Version July 2025
INTRODUCTION —
The initial evaluation of a patient with a thrombotic microangiopathy (TMA) syndrome must focus on distinguishing thrombotic thrombocytopenic purpura (TTP) and complement-mediated TMA (CM-TMA), which require early and specific treatments, from other TMAs or 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 TMA syndromes including TTP and CM-TMA are presented in separate topic reviews on these syndromes, which are listed below. (See 'Specific TMA syndromes' below.)
TERMINOLOGY
MAHA — Microangiopathic hemolytic anemia (MAHA) is a descriptive term for non-immune hemolysis resulting from intravascular red blood cell (RBC) fragmentation that produces schistocytes on the peripheral blood smear (picture 1) [1].
Causes include:
●Microvascular thrombosis – Thrombosis in the microvasculature, including small arterioles and capillaries, are frequently involved. (See 'TMA' below.)
●Intravascular devices – Intravascular devices such as prosthetic heart valves or assist devices may also cause MAHA.
●Other causes of fragmentation – Additional rare causes are discussed separately. (See "Non-immune (Coombs-negative) hemolytic anemias in adults", section on 'Fragmentation'.)
Characteristic laboratory data for MAHA are an increased lactate dehydrogenase (LDH), increased indirect bilirubin, and low haptoglobin, as listed in the table (table 1), and schistocytes on the blood smear. The direct antiglobulin (Coombs) test (DAT) is typically negative, but a positive DAT does not exclude MAHA.
The figure summarizes a general approach to determining the cause of non-immune hemolysis (algorithm 1).
TMA — Thrombotic microangiopathy (TMA) describes a specific pathologic lesion in which abnormalities in the arterioles and capillaries lead to microvascular thromboses [2]. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)".)
●Not all episodes of MAHA are caused by a TMA, and not all TMAs will present with MAHA and thrombocytopenia. For example, some TMA syndromes are limited to the kidney.
●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, and biopsy is not always required to make the diagnosis. (See "Evaluation of the peripheral blood smear", section on 'Schistocytes'.)
●We preferentially use terminology that reflects the mechanisms and etiology of the TMA. The TMA syndromes include thrombotic thrombocytopenic purpura (TTP, caused by congenital or acquired ADAMTS13 deficiency), complement-mediated TMA (CM-TMA), and rare inherited disorders of coagulation or vitamin B12 metabolism. These syndromes (previously classified as primary TMAs) require urgent, targeted treatment directed at the TMA pathophysiology. (See 'Immediate management decisions' below.)
Other TMAs, which were previously classified as secondary TMAs, include those that occur in association with malignancy, medications (drug-induced TMA [DITMA] or TMA after hematopoietic stem cell or solid organ transplantation), pregnancy-associated syndromes (preeclampsia with severe features and HELLP [hemolysis, elevated liver function tests, and low platelets]), infections including Shiga toxin-mediated hemolytic uremic syndrome (ST-HUS), and autoimmune disorders such as systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). These are generally treated with supportive measures and by addressing the underlying condition. (See 'All TMAs: Supportive care' below.)
●Terminology we avoid:
•We avoid the term "atypical hemolytic uremic syndrome (aHUS)" because this term has no specificity and provides no insight into the underlying pathology of the TMA. aHUS was used historically to describe children with MAHA, thrombocytopenia, and kidney failure not associated with diarrhea. The term is often used to describe any patient with a TMA who does not have severe ADAMTS13 deficiency or documented Shiga toxin. While it has little clinical usefulness, it is frequently used in practice, since terminal complement inhibitors are approved for the specific indication of aHUS.
•We do not use the term "idiopathic" to describe any of the TMA syndromes. This term was used historically to imply ADAMTS13 deficiency in patients who did not have other recognized conditions that may cause TMA. However, the term "idiopathic" also has no specificity and should be avoided.
•We no longer refer to TMA syndromes as primary or secondary, since terminology that reflects the mechanisms and causes of the TMA are now available.
Specific TMA syndromes — TMA syndromes can be broadly categorized into two groups.
●The first category includes TMAs with specific mechanisms and requiring specific treatment that occur in the absence of underlying causative exposures. This category includes TTP, CM-TMA, and coagulation and metabolic TMAs; these were previously classified as primary TMAs [3].
●The second category includes TMAs occurring in the setting of causative events including infections, pregnancy, hematopoietic stem cell or solid organ transplantation, drugs associated with TMA, or autoimmune disease.
It is occasionally difficult to distinguish between CM-TMA in a predisposed individual that is "triggered" by a complement-amplifying condition such as infection or flare of an inflammatory disorder, versus a TMA that is "caused" by another condition (infection, drug, pregnancy). TMAs in individuals with an underlying predisposition for complement dysregulation (for example, an individual with a pathogenic C3 gene variant) should be classified as CM-TMA [3].
TMAs that occur in the absence of causative exposures include:
●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 following their secretion from endothelial cells, and its deficiency allows the accumulation of very large von Willebrand factor molecules. TTP occurs when turbulent circulation causes unfolding of von Willebrand factor and allows platelet binding causing microvascular thrombosis. The initial diagnosis of TTP usually relies on clinical judgment, since ADAMTS13 measurements are often not available for several days, and testing may be unreliable [4]. Deficiency of ADAMTS13 can be hereditary (Upshaw-Shulman syndrome) or immune, from an anti-ADAMTS13 autoantibody. (See "Diagnosis of immune TTP" and "Hereditary thrombotic thrombocytopenic purpura (hTTP)".)
●Complement-mediated TMA – CM-TMA is a hereditary abnormality of proteins that normally regulate the alternative pathway of complement (complement factor H [CFH], CFI, membrane cofactor protein [MCP, CD46]) or that accelerate activation of this pathway (CFB, C3). This loss of regulation can lead to uncontrolled activation of complement on cell membranes, including the vascular endothelium and kidney cells [5]. Deficiency of CFH can also be caused by an inhibitory autoantibody. (See "Complement-mediated hemolytic uremic syndrome in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)
●Metabolism-mediated TMA – Disorders of intracellular vitamin B12 (cobalamin) metabolism can cause TMA; the incidence is unknown [6]. The cause is a pathogenic variant in the MMACHC gene (MethylMalonic ACiduria and Homocystinuria type C); presentation may be in infancy or adulthood [7]. Elevated homocysteine and low methionine levels are seen in plasma, and urine may show methylmalonic aciduria. (See "Organic acidemias: An overview and specific defects", section on 'Methylmalonic acidemia'.)
●Coagulation-mediated TMA – Pathogenic variants in genes encoding thrombomodulin (THBD), plasminogen (PLG), and diacylglycerol kinase epsilon (DGKE) have been reported to be associated with TMA [8]. These syndromes differ from the abnormalities associated with hereditary thrombophilia, which cause thromboembolism in large vessels rather than systemic microvascular thrombosis.
TMAs that are caused by other conditions include:
●Infection-associated TMA – Infections are a common cause of TMA [9].
•ST-HUS – Shiga toxin-mediated HUS (ST-HUS) is the most well-recognized cause of infection-associated TMA [10]. Shiga toxins are produced by Shigella dysenteriae and some serotypes of Escherichia coli, such as O157:H7 and O104:H4. Although most cases are sporadic, large outbreaks related to sanitation or food contamination regularly occur. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)
•Streptococcus pneumoniae – S. pneumoniae is another recognized cause [10-12].
•Others – The table summarizes other bacterial and viral infectious causes (table 2) [3,9,13].
●Drug-induced TMA – Two distinct categories of drug-induced TMA are immune-mediated and dose-dependent (non-immune) [14]; these are discussed in more detail separately. (See "Drug-induced thrombotic microangiopathy (DITMA)".)
•Immune-mediated – This involves drug-dependent antibodies that react with platelets, neutrophils, endothelial cells, and/or other cells [15]. Quinine is the best-described etiology, but quinine-induced disorders have become rare in the United States since the US Food and Drug Administration (FDA) restricted access to quinine [16,17].
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 mistakenly 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.
For other drugs such as gemcitabine, oxaliplatin, and quetiapine, clinical features are consistent with an immune mechanism, but drug-dependent antibodies have not been identified [14].
•Dose-dependent, non-immune – These disorders can be acute, caused by an approved or illegal drug, or chronic, occurring after weeks or months of drug administration, with gradual onset of weakness, fatigue, and symptoms related to hypertension over weeks or months. Dose-dependent, non-immune DITMA is primarily caused by four classes of drugs: chemotherapeutic agents (gemcitabine, mitomycin), immunosuppressive agents (cyclosporine, tacrolimus), vascular endothelial growth factor (VEGF) inhibitors (bevacizumab), opioids taken inappropriately (oxymorphone extended release, intended or oral use and injected intravenously), and cocaine. Some drugs (gemcitabine, oxaliplatin) may cause DITMA by either immune-mediated or non-immune mechanisms.
•Hematopoietic stem cell or organ transplantation – Transplantation-associated thrombotic microangiopathy (TA-TMA; also called post-transplant TMA) is a potentially life-threatening complication of transplantation that manifests as kidney dysfunction and/or unexplained neurologic dysfunction with intravascular hemolysis, typically developing 20 to 100 days after transplantation [18-22]. Pathogenesis involves endothelial injury, which may be incited by factors such as chemotherapy, calcineurin inhibitors, graft-versus-host disease, total body irradiation, and infections. Abnormalities of complement pathways have been implicated; complement inhibition has been used to treat TA-TMA with variable success. (See "Early complications of hematopoietic cell transplantation", section on 'Thrombotic microangiopathy' and "Kidney disease following hematopoietic cell transplantation", section on 'Thrombotic microangiopathy'.)
●Systemic autoimmune disorders – Systemic autoimmune disorders, including systemic lupus erythematosus (SLE), systemic sclerosis, Sjogren's disease, vasculitides, and antiphospholipid syndrome (APS), can present with TMA that commonly affects the kidney [23-25]. Treatment of the underlying autoimmune disorder with immunosuppression often leads to improvement in the TMA.
●Pregnancy – Preeclampsia with severe features and HELLP (hemolysis, elevated liver enzymes, and low platelets) are a continuum of pregnancy-related disorders that typically occur closer to term. MAHA and thrombocytopenia before gestational age of 25 weeks or more than 48 to 72 hours after delivery, or a platelet count <30,000/microL are rare in preeclampsia/HELLP, occurring in <5 percent and rarely causing platelet counts <30,000/microL [26,27].
In some cases, additional aspects of the history or specific physical findings may suggest a specific etiology of TMA (table 3). (See 'Key distinguishing features among different TMA syndromes' below.)
The pathophysiologies of individual TMA syndromes are presented separately. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'TTP pathogenesis' and "Complement-mediated hemolytic uremic syndrome in children", section on 'Pathogenesis' and "Overview of hemolytic uremic syndrome in children".)
INITIAL EVALUATION (ALL PATIENTS)
Rapid overview of our approach — Individuals with a TMA may come to medical attention with a variety of presentations including unexplained anemia or thrombocytopenia, unexplained neurologic findings (suspected stroke or transient ischemic attack), kidney injury, or other acute illnesses.
The initial evaluation is focused on confirming that the patient has microangiopathic hemolytic anemia (MAHA) with thrombocytopenia and anemia on the complete blood count (CBC) and schistocytes on the blood smear, as well as excluding systemic disorders that manifest these findings, based on a consideration of presenting findings and likely causes (algorithm 2) [2,28]. (See 'Verify MAHA and thrombocytopenia' below.)
We start with a thorough history and physical examination that guides selected use of laboratory tests rather than performing 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. Salient features include a history of infection, malignancy, or connective tissue disorder; fever; or other signs of these conditions. Medication exposures and diarrheal illness are also relevant as they may help identify the cause of the findings. (See 'Key distinguishing features among different TMA syndromes' below.)
Once thrombocytopenia and MAHA have been confirmed and systemic disorders other than TMA have been excluded (eg, sepsis, systemic malignancy), the main goal is to identify the type of TMA. This is because there are specific treatments available for TTP and complement-mediated TMA that need to be initiated as soon as possible.
●The probability of TTP can be calculated by the PLASMIC score (calculator 1) [29]. Once results of ADAMTS13 activity testing are available, these are also incorporated. (See 'Determine likelihood of TTP, which requires urgent plasma exchange' below and 'Presumptive diagnosis of TTP: Start therapeutic plasma exchange (TPE) and possibly caplacizumab' below.)
●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, if it is available, in patients with rapidly advancing kidney failure. (See 'Suspected complement-mediated TMA: Use anti-complement therapy' below.)
●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 quickly identifying these disorders. (See 'Exclude systemic disorders causing MAHA and thrombocytopenia' below.)
●Institutions may adapt 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 in populations with kidney transplantation or hematopoietic stem cell transplantation), but these should not substitute for the judgment of the clinician evaluating the patient [30].
Verify MAHA and thrombocytopenia — MAHA and thrombocytopenia are confirmed by reviewing the CBC and examining the peripheral blood smear. Review by a hematologist, other clinician with expertise in TMA syndromes, or experienced laboratory personnel is required. (See "Evaluation of the peripheral blood smear", section on 'Schistocytes' and "Diagnosis of immune TTP", section on 'MAHA and thrombocytopenia'.)
Rarely, schistocytes may not be appreciably increased early in the presentation of TMA, and another blood smear should be examined 12 to 24 hours later (picture 2), especially when the clinical picture is otherwise highly suspicious for TMA [31].
If MAHA is present, other conditions in the differential diagnosis include systemic illness or RBC fragmentation due to a mechanical cause such as a prosthetic heart valve or vascular lesion. (See "Non-immune (Coombs-negative) hemolytic anemias in adults", section on 'Fragmentation'.)
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 "Acquired aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis" and "Clinical manifestations and diagnosis of Felty syndrome" and "Systemic lupus erythematosus: Hematologic manifestations".)
Determine likelihood of TTP, which requires urgent plasma exchange — Once MAHA and thrombocytopenia are confirmed and systemic disorders causing a TMA have been excluded, the focus moves to identifying which TMA syndrome is most likely. The primary focus is on identifying or excluding TTP, which can be rapidly fatal if untreated and requires mobilization of resources for therapeutic plasma exchange (TPE). (See 'Presumptive diagnosis of TTP: Start therapeutic plasma exchange (TPE) and possibly caplacizumab' below.)
There are no specific clinical features that distinguish TTP from other TMAs. ADAMTS13 activity should be ordered, and activity ≤10 percent is confirmatory, but this testing can take several days, and treatment must be initiated based on a presumptive diagnosis while awaiting the results. An expert in TMAs should be consulted to assist with decision-making about diagnosis and treatment and to help balance likelihood of TTP versus another etiology for MAHA and thrombocytopenia (table 3).
●Plasmic score – Often, the presence of certain findings and absence of other findings is sufficient to make a presumptive diagnosis, order ADAMTS13 activity testing, and start treatment, which may be life-saving. Many of these findings are included in the PLASMIC score, which is intended for use in individuals with MAHA (schistocytes) and thrombocytopenia.
The PLASMIC score (calculator 1) is a simple algorithm that was developed and validated to estimate the probability of ADAMTS13 activity ≤10 percent (and therefore the probability of TTP) in a patient with MAHA and thrombocytopenia [29]. In a patient presenting with MAHA and thrombocytopenia, a PLASMIC score ≥5 can be used to make a presumptive diagnosis of TTP and initiate emergency treatment with plasma exchange. (See "Diagnosis of immune TTP", section on 'PLASMIC score' and 'Presumptive diagnosis of TTP: Start therapeutic plasma exchange (TPE) and possibly caplacizumab' below.)
The sensitivity of the PLASMIC score is slightly lower in adults >60 years, who may present with atypical features such as worse kidney function and less profound thrombocytopenia, and in individuals in early relapse, due to more frequent laboratory surveillance and/or patients' familiarity with symptoms [32]. In these situations, if clinical suspicion for TTP is high and an alternative diagnosis is not apparent, it is most prudent to presumptively treat as TTP until ADAMTS13 results are available.
●Additional features – Other than MAHA and thrombocytopenia with minimal kidney involvement, additional features that may be helpful in making or excluding a presumptive diagnosis of TTP include:
•General symptoms – Most patients with TTP present with several days of nonspecific symptoms:
-Progressive weakness
-Fatigue
-Purpura
-Gastrointestinal symptoms (nausea, diarrhea)
Some patients have minimal symptoms and TTP is suspected only when anemia and thrombocytopenia are discovered. Fever is uncommon; high fever with shaking chills rarely occurs and should prompt consideration of sepsis.
•Neurologic symptoms – Approximately one-third of patients with TTP have no neurologic symptoms; one-third may have nonspecific symptoms (confusion, headache); and one-third will have more severe neurologic symptoms (transient focal neurologic abnormalities, aphasia, diplopia, or weakness, clumsiness, numbness of an arm or hand). Focal symptoms often occur transiently.
•Minimal kidney dysfunction – TTP is unique among the TMA syndromes for minimal abnormalities of kidney function, despite microthrombi observed throughout the kidney at autopsy.
•Thrombocytopenia and purpura – TTP typically causes more severe thrombocytopenia than other TMAs, with the exceptions of individuals >60 years and those with TTP relapse, who may present earlier when thrombocytopenia is milder.
Patients with TTP often have minor purpura despite severe thrombocytopenia; they rarely have clinically significant bleeding [33].
Approximately 20 percent of patients with TTP are initially misdiagnosed as having immune thrombocytopenia (ITP), particularly when they have less profound anemia or organ dysfunction at presentation [34]. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Differential diagnosis'.)
•Organ injury – TTP typically causes more systemic manifestations of organ injury than the other TMAs. 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 [35].
•ADAMTS13 activity – If ADAMTS13 activity is immediately available, it can be used to provide more definitive evidence for or against TTP. However, therapy should not be delayed while awaiting results of this testing, which can take days. Such a delay could be life-threatening. (See "Diagnosis of immune TTP", section on 'ADAMTS13 testing'.)
TTP is the disorder with the greatest acute mortality; as high as 90 percent in the era before TPE was used [36]. Initiating TPE for TTP is urgent, along with other therapies (a glucocorticoid; in some cases, caplacizumab if available and deemed appropriate). TPE and other therapies can be initiated while the diagnostic evaluation, including ADAMTS13 testing, continues. In appropriately triaged patients in some expert centers, the initial management of TTP may rely on caplacizumab in place of TPE; however, for most centers, initial therapy remains TPE with supplemental caplacizumab if available. (See 'Presumptive diagnosis of TTP: Start therapeutic plasma exchange (TPE) and possibly caplacizumab' below.)
However, if the patient is not critically ill and the suspicion for other TMAs is greater than the suspicion for TTP, then it may be appropriate to defer TPE and/or caplacizumab while the evaluation continues.
Exclude systemic disorders causing MAHA and thrombocytopenia — Once MAHA and thrombocytopenia are confirmed, it is important to exclude systemic disorders as the cause of these findings. The key decision point after identifying a TMA is the confidence of the treating clinicians that TTP is the correct diagnosis versus the myriad other causes listed in the table (table 3).
If one of these disorders is suspected, additional laboratory testing can be especially helpful, although initial treatment decisions must be made before the results of testing are available. (See 'Additional evaluations for selected patients' below.)
●Pregnancy – Preeclampsia with severe features and HELLP (hemolysis, elevated liver enzymes, and low platelets) are a continuum of pregnancy-related disorders that typically occur closer to term. MAHA and thrombocytopenia before gestational age of 25 weeks or more than 48 to 72 hours after delivery, or a platelet count <30,000/microL are rare in preeclampsia/HELLP, occurring in <5 percent and rarely causing platelet counts <30,000/microL [26,27].
However, TTP and CM-TMA can occur in association with pregnancy and may be triggered by pregnancy [37,38]. Distinguishing these disorders from TTP may be difficult because pregnancy may also trigger acute episodes of TTP (hereditary or immune). Lack of improvement within several hours to three days after delivery of a pregnant patient decreases confidence that the symptoms were due to preeclampsia/HELLP and increases the likelihood of TTP or CM-TMA. CM-TMA may cause severe postpartum acute kidney injury. SLE may also flare during pregnancy. Diagnostic evaluation and decisions regarding delivery are discussed separately. (See "Thrombocytopenia in pregnancy".)
●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 TMAs such as TTP, CM-TMA, and TMA due to medications or infections. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)
●Transplantation or drug exposures – Recent hematopoietic stem cell transplantation (autologous or allogeneic) or exposure to drugs known to be associated with TMA (eg, calcineurin inhibitors, gemcitabine, bevacizumab) should prompt consideration of transplantation-associated TMA or drug-induced TMA.
Contributing factors include regimens for bone marrow ablation (eg, total body radiation, high-dose chemotherapy) or immunosuppressive drugs to prevent graft-versus-host disease (eg, calcineurin inhibitors) [39,40]. Organ transplantation may also be associated with a drug-induced TMA 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".)
Exposure to heparin raises the possibility of heparin-induced thrombocytopenia (HIT), which is caused by autoantibodies against platelet factor 4 (PF4) that also cause thrombosis. However, classic HIT is not associated with schistocytes. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)
●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".)
If possible, it is important to clarify the temporal relationship between the hematologic abnormalities and the hypertension. This is because, in some patients, kidney disease due to the TMA may be the cause of severe hypertension. New or worsening hypertension is common in CM-TMA (affecting 8 to 54 percent), and CM-TMA should be considered in patients with new onset hypertension, especially if they are younger, have a poor response to antihypertensive therapy, or the TMA does not improve with antihypertensive therapy alone [5,41,42].
●Systemic infections – Many systemic infections (bacterial, viral, rickettsial, and fungal) can cause MAHA and thrombocytopenia [43]. Common examples include (table 2):
•Bacterial endocarditis. (See "Native valve endocarditis: Epidemiology, risk factors, and microbiology".)
•Human immunodeficiency virus (HIV) infection. (See "HIV-associated cytopenias".)
•Cytomegalovirus (CMV) infection. (See "Approach to the diagnosis of cytomegalovirus infection".)
•Rocky Mountain spotted fever. (See "Epidemiology, clinical manifestations, and diagnosis of Rocky Mountain spotted fever".)
•Red blood cell parasites (eg, malaria, babesia). (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children" and "Babesiosis: Clinical manifestations and diagnosis".)
•Systemic aspergillosis. (See "Epidemiology and clinical manifestations of invasive aspergillosis".)
●Systemic malignancies – A history of cancer requires consideration of systemic metastatic cancer-associated TMA.
Cancer may not be initially apparent and may require other testing. If there is a 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 are 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, guided by clinical presentation [44]. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Cancer-associated hypercoagulable state: Causes and mechanisms".)
Any systemic malignancy can cause MAHA and thrombocytopenia [45]. In some patients, these findings are caused by microvascular metastases without overt evidence of disseminated intravascular coagulation (DIC).
●Systemic rheumatic/autoimmune 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 non-immune mechanisms [46]. They may also manifest TMA on kidney biopsies. (See "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)" and "Systemic lupus erythematosus: Hematologic manifestations", section on 'Thrombotic microangiopathies (eg, TTP)'.)
●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 [47-50].
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) [51]. 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 level, and a lower PLASMIC score.
A variety of other systemic conditions that can cause MAHA and thrombocytopenia, including additional infections (table 2) and pancreatitis, have also been reported [43,52].
Key distinguishing features among different TMA syndromes — The TMA syndromes can have a variety of presentations (eg, child or older adult, sudden onset with severe illness, gradual onset with minimal symptoms). There may be anuric acute kidney injury or normal kidney function.
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 develop, exposure history, 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. Nearly half of newborn infants with hereditary TTP have severe jaundice, but hereditary TTP is rarely diagnosed at birth [53]. Jaundice in newborn infants is sometimes mistakenly diagnosed as red blood cell immunization and treated with plasma infusion, which is lifesaving for infants with hereditary TTP [54-56].
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 [57].
•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 complement-mediated TMA.
●Rate of onset of the presenting symptoms – Most primary TMA syndromes present with gradually increasing symptoms over several days.
The onset of complement-mediated TMA is generally sudden. (See "Complement-mediated hemolytic uremic syndrome in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)
DITMA can have an explosive onset of severe, systemic symptoms (eg, neurologic changes, fever, severe fatigue) beginning within hours of drug exposure (table 4). In contrast, toxic, dose-dependent, drug-induced TMA may be associated with chronic kidney injury that develops over weeks or months.
●Exposures – Exposures to certain causative agents can be especially helpful in guiding the diagnosis.
•Medications – Several drugs have been implicated in drug-induced TMA (table 4). (See "Drug-induced thrombotic microangiopathy (DITMA)".)
Multiple reports describe TTP associated with immune checkpoint inhibitors, infliximab, and dasatinib, with probable causal associations [58]. 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 [59]. The report used established criteria for determining a drug's causal association with TMA [14]
•Infectious agents – Individuals with Shiga toxin-induced HUS may have a history of exposure to farm animals, undercooked 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 [60]. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)
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.
A preceding infection including a diarrheal illness may be present in up to 80 percent of children and 50 percent of adults with complement-mediated TMA [5,61].
●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. Complement-mediated TMA can also develop rapid onset of compromised kidney function.
•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.
Laboratory testing for all patients
●Daily testing – 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) and bilirubin (total and direct), to follow the intensity of hemolysis
•Serum creatinine, to follow the severity and progression of kidney dysfunction
•For patients with kidney injury, the daily urine output should also be monitored
●Testing at least once – Additional laboratory evaluation that should be completed at least once at presentation includes the following:
•Blood smear for schistocytes.
•Prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen level to evaluate for DIC. These are usually normal in TTP, CM-TMA, and metabolism- and coagulation-mediated TMAs.
•Liver function tests.
•Electrocardiogram and cardiac troponin to determine the presence of organ injury, which is an adverse prognostic factor in TTP.
●ADAMTS13 – 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'.)
ADAMTS13 testing 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).
ADDITIONAL EVALUATIONS FOR SELECTED PATIENTS
Pregnancy and postpartum — Details of pregnancy-associated syndromes and their evaluations are discussed separately. (See "Thrombocytopenia in pregnancy", section on 'Thrombotic microangiopathy (TMA)' and "Hereditary thrombotic thrombocytopenic purpura (hTTP)", section on 'Pregnancy' and "Preeclampsia: Clinical features and diagnosis" and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)".)
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 E. coli (EHEC). This testing requires specific culture media, distinct from the stool cultures for routine enteric pathogens. (See "Shiga toxin-producing Escherichia coli: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)
S. 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 "Shigella infection: Epidemiology, clinical manifestations, and diagnosis".)
Homocysteine and MMA testing — All patients with MAHA and thrombocytopenia who have negative testing for TTP (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).
The incidence of cobalamin C deficiency-mediated TMA is unknown but likely to be rare. (See 'Specific TMA syndromes' above.)
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 [6,62].
Complement testing — Most clinically available complement testing cannot confirm or refute the diagnosis of complement-mediated TMA (CM-TMA). Testing for complement activation by measuring complement proteins (eg, C3,C4, C5, soluble C5b9) has low sensitivity and specificity to identify CM-TMA since there is significant overlap in levels between various TMAs and healthy individuals. Measuring CH50 is helpful in monitoring eculizumab therapy but not for diagnosis of CM-TMA.
●Complement factor H or factor I levels – Low plasma levels of complement factor H or I, or the presence of anti-complement factor H (CFH) antibodies, suggests a CM-TMA; however, normal levels do not rule out CM-TMA, and therapy cannot be based exclusively on this testing.
●Functional assays – Assays that measure complement activation on cell surfaces are better at identifying complement activation in CM-TMA [63-65]. Previously restricted to research laboratories, one of these assays, the modified Ham (mHAM) test is available for clinical use in the United States and may be used as an adjunct for the diagnosis of CM-TMA.
●Genetic testing – We generally test the following patients presenting with MAHA and thrombocytopenia for pathogenic variants 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 with rapidly progressive acute kidney injury following delivery.
Details of which genes to test for are discussed separately. (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Genetic testing (complement genes)'.)
Complement testing (eg, testing for inhibitory antibodies, genetic testing) is available at several specialized centers; 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 for germline variants and autoantibodies'.)
Results of most 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 CM-TMA. Thus, management is based on clinical features such as the severity of thrombocytopenia and kidney injury. The decision to initiate therapy for CM-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'.)
Genetic testing — Genetic testing may be appropriate for selected patients with TTP thought to be due to an ADAMTS13 variant (individuals with presentation in infancy or severe ADAMTS13 deficiency without an inhibitor). (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)", section on 'Genetic testing'.)
Genetic testing for pathogenic variants in complement genes is done in complement-mediated TMA, as discussed above and separately. (See 'Complement testing' above and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Genetic testing (complement genes)'.)
Testing for pathogenic variants in MMACHC should occur reflexively for individuals with TMA who have hyperhomocysteinemia/methylmalonic 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 [66].
Kidney biopsy — Kidney biopsy is not required to diagnose TMA but may be helpful to distinguish TMA from other causes of acute kidney injury such as acute tubular necrosis or interstitial nephritis caused by hypotension or drug toxicity. (See "Evaluation of acute kidney injury among hospitalized adult patients", section on 'Role of kidney biopsy' and "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting".)
Kidney biopsy is not helpful for determining the etiology of a TMA syndrome or distinguishing TMAs from other disorders such as SLE, systemic sclerosis, or severe hypertension, which can also manifest the typical pathologic features of TMA [67].
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" 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) and other therapies for TTP?
●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 and sometimes caplacizumab; 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.)
Patients with complement-mediated TMA (CM-TMA) also require urgent anti-complement treatment to prevent irreversible kidney damage and to minimize exposure to potentially harmful interventions such as central line placement and exposure to plasma.
TMAs occurring with conditions such as infection (including ST-HUS), malignancy, medications known to be associated with TMA, pregnancy, and solid organ or hematopoietic stem cell transplantation are treated with supportive care, at least for the initial day or two (algorithm 2).
Details of these therapies are discussed in the following sections.
Presumptive diagnosis of TTP: Start therapeutic plasma exchange (TPE) and possibly caplacizumab — TPE is started in all patients with a presumptive diagnosis of TTP while awaiting the results of ADAMTS13 activity, with rare exceptions such as a Jehovah's witness who declines plasma. (See "Immune TTP: Initial treatment", section on 'Therapeutic plasma exchange (TPE)'.)
TTP is the well-documented essential treatment for TTP; the possible benefit of TPE for other TMA syndromes is less clear and therefore less urgent [68]. Therefore, the decision 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 [4,69]. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications" and "Immune TTP: Initial treatment", section on 'TPE complications'.)
Examples of decision-making include the following:
●For 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, TTP must be suspected, as this is a common presentation of TTP. Such patients require urgent initiation of TPE and possibly caplacizumab. (See "Diagnosis of immune TTP", section on 'Typical presentation'.)
●For a patient with a history consistent with a drug-induced TMA, it may be possible to avoid TPE. Examples include abrupt onset of nausea and anuria hours after injection of an opioid or ingestion of a quinine-containing beverage, or gradual development of hypertension and kidney failure several weeks or longer after treatment with a calcineurin inhibitor or chemotherapy. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Management'.)
●For a pregnant patient with rapid postpartum development of acute kidney injury with anticipated need for dialysis, complement-mediated TMA is likely. Anti-complement treatment should be administered promptly, without TPE. Apart from functional complement assays, most complement testing is unaffected by this therapy. (See 'Complement testing' above and 'Suspected complement-mediated TMA: Use anti-complement therapy' below.)
In many 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.
Additional therapies for TTP and alternatives to TPE for rare patients who cannot receive plasma are discussed separately. (See "Immune TTP: Initial treatment".)
A lack of early response within two to three days following TPE and caplacizumab (if deemed appropriate and used) encourages us to continue to seek other causes of the patient's symptoms.
Suspected complement-mediated TMA: Use anti-complement therapy — Complement-mediated TMA (CM-TMA) is suspected in a patient with MAHA and thrombocytopenia of rapid onset with severe kidney injury, which may be acute or gradual, without another explanation. Other supporting features include a positive family history and absence of drug exposures that could cause a TMA. (See 'Key distinguishing features among different TMA syndromes' above.)
Confirmatory testing can take days to weeks, and therapy should not be delayed while awaiting the results of this testing if the clinical suspicion is high. (See 'Complement testing' above and 'Genetic testing' above.)
An expert in TMAs should be consulted to assist with decision-making about diagnosis and treatment and to help balance likelihood of TTP versus another etiology for MAHA and thrombocytopenia (table 3).
Individuals with a presumptive clinical diagnosis of CM-TMA are treated with anti-complement therapy, which should be started as soon as possible, preferably within 24 to 48 hours. The goal is to limit irreversible kidney injury. The rationale includes the effectiveness of anti-complement therapy if the diagnosis is correct and the avoidance of risks associated with other, less effective therapies (eg, catheter-related complications and transfusion reactions associated with TPE). TPE can be started when complement inhibition therapy is unavailable.
Details of therapy, including dose and duration, as well as the risk for meningococcal infection and need for prophylaxis and vaccination, and the role of kidney transplantation, are discussed separately:
●Children – (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Treatment'.)
●Adults – (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Management'.)
●Pregnancy or postpartum – (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Management'.)
Other suspected TMAs: Interventions — The following interventions are appropriate for other suspected TMAs:
●Cobalamin C deficiency-mediated TMA – High-dose hydroxocobalamin (also called hydroxycobalamin); betaine and folinic acid (also called leucovorin) may also be given. (See "Methylmalonic acidemia", section on 'Management'.)
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 variant in MMACHC [62]. Treatment with high-dose vitamin B12, betaine, and folinic acid (leucovorin) resulted in a dramatic recovery. His brother died from complications of a similar syndrome at the same age.
●Drug-induced TMA – Stop the implicated drug. If the TMA does not resolve or kidney function does not improve, treatment with anti-complement therapy may be reasonable [67,70-72]. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Management'.)
●TMA following hematopoietic stem cell or solid organ transplantation – (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'.)
●Pregnancy-associated TMAs – Intervention depends on the specific TMA suspected. (See "Thrombocytopenia in pregnancy", section on 'Management decisions'.)
●Infection-associated TMA – Treatment of the infection and supportive care. (See 'All TMAs: Supportive care' below.)
Increased complement activation, which is a hallmark of CM-TMA, is also seen in ST-HUS and may contribute to the pathogenesis of the TMA [73,74]. However, responses to complement inhibition are not as compelling as CM-TMA [75,76].
●TMA associated with autoimmune disorders – Treatment of the underlying disorder.
Some studies support a role of complement as a pathogenic driver in some of these TMAs, such as those associated with systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS) [67]. Treatment with anti-complement therapy may be reasonable if the TMA does not resolve or kidney function does not improve [70-72]. Case series have described response rates with eculizumab of 68 to 93 percent [70,77,78]. Plasma exchange is not effective in APS.
Catastrophic APS (CAPS) is treated with TPE, anticoagulation, and immunosuppression. (See "Catastrophic antiphospholipid syndrome (CAPS)".)
All TMAs: Supportive care — The following may be appropriate for all TMAs:
●RBC transfusions for severe or symptomatic anemia. (See "Indications and hemoglobin thresholds for RBC transfusion in adults", section on 'Overview of our approach'.)
●Platelet transfusion for severe thrombocytopenia (eg, platelet count <20,000/microL) and overt bleeding and for platelet count <50,000/microL in patients who require surgery or 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'.)
Additional considerations for platelet transfusion in patients with suspected TTP are discussed in more detail separately. (See "Immune TTP: Initial treatment", section on 'Bleeding/platelet transfusion'.)
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 caused by 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; it is often inferred from findings on the complete blood count (CBC) and blood smear without a biopsy. Not all MAHA is caused by a TMA, but nearly all TMAs cause MAHA and thrombocytopenia. Specific TMAs and preferred terminology are defined above. (See 'Terminology' above.)
●Evaluation for TMA – The initial evaluation focuses on confirming MAHA and thrombocytopenia and excluding systemic disorders that manifest these findings (table 3). All patients require a CBC with platelet count, blood smear review by an experienced clinician (picture 2), lactate dehydrogenase (LDH), bilirubin, creatinine, coagulation testing, liver function tests, troponin, and electrocardiogram. (See 'Rapid overview of our approach' above and 'Verify MAHA and thrombocytopenia' above and 'Laboratory testing for all patients' above.)
●Determine likelihood of TTP – Determining the likelihood of thrombotic thrombocytopenic purpura (TTP) is critical because urgent therapeutic plasma exchange (TPE) requires mobilization of significant resources. Typical presentation is with nonspecific symptoms, preserved kidney function, and variable neurologic symptoms.
The PLASMIC score (calculator 1) estimates the probability of ADAMTS13 activity ≤10, characteristic of TTP. For most individuals with MAHA, thrombocytopenia, and a PLASMIC score of ≥5 without another explanation, we make a presumptive diagnosis of TTP. Exceptions (individuals >60 years, suspected relapse) are discussed above. (See 'Determine likelihood of TTP, which requires urgent plasma exchange' above.)
●Distinguish among other TMAs and systemic conditions – Other possible diagnoses include:
•Pregnancy-associated syndromes (preeclampsia/HELLP)
•Disseminated intravascular coagulation (DIC)
•Drug-induced cytopenias, including drug-induced TMA, transplantation-induced TMA, and heparin-induced thrombocytopenia (HIT)
•Severe hypertension
•Infections, including Shiga toxin-mediated hemolytic uremic syndrome (ST-HUS)
•Vitamin B12 deficiency or metabolism-mediated TMA
•Rheumatologic/autoimmune disorders
•Coagulation-mediated TMA
Helpful distinguishing features include patient age, rate of symptom onset, medications and other exposures, severity of thrombocytopenia, and presence of kidney injury (algorithm 2); clinical features and laboratory testing are discussed above. (See 'Exclude systemic disorders causing MAHA and thrombocytopenia' above and 'Key distinguishing features among different TMA syndromes' above and 'Additional evaluations for selected patients' above.)
●Urgent interventions – The immediate management decision is whether to perform TPE together with initiating a glucocorticoid and possibly caplacizumab or to start anti-complement therapy.
•For presumptive diagnosis of TTP – For individuals with a presumptive diagnosis of TTP based on assessment by an expert clinician and supported by a PLASMIC score ≥5 in the appropriate clinical setting, we initiate treatment for TTP while awaiting the results of ADAMTS13 activity testing. (See 'Immediate management decisions' above and "Immune TTP: Initial treatment", section on 'Overview of treatment approach'.)
•For suspected CM-TMA – For individuals with suspected CM-TMA based on MAHA and thrombocytopenia plus acute kidney injury without another cause, we initiate treatment for CM-TMA while awaiting results of complement testing (modified Ham test, genetic testing, and complement factor H and factor I autoantibodies). (See 'Suspected complement-mediated TMA: Use anti-complement therapy' above and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Management' and "Complement-mediated hemolytic uremic syndrome in children", section on 'Treatment'.)
•Presumed drug-induced TMA – Drug discontinuation. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Management'.)
•Metabolism-mediated TMA – Hydroxocobalamin, betaine, and folinic acid (leucovorin). (See 'Other suspected TMAs: Interventions' above.)
•Severe anemia or bleeding – Transfusions. (See 'All TMAs: Supportive care' above.)
●Further management – Additional management depends on the specific syndrome, as discussed separately. (See "Immune TTP: Initial treatment" and "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome 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 and Carla M Nester, MD, MSA, FASN, who contributed to earlier versions of this topic review.
