic disorders require therapy directed at the underlying disorder rather than specific therapy for the TMA. (See "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)" and "Evaluation and treatment of hypertensive emergencies in adults" and "Catastrophic antiphospholipid syndrome (CAPS)" and "Early complications of hematopoietic cell transplantation", section on 'Thrombotic microangiopathy'.)
INITIAL EVALUATION (ALL PATIENTS) — Individuals with a TMA may come to medical attention with any of a variety of presentations including unexplained anemia or thrombocytopenia, unexplained neurologic findings (suspected stroke or transient ischemic attack), or other acute illness.
The initial evaluation is focused on confirming that the patient has microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, and excluding systemic disorders that manifest these findings, based on a consideration of presenting findings and likely causes (algorithm 1) . Once systemic disorders have been excluded, the focus changes to identifying which primary TMA syndrome(s) are most likely and require immediate treatment.
We favor starting with a thorough history and physical examination that guides selected use of laboratory tests rather than a battery of tests to confirm or exclude a large number of diagnoses, especially as many available tests are not highly sensitive or specific for a single diagnosis. Institutions may develop their own approaches depending on their case mix and associated likely diagnoses (eg, higher likelihood of HUS in children; higher likelihood of drug-induced TMA (DITMA) in populations with kidney transplant or hematopoietic stem cell transplant), but these should not substitute for the judgement of the clinician evaluating the patient .
Verify MAHA and thrombocytopenia — The first step is to confirm the presence of MAHA and thrombocytopenia by examination of the patient's peripheral blood smear. This requires review of the blood smear by a hematologist or other clinician with expertise in TMA syndromes, or experienced laboratory personnel. Details of this evaluation are provided in separate topic reviews. (See "Evaluation of the peripheral blood smear" and "Diagnosis of immune TTP", section on 'MAHA and thrombocytopenia'.)
If MAHA is not present, other acute systemic illnesses associated with pancytopenia must be considered. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis" and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria" and "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis" and "Clinical manifestations and diagnosis of Felty syndrome" and "Hematologic manifestations of systemic lupus erythematosus".)
If MAHA is present, considerations include systemic illness or MAHA due to a mechanical cause (eg, without a disease). (See "Non-immune (Coombs-negative) hemolytic anemias in adults", section on 'Fragmentation'.)
Decision to use plasma exchange before diagnosis is known — Initiating therapeutic plasma exchange (TPE) treatment for TTP is urgent. Therefore, the initial evaluation and management must balance the level of confidence in a TTP diagnosis versus the suspicion of another etiology for the MAHA and thrombocytopenia (table 1).
The PLASMIC score is a simple algorithm that has been developed and validated to estimate the probability of ADAMTS13 activity ≤10 percent (and therefore the probability of the diagnosis of TTP) in a patient with MAHA and thrombocytopenia . Use of such an algorithm provides confidence for a diagnosis of TTP before the results of ADAMTS13 activity testing is available. (See "Diagnosis of immune TTP", section on 'Evaluation and diagnosis'.)
If the concern for the diagnosis of TTP is strong, then TPE may need to be initiated while the diagnostic evaluation continues. (See 'Suspected TTP: Start therapeutic plasma exchange (TPE)' below.)
However, if the patient is not critically ill and the suspicion for the disorders discussed below is greater than the suspicion for TTP, then it may be appropriate to defer TPE while the evaluation continues. The degree of symptoms and timing of recovery with initial therapy contribute to the degree of confidence in a particular diagnosis:
●Occurrence before gestational age of 25 weeks or a platelet count <30,000/microL are rare in pregnancy syndromes (preeclampsia/HELLP [hemolysis, elevated liver enzymes, and low platelets]) .
●Lack of improvement within several hours to three days after delivery of a pregnant patient decreases confidence that the symptoms were due to a pregnancy syndrome (preeclampsia/HELLP).
●A longer duration of severe back pain (eg, weeks) or pulmonary symptoms increases suspicion for a malignancy and decreases confidence in a primary TMA.
●A history of cancer should cause consideration of systemic metastatic cancer-associated TMA. Bone marrow biopsy with special stains for cancer cells is indicated .
●High fever increases suspicion for a systemic infection and decreases confidence in a primary TMA.
●Severe hypertension with MAHA, thrombocytopenia, kidney failure, and neurologic abnormalities, even with documentation of TMA on a kidney biopsy, may be most effectively managed by treatment of the hypertension rather than TPE for a suspicion of TTP.
●An established diagnosis of systemic lupus erythematosus (SLE) with MAHA, thrombocytopenia, and nephritis, even with documentation of TMA on a kidney biopsy, may be most effectively managed by treatment of the SLE rather than TPE for a suspicion of TTP.
●A lack of early response to TPE (eg, first three or four days) for suspected TTP encourages us to continue to seek other causes of the patient's symptoms.
Exclude systemic disorders associated with MAHA and thrombocytopenia — Once MAHA and thrombocytopenia are confirmed, it is important to exclude systemic disorders as the cause of these findings.
Many systemic disorders can cause MAHA and thrombocytopenia. Involvement of a clinician with expertise in these disorders (and their distinction from TTP and HUS) is important.
Some systemic disorders, such as severe hypertension and preeclampsia/HELLP syndrome, are obvious. However, systemic malignancies may not be initially apparent and may require other testing (eg, chest radiography, bone marrow examination) for diagnosis. Systemic infections may not be obvious, and they may mimic all clinical features of TTP, and thus microbial testing may be required to identify an infectious organism.
Some of the more common and well-described conditions include the following:
●Pregnancy complications – Preeclampsia with severe features and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) are a continuum of pregnancy-related disorders. They characteristically cause MAHA and thrombocytopenia [5,7]. Less than 5 percent of Preeclampsia/HELLP syndromes are rare before gestational age 25 weeks (<5 percent) and generally do not produce platelet counts <30,000/microL (≤5 percent) . Also, individuals with SLE may experience a clinical "flare" during pregnancy. Distinguishing these disorders from TTP may be difficult because pregnancy may also trigger acute episodes of TTP (hereditary or immune). CM-TMA may cause severe postpartum acute kidney injury. Diagnostic evaluation of pregnant patients and decisions regarding delivery are discussed separately. (See "Thrombocytopenia in pregnancy".)
●Severe hypertension – Severe hypertension (eg, systolic blood pressure >220 mmHg; diastolic blood pressure >100 mmHg) can cause MAHA and thrombocytopenia. Kidney injury may be present, but sometimes kidney dysfunction is modest or absent. In patients with severe hypertension, control of the blood pressure is the most critical initial management and may be the only intervention required. (See "Evaluation and treatment of hypertensive emergencies in adults".)
Chronic, severe hypertension can also cause the characteristic pathologic features of TMA and varying degrees of kidney failure. However, in some patients, chronic kidney disease related to a primary TMA syndrome may be the cause of the severe hypertension.
If possible, it is important to clarify the temporal relationship between the hematologic abnormalities and the hypertension.
●Systemic infections – Many systemic infections (bacterial, viral, rickettsial, and fungal) can cause MAHA and thrombocytopenia . Common examples include bacterial endocarditis, human immunodeficiency virus (HIV) infection, cytomegalovirus (CMV) infection, Rocky Mountain spotted fever, red blood cell parasites (eg, malaria, babesia) and systemic aspergillosis (table 2). (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Acute and early HIV infection: Clinical manifestations and diagnosis" and "Approach to the diagnosis of cytomegalovirus infection" and "Clinical manifestations and diagnosis of Rocky Mountain spotted fever" and "Epidemiology and clinical manifestations of invasive aspergillosis" and "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children" and "Babesiosis: Clinical manifestations and diagnosis".)
●Systemic malignancies – Any systemic malignancy can cause MAHA and thrombocytopenia . In some patients, these findings are caused by microvascular metastases without overt evidence of disseminated intravascular coagulation (DIC). If there is any past history of cancer or any symptom suggestive of malignancy, such as persistent back pain or prominent pulmonary symptoms, a thorough physical examination and other testing to evaluate for a systemic malignancy is imperative, including bone marrow evaluation, chest radiography and other testing as indicated by symptoms. Identification of cancer cells in a marrow biopsy confirms the diagnosis of systemic malignancy. Identification of cancer cells may require special stains . (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Cancer-associated hypercoagulable state: Causes and mechanisms".)
●Systemic rheumatic disorders – Systemic rheumatic disorders, such as SLE, systemic sclerosis (SSc, scleroderma), and antiphospholipid syndrome (APS), especially catastrophic APS (CAPS) can cause MAHA and thrombocytopenia by both immune and nonimmune mechanisms . They may also manifest TMA on kidney biopsies. (See "Hematologic manifestations of systemic lupus erythematosus", section on 'Microangiopathic hemolytic anemia' and "Clinical manifestations of antiphospholipid syndrome", section on 'Hematologic abnormalities' and "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis" and "Catastrophic antiphospholipid syndrome (CAPS)".)
●Hematopoietic stem cell transplant or organ transplantation – Patients who have undergone autologous or allogeneic hematopoietic cell transplant (HCT) are at risk for MAHA and thrombocytopenia from regimens for bone marrow ablation (eg, total body radiation, high-dose chemotherapy) or immunosuppressive drugs to prevent graft-versus-host disease (eg, calcineurin inhibitors) . Organ transplantation may also be associated with a drug-induced TMA (DITMA) due to a calcineurin inhibitor. (See "Early complications of hematopoietic cell transplantation", section on 'Thrombotic microangiopathy' and "Drug-induced thrombotic microangiopathy (DITMA)" and "Kidney disease following hematopoietic cell transplantation", section on 'Thrombotic microangiopathy'.)
Acute rejection of a transplanted kidney can also cause MAHA and thrombocytopenia. (See "Thrombotic microangiopathy after kidney transplantation".)
●Disseminated intravascular coagulation (DIC) – DIC can develop in many clinical situations. Coagulation assays, including plasma fibrinogen concentration and D-dimer, are abnormal in DIC but are typically normal in the primary TMA syndromes. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)
●Severe vitamin B12 deficiency – Other hematologic disorders such as severe vitamin B12 deficiency can cause thrombocytopenia and ineffective erythropoiesis, which may be accompanied by hemolysis and RBC morphology resembling MAHA [12,13]. In a retrospective series of 2699 individuals with vitamin B12 deficiency, 16 (0.6 percent) had findings consistent with a TMA including schistocytes on the blood smear, thrombocytopenia, and/or laboratory evidence of hemolysis with increased lactate dehydrogenase (LDH) . Compared with a matched cohort of individuals with TTP, those with vitamin B12 deficiency were more likely to have teardrop cells on the blood smear, a very high LDH, and a lower PLASMIC score.
●Autoimmune HIT syndromes – Autoimmune heparin-induced thrombocytopenia (HIT) syndromes involve anti-PF4 antibody-mediated platelet activation, with thrombocytopenia and thrombosis, including venous and arterial thrombosis. Unlike classic HIT, in autoimmune HIT this occurs in the absence of heparin exposure. Coronavirus disease 2019 (COVID-19) vaccine-induced immune thrombotic thrombocytopenia (VITT) is considered a form of autoimmune HIT. HIT syndromes can cause thrombosis but are not associated with MAHA. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Terminology and HIT variants' and "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)
EVALUATION FOR PRIMARY TMA SYNDROMES — Primary TMA syndromes can have a variety of presentations (eg, child or older adult; sudden onset with severe illness or gradual onset with minimal symptoms). There may be anuric acute kidney injury or normal kidney function. The key decision point in the evaluation for primary TMA syndromes is the confidence of the treating clinicians that TTP is the correct ultimate diagnosis. The rationale for focusing on this distinction is that TTP requires urgent intervention with therapeutic plasma exchange (TPE; eg, within hours rather than days) to prevent serious or potentially life-threatening complications. Patients with complement-mediated TMA, such as patients with postpartum acute kidney injury, may also require urgent anti-complement treatment to prevent irreversible kidney damage. The other primary TMAs generally are treated with supportive care, at least for the initial day or two (algorithm 1).
Rapid overview of our approach — Once thrombocytopenia and microangiopathic hemolytic anemia (MAHA) have been confirmed and systemic disorders other than TMA have been excluded (eg, sepsis), the main goal is to identify the type of primary TMA. This is because there are specific treatments available for TTP (TPE; caplacizumab) and complement-mediated TMA (eculizumab or ravulizumab) and they need to be initiated as soon as possible.
●The probability of TTP can be calculated by the PLASMIC score (calculator 1) . Once results of ADAMTS13 activity testing are available, these are also incorporated. (See "Diagnosis of immune TTP", section on 'Evaluation and diagnosis'.)
●The probability of complement-mediated TMA requires the exclusion of other causes of MAHA and thrombocytopenia associated with severe acute kidney injury. Because terminal complement blockade may prevent end-stage kidney disease and reverse acute kidney injury, its empiric use is appropriate in patients with rapidly advanced kidney failure. (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS" and "Overview of hemolytic uremic syndrome in children" and "Complement-mediated hemolytic uremic syndrome in children".)
Importantly, other disorders that are not primary TMAs may also require urgent interventions (eg, antibiotics for sepsis, delivery for severe preeclampsia), which provides the rationale for excluding these disorders as described above. (See 'Exclude systemic disorders associated with MAHA and thrombocytopenia' above.)
Overview of primary TMA syndromes — Primary TMA syndromes are specific disorders with a probable cause that requires specific treatment; they include hereditary and acquired disorders [2,16].
●Thrombotic thrombocytopenic purpura (TTP) – TTP is defined by a severe deficiency of ADAMTS13 (typically, activity <10 percent). ADAMTS13 is the protease that cleaves large von Willebrand factor multimers in the vasculature, and its deficiency promotes formation of platelet microthrombi. The diagnosis of TTP ultimately relies on clinical judgment since ADAMTS13 measures are often not available for several days, and testing may be unreliable . Deficiency of ADAMTS13 can be hereditary (Upshaw-Shulman syndrome) or immune, as a result of inhibition of ADAMTS13 activity by an autoantibody. (See "Diagnosis of immune TTP" and "Hereditary thrombotic thrombocytopenic purpura (hTTP)".)
Episodes of TTP may be associated with certain medications. However, a 2023 systematic review of 90 patients (35 different drugs) determined that none of the reports provided data supporting a definite or probable causal association with TTP . The report used established criteria for determining a drug's causal association with TMA ; however, this may not be appropriate for determining a causal association with autoimmune disorders such as TTP. For example, drug-induced systemic lupus erythematosus (SLE) requires a longer duration of drug exposure than is required for drug-induced TMA (DITMA) or drug-induced thrombocytopenia .
TTP is unique among the primary TMA syndromes for minimal abnormalities of kidney function, despite microthrombi observed throughout the kidney at autopsy. TTP typically has more severe thrombocytopenia and more systemic manifestations of organ injury than the other primary TMA syndromes. In TTP, abnormalities of the central nervous system, heart, pancreas, thyroid, adrenal glands, intestinal mucosa, and other tissues may occur. The lungs are typically spared from ischemic injury .
There are no specific clinical features that distinguish TTP. Most patients present with several days of nonspecific symptoms, such as progressive weakness, fatigue, purpura, and gastrointestinal symptoms (eg, nausea, diarrhea). However, some patients have minimal symptoms and TTP is suspected only when anemia and thrombocytopenia are discovered. Approximately one-third of patients have no neurologic symptoms; one-third may have nonspecific symptoms, such as confusion and headache; and one-third will have more severe neurologic symptoms, such as transient focal neurologic abnormalities, aphasia, diplopia, or weakness, clumsiness, and numbness of an arm or hand. In many cases, the focal symptoms occur transiently. Patients with TTP often have minor purpura despite severe thrombocytopenia; they rarely have overt bleeding. Fever is uncommon; high fever with shaking chills rarely occurs and should prompt consideration of sepsis. (See "Diagnosis of immune TTP".)
●Shiga toxin-mediated hemolytic uremic syndrome (ST-HUS) – Shiga toxins are produced by Shigella dysenteriae and some serotypes of Escherichia coli, such as O157:H7 and O104:H4. Shiga toxins cause direct damage to kidney epithelial cells (podocytes and tubular cells), kidney mesangial cells, and vascular endothelial cells. Although most cases are sporadic, large outbreaks related to sanitation or food contamination issues regularly occur. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)
Patients often have a history of exposure to farm animals, under-cooked meat, inadequately cleaned commercially prepared vegetables, or contaminated water; typically this occurs several days before the onset of symptoms. Outbreaks of ST-HUS are highly publicized, but most cases are sporadic . Presenting symptoms include severe abdominal pain with nausea, vomiting, and diarrhea. An acute abdominal surgical disorder, such as appendicitis, is often initially suspected. The diarrhea typically becomes overtly bloody; in older adults, ischemic colitis is then often suspected. Kidney injury, microangiopathic hemolytic anemia, and thrombocytopenia occur several days after the onset of abdominal pain and diarrhea, when the initial symptoms begin to resolve. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)
●Complement-mediated TMA – A hereditary abnormality of proteins that normally regulate the alternative pathway of complement (eg, complement factor H [CFH], CFI, membrane cofactor protein [MCP, CD46]), or a hereditary abnormality of proteins that accelerate activation of this pathway (eg, CFB, C3), can lead to uncontrolled activation of complement on cell membranes, including the vascular endothelium and kidney cells . Deficiency of complement factor H (CFH) can also be acquired, caused by an autoantibody that inhibits CFH activity. (See "Complement-mediated hemolytic uremic syndrome in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)
The onset of complement-mediated TMA is generally sudden. A preceding infection including a diarrheal illness may be present in up to 80 percent of children and 50 percent of adults [23,24]. Symptoms include pallor, general malaise, and poor appetite. Edema may be present. Upon clinical evaluation, hypertension and laboratory values suggesting compromised kidney function are often present. Extra-renal manifestations are observed in up to 20 percent and include central nervous system (CNS) manifestations (the most common extra-renal finding), cardiac ischemic events, pulmonary hemorrhage and failure, pancreatitis, hepatic cytolysis, and intestinal bleeding [23,24]. (See "Complement-mediated hemolytic uremic syndrome in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)
•Immune-mediated – Some agents can cause immune-mediated TMA due to drug-dependent antibodies that react with platelets, neutrophils, endothelial cells, and/or other cells . Quinine is the most common and best-described etiology of immune-mediated DITMA ; however, quinine-induced disorders have become rare in the United States since the US Food and Drug Administration (FDA) restricted access to quinine . Gemcitabine, oxaliplatin, and quetiapine may also cause acute episodes of TMA that appear to be immune-mediated, but drug-dependent antibodies have only been identified in patients with quinine-induced TMA . For other drug-induced TMA, the consideration of immune-mediated is based on clinical features. Acute kidney injury in quinine-induced, immune-mediated TMA is typically severe.
Patients with immune-mediated DITMA may have sudden and severe symptoms. They may notice that they have been anuric since the onset of symptoms; this may be attributed to dehydration. When a drug-induced etiology is suspected, potentially causative drugs are those that have been taken daily for less than two to three weeks or those taken intermittently over many years.
•Dose-dependent, non-immune – A variety of medications can cause dose-dependent, non-immune DITMA syndromes due to direct cellular damage. These disorders can be acute, caused by an approved or illegal drug, or chronic, occurring after weeks or months of drug administration. Dose-dependent, non-immune DITMA is primarily caused by four classes of drugs: chemotherapeutic agents (such as gemcitabine and mitomycin), immunosuppressive agents (such as cyclosporine and tacrolimus), vascular endothelial growth factor (VEGF) inhibitors (such as bevacizumab), and opioids taken inappropriately or illegal agents (such as oxymorphone and cocaine).
Patients with non-immune DITMA may also have sudden onset of symptoms. An example is the intravenous injection of Opana ER (oxymorphone extended release, intended for oral use). The history of illegal drug use or intravenous drug abuse may be difficult to obtain. For other drugs (eg, chemotherapy medications, calcineurin inhibitors), the onset is chronic and there are no symptoms other than the gradual onset of weakness, fatigue, and symptoms related to hypertension over weeks or months. (See "Drug-induced thrombotic microangiopathy (DITMA)".)
●Metabolism-mediated TMA – Disorders of intracellular vitamin B12 (cobalamin) metabolism can cause TMA, the true incidence of which is unknown . These syndromes appear to be exclusively hereditary due to mutations in the MMACHC gene (MethylMalonic ACiduria and Homocystinuria type C); however, patients may present with a TMA as an infant or adult . Elevated homocysteine and low methionine levels are seen in plasma, and urine may show methylmalonic aciduria. A dramatic case report described a previously healthy 18-year-old who presented with MAHA, thrombocytopenia, and kidney failure who had negative testing for TTP and ST-HUS and was subsequently found to have cobalamin C deficiency due to a MMACHC mutation . Treatment with high-dose vitamin B12, betaine, and folinic acid (leucovorin) resulted in a dramatic recovery. His brother had died from complications of a similar syndrome at the same age. (See "Organic acidemias: An overview and specific defects", section on 'Methylmalonic acidemia'.)
●Coagulation-mediated TMA – Hereditary deficiency of proteins involved in coagulation can cause TMA. These syndromes differ from the abnormalities associated with hereditary thrombophilia, which cause thromboembolism in large vessels rather than systemic microvascular thrombosis. Mutations in genes encoding thrombomodulin, plasminogen, and diacylglycerol kinase epsilon (DGKE) have been reported to be associated with TMA .
●Glucose-6-phosphate dehydrogenase (G6PD) deficiency – Patients with G6PD deficiency can present with a kidney TMA associated with hemolysis and thrombocytopenia .
Additional details regarding the pathophysiology of individual TMA syndromes are presented separately. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'TTP pathogenesis' and "Overview of hemolytic uremic syndrome in children", section on 'Acquired infectious-induced HUS' and "Complement-mediated hemolytic uremic syndrome in children", section on 'Pathogenesis'.)
In some cases, additional aspects of the history or specific physical findings may suggest a specific primary TMA (table 1).
Key distinguishing features among the primary TMA syndromes — While no single clinical feature can be used to determine which primary TMA is responsible for a patient’s symptoms, key distinguishing factors include the patient’s age, the time course over which symptoms developed, and the severity of kidney injury.
●Patient age – All of the primary TMA syndromes may occur at any age; however, some syndromes are more likely to be seen at specific ages.
•Infants/young children – The first days of life are a critical period for patients with hereditary TTP. The finding of severe hyperbilirubinemia and thrombocytopenia require suspicion of TTP and measurement of ADAMTS13 activity. Plasma infusion is lifesaving; without plasma, infants die [33-35]. Shiga toxin-related hemolytic uremic syndrome (ST-HUS) is the most common TMA syndrome in young children. Young children can also be affected by any of the other primary TMA syndromes including complement-mediated TMA (hereditary or immune), hereditary TTP, or hereditary metabolism-mediated or coagulation-mediated TMAs (eg, TMA due to genetic defects in vitamin B12 metabolism or diacylglycerol kinase epsilon [DGKE]). Coagulation- and metabolism-mediated TMAs typically present in young children and are very rare. Immune TTP is also rare in infants and young children .
•Adults – Adults can be affected with any of the acquired or hereditary TMA syndromes. However, adults more commonly present with immune TTP, drug-induced TMA (DITMA), or hereditary complement-mediated TMA.
●Rate of onset of the presenting symptoms – Most primary TMA syndromes present with gradually increasing symptoms over several days. DITMA can have an explosive onset of severe, systemic symptoms (eg, neurologic changes, fever, severe fatigue) beginning within hours of drug exposure. In contrast, toxic, dose-dependent, drug-induced TMA may be associated with chronic kidney injury that develops over weeks or months.
●Kidney injury – All of the primary TMAs can be associated with some degree of kidney injury. However, the degree of injury (magnitude of decrease in estimated glomerular filtration rate [GFR]) may be a helpful distinguishing feature.
•Minimal to no kidney injury – The absence of kidney injury, or the presence of only minimal kidney impairment, supports a diagnosis of hereditary or immune TTP.
•Sudden, severe kidney injury – Sudden onset acute kidney injury, especially when associated with anuria, supports immune-mediated DITMA or an acute dose-dependent, non-immune DITMA.
•Onset of kidney injury over days – The gradual development of kidney injury following several days of abdominal pain and diarrhea is characteristic of ST-HUS, complement-mediated TMA, or metabolism-mediated or coagulation-mediated TMAs.
•Onset of kidney injury over weeks to months – Very gradual onset of kidney injury may be seen in patients with DITMA caused by toxic chemotherapeutic or immunosuppressive drugs.
All patients — The important laboratory tests that must be performed for all patients (and repeated daily) include the following:
●Complete blood count (CBC) with platelet count, to assess the degree of anemia and thrombocytopenia
●Lactate dehydrogenase (LDH), to follow the intensity of hemolysis or organ injury
●Serum creatinine, to follow the severity and progression of kidney dysfunction
●For patients with kidney injury, the daily urine output should also be monitored
All patients with microangiopathic hemolytic anemia (MAHA) and thrombocytopenia without an obvious systemic illness responsible for these findings should have urgent measurement of ADAMTS13 activity to assess the possibility of TTP (see "Diagnosis of immune TTP", section on 'Evaluation and diagnosis'). This is especially important in individuals with minimal or no kidney function abnormalities, which is the common finding in TTP. The only exception is a patient with findings that are highly suggestive of another primary TMA (eg, diarrheal illness in a young child in the midst of an ST-HUS outbreak).
Results of ADAMTS13 activity measurements may take several days, and patients with a clinical diagnosis of TTP require urgent therapy with TPE. Thus, individuals without another obvious primary TMA usually require presumptive treatment for TTP with TPE while awaiting the results of ADAMTS13 activity measurements. If TPE was already initiated, ADAMTS13 activity can be measured on a specimen obtained after TPE was started, because severe deficiency may persist for one or more days of TPE. These issues are discussed in more detail separately. (See "Immune TTP: Initial treatment", section on 'Therapeutic plasma exchange'.)
Despite the central role of severe ADAMTS13 deficiency in the pathophysiology of TTP, diagnosis of TTP remains a clinical diagnosis supported by the results of this testing, and the ADAMTS13 activity level cannot be used in isolation to make the diagnosis of TTP. The rationale is based on disease and laboratory issues.
●Disease considerations – In general, the finding of severe ADAMTS13 deficiency (activity <10 percent) is consistent with the diagnosis of TTP, and individuals with normal or moderately low activity (eg, ≥10 percent) should have additional evaluation for the alternate causes of their symptoms. Rarely, severe systemic disorders may cause marked reductions in ADAMTS13 activity in the absence of TTP . In some cases, individuals with TTP may have ADAMTS13 activity levels above 10 percent . Rarely, patients who have critical illness but clearly do not have TTP (as documented from autopsy results) may have ADAMTS13 activity <10 percent. Thus, the ultimate diagnosis of TTP or another condition remains a clinical decision and cannot be based solely on ADAMTS13 activity.
●Laboratory issues – Laboratory testing for ADAMTS13 activity is useful for distinguishing TTP from other TMA syndromes, but the diagnostic accuracy remains imperfect [38,39]. Several types of assays are used, and they may yield conflicting results [17,40]. Thus, the activity value must be taken in the context of clinical features and may need to be repeated if the findings are inconsistent with clinical suspicions. This issue is discussed in more detail separately. (See "Diagnosis of immune TTP", section on 'Reduced ADAMTS13 activity'.)
Diarrhea/known infectious diarrhea exposure — All patients with MAHA and thrombocytopenia without an obvious systemic illness responsible for these findings who have had severe abdominal pain with diarrhea, or who have been exposed to a known outbreak of infectious diarrhea, should have a stool culture for enterohemorrhagic Escherichia coli (EHEC). This testing requires specific culture media, distinct from the stool cultures for routine enteric pathogens. Shigella dysenteriae is a more common cause of TMA in Asia but is not a common cause in the Americas or Europe. Testing for Shiga toxin by immunoassay is also important. (See "Shiga toxin-producing Escherichia coli: Clinical manifestations, diagnosis, and treatment" and "Shigella infection: Epidemiology, clinical manifestations, and diagnosis" and "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)
Homocysteine and MMA testing — All patients with MAHA and thrombocytopenia who have negative testing for TTP and ST-HUS (ie, patients with ADAMTS13 activity ≥10 percent and no evidence of Shiga toxin-producing enteric infection) should be tested for cobalamin C deficiency-mediated TMA using measurement of serum homocysteine and methylmalonic acid (MMA). As noted above, the incidence of cobalamin C deficiency-mediated TMA is unknown but likely to be rare (see 'Overview of primary TMA syndromes' above). However, this testing can be performed rapidly with low expense, as it is commonly used in the evaluation of patients with suspected vitamin B12 deficiency, and a positive finding of cobalamin C deficiency-mediated TMA suggests the potential for substantial improvement with inexpensive treatment [28,30].
Role of complement testing — The role of testing for complement dysregulation by measuring complement proteins (eg, C3 and C4, CH50) remains unclear. Decreased levels of complement factors or the presence of anti-complement factor H (CFH) antibodies may be helpful in suggesting a complement-mediated TMA; however, normal complement levels do not eliminate the possibility of a complement-mediated TMA, and therapy cannot be based exclusively on this testing.
We generally test the following patients presenting with MAHA and thrombocytopenia for mutations in genes encoding complement regulatory proteins:
●Children with TMA and kidney insufficiency who do not have the clinical features of ST-HUS or who test negative for Shiga toxin
●Adults with TMA and acute kidney injury who have normal or only moderately low ADAMTS13 activity and who do not have a history indicating a drug-induced etiology
●Postpartum individuals rapidly progressive acute kidney injury following delivery
Complement testing (eg, testing for inhibitory antibodies, genetic testing) is available at several specialized centers such as the University of Iowa, Cincinnati Children's Hospital, and the Versiti; additional resources are available on the Genetic Testing Registry website. Further information regarding this testing is presented separately. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Diagnosis' and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Complement testing'.)
However, results of complement testing will not be available immediately, and testing may fail to identify up to 30 percent of patients with a clinical diagnosis highly suggestive of complement-mediated TMA. Thus, management is based on clinical features such as the severity and persistence of kidney injury. The decision to initiate therapy for complement-mediated TMA and the choice of therapy, including TPE and/or anti-complement agents, is presented in detail separately. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Treatment' and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Terminal complement blockade'.)
Role of molecular testing — Testing for pathogenic variants in MMACHC should occur reflexively for individuals with TMA who have hyperhomocysteinemia/methyl-malonic aciduria. The role of additional molecular testing (eg, for variants in DGKE and/or MMACHC) in others is unclear. If not already available through a panel testing approach, we generally reserve this testing for patients for whom the confidence in an alternative diagnosis is low. Examples include children with kidney insufficiency who do not have the clinical features of ST-HUS and adults who have normal or moderately low ADAMTS13 activity and who do not have a history indicating a drug-induced etiology. Resources for obtaining this testing are available on the Genetic Testing Registry website . Additional guidance is available from a consensus document .
Role of kidney biopsy — Kidney biopsy may be essential to distinguish TMA from other causes of acute kidney injury such as acute tubular necrosis or interstitial nephritis caused by hypotension or drug toxicity. Kidney biopsy is not helpful for determining the etiology of a primary TMA syndrome; particularly, it may not distinguish primary TMA syndromes from other disorders such as SLE, systemic sclerosis, or severe hypertension, which can also manifest the typical pathologic features of TMA. Rarely, a biopsy that was done to evaluate kidney disease may reveal an unsuspected TMA that has not caused MAHA or thrombocytopenia. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting", section on 'Serologic testing and role of kidney biopsy' and "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney allograft dysfunction".)
IMMEDIATE MANAGEMENT DECISIONS — The major management decisions in a patient with a suspected TMA are:
●Does the patient need urgent therapeutic plasma exchange (TPE)?
●Should the patient receive anti-complement therapy?
●Are there any other treatment options available?
Individuals with a high suspicion for TTP are treated with TPE; those with a high suspicion for complement-mediated TMA are treated with anti-complement therapy; and those with a high suspicion for other systemic disorders such as sepsis are treated for those disorders, as outlined above. (See 'Rapid overview of our approach' above.)
Details of these therapies are discussed in the following sections.
Suspected TTP: Start therapeutic plasma exchange (TPE) — The immediate issue in a patient with a suspected TMA is whether to initiate TPE for presumed TTP or temporarily withhold TPE while considering other primary TMA syndromes. Among the primary TMA syndromes, TTP is the disorder with the greatest acute mortality; as high as 90 percent in the era before TPE was used . (See "Immune TTP: Initial treatment", section on 'Therapeutic plasma exchange'.)
TPE is the well-documented essential treatment for TTP; the possible benefit of TPE for other primary TMA syndromes is less clear and therefore less urgent . Therefore, the decision regarding whether to initiate urgent TPE must balance the confidence in the diagnosis of TTP against the risks of TPE, which include a high frequency of major complications such as central venous catheter-associated hemorrhage, infections, or thrombosis; and plasma-associated transfusion reactions [17,45]. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications" and "Immune TTP: Initial treatment", section on 'TPE complications'.)
Examples of patients for whom we would or would not start urgent TPE include the following:
●A patient who walks into the primary care office after several days of not feeling well with severe anemia, severe thrombocytopenia, fragmented red blood cells (RBCs), and no or negligible kidney failure must be suspected to have TTP, and urgent initiation of TPE is appropriate. This is a common presentation of TTP.
●If there is a history consistent with a drug-induced TMA (DITMA; eg, abrupt onset of nausea and anuria hours after injection of an opioid such as Opana ER, or a quinine-containing beverage, or after intravenous drug use, or if there is the gradual development of hypertension and kidney failure after several weeks or longer of treatment with a calcineurin inhibitor or chemotherapy), it may be possible to avoid TPE.
●Following delivery in a pregnant patient, if there is rapid development of acute kidney injury with anticipated need for dialysis, postpartum complement-mediated TMA is likely; anti-complement treatment should occur promptly, without TPE. Testing for abnormalities of complement regulation is unaffected by this therapy. (See 'Role of complement testing' above.)
In some patients, initiation of TPE may require transfer to another hospital. In these patients, or in patients for whom there is delay in insertion of the central venous catheter required for TPE, plasma infusion may be effective as a temporizing measure. However, plasma infusion is not an appropriate substitute for TPE. When TPE is begun for a diagnosis of TTP, glucocorticoids are also administered routinely. These issues, and additional details related to the use of TPE for TTP, are presented separately. (See "Immune TTP: Initial treatment".)
In rare patients who have severe, anaphylactic reactions to plasma or in patients who cannot receive any blood products for religious reasons, caplacizumab is indicated, in addition to intensive immunosuppression . Plasma removal by apheresis may also be appropriate. (See "Immune TTP: Initial treatment", section on 'Evidence for efficacy of TPE'.)
A response to TPE is assessed by normalization of the platelet count. Our practice is to stop TPE after the patient has had a normal platelet count for two days (see "Immune TTP: Initial treatment"). However, exacerbations, defined by a decreasing platelet count when TPE is stopped, may occur, usually within the first week. This issue is discussed in detail separately. (See "Immune TTP: Treatment of clinical relapse".)
Suspected complement-mediated TMA: Use anti-complement therapy — The decision to use anti-complement therapy must be based on a presumptive clinical diagnosis of complement-mediated TMA because immediately available confirmatory tests are lacking. When complement-mediated TMA is suspected, anti-complement therapy (eg, eculizumab) should be started as soon as possible (preferably, within 24 to 48 hours). The goal is to limit irreversible kidney injury.
●Children – It is reasonable to begin anti-complement therapy as first-line therapy in children with microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and kidney failure who do not have bloody diarrhea (which is suggestive of ST-HUS) and who lack any other apparent alternative diagnosis. The rationale includes the effectiveness of anti-complement therapy if the diagnosis is correct, and the avoidance of risks associated with other therapies (eg, catheter-related complications and transfusion reactions associated with TPE). (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Treatment'.)
●Postpartum – Complement-mediated TMA must be considered when MAHA, thrombocytopenia, and kidney failure occur postpartum. The diagnosis can be supported by documentation of TMA on a kidney biopsy. The risk for end-stage kidney disease is high in this setting, and therefore it is reasonable to begin anti-complement therapy urgently to limit preventable kidney damage while the diagnosis is being confirmed (or eliminated). (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Management'.)
In contrast, in other (non-pregnant) adults with MAHA, severe thrombocytopenia, and minimal or no kidney failure for whom the diagnosis is unclear, we generally initiate TPE rather than anti-complement therapy (see 'Suspected TTP: Start therapeutic plasma exchange (TPE)' above). If subsequent testing does not reveal a specific primary TMA diagnosis or evidence of a systemic disorder associated with MAHA and thrombocytopenia, management is individualized. TPE may be discontinued and a decision made regarding the use of anti-complement therapy.
Importantly, if anti-complement therapy is deemed to be appropriate, acute treatment should not be delayed while awaiting the results of serologic testing or molecular (genetic) studies for abnormalities of complement regulation. Treatment with anti-complement therapy should be stopped if laboratory results and/or the clinical scenario shift to favoring an alternative diagnosis.
Terminal complement blockade is removed by TPE and diluted by plasma infusion; thus, if these therapies are used concomitantly, additional doses of eculizumab following each TPE procedure are required. This is extremely expensive. There is increased risk for meningococcal infection, and therefore meningococcal vaccine is required prior to starting eculizumab. The vaccine decreases but does not eliminate the risk of meningococcal infection. Patients are given antibiotics during at least the two-week period before vaccination becomes effective (if eculizumab is required urgently). Some clinicians suggest that prophylactic antibiotics should be continued as long as eculizumab is continued. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Adverse effects'.)
Of note, the use of eculizumab may be further complicated by the lack of available information regarding the appropriate duration of therapy and by the high cost of therapy. These issues, and other therapies such as kidney transplantation in patients with a confirmed diagnosis of complement-mediated TMA, are presented separately. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Treatment'.)
Suspected DITMA or other primary TMAs — The primary TMA syndromes of TTP, complement-mediated TMA, and metabolism-mediated TMA are managed with disease specific interventions.
For DITMA, the implicated drug is discontinued. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Management'.)
For cobalamin C deficiency-mediated TMA, the patient is treated with high-dose hydroxocobalamin (also called hydroxycobalamin); betaine and folinic acid (also called leucovorin) may also be given. (See "Methylmalonic acidemia", section on 'Management'.)
The remaining primary TMAs are managed with supportive care. The following may be appropriate:
●Transfusion of red blood cells for severe or symptomatic anemia. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Overview of our approach'.)
●Transfusion of platelets for patients with severe thrombocytopenia (eg, platelet count <20,000/microL) and overt bleeding and for patients with severe thrombocytopenia (eg, platelet count <50,000/microL) who require a major invasive procedure. Platelet transfusion generally is not required for central venous catheter placement; the ultimate decision resides with the person performing the procedure. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Indications for platelet transfusion'.)
Issues related to platelet transfusion in patients with suspected TTP are discussed in more detail separately. (See "Immune TTP: Initial treatment", section on 'Bleeding/platelet transfusion'.)
Management of TMA following hematopoietic stem cell transplantation or kidney transplantation is discussed separately. (See "Early complications of hematopoietic cell transplantation", section on 'Thrombotic microangiopathy' and "Thrombotic microangiopathy after kidney transplantation" and "Kidney disease following hematopoietic cell transplantation", section on 'Thrombotic microangiopathy'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Thrombotic microangiopathies (TTP, HUS, and related disorders)".)
PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Thrombotic thrombocytopenic purpura (TTP)".)
SUMMARY AND RECOMMENDATIONS
●Definitions – Microangiopathic hemolytic anemia (MAHA) is a descriptive term for non-immune hemolytic anemia from intravascular red blood cell fragmentation that produces schistocytes on the peripheral blood smear (picture 1). Thrombotic microangiopathy (TMA) describes a pathologic lesion of arterioles and capillaries that produces microvascular thrombosis. Not all MAHA is caused by a TMA, but nearly all TMAs cause MAHA and thrombocytopenia. (See 'Terminology' above.)
●Primary TMAs – Primary TMAs include thrombotic thrombocytopenic purpura (TTP; hereditary or immune, due to severe ADAMTS13 deficiency), Shiga toxin-mediated hemolytic uremic syndrome (ST-HUS), complement-mediated TMA (hereditary or acquired), drug-induced TMA (DITMA; immune or toxic), metabolism-mediated TMA (hereditary disorder of vitamin B12 metabolism), and coagulation-mediated TMA (hereditary deficiency of a coagulation regulator) (table 1). (See 'Overview of primary TMA syndromes' above.)
●Evaluation for TMA – The initial evaluation is focused on confirming MAHA and thrombocytopenia and excluding systemic disorders (table 1) that manifest these findings (algorithm 1). Some systemic disorders (severe hypertension, preeclampsia/HELLP) are obvious. Systemic cancer may require other testing for diagnosis. Infections should be obvious but may mimic TTP. Rheumatologic disorders such as catastrophic antiphospholipid syndrome (CAPS) and conditions such as autoimmune heparin-induced thrombocytopenia may also be considered. The decision to use therapeutic plasma exchange (TPE) while evaluating for these disorders depends on the confidence that the diagnosis is not TTP. (See 'Exclude systemic disorders associated with MAHA and thrombocytopenia' above and 'Initial evaluation (all patients)' above.)
●Distinguish among TMAs – Helpful clinical features include age (child versus adult), rate of symptom onset, the severity of thrombocytopenia, and kidney injury (table 1). Several days of nonspecific symptoms, with or without neurologic abnormalities, is characteristic for TTP (calculator 1). Exposure to farm animals, under-cooked meat, improperly prepared vegetables, or contaminated water several days prior to gastrointestinal symptoms is often seen in ST-HUS. Ingestion of a quinine-containing beverage followed by the abrupt onset of fever, chills, and gastrointestinal symptoms is typical of DITMA. (See 'Key distinguishing features among the primary TMA syndromes' above.)
●Laboratory – All patients with a suspected primary TMA should have a daily complete blood count (CBC), platelet count, lactate dehydrogenase (LDH), and serum creatinine. ADAMTS13 activity is measured prior to starting TPE. Patients with kidney injury should have urine output measured. Those with severe abdominal pain, diarrhea, or exposure to infectious diarrhea should have a stool culture for enterohemorrhagic Escherichia coli (or Shigella dysenteriae in Asia) and immunoassay for Shiga toxin. Those with negative testing for TTP and ST-HUS should have serum levels of homocysteine and methylmalonic acid measured. (See 'Laboratory evaluation' above.)
●Urgent interventions – The immediate management decision is whether to perform TPE or to start anti-complement therapy. Other interventions include drug discontinuation for presumed DITMA; hydroxocobalamin, betaine, and folinic acid (leucovorin) for cobalamin C deficiency-mediated TMA; and supportive care. (See 'Immediate management decisions' above.)
●Management – Management depends on the specific syndrome. (See "Immune TTP: Initial treatment" and "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children" and "Complement-mediated hemolytic uremic syndrome in children" and "Drug-induced thrombotic microangiopathy (DITMA)" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Lawrence LK Leung, MD, who contributed to earlier versions of this topic review.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟