Drug-induced thrombotic microangiopathy (DITMA)

INTRODUCTION — Thrombotic microangiopathies (TMAs) are potentially life-threatening conditions caused by small-vessel platelet thrombi. Characteristic clinical features are microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. Acute kidney injury (AKI), neurologic abnormalities, and/or cardiac ischemia may be seen. (See 'Clinical manifestations' below.)

Drug-induced TMA (DITMA) is challenging to diagnose because laboratory tests to identify a drug etiology may not be available. Some of the implicated substances may not be acknowledged by the patient, and quinine exposure may be from a beverage such as tonic water.

The principal treatment of DITMA is withdrawing the suspected drug and providing supportive care. Management may be challenging because it may be difficult to distinguish DITMA from other primary TMAs. (See 'Management' below and 'Differential diagnosis' below.)

Here we discuss our approach to the evaluation and management of a patient with a suspected DITMA.

Separate topic reviews discuss:

●General approach to evaluating TMAs – (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

●Thrombotic thrombocytopenic purpura (TTP) diagnosis – (See "Diagnosis of immune TTP" and "Hereditary thrombotic thrombocytopenic purpura (hTTP)", section on 'Diagnostic evaluation'.)

●TTP treatment – (See "Immune TTP: Initial treatment".)

●Complement-mediated TMAs – (See "Complement-mediated hemolytic uremic syndrome in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)

TERMINOLOGY — Terminology for the TMA syndromes is evolving as disease understanding increases and diagnostic testing allows identification of specific causes. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Terminology'.)

●DITMA versus DI-TTP – Drug-induced TMA (DITMA) is a TMA without ADAMTS13 deficiency, caused by exposure to a drug or other substance such as a food or beverage.

The term drug-induced thrombotic thrombocytopenic purpura (DI-TTP) is used when the diagnosis of TTP is supported by severe ADAMTS13 deficiency (activity ≤10 percent) and the etiology of TTP can be confidently attributed to a drug such as an immune checkpoint inhibitor or other drug. DI-TTP is discussed separately. (See "Diagnosis of immune TTP", section on 'Evaluation and diagnosis'.)

●Immune versus non-immune DITMA – We divide DITMA into immune-mediated syndromes, which can occur after exposure to any amount of the drug and are due to an idiosyncratic, antibody-dependent mechanism, and non-immune syndromes, which do not involve drug-dependent antibodies; the non-immune syndromes are much more common and generally are dose related [1,2].

Implications of this distinction include differences in presentation, management, and prognosis; however, for many reports, the mechanism (immune versus non-immune) is uncertain. (See 'Clinical manifestations' below and 'Management' below and 'Prognosis/expected recovery' below.)

Gemcitabine is the only drug for which immune- and non-immune-mediated mechanisms have been documented; however, as with other drugs, most case reports for gemcitabine lack evidence sufficient for a probable or definite causal association. (See 'Gemcitabine' below.)

PATHOPHYSIOLOGY

Overview of pathophysiology — Immune DITMA results from exposure to a drug (medication, other substance) that interacts with a naturally occurring antibody that can then bind to a cell surface epitope [3]. Non-immune DITMA is caused by direct tissue injury. Unlike some secondary TMAs, DITMA does not appear to be associated with an increased prevalence of pathogenic variants in complement genes.

As with other TMAs, thrombocytopenia results from platelet consumption in microthrombi, and microangiopathic hemolytic anemia (MAHA) occurs as red blood cells (RBCs) become fragmented by the turbulent circulation as they pass across these thrombi. Organ ischemia and infarction may also occur as a result of small-vessel thrombosis. The kidney appears to be especially susceptible in DITMA syndromes.

Additional information about the pathogenesis of TMAs is presented separately. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)".)

Immune-mediated mechanisms — Immune-mediated DITMA is caused by drug-dependent antibodies, as illustrated in the figure (figure 1).

Patients who are susceptible to immune DITMA have pre-existing antibodies that react very weakly with multiple cells including platelets, neutrophils, and endothelial cells in the absence of the drug [3,4]. Strong binding of these antibodies only occurs in the presence of the drug (or drug metabolite). These antibodies are described as drug-dependent antibodies.

Characteristics of the drug-dependent antibodies:

●May be highly specific for the structure of the implicated drug [3].

●Require the drug (or a drug metabolite) to be present to cause cellular damage.

●Once the drug is cleared from the circulation (hours to days for most drugs), no new organ injury occurs. However, tissue damage (especially kidney injury) may recover slowly and/or incompletely, and MAHA and thrombocytopenia may be slow to resolve. (See 'Prognosis/expected recovery' below.)

Non-immune mechanism — Non-immune DITMA may develop by multiple mechanisms. It may occur with high cumulative doses of a drug over a long time period, or it may occur with a single exposure.

Non-immune DITMA generally results from direct tissue injury from the implicated agent.

DRUGS ASSOCIATED WITH DITMA

Overview of drugs and criteria — A number of drugs have been implicated in causing DITMA (sometimes reported as drug-induced thrombotic thrombocytopenic purpura [DI-TTP] or drug-induced hemolytic uremic syndrome [HUS]). We reserve DI-TTP for drug-induced TMA with severe ADAMTS13 deficiency. (See 'Terminology' above.)

The most common drugs with the strongest evidence for a causal association with DITMA are listed in the table (table 1); these are drugs for which at least one report has documented definite evidence for a causal association with TMA, or two reports documenting probable evidence. Selected drugs are discussed below. (See 'Drugs (immune mechanism)' below and 'Drugs (non-immune mechanism)' below.)

Many additional drugs have been reported to cause DITMA without data supporting a definite or probable association. The evidence for the role of these drugs was evaluated in a systematic review of published reports based on stringent criteria for the level of supporting evidence [1,2,5,6].

Evidence is lacking for a role of the thienopyridine antiplatelet agents that block the platelet P2Y₁₂ receptor (clopidogrel, ticlopidine), despite multiple published reports [7,8]. Patients receiving these agents were also receiving multiple other medications, or their TMA recurred without re-exposure to the drug.

For drugs that have not been reported but that have a presentation consistent with an immune-mediated mechanism (abrupt onset, history of previous drug exposure associated with systemic symptoms only appreciated in retrospect), testing for drug-dependent antibodies is important for establishing the diagnosis, advising the patient whether the drug should be avoided, and reporting of new DITMA associations. (See 'Laboratory testing' below.)

Drugs (immune mechanism)

Quinine — Until 2010, quinine was the most common cause of immune-mediated DITMA [9]. Quinine-induced DITMA has subsequently become rare since the US Food and Drug Administration (FDA) began requiring a prescription for quinine tablets and the approval of quinine was limited to treatment of malaria. DITMA can be caused by quinine in beverages such as tonic water, but this is rare [4].

Antimicrobials — The antibiotic with the best evidence is trimethoprim-sulfamethoxazole. A number of other antibiotics have evidence for causing immune-mediated DITMA in single case reports, including [1]:

●Sulfisoxazole

●Ciprofloxacin

●Penicillin

●Metronidazole

●Mefloquine (antimalarial)

●Famciclovir (antiviral)

Rifampin has been associated with DITMA according to the prescribing information [10]. Case reports have been published associating DITMA or DI-TTP with rifampin, although causation has not been well-established [11,12].

Gemcitabine — Gemcitabine has been reported to cause non-immune DITMA (see 'Cancer therapies' below); there is also a report of immune-mediated DITMA from gemcitabine [13]. Immune-mediated DITMA from gemcitabine is less common than the non-immune mechanism.

Oxaliplatin — One report has described definite evidence for DITMA caused by oxaliplatin with the clinical features of an immune-mediated etiology (although the authors of this report attributed the TMA to gemcitabine) [14]. The laboratory of the Versiti Blood Center of Wisconsin (Milwaukee) has also identified oxaliplatin-dependent, platelet-reactive antibodies in a patient with clinical features of TMA [2].

Quetiapine — The antipsychotic agent quetiapine has been associated with DITMA that recurred with repeated exposures, suggestive of an immune mechanism [15].

Immunomodulatory agents — The anti-T cell monoclonal antibody muromonab-CD3 (OKT3) and the anti-tumor necrosis factor (TNF) monoclonal antibody adalimumab have been reported to cause immune-mediated DITMA [16-18]. Calcineurin inhibitors appear to cause non-immune DITMA. (See 'Immunosuppressive agents' below.)

Drugs (non-immune mechanism) — The three major categories of drugs associated with non-immune DITMA are cancer therapies, immunosuppressive agents, and drugs of abuse. The hemophilia A therapy emicizumab has also been reported to cause DITMA.

Cancer therapies — DITMA from chemotherapeutic agents often results from dose-dependent toxicity, which may be either from a cumulative dose over weeks to months or from an unusually high individual dose. When DITMA occurs from a cumulative dose, the clinical course is characterized by gradual development of kidney injury (acute kidney injury or chronic kidney disease), sometimes occurring even after the chemotherapy has been stopped. When it occurs because of an unusually high dose, the onset is sudden, similar to immune DITMA. (See 'Clinical features of immune DITMA' below.)

●Gemcitabine – Over 100 cases of gemcitabine-induced DITMA have been reported [1,5]. However, only 17 of these reports described definite or probable evidence for a causal association with TMA.

The mechanism appears to be dose related in most patients. One series of 264 patients who received gemcitabine reported development of a TMA in three (1 percent) [19]. One patient had a relatively large cumulative dose; the other two did not. There is also a report of immune-mediated DITMA from gemcitabine [13]. (See 'Drugs (immune mechanism)' above.)

●Mitomycin – Mitomycin has been the subject of at least 71 DITMA case reports [1]. Only six reports have presented definite or probable evidence for mitomycin as the cause because mitomycin is almost always given in combination with other drugs [20-28].

●Pentostatin – Two reports have described definite evidence supporting a causal association of pentostatin with DITMA [29,30].

●Vincristine – One report has described definite evidence supporting a causal association of vincristine with DITMA [31].

●Proteasome inhibitors – Several cases of DITMA have been described with proteasome inhibitors (bortezomib, carfilzomib, and ixazomib) [5,32-38]. Some had recurrence of TMA following re-exposure to the drug.

●Vascular endothelial growth factor (VEGF) inhibitors and tyrosine kinase inhibitors – VEGF inhibition in glomerular endothelial cells impairs the unique permeability characteristics of these cells and promotes microvascular injury [39].

Implicated agents include the antiangiogenic monoclonal antibody bevacizumab and the small molecule tyrosine kinase inhibitor sunitinib [39-43]. The small molecule BCR-ABL tyrosine kinase inhibitor ponatinib has also been implicated [44,45]. (See "Overview of angiogenesis inhibitors" and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects".)

●Hematopoietic cell transplantation – TMA has been described after hematopoietic stem cell transplant (allogeneic or autologous); the incidence varies from 1 to 20 percent [46,47]. (See "Early complications of hematopoietic cell transplantation", section on 'Thrombotic microangiopathy' and "Kidney disease following hematopoietic cell transplantation", section on 'Thrombotic microangiopathy'.)

DITMA may be the etiology of TMA in these patients because they have typically received cytotoxic chemotherapy and/or immunosuppressive therapy.

The monoclonal antibody moxetumomab has been reported to cause DITMA and has a Boxed Warning about this in the United States prescribing information, but the report does not provide definite or probable evidence. The diagnostic criteria used to make the diagnosis of DITMA and the clinical course of the patients were not described.

Immunosuppressive agents — Calcineurin inhibitors such as cyclosporine A (CSA) and tacrolimus cause dose-dependent endothelial dysfunction and increased platelet aggregation, possibly by inhibiting prostacyclins [48]. Organ involvement typically is restricted to the kidneys [49].

Sirolimus, which inhibits the mechanistic target of rapamycin (mTOR), can also cause DITMA, alone or in combination with CSA [50]. (See "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors", section on 'Hemolytic uremic syndrome/thrombotic microangiopathy'.)

DITMA from the monoclonal antibody OKT3 and from the immunomodulatory agent adalimumab appears to be immune mediated. (See 'Immunomodulatory agents' above.)

A causative role for interferon was suggested in a series of eight patients with multiple sclerosis who developed TMA during treatment with interferon beta, as there did not appear to be other causes [51,52]. DITMA occurred exclusively in those who received an interferon dose above 50 mcg per week, and the effect appeared to be dose dependent. Subsequent studies in transgenic mice engineered to produce type 1 interferon in the brain demonstrated that interferon caused dose-dependent TMA [51].

Drugs of abuse — DITMA has been reported with certain drugs of abuse, including [53-56]:

●Intravenous use of the extended-release opioid oxymorphone

●Ecstasy (MDMA, also known as Molly)

●Cocaine

A unique mechanism is the increased blood viscosity caused by Opana ER and oxycodone [56-59]. Opana ER and oxycodone (OxyContin) contain a high molecular weight inert ingredient, polyethylene oxide (PEO; molecular weight, approximately 7 million Daltons), that mediates DITMA.

PEO was added to oxymorphone tablets in 2012 to resist crushing and solubilization and to decrease the risk of intravenous abuse. However, PEO causes increased blood viscosity, hemolysis, and hemoglobinuric kidney injury [56]. Subsequently, DITMA was reported with intravenous use of oxycodone intended for oral administration that had added PEO [57-59].

Emicizumab — Emicizumab is used for prophylaxis against bleeding in individuals with hemophilia A (factor VIII deficiency). (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab for hemophilia A'.)

Early experience identified TMA in three individuals with hemophilia A who had factor VIII inhibitors and were treated with emicizumab along with high doses of activated prothrombin complex concentrate (aPCC; factor eight inhibitor bypassing agent [FEIBA]) [60]. Discontinuation of aPCC led to resolution of the TMA in all three. This led to a Boxed Warning in the product information and advice to avoid combining high doses of emicizumab with an aPCC. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Pathogenesis' and "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'Regulators of clotting or fibrinolysis'.)

Gene therapy (mechanism unclear) — A few case reports have described DITMA in patients treated with certain gene therapy constructs.

●SMA – The gene therapy construct onasemnogene abeparvovec provides a normal copy of the SMN1 gene to patients with spinal muscular atrophy (SMA). The construct uses an adeno-associated virus (AAV) vector with tropism to the liver and other tissues [61]. (See "Spinal muscular atrophy", section on 'Onasemnogene abeparvovec'.)

Several cases of TMA have been reported, including TMA with fatal complications, in infants and young children treated with onasemnogene abeparvovec [62,63]. The time course was rapid (within one week to 10 days). The clinical presentations included severe thrombocytopenia, microangiopathic hemolysis with schistocytes on the blood film, transaminase elevations, and acute kidney injury (AKI) progressing to kidney failure. The role of complement abnormalities is unclear; one individual had a variant of uncertain significance (VUS) in the gene for complement factor I [62]. Some had concomitant infections.

●Other conditions – TMA may have occurred with other gene therapy constructs, but details are limited. Thrombocytopenia with complement activation was seen in some individuals treated with an investigational gene therapy construct for degenerative muscular dystrophy (DMD), and one case of TMA was seen following treatment with an investigational gene therapy construct for Danon disease, although specific findings have not been published [64,65].

Possible mechanisms of TMA may include the gene therapy construct itself; inflammation induced by the gene therapy, underlying condition, or other interventions; complement dysregulation; other genetic variants; or other aspects of the patient's underlying disorder. Further research is needed. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'Complement-mediated TMA pathogenesis'.)

EPIDEMIOLOGY — DITMA is uncommon. In a review of 487 patients in the Oklahoma TTP Registry that included all patients with microangiopathic hemolytic anemia (MAHA) and thrombocytopenia referred for plasma exchange, DITMA with definite or probable evidence supporting a causal association with the suspected drug accounted for 23 cases (5 percent) [2].

DITMA is mostly seen in adults although, rarely, children may be affected. This distribution probably reflects the greater likelihood that adults are exposed to implicated drugs.

CLINICAL MANIFESTATIONS — Characteristic clinical features of DITMA are microangiopathic hemolytic anemia (MAHA) and thrombocytopenia; acute kidney injury (AKI), neurologic abnormalities, and/or cardiac ischemia may be seen [66].

Disease severity varies widely. All patients have MAHA and thrombocytopenia, and most have kidney injury.

Clinical features of immune DITMA — Patients with immune-mediated DITMA may have a history of daily exposure to the implicated drug for less than two to three weeks; a longer duration of daily drug exposure makes immune-mediated DITMA much less likely. There may have been intermittent exposure for years without any apparent illness or a history of nonspecific illness with previous exposures that was not attributed to the drug at the time they occurred [4,9].

The classic clinical features of immune-mediated DITMA are illustrated by the experience with quinine-induced DITMA [4,9]:

●The onset is sudden (within hours after quinine exposure).

●Severe systemic symptoms include chills, fever, abdominal pain, diarrhea, and/or nausea/vomiting.

●Patients can often recall the exact time and place when these symptoms began.

●Anuric AKI is often misinterpreted as a manifestation of dehydration. Often, the onset of anuria is abrupt (within hours).

●Neurologic findings may range from mild confusion to coma.

●Acute gastrointestinal symptoms may manifest as nausea, vomiting, diarrhea, or abdominal pain.

Patients with quinine-induced DITMA may also have additional organ involvement [67]. There may be disseminated intravascular coagulation (DIC) mimicking sepsis [68-70]. Rhabdomyolysis or acute liver injury may occur [68,71]. Many organ systems may be involved (fever, chills, hypotension, DIC, abnormal liver function, rhabdomyolysis, and cardiac ischemia) [72].

Clinical features of non-immune DITMA — DITMA caused by a dose-dependent mechanism may develop gradually over weeks to months with weakness, fatigue, symptoms of hypertension such as headache, and/or kidney failure [66].

For chemotherapeutic agents, the findings may occur after several cycles of chemotherapy; some patients have a systemic malignancy, whereas others have a small tumor burden or no sign of disease [73-76]. There may be weeks to months of progressive kidney injury that may be attributed to other comorbidities. Neurologic findings may range from mild confusion to coma.

DITMA associated with cocaine or intravenous use of extended-release oxymorphone (Opana ER) may present with sudden-onset MAHA, thrombocytopenia, and AKI [53,56-59,77].

Other laboratory findings are discussed below. (See 'Laboratory testing' below.)

DIAGNOSTIC EVALUATION

When to suspect DITMA — DITMA may be suspected in any individual who presents with an unexplained decrease in platelet count and schistocytes on the blood smear, typically with worsening kidney function. Most individuals have thrombocytopenia and hemolytic anemia and are receiving one of the implicated drugs.

DITMA may be considered even in the absence of these findings, such as when there is compensated hemolysis or an early change in platelet count or creatinine that is not severe enough to trigger a laboratory flag.

History and physical examination — The history should focus on drugs that have been reported with definite or probable evidence for a causal association (table 1).

Especially important are over-the-counter remedies and illicit drug use, which are not considered medications and are generally not reported by patients unless specifically queried.

Implicated recreational drugs include ecstasy (MDMA, also known as Molly), cocaine, and opioid medications used by an inappropriate route (eg, intravenous administration of extended-release oxymorphone [Opana ER] or oxycodone [OxyContin], which are intended to be taken orally).

The remainder of the history and physical examination is similar to other suspected primary TMAs. A high level of suspicion for other potential systemic causes of microangiopathic hemolytic anemia (MAHA) and thrombocytopenia and other primary TMAs should be maintained. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Initial evaluation (all patients)'.)

Laboratory testing — Laboratory testing includes the testing done for all patients with a suspected primary TMA.

Testing for all patients — Some tests are used to find alternative causes of MAHA and thrombocytopenia. The following is appropriate, if not done already:

●Complete blood count (CBC) with platelet count and examination of a peripheral blood smear

●Serum metabolic profile and creatinine

●Lactate dehydrogenase (LDH)

●Coombs testing (also called direct antiglobulin testing [DAT])

●Coagulation testing with prothrombin time (PT) and activated partial thromboplastin time (aPTT)

●ADAMTS13 activity level

●Urinalysis (table 2) (see "Urinalysis in the diagnosis of kidney disease")

●Stool testing for Shiga toxin if diarrhea is present

DITMA is characterized by:

●Thrombocytopenia

●Anemia with high LDH and schistocytes (picture 1) on the blood smear

●Negative DAT

●Normal PT and aPTT

●ADAMTS13 activity >20 percent

It is also possible to have a platelet count within the normal range if the count represents a significant decrease from the patient's baseline (eg, decline from 350,000/microL to 150,000/microL).

Kidney insufficiency with increased serum creatinine, proteinuria, and a bland urine sediment is common.

Evidence of severe complement dysregulation is also absent, but nonspecific findings such as low C3 or C4 may be seen.

Stool studies in DITMA are negative for Shiga toxin-producing Escherichia coli or other diarrheal organisms.

Acute kidney injury (AKI) that is progressive or requires dialysis may indicate complement-mediated TMA, which requires anticomplement therapy. Evaluation and management of complement-mediated TMA are presented separately. (See "Complement-mediated hemolytic uremic syndrome in children".)

ADAMTS13 activity is normal or only mildly decreased in DITMA. A finding of severe ADAMTS13 deficiency (activity ≤10 percent) at any time during the evaluation for DITMA is strong evidence for the diagnosis of thrombotic thrombocytopenic purpura (TTP), which requires urgent therapeutic plasma exchange (TPE) and other therapies. Drug-induced TTP (DI-TTP) with severe ADAMTS13 deficiency is considered a type of TTP rather than DITMA. (See 'Differential diagnosis' below.)

Additional testing for selected individuals

●Kidney biopsy – Kidney biopsy is not required in the evaluation of DITMA, nor is it helpful in confirming the diagnosis or eliminating other causes of TMA. However, a kidney biopsy may appropriately be performed if the etiology of the AKI is not apparent (eg, possible acute tubular necrosis [ATN] in the setting of hypotension).

Kidney biopsy may be especially useful in individuals with heavy (nephrotic range) proteinuria, who may have nephrotic syndrome due to another cause (eg, paraneoplastic membranous nephropathy or minimal change disease in a patient with cancer).

If kidney biopsy (or biopsy of another affected organ) is performed, it is likely to show typical findings of TMA such as platelet-rich thrombi in small arterioles and capillaries, which are described in detail separately. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'Histopathology of TMA'.)

●Drug-dependent antibodies – Patients with suspected immune-mediated DITMA based on the history and clinical presentation may benefit from testing for drug-dependent antibodies, especially in cases where it is necessary to determine which of several potential drugs is responsible or if knowledge of the need to avoid a specific drug or substance for life would be valuable to the patient. This testing is available at the Versiti Blood Center of Wisconsin [78].

The finding of drug-dependent antibodies necessitates complete avoidance of the implicated drug or substance for life; however, the converse is not true (lack of identification of drug-dependent antibodies cannot be used as evidence that a drug is safe), and decisions regarding future drug avoidance must be made on a case-by-case basis. (See 'Future drug avoidance' below.)

Identification of drug-dependent antibodies associated with a drug not previously reported to cause DITMA is valuable both for management of the individual patient as well as making other clinicians aware of the potential association (eg, by description in a publication or reporting to the US Food and Drug Administration [FDA] MedWatch program in the United States) [79].

Diagnosis — The diagnosis of DITMA is made clinically, based on MAHA and thrombocytopenia with the appropriate history of exposure to a drug previously documented to be associated with TMA (table 1). There is no specific diagnostic test; however, drug-dependent antibodies may be demonstrated.

Our confidence in the diagnosis is increased when the drug has previously been reported to be associated with DITMA based on definite or probable evidence for a causal relationship (presence of drug-dependent antibodies, no other drug exposures, appropriate temporal relationship) [1,2].

If severe ADAMTS13 deficiency (activity ≤10) or ADAMTS13 activity of 11 to 20 percent is documented, the diagnosis is probably TTP or DI-TTP. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — There is clinical overlap between DITMA and other primary TMAs, and clinical features that clearly distinguish DITMA from other primary TMAs are lacking.

●Other primary TMAs – Other primary TMAs include thrombotic thrombocytopenic purpura (TTP), complement-mediated TMA, Shiga toxin-mediated hemolytic uremic syndrome (ST-HUS), and TMA due to inherited defects in genes involved in regulating hemostasis or cobalamin metabolism. Like DITMA, these conditions can present with an acute, life-threatening illness, microangiopathic/fragmentation hemolysis, thrombocytopenia, and organ damage, especially kidney failure. Unlike DITMA, these other TMAs often reveal a specific diagnosis from appropriate laboratory testing, such as severe ADAMTS13 deficiency or a Shiga toxin-producing diarrheal organism. Other distinguishing factors are discussed in more detail separately. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

●Other drug-induced thrombocytopenias – Other drug-induced thrombocytopenias include drug-induced immune thrombocytopenia (DITP), drug-induced thrombotic thrombocytopenic purpura (DI-TTP) and drug-induced bone marrow suppression. Like DITMA, a temporal relationship with a drug may be elicited. Unlike DITMA, other forms of drug-induced thrombocytopenia (with the exception of DI-TTP) are not associated with microangiopathic hemolysis or organ damage from microvascular thrombosis. (See "Drug-induced immune thrombocytopenia".)

●Other drug-induced anemias – Other drug-induced anemias include immune-mediated hemolysis and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Like DITMA, other drug-induced causes of hemolytic anemia are associated with a temporal relationship to drug exposure, and the Coombs test may be negative. Unlike DITMA, other drug-induced anemias typically do not cause fragmentation hemolysis, thrombocytopenia, kidney injury, or other end-organ manifestations. (See "Drug-induced hemolytic anemia".)

●Other drug-induced kidney injury – Many drugs are potentially nephrotoxic, and the possibility of direct kidney injury rather than injury mediated by the vascular lesion of TMA must be considered. Like DITMA, drug-induced kidney injury is associated with a temporal relation to drug exposure, rising serum creatinine, and in some cases anuria. Unlike DITMA there is no microangiopathic/fragmentation hemolysis or thrombocytopenia. (See "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults", section on 'Nephrotoxins' and "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Drugs'.)

MANAGEMENT

Initial interventions — Management of DITMA involves drug discontinuation and supportive care.

When our confidence in the diagnosis of DITMA is high, we do not use therapeutic plasma exchange (TPE) or anticomplement therapy. However, TPE may be appropriate when there is uncertainty about the diagnosis of DITMA versus thrombotic thrombocytopenic purpura (TTP); anticomplement therapy may be appropriate in patients with rapidly progressing kidney failure and uncertainty about the diagnosis of DITMA versus complement-mediated TMA. (See 'Complement inhibition' below.)

Early involvement of the consulting specialist is advised because there is a need to balance the risks and benefits of using or not using these other therapies, both of which have their own associated risks.

Our avoidance of TPE when there is a high level of confidence in the diagnosis of DITMA is supported by a lack of high-quality evidence for a benefit of TPE in DITMA and is consistent with recommendations from the American Society for Apheresis (ASFA), which publishes an evidence-based categorization of the usefulness of TPE on review of available evidence and considers quinine and gemcitabine to be category IV (TPE ineffective or harmful) [80].

For patients in whom TPE or anticomplement therapy has already been initiated, we base our decisions regarding continuation or discontinuation on our confidence that DITMA is the most likely diagnosis, and on the patient's clinical course. These decisions can be re-evaluated when additional clinical information becomes available, including the response to therapy, identification of alternative causes of the patient's symptoms, and results of other diagnostic testing. However, improvement during TPE or anticomplement therapy may be coincidental and does not necessarily imply a treatment response. (See "Immune TTP: Initial treatment", section on 'Continuation and completion of therapy'.)

Immunosuppressive therapy is not a component of DITMA management, although it may be appropriate if the diagnosis is unclear (glucocorticoids for patients in whom the diagnosis of immune TTP is suspected).

Supportive care may be needed:

●It is appropriate to transfuse platelets for severe thrombocytopenia associated with clinically important bleeding. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Actively bleeding patient' and "Platelet transfusion: Indications, ordering, and associated risks", section on 'TTP or HIT'.)

●Indications for dialysis and avoidance of nephrotoxic drugs are similar as with other patients with renal failure. (See "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose".)

●Dose reductions of nephrotoxic chemotherapeutic agents may be required for patients with residual kidney disease and reduced glomerular filtration rate. (See "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Conventional cytotoxic agents" and "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Molecularly targeted agents and immunotherapies".)

Investigational therapies for DITMA that does not resolve with drug discontinuation

Complement inhibition — There have been reports of patients with non-immune DITMA attributed to gemcitabine, mitomycin, interferon, doxorubicin, and other drugs; and case reports have described patients with acute kidney injury (AKI) attributed to gemcitabine that improved after treatment targeting complement activation [81,82]. We believe it is reasonable to consider eculizumab in persistent non-immune DITMA that does not improve with supportive care and withdrawal of the offending agent, or in patients with acute, severe immune-mediated DITMA who are at risk for the development of chronic kidney disease [83].

N-acetylcysteine — N-acetylcysteine (NAC) is a sulfhydryl-containing compound with potential roles in oxygen scavenging, endothelial cell relaxation, glutathione recycling, and reducing protein multimerization mediated by disulfide bonds.

NAC is safe, inexpensive, and may be effective for some cases of DITMA. We would have a low threshold for trying NAC in a patient with DITMA that does not resolve with drug discontinuation alone.

Supporting evidence includes:

●NAC was shown to reduce the concentration of ultra-large von Willebrand factor (VWF) multimers in vitro and in an animal model of TTP, suggesting that it may be an effective treatment in individuals with immune TTP by a similar mechanism (ie, it might reduce accumulation of ultra-large VWF multimers in the microvasculature) [84,85]. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'TTP pathogenesis'.)

●NAC was administered to a patient with ponatinib-associated DITMA affecting the coronary microvasculature [45]. The patient had dramatic resolution of abnormal electrocardiogram (ECG) findings following treatment with NAC (150 mg/kg loading dose followed by two doses of 50 mg/kg given 12 hours apart).

Future drug avoidance — The importance of future drug avoidance depends on whether the DITMA is immune-mediated or non-immune.

●Immune-mediated – The implicated agent must be completely avoided for life. Subsequent exposures can result in severe symptoms that may be fatal, even with lower doses or levels of exposure. Strict avoidance of the implicated drug should be noted clearly in the medical record. Patients who have recovered from quinine-induced TMA must be warned that even the low concentrations of quinine in beverages such as tonic water can cause a recurrent, severe episode. (See 'Drugs (immune mechanism)' above.)

A patient should never be re-exposed to a drug potentially implicated in immune-mediated DITMA solely for the purpose of establishing the role of the drug, as this could be life threatening.

A patient with immune-mediated DITMA may be able to receive an alternative agent within the same drug class, since drug-dependent antibodies may be specific for the individual drug. Antibodies against quinine may not react with quinidine, which is structurally similar. (See 'Immune-mediated mechanisms' above.)

●Non-immune – For non-immune DITMA that appears to be dose related, re-exposure to the implicated drug may be possible in selected cases. The decision must balance the potential risks of recurrent DITMA, which may be negligible with lower doses of the medication, versus the potential benefits of drug administration.

•Kidney injury with features of TMA may be seen with high doses of a calcineurin inhibitor but may not recur with lower doses.

•It may be appropriate to avoid an implicated chemotherapy agent in the palliative setting when other alternatives are available.

•It may be possible to re-administer emicizumab if appropriate, as long as it is not coadministered with an activated prothrombin complex concentrate (aPCC).

Alternative options for immunosuppression following hematopoietic stem cell and solid organ transplantation are presented separately. (See "Thrombotic microangiopathy after kidney transplantation" and "Kidney function and non-kidney solid organ transplantation" and "Cyclosporine and tacrolimus nephrotoxicity" and "Kidney disease following hematopoietic cell transplantation", section on 'Thrombotic microangiopathy'.)

PROGNOSIS/EXPECTED RECOVERY — Thrombocytopenia should begin to recover within several days.

Recovery of kidney function may be very slow and incomplete. Chronic kidney disease (creatinine clearance <60 mL/min) was common in patients with quinine-induced TMA [86].

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)".)

SUMMARY AND RECOMMENDATIONS

●Classification – We divide drug-induced thrombotic microangiopathy (DITMA) into immune-mediated syndromes and non-immune syndromes. (See 'Terminology' above.)

●Mechanism – Immune-mediated DITMA can occur after exposure to small amounts of a substance via an antibody-dependent mechanism (figure 1). Non-immune DITMA has multiple mechanisms and is often dose dependent. (See 'Pathophysiology' above.)

●Implicated drugs – Drugs most commonly associated with DITMA are listed in the table (table 1). (See 'Drugs associated with DITMA' above.)

•Immune – Causes include antimicrobials, gemcitabine, oxaliplatin, quetiapine, and immunomodulatory agents. (See 'Drugs (immune mechanism)' above.)

•Non-immune – Common causes include type 1 interferon, some cancer therapies (gemcitabine, bevacizumab, sunitinib, ponatinib, proteasome inhibitors), calcineurin inhibitors (cyclosporine, tacrolimus), and drugs of abuse (cocaine, intravenous use of oxycodone or extended-release oxymorphone). (See 'Drugs (non-immune mechanism)' above.)

●Presentation

•Immune – Sudden onset of chills, fever, abdominal pain, diarrhea, nausea/vomiting, and/or hypotension, within hours after exposure to a drug (taken occasionally over years or new drug over two to three weeks). (See 'Clinical features of immune DITMA' above.)

•Non-immune – Gradual weakness, fatigue, headache, and/or kidney failure over weeks to months. DITMA from drugs of abuse may cause sudden-onset systemic symptoms and acute kidney injury (AKI). (See 'Clinical features of non-immune DITMA' above.)

●Laboratory testing – Testing includes complete blood count (CBC), blood smear review, hemolysis testing, kidney function, and coagulation testing. (See 'Diagnostic evaluation' above.)

●Diagnosis – The diagnosis is made clinically with the appropriate exposure history and findings of thrombotic microangiopathy (TMA) including schistocytes on the blood smear, thrombocytopenia, and typically kidney injury. ADAMTS13 activity is >10 percent. Drug-dependent antibodies may be identified in immune-mediated DITMA. (See 'Diagnostic evaluation' above.)

●Differential – The differential diagnosis includes other primary TMAs such as thrombotic thrombocytopenic purpura (TTP) and other causes of AKI. Drug-induced TMA with ADAMTS13 activity ≤10 percent is considered drug-induced TTP (DI-TTP). (See 'Differential diagnosis' above and "Early complications of hematopoietic cell transplantation", section on 'Thrombotic microangiopathy' and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Kidney disease following hematopoietic cell transplantation", section on 'Thrombotic microangiopathy'.)

●Treatment – Management involves drug discontinuation and supportive care. Therapeutic plasma exchange (TPE) may be appropriate when there is uncertainty about possible TTP. Anticomplement therapy may be appropriate in patients with rapidly progressing kidney failure and possible complement-mediated TMA. Early involvement of the consulting specialist is advised. (See 'Initial interventions' above and 'Investigational therapies for DITMA that does not resolve with drug discontinuation' above.)

●Prevention – For immune-mediated DITMA, the implicated drug must be avoided for life. For non-immune DITMA, re-exposure may be possible in selected cases. (See 'Future drug avoidance' above.)

●Recovery – Recovery may be incomplete because kidney damage may be severe. Thrombocytopenia begins to resolve within days. (See 'Prognosis/expected recovery' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Lawrence LK Leung, MD, who contributed to earlier versions of this topic review.