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Drug-induced hemolytic anemia

Drug-induced hemolytic anemia
Literature review current through: Jan 2024.
This topic last updated: Jul 11, 2022.

INTRODUCTION — Drugs are not the most common cause of hemolytic anemia. However, when a patient develops hemolysis that may be drug induced, there are several challenges in evaluation and management including determining whether a drug is responsible, which drug is the likely culprit, and whether additional interventions are indicated other than stopping the drug.

This topic discusses common drugs implicated in causing hemolysis, their mechanisms, patient evaluation, and management. Separate topic reviews discuss the general approach to evaluating hemolytic anemias.

Children – (See "Overview of hemolytic anemias in children".)

Adults - (See "Diagnosis of hemolytic anemia in adults".)

LISTS OF COMMONLY IMPLICATED DRUGS — Drugs that commonly cause hemolytic anemia are listed in the tables; details of their mechanisms are discussed below:

Immune hemolysis – Immune hemolytic anemia is often caused by antibiotics, especially cephalosporins or penicillins, as well as anti-cancer drugs including platinum compounds and immune checkpoint inhibitors [1-3]. These other implicated drugs are listed in the table (table 1). (See 'Immune-mediated' below.)

The relative frequency of specific drugs is illustrated in the following case series:

A 2015 report of 73 patients with drug-induced immune hemolysis identified the following as major causative agents [4]:

-Diclofenac – 32 percent

-Piperacillin – 18 percent

-Ceftriaxone – 16 percent

-Oxaliplatin – 14 percent

The Berlin Case-Control Surveillance Study from 2011, which included 134 cases of drug-induced autoimmune hemolytic anemia (AIHA), mostly in an outpatient setting, reported commonly implicated drugs to include beta-lactam antibiotics, cotrimoxazole, ciprofloxacin, fludarabine, lorazepam, and diclofenac [5].

Two series from the early 2000s reported that cephalosporins were responsible for approximately half of the cases of drug-induced AIHA, followed by penicillins, nonsteroidal antiinflammatory drugs, quinine/quinidine, and other miscellaneous drugs (oxaliplatin, carboplatin, rifampin, diclofenac, cimetidine, trimethoprim, and sulfamethoxazole) [6,7]. The 2017 Guidelines from the British Society for Haematology on the management of drug-induced AIHA confirm most of these findings [8].

A 2022 study reported 82 cases of AIHA associated with immune checkpoint inhibitors, mainly occurring after nivolumab, followed by pembrolizumab, ipilimumab, and atezolizumab [3]. Some cases of AIHA have been reported after chimeric antigen receptor (CAR) T cell infusions. (See "Principles of cancer immunotherapy", section on 'Checkpoint inhibitor immunotherapy' and "Principles of cancer immunotherapy", section on 'CAR-T cells'.)

Oxidation – Oxidant injury may be caused by a number of antibiotics and other medicines (table 2). Common examples include primaquine, dapsone, and phenazopyridine [9-18]. (See 'Oxidant injury' below.)

Oxidant injury may be exacerbated by glucose-6-phosphate dehydrogenase (G6PD) deficiency but can occur in individuals without G6PD deficiency as well. Details are discussed separately. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Avoidance of unsafe drugs and chemicals'.)

Methemoglobinemia – Methemoglobinemia may be caused by topical anesthetics, certain antibiotics, and nitrites, among others (table 3). (See 'Methemoglobinemia' below.)

Topical anesthesia using benzocaine spray or cream or lidocaine (eg, for endoscopy) can cause severe methemoglobinemia with cyanosis and dyspnea [19-24].

In some cases, this may be followed by hemolysis, especially after exposure to drugs such as dapsone or sulfasalazine [25]. The symptoms of methemoglobinemia (dyspnea, cyanosis) can be severe [19-23].

Other implicated drugs include nitrites (amyl nitrite and butyl nitrite), which may be used to increase sexual arousal; these are primarily inhaled [26-29]. These may be referred to by names such as "locker room," "sweat," "rush," or "poppers."

Additional information is presented separately. (See "Methemoglobinemia", section on 'Acquired causes'.)

Thrombotic microangiopathy – Drugs can cause thrombotic microangiopathy by immune and non-immune mechanisms. Examples are listed in the table (table 4) and discussed separately. (See 'Thrombotic microangiopathy' below and "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Drugs associated with DITMA'.)

MECHANISMS — The two major mechanisms of drug-induced hemolysis are immune destruction of red blood cells (RBCs) and destruction due to oxidant injury, which may be associated with methemoglobinemia. (See 'Immune-mediated' below and 'Oxidant injury' below.)

Immune-mediated — Immune destruction of RBCs is generally antibody-mediated. The mechanisms can include several types of antigen-antibody interactions [5-7,30]. In most cases, the antibody-bound (opsonized) RBCs are phagocytosed by reticuloendothelial macrophages in the spleen and/or liver, resulting in extravascular hemolysis. The direct antiglobulin test (DAT; direct Coombs test) is typically positive (figure 1), although not always so. Occasionally, a metabolite of the drug but not the parent drug itself is responsible, making diagnosis difficult [6].

Drug-dependent – In drug-dependent reactions, the drug binds to the RBC surface and becomes part of the antigen with which the antibody interacts. These reactions require the drug. The mechanism can be further subdivided based on whether the drug must remain firmly bound to the RBC membrane for antibody binding.

Penicillin type – In the penicillin type of hapten reaction, the drug remains present on the RBC surface and is required for antibody binding. There are a number of penicillin and cephalosporin antibiotics that can cause hemolysis by this mechanism.

Immune complex type – In the immune complex type (also called innocent bystander, fuadin type, nonpenicillin type, or ternary complex type) of reaction, the drug causes formation of immune complexes that bind to the RBCs and cause complement activation.

Passive absorption – In the passive absorption type, administration of antibody preparations introduces antibodies that can react with the recipient's RBCs. Intravenous immune globulin (IVIG) or Rho(D) immune globulin frequently contain alloantibodies that react with the recipient's RBC antigens (eg, anti-D, anti-A, or anti-B) producing alloimmune hemolysis [31-35]. (See "Intravenous immune globulin: Adverse effects", section on 'Hemolysis'.)

Alteration of RBC surface antigen – In this type of reaction, the drug alters a normal membrane component of the RBC membrane. It can cause immune hemolysis several weeks to months after drug initiation. The DAT (direct Coombs) test is positive, and hemolytic anemia occurs in approximately 10 percent of individuals. This mechanism is less common than the hapten reactions discussed above.

Oxidant injury — All RBCs can be affected by oxidant injury from a variety of drugs. The common denominator among drugs that cause oxidative hemolysis is their interaction with hemoglobin and oxygen, leading to the intracellular formation of hydrogen peroxide (H2O2) and other oxidizing radicals. (See 'Lists of commonly implicated drugs' above.)

Two notable underlying disorders can increase susceptibility to oxidant injury, although an underlying disorder does not need to be present:

G6PD deficiency – Red blood cells are normally protected from oxidant injury by several enzymatic systems including glutathione and nicotinamide adenine dinucleotide phosphate (NADPH); generation of NADPH requires glucose-6-phosphate dehydrogenase (G6PD) (figure 2). Individuals with G6PD deficiency have increased susceptibility to oxidant drugs. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Inciting drugs, chemicals, foods, illnesses'.)

Oxidant injury can be especially severe in individuals with G6PD deficiency; however, some drugs can cause oxidant injury in individuals without G6PD deficiency. Thus, a history of G6PD deficiency may be helpful if present, but a negative history cannot be used to eliminate the possibility of oxidative hemolysis. (See 'Typical presentation/when to suspect drug-induced hemolysis' below.)

Hemoglobin H disease – Thalassemic RBCs have increased generation of reactive oxygen species, and elevated levels of antioxidant enzymes in RBCs from individuals with thalassemia suggest ongoing induction of antioxidant mechanisms [36]. Individuals with hemoglobin H disease (alpha thalassemia with loss of three alpha chain genes) may be especially susceptible.

Oxidant injury can cause hemolysis via oxygen radical damage to RBC membrane components and cellular proteins. Oxidative injury can also lead to lipid peroxidation, crosslinking of membrane proteins, and the formation of adducts between spectrin and denatured globin [37]. Hemichromes and Heinz bodies (denatured hemoglobin intermediates and precipitated forms, respectively) can interfere with membrane function both directly or via oxidation of membrane proteins and lipids [38]. (See "Unstable hemoglobin variants", section on 'Hemoglobin precipitation and Heinz body formation'.)

These erythrocytes also have decreased deformability, a characteristic that promotes trapping in the spleen and in other sinusoidal structures. This trapping can occur regardless of whether Heinz bodies are located against the membrane. Susceptibility to phagocytosis by macrophages may also be increased. This in turn leads to splenic culling of damaged cells by splenic macrophages. (See "Splenomegaly and other splenic disorders in adults", section on 'Properties of the normal spleen'.)

In some cases, the oxidative lesions are so severe that there is also intravascular hemolysis, with hemoglobinemia and hemoglobinuria.

Oxidative stress is associated with the formation of blister cells (picture 1) and bite cells. Blister cells result from puddling of hemoglobin on one side of the cell and an empty veil of membrane on the other side. Bite cells result from splenic macrophage-mediated removal of this hemoglobin at the edge of the cell. (See 'Peripheral blood smear review' below.)

Methemoglobinemia — Methemoglobinemia is not always associated with hemolysis but may cause hemolysis in some cases, and treatment of methemoglobinemia with methylene blue can cause hemolysis by increasing oxidative stress in individuals with G6PD deficiency. Ascorbic acid (vitamin C) is recommended to treat methemoglobinemia in G6PD-deficient patients. (See "Methemoglobinemia", section on 'Ascorbic acid (vitamin C)'.)

Methemoglobin results from oxidation of the iron in heme (removal of an electron, with conversion from the reduced form [ferrous iron; Fe2+] to the oxidized form [ferric iron; Fe3+]) [39]. In normal physiology, this process can be coupled with one of several other redox reactions such as the reduction of nicotinamide-adenine dinucleotide (NAD) to NADH or the reduction of hydrogen peroxide (H2O2) to water (H2O). (See "Methemoglobinemia", section on 'What is methemoglobin?'.)

Methemoglobin levels are usually kept low (typically <1 to 3 percent) by the enzymes cytochrome b5 reductase (also called diaphorase or methemoglobin reductase) and NADPH-(flavin) methemoglobin reductase or by nonenzymatic processes [37,38]. However, these processes can become overwhelmed in the setting of significant oxidant stress induced by drugs. (See "Methemoglobinemia", section on 'How are the levels regulated?'.)

The 2021 Recommendations for diagnosis and treatment of methemoglobinemia provide an overview of acquired forms (the most common, mainly due to oxidating substances) and inherited forms, which are due either to autosomal recessive variants in the cytochrome b5 reductase gene or to autosomal dominant variants in the globin genes, collectively known as Hb M disease [40]. Commonly implicated drugs include topical anesthetics such as benzocaine or lidocaine (sprays or creams used for endoscopy or transesophageal echocardiography, even at small doses), primaquine, dapsone, and nitrites (nitroglycerin or nitric oxide) [39,41]. (See "Methemoglobinemia", section on 'Causes of methemoglobinemia'.)

Some of these drugs cause methemoglobin formation via direct oxidation of the heme in hemoglobin; others produce oxygen free radicals that oxidize the heme [25].

There are two major adverse consequences:

Decreased tissue oxygenation – The ferric hemes in methemoglobin cannot bind oxygen, and the ferrous hemes complexed with them have a left-shifted hemoglobin-oxygen dissociation curve (figure 3) [42]. Patients can become severely cyanotic due to decreased oxygen delivery to the tissues.

Hemolysis – Methemoglobin is not directly harmful to red cells. However, if there is a large oxidative assault, methemoglobin is converted to hemichromes (variably denatured hemoglobin intermediates). Continued oxidation results in irreversible hemichrome oxidation, precipitation, and eventually the formation of Heinz bodies. Removal of membrane-attached Heinz bodies via the monocyte-macrophage system in the spleen can produce bite cells (picture 1) [43,44].

Intravenous methylene blue is the primary treatment for symptomatic methemoglobinemia; methylene blue is converted to leukomethylene blue, which then reduces the heme group from methemoglobin to hemoglobin via the NADPH-dependent hexose monophosphate shunt pathway. (See 'Therapy for methemoglobinemia' below.)

The reduction of methemoglobin by methylene blue depends on NADPH generated by G6PD. In individuals with G6PD deficiency, methylene blue may be ineffective and is potentially dangerous since it has oxidant potential that may worsen hemolysis [45-47]. (See 'Considerations in individuals with G6PD deficiency' below.)

Thrombotic microangiopathy — The mechanisms of drug-induced thrombotic microangiopathy (DITMA), which can include immune-mediated and non-immune processes (table 4), are discussed separately. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Pathophysiology'.)

Purine analogs — Purine analogs (fludarabine, pentostatin, and cladribine) are all associated with a higher risk of autoimmune hemolytic anemia when administered in the setting of lymphoproliferative disorders. The data are most compelling with fludarabine, especially in the setting of chronic lymphocytic leukemia (CLL). Most, but not all cases, are associated with a positive direct antiglobulin test [48,49]. (See "Overview of the complications of chronic lymphocytic leukemia", section on 'Autoimmune hemolytic anemia'.)

Management includes discontinuation of the purine analog and treatment with a glucocorticoid, similar to other drug-induced immune hemolysis. (See 'Drug discontinuation' below and 'Therapies for AIHA' below.)

Other mechanisms

Ribavirin is an orally active nucleoside analog antiviral agent used to treat hepatitis C virus (HCV) infection. It has been associated with a dose-dependent hemolytic anemia associated with a reduction in erythrocyte ATP. Polymorphisms of the enzyme inosine triphosphatase (ITPA) may be involved in this process. Hemolysis resolves upon discontinuation and stabilizes with dose reduction. This subject is discussed separately. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Ribavirin'.)

Artesunate, an artemisinin derivative, is a potent antimalarial agent. The drug kills malarial parasites, following which splenic "pitting" (removal of dead parasites from the RBCs) occurs, with reduced RBC survival in the circulation [50-52]. Clinically, this phenomenon has been associated with a brief, self-limited episode of hemolytic anemia occurring more than one week after treatment of severe malaria with parenteral artesunate (after symptoms of malaria have resolved) [53,54]. (See "Treatment of severe malaria".)

Acute and occasionally severe hemolytic anemia is a rare complication of therapy with interferon alfa [55-60]. Most patients have an immune mechanism of hemolysis, but the Coombs test may be negative [60,61]. (See 'Immune-mediated' above.)

EVALUATION — The first step in evaluating suspected drug-induced hemolytic anemia is to recognize the signs and symptoms of hemolysis. (See "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults", section on 'Laboratory confirmation of hemolysis'.)

Symptoms should be reviewed and a history of exposures obtained, with a focus on new medications as well as other possible drug or chemical exposures when the hemolysis began (and the timing relative to the initiation of new medicines). Causative drugs are listed above. (See 'Lists of commonly implicated drugs' above.)

When drug-induced hemolytic anemia is suspected, inspection of the peripheral blood smear can help determine the suspected type of hemolysis, which can have major implications for further testing and for management. (See 'Peripheral blood smear review' below.)

More specialized testing is based on the implicated drug(s) and on other clinical manifestations. (See 'Laboratory testing based on initial findings' below.)

Typical presentation/when to suspect drug-induced hemolysis — Drug-induced hemolytic anemia is often acute and severe, and it may occur at various intervals following introduction of the drug. In a series of children who developed hemolytic anemia with ceftriaxone, symptom onset was sudden and often within one hour of receiving the drug, with intravascular hemolysis and hemoglobin levels decreasing to <5 g/dL [62]. Many of these children had received ceftriaxone on previous occasions without obvious reactions.

When hemolysis is severe, patients may experience sudden onset of pallor, fatigue, jaundice, dark urine, abdominal pain, or back pain. Typical symptoms of hemolytic anemia include those associated with anemia (fatigue, weakness, dyspnea, symptoms related to volume depletion) as well as hemolysis (jaundice; in some cases dark or red urine due to hemoglobinuria). These are discussed in more detail separately. (See "Diagnosis of hemolytic anemia in adults", section on 'History and physical examination'.)

In others, hemolysis begins within days to weeks of exposure to a new drug. Oxidative stress is usually the most acute, followed by drug-induced autoimmune hemolytic anemia (AIHA). Drug-induced thrombotic microangiopathies (DITMA) may have an acute or subacute onset and may start weeks or even months after exposure to the putative agent.

Certain types of drug-induced hemolysis have other characteristic features that may increase the clinical suspicion:

Oxidative hemolysis – Glucose-6-phosphate dehydrogenase (G6PD) deficiency is more common in persons with African, Asian, or Mediterranean ancestry; however, it can be observed in any ethnic background and many drugs can cause oxidative hemolysis in individuals who do not have G6PD deficiency (table 2). Any history of prior similar episodes with oxidant drug or food exposure that would suggest G6PD deficiency is also relevant. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

Autoimmune hemolysis – There may be a history of exposure to a drug known to cause AIHA (table 1).

Thrombotic microangiopathy – There may be a history of exposure to quinine (table 5) or a drug associated with DITMA (table 4).

Methemoglobinemia – Classic symptoms of methemoglobinemia include cyanosis with a normal arterial oxygen tension (PaO2) and a dark brown (chocolate color, dark red, or brownish blue) appearance of the blood that does not resolve upon oxygenation. Methemoglobin levels less than 15 percent are usually asymptomatic; levels of 50 percent or more are life-threatening. Methemoglobinemia and associated hemolysis may be more pronounced in individuals with G6PD deficiency [29]. Inherited forms, both the autosomal recessive variants of the cytochrome b5 reductase or the autosomal dominant Hb M diseases, are more susceptible to oxidants. The diagnosis requires specialized enzyme activity and genetic testing. (See "Methemoglobinemia".)

Peripheral blood smear review — Suspected drug-induced hemolytic anemia is evaluated by reviewing the blood smear, which can be used to determine the likely cause(s) and appropriate laboratory testing. Attention should be paid to the following:

Bite cells, blister cells, or irregularly shaped red blood cells (poikilocytosis) suggest oxidative hemolysis (picture 1).

Spherocytes or microspherocytes suggest immune hemolysis (picture 2).

Schistocytes suggest a thrombotic microangiopathy (TMA) or other cause of microangiopathic hemolytic anemia such as disseminated intravascular coagulation (DIC) (picture 3).

Additional findings that may be present on the blood smear are discussed in more detail separately. (See "Evaluation of the peripheral blood smear".)

Laboratory testing based on initial findings

Commonly used tests — Patients being evaluated for drug-induced hemolysis or drug-induced hemolytic anemia are presumed to already have documented hemolytic anemia, with one or more of the typical findings such as low haptoglobin, elevated reticulocyte count, and high lactate dehydrogenase (LDH) or indirect bilirubin, as listed in the table (table 6). Haptoglobin is an acute phase reactant; thus, it may be normal in patients with concomitant infection or inflammation [63]. The general approach to evaluating and confirming hemolytic anemia is presented separately. (See "Diagnosis of hemolytic anemia in adults", section on 'Diagnostic approach'.)

The following tests are often appropriate for suspected drug-induced hemolysis:

DAT (Coombs test) – The direct antiglobulin test (DAT) is one of the first tests done when the cause of hemolysis is unclear. If a drug is suspected and the mechanism is not obvious, DAT (Coombs) testing is appropriate. (See "Diagnosis of hemolytic anemia in adults", section on 'Cause not obvious - start with Coombs test'.)

Reports have described positive DAT for immunoglobulin (Ig) G and complement (C3, related to ceftriaxone), as well as IgM antibodies in serum [62]. Penicillin reactions may be negative for C3 [64].

A positive DAT (Coombs test) is consistent with immune hemolysis. It does not distinguish between drug-induced autoimmune hemolysis, autoimmune hemolysis unrelated to a drug, or alloimmune hemolysis (associated with transfusion or other exposure to allogeneic blood). However, a positive DAT does not eliminate the possibility of a non-immune mechanism since some individuals have a positive DAT that is not clinically significant. Likewise, a negative DAT does not always eliminate the possibility of an immune mechanism. (See 'Purine analogs' above.)

Hapten and drug-independent antibodies (eg, methyldopa) most often have a DAT positive for IgG, while the immune complex type is typically only positive for complement. A type and screen should also always be performed. The immune complex type and hapten type do not generally have any reactivity in the standard indirect antiglobulin test. A panagglutinin suggests a drug-independent type of antibody. To distinguish, an eluate can be performed, which should be positive with drug-independent and negative if hapten or immune complex type. The type and screen will also be useful if the patient needs a transfusion (and the serology may be complex for ruling out underlying alloantibodies, especially drug-independent types).

Additional details of the evaluation are presented separately. (See "Overview of hemolytic anemias in children", section on 'Diagnostic approach' and "Diagnosis of hemolytic anemia in adults".)

G6PD testing – Testing for G6PD deficiency is appropriate if oxidative hemolysis is suspected. Typically this involves using an assay of G6PD activity. This testing may be negative in the setting of severe hemolysis (because all of the G6PD-deficient cells have been destroyed), and repeat testing following recovery may be warranted. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Diagnostic evaluation'.)

Additional tests for selected individuals — Additional testing may be appropriate for certain drugs and certain clinical manifestations.

Testing for intravascular hemolysis — Hemolysis can occur extravascularly (in the spleen and/or liver) or intravascularly (in the circulation). Extravascular hemolysis is typical of drug-induced AIHA and oxidant injury, but in severe cases, there may be a component of intravascular and extravascular hemolysis.

Intravascular hemolysis due to a drug can occur in drug-induced thrombotic microangiopathy (DITMA) (see 'Thrombotic microangiopathy' above). This can cause serious complications including acute kidney injury and disseminated intravascular coagulation due to the release of free hemoglobin or heme into the circulation. (See "Diagnosis of hemolytic anemia in adults", section on 'Site of RBC destruction'.)

Intravascular hemolysis may be suspected in an individual with abdominal or back pain, dark (or red) urine, or dark (or red) serum or plasma. If suspected, testing should be performed with the following:

Serum or plasma for free hemoglobin

Coagulation testing (prothrombin time [PT], activated partial thromboplastin time [aPTT], and fibrinogen)

Review of the blood smear for other causes of intravascular hemolysis (eg, schistocytes, suggestive of disseminated intravascular coagulation [DIC] or a TMA). (See 'Testing for a TMA' below.)

Flow cytometry to evaluate for possible paroxysmal nocturnal hemoglobinuria (PNH; may be omitted if there are obvious schistocytes on the blood smear)

Testing for a TMA — Thrombotic microangiopathies (TMAs) can be drug-induced or due to another condition such as thrombotic thrombocytopenic purpura (TTP; due to severe ADAMTS13 deficiency) or a defect in complement regulation.

It is often appropriate to test for TTP in patients with suspected TMA because TTP is potentially life-threatening and therapeutic plasma exchange can be life-saving. The approach to suspected TMA and typical findings related to DITMA are discussed in detail separately. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Drug-induced thrombotic microangiopathy (DITMA)".)

Drug-dependent antibody testing — Drug-dependent antibody testing can be used to evaluate suspected drug-induced autoimmune hemolytic anemia (AIHA), such as with drugs known to cause AIHA (table 1) or microspherocytes on the blood smear.

However, there are several caveats with the use of this testing that make it unsuitable for immediate management decisions:

It is often impossible to reliably distinguish between the blood smear findings of warm AIHA from drug-induced AIHA because microspherocytes will be present in both cases.

Testing for drug-dependent antibodies can only be performed in specialized laboratories, and the turnaround time is approximately one week.

Thus, detection of drug-dependent antibodies does not appreciably alter immediate management, as long as the responsible drug has been stopped.

Detection of drug-dependent antibodies can be useful to avoid future drug-induced hemolytic anemia, and this testing can be especially helpful in patients with acute-onset, unexplained hemolytic anemia temporally associated with the addition of a medication or drug that is associated with drug-induced hemolytic anemia (eg, a penicillin or a cephalosporin).

MANAGEMENT

Overview of management — The intensity of intervention depends on the severity of hemolysis, which can range from mild, asymptomatic or unrecognized hemolysis without anemia to fatal hemolytic reactions [2,62]. The severity of hemolysis is typically apparent from the degree of anemia, lactate dehydrogenase (LDH) and bilirubin elevations, and presence of free heme in the serum and urine. (See 'Commonly used tests' above and 'Testing for intravascular hemolysis' above.)

Discontinuation of the presumed offending drug is the cornerstone of treatment. (See 'Drug discontinuation' below.)

In severe disease, aggressive therapy must be directed toward the anemia (eg, transfusion). Transfusion may be helpful in patients who are in shock [65]. If present, other hematologic complications of the drug such as thrombocytopenia may also require treatment. (See 'Indications for transfusions' below and "Drug-induced thrombotic microangiopathy (DITMA)".)

Individuals with intravascular hemolysis who develop acute kidney injury (AKI), kidney failure, and/or disseminated intravascular coagulation (DIC) may require aggressive hydration, dialysis, and other supportive care. (See "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

For some individuals with hemolytic anemia of unclear mechanism in which the role of a medication(s) is unclear, it may be prudent to give presumptive treatment for the other possible causes until the results of definitive testing are available. Hematology and transfusion medicine input may be sought in these decisions. (See 'Therapies for AIHA' below.)

Autoimmune hemolytic anemia (AIHA) cases following immune checkpoint inhibitors, which are often severe, require discontinuation of the drug, transfusions, administration of steroids, intravenous immune globulins, plasma-exchange, and rituximab in some relapsed/refractory patients. One of the main discussed issues is the rechallenge with immune checkpoint inhibitor after complete resolution of AIHA, as experience is very limited.

For those with methemoglobinemia, therapy such as methylene blue may be appropriate, as long as the individual does not have glucose-6-phosphate dehydrogenase (G6PD) deficiency. Treatment of methemoglobinemia in the setting of G6PD deficiency is usually done with ascorbic acid. (See 'Therapy for methemoglobinemia' below and 'Considerations in individuals with G6PD deficiency' below.)

Drug discontinuation — The principle treatment for drug-induced hemolytic anemia is removing the exposure by discontinuing the implicated drug(s). This is done in virtually all patients with hemolytic anemia and a high likelihood of a drug-induced mechanism.

In most cases, eliminating exposure to the implicated drug is sufficient for management. Hemolysis will abate, and the hemoglobin level will rise over the next few days to weeks, with no further interventions needed. The rate of recovery depends on the rate of clearance of the drug (or a drug metabolite responsible for hemolysis).

The implicated drug should be clearly noted in the patient's medical record and is generally avoided indefinitely. It is appropriate to list the medication in the drug allergy section of the medical record. In some cases such as oxidant hemolysis leading to a new diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency, other drugs in the same class should also be avoided. (See 'Considerations in individuals with G6PD deficiency' below.)

Generally, individuals with chronic lymphocytic leukemia (CLL) who develop immune hemolysis related to a purine analog (such as fludarabine) should avoid the drug, especially since many other options are available. There may be individuals for whom fludarabine can be restarted as part of a combination regimen, although this is rare since fludarabine is seldom used for CLL. (See "Overview of the treatment of chronic lymphocytic leukemia".)

Indications for transfusions — Red blood cell transfusions are given for severe, symptomatic anemia or anemia that is rapidly progressing and expected to become severe without transfusion.

Typically a threshold of 7 g/dL is used, but this does not replace the judgment of the treating clinician(s) in deciding whether a higher or lower threshold is suitable for the patient based on their age (young people can often tolerate a lower hemoglobin level), medical history, and severity of symptoms. (See "Red blood cell transfusion in infants and children: Indications" and "Indications and hemoglobin thresholds for RBC transfusion in adults".)

If possible, blood for certain testing may be obtained prior to starting the transfusions, but if needed, transfusions should not be withheld while obtaining or awaiting the results of laboratory testing. (See 'Laboratory testing based on initial findings' above.)

It may be challenging to find crossmatch-compatible blood in an individual with a positive indirect antiglobulin test (IAT; indirect Coombs test) (see 'Commonly used tests' above), as this may mask underlying alloantibodies. However, blood should not be withheld due to crossmatch incompatibility for individuals with serious or life-threatening anemia. The transfusion medicine service or blood bank can assist in weighing the risks and benefits of transfusion in this setting. Transfusion may be lifesaving in individuals with severe anemia. (See "Red blood cell (RBC) transfusion in individuals with serologic complexity", section on 'Communication'.)

Therapies for AIHA — The primary therapy for drug-induced AIHA is drug discontinuation.

Symptomatic autoimmune hemolytic anemia (AIHA), including drug-induced AIHA, can be treated with immunomodulatory therapies including glucocorticoids and/or intravenous immune globulin (IVIG). Often these therapies are used when it is not immediately clear whether the cause is drug induced or autoimmune without a drug and/or when the anemia is severe and there is insufficient time to observe for a response to drug discontinuation. Typical dosing is equivalent to prednisone 1 to 2 mg/kg daily. Details of dosing and supporting evidence are presented separately. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Glucocorticoids with or without rituximab as first-line agents'.)

Glucocorticoids and IVIG may be omitted in asymptomatic individuals.

In a series from 2019, glucocorticoids were effective for most cases of AIHA associated with immune checkpoint inhibitors [2]. Severe and relapsing cases of AIHA following immune checkpoint inhibitor therapy may require further therapies including IVIG, therapeutic plasma exchange, and/or rituximab.

Therapy for methemoglobinemia — Hemolysis is often a consequence of drug-induced methemoglobinemia (table 3). Symptoms typically occur with methemoglobin levels greater than 15 to 20 percent; levels of 50 percent or more are life-threatening (table 7). (See 'Methemoglobinemia' above.)

Treatment to reduce the level of methemoglobin is indicated in symptomatic patients. This is discussed in detail separately and summarized briefly below. (See "Methemoglobinemia", section on 'Management (acquired/toxic)'.)

Methylene blue – First-line therapy for symptomatic methemoglobinemia typically involves administration of methylene blue (MB; given intravenously at a dose of 1 to 2 mg/kg over 5 minutes [in a 1 g/dL solution]). MB provides an artificial electron acceptor for the reduction of methemoglobin to hemoglobin. It has a rapid and dramatic action and is the treatment of choice in the majority of patients who require treatment. However, MB should be avoided in individuals with G6PD deficiency, and caution should be used to avoid overdosage. Since co-oximetry detects MB as methemoglobin, this technique cannot be used to follow the response of methemoglobin levels to treatment with MB. Dosing and details of MB administration are presented separately. (See "Methemoglobinemia", section on 'Methylene blue (MB)'.)

Lack of a rapid response to methylene blue (failure of the blood to turn from chocolate color to normal red color; failure of the methemoglobin level to decrease) is highly suggestive of concomitant G6PD deficiency. (See 'Mechanisms' above.)

Supportive care including dextrose – Supportive care may include hydration, oxygenation, or mechanical ventilation. Dextrose should be given, as it provides a source of nicotinamide adenine dinucleotide (NADH) via glycolysis [25].

Ascorbic acid – Ascorbic acid (vitamin C) is an alternative treatment for symptomatic methemoglobinemia; this is the treatment of choice in individuals with G6PD deficiency. In the acute setting, it should be administered intravenously with doses up to 10 grams daily. (See 'Considerations in individuals with G6PD deficiency' below.)

Oral vitamin C at a dose of 300 to 600 mg daily can be used as an adjuvant to methylene blue in patients without G6PD deficiency.

Hemoperfusion – In certain poisonings such as with paraquat (inadvertent or by attempted suicide), profound methemoglobinemia can develop rapidly (to levels of 20 to 100 percent within hours) and may be followed by Heinz body hemolytic anemia [66,67]. Treatment may include hemoperfusion. (See "Enhanced elimination of poisons", section on 'Extracorporeal removal'.)

Considerations in individuals with G6PD deficiency — Individuals with suspected or documented G6PD deficiency generally can be treated with drug discontinuation. However, additional considerations may apply in some cases:

Severe anemia – Transfusions may be indicated for severe anemia and aggressive hydration may be prudent if there is a major component of intravascular hemolysis. (See 'Indications for transfusions' above and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Treatment of acute hemolytic episodes'.)

Methemoglobinemia – Individuals with G6PD deficiency who also have methemoglobinemia should not be treated with methylene blue, because methylene blue can cause oxidative hemolysis in these individuals and potentially worsen anemia. Further, methylene blue is unlikely to help in the setting of G6PD deficiency because its mechanism of action requires generation of nicotinamide adenine dinucleotide phosphate (NADPH), which is impaired in G6PD-deficient individuals.(See 'Oxidant injury' above.)

Options for treating methemoglobinemia in individuals with G6PD deficiency who have symptomatic methemoglobinemia include ascorbic acid (vitamin C) and exchange transfusions. Vitamin C is given intravenously at doses up to 10 grams daily [68,69]. Exchange transfusions have been used with reported success in severe cases [45,46,70]. (See "Methemoglobinemia", section on 'Management (acquired/toxic)'.)

Avoidance of other unsafe drugs – Members of the care team should be made aware of the diagnosis of G6PD deficiency, and the importance of avoiding other unsafe drugs and unsafe foods should be emphasized. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Avoidance of unsafe drugs and chemicals' and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Dietary restrictions'.)

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: Anemia in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Glucose-6-phosphate dehydrogenase deficiency (The Basics)" and "Patient education: Autoimmune hemolytic anemia (The Basics)")

SUMMARY AND RECOMMENDATIONS

Lists of drugs – Drugs can cause hemolysis by various mechanisms. The tables list commonly implicated drugs based on mechanism:

Immune (antibody-mediated), which can be drug-dependent or drug-independent (table 1)

Oxidation (table 2)

Methemoglobinemia (table 3)

Thrombotic microangiopathy (TMA) (table 4)

Details are discussed above. (See 'Lists of commonly implicated drugs' above and 'Mechanisms' above.)

Initial evaluation – The first step is recognizing signs and symptoms of hemolysis. The exposure history focuses on new medications and other drug or chemical exposures. (See 'Typical presentation/when to suspect drug-induced hemolysis' above.)

Blood smear – The peripheral blood smear helps determine the suspected type of hemolysis. Bite and blister cells suggest oxidative hemolysis (picture 1), which can occur in individuals with or without glucose-6-phosphate dehydrogenase (G6PD) deficiency; spherocytes suggest immune hemolysis (picture 2); and schistocytes suggest a TMA (picture 3). Some causes of drug-induced hemolysis are medical emergencies; if a blood smear is not available it should be requested and reviewed as promptly as possible. (See 'Peripheral blood smear review' above.)

Laboratory testing – Testing is guided by the clinical presentation and suspected culprit drug(s). Typical findings associated with hemolysis include decreased haptoglobin, increased lactate dehydrogenase (LDH), and increased indirect bilirubin, as summarized in the table (table 6). (See 'Laboratory testing based on initial findings' above.)

Immune hemolysis causes a positive direct antiglobulin (Coombs) test (DAT). Intravascular hemolysis produces free heme in blood or urine. Individuals with thrombotic thrombocytopenia (schistocytes on the blood smear) have ADAMTS13 deficiency. Type and screen may be performed. Drug-dependent antibody testing is generally not needed for managing acute immune-mediated hemolysis but may be helpful for guiding future drug avoidance. (See 'Additional tests for selected individuals' above.)

Stop the drug – The main treatment for drug-induced hemolysis is drug discontinuation; in most cases, the hemoglobin level increased over days to weeks. The drug should be avoided indefinitely. In some cases, drugs of a similar class are also avoided. The plan for future drug avoidance should be clearly indicated in the medical record. (See 'Drug discontinuation' above.)

Transfusions – Blood transfusions are given for severe anemia (eg, hemoglobin <7 g/dL), or anemia that is expected to become severe without transfusion. Transfusions should not be withheld while obtaining or awaiting the results of laboratory testing or in complex crossmatching situations due to drug-induced red blood cell antibodies. The transfusion medicine service or blood bank can help weigh the risks and benefits of transfusion and provide emergency release blood if needed. (See 'Indications for transfusions' above.)

Other interventions – Additional therapies may be required for selected individuals:

Glucocorticoids and/or intravenous immune globulin (IVIG) for immune hemolysis. (See 'Therapies for AIHA' above.)

Methylene blue, ascorbic acid, or hemoperfusion for methemoglobinemia. (See 'Therapy for methemoglobinemia' above.)

Non-drug causes of hemolysis – General approaches to evaluating hemolysis are presented separately. (See "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults".)

ACKNOWLEDGMENTS — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

The UpToDate editorial staff also acknowledges the extensive contributions of William C Mentzer, MD, to earlier versions of this and many other topic reviews.

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