Drug-Induced+Hematologic+Disorders_Bailey_2024.pdf

Drug-Induced Hematologic Disorders Lauren Bailey, PharmD, BCOP Clinical Pharmacy Specialist Harris Health System Integrated Hematology/Oncology Module – PHAR 5367 January 16, 2024 Learning Objectives Integrated Hematology/Oncology Module - PHAR 5367 1. Differentiate between the most common drug-...

Drug-Induced Hematologic Disorders Lauren Bailey, PharmD, BCOP Clinical Pharmacy Specialist Harris Health System Integrated Hematology/Oncology Module – PHAR 5367 January 16, 2024 Learning Objectives Integrated Hematology/Oncology Module - PHAR 5367 1. Differentiate between the most common drug-induced hematologic disorders, their pathophysiology, and diagnoses criteria 2. Describe the proposed mechanisms for the development of druginduced hematologic disorders 3. Recognize common drugs that can lead to common hematologic disorders 4. Determine the management of patients with drug-induced hematologic disorders Introduction • Hematologic disorders are a long potential risk of modern pharmacotherapy • Sulfanilamide was first reported to be associated with agranulocytosis back in 1938 • Most common drug-induced hematologic disorders are • • • • • Aplastic anemia Agranulocytosis Megaloblastic anemia Hemolytic anemia Thrombocytopenia Epidemiology • Women are more susceptible than men to the hematologic effects of drugs • More common in elderly than the young; risk of death is greater with increasing age • Drug-induced thrombocytopenia is the most common; 0.1% – 5% of patients who receive heparin develop heparin-induced thrombocytopenia (HIT) • Berlin Case-Control Surveillance Study found that ~30% of all cases of blood dyscrasias were “possibly” attributable to drug therapy Drug-Induced Hematologic Disorders (DIHD) • Associated with significant morbidity and mortality – aplastic anemia being the leading cause of death • Re-challenging a patient with a suspected agent in an attempt to confirm a diagnosis is not recommended • Can do in vitro studies with the offending agent and patient’s blood to determine causality, but this is expensive, and facility expertise are not available • Lab confirmation is not always necessary to interrupt/discontinue therapy – practitioners should clinically evaluate and interrupt therapy as needed Hematopoiesis • Stem cells further differentiate to progenitor cells • Committed to a particular cell line, progenitor cells differentiate into each type of blood cell • DIHD can affect any cell line Drug-Induced Aplastic Anemia • A rare, serious disease characterized by pancytopenia (anemia, neutropenia, thrombocytopenia), and hypocellular bone marrow • Bone marrow shows an absence/reduction of hematopoietic stem cells & and increase in fat cells Diagnosis of Drug-Induced Aplastic Anemia • Requires the presence of 2 of the following 3 criteria: • WBC count of ≤ 3,500 cells/mm3 (3.5 x 109/L) • Platelet count of ≤ 55,000 cells/mm3 (55 x 109/L) • Hemoglobin of ≤ 10 g/dL with a reticulocyte count of ≤ 30,000 cells/mm3 (30 x 109/L) • Requires a bone marrow biopsy to rule out other causes of pancytopenia • Patient must not have had previous exposure to cytotoxic chemotherapy or intensive radiation • Depending on the blood counts, can be classified as moderate, severe, or very severe Diagnosis of Aplastic Anemia 2 of the following 3 criteria! Moderate aplastic anemia (MAA) Neutrophils Platelets Hemoglobin <1,500 cells/mm3 (1.5 x 109/L) <50,000 cells/mm3 (50 x 109/L) < 10 g/dL Neutrophils Platelets Reticulocytes <20,000 cells/mm3 (20 x 109/L) < 1% Neutrophils Platelets Reticulocytes <200 cells/mm3 (0.2 x 109/L) <20,000 cells/mm3 (20 x 109/L) < 1% Severe aplastic anemia (SAA) <500 cells/mm3 (0.5 x 109/L) Very severe aplastic anemia (VSAA) Mechanism of Drug-Induced Aplastic Anemia • Inherited • Results in bone marrow failure, fatty infiltration of the marrow, and loss of circulating blood cells • Examples: Fanconi’s anemia and Blackfan Diamond anemia • Acquired • Results from drugs, radiation, viruses, or chemical exposure; accounts for most cases of aplastic anemia • An idiosyncratic reaction, with unpredictable severity and time to recovery 3 Mechanisms of Acquired Aplastic Anemia 1. Direct toxicity • Characterized by dose independence, a latent period before the onset of anemia, continued marrow injury after drug discontinuation 2. Metabolite-driven toxicity • Metabolites of drugs bind to proteins and DNA on hematopoietic cells, bone marrow failure can occur 3. Immune-mediated mechanisms (most common) • Exposure to the drug (inciting antigen) activates the immune system, leading to the death of stem cells • Explains the responsiveness of the disease to immunosuppressive therapy Chloramphenicol • Example of an idiosyncratic mechanism • A broad spectrum antibiotic introduced in 1948, but now rarely used since it was shown to cause serious and fatal aplastic anemia • Incidence of chloramphenicol-induced aplastic anemia is 1 in 20,000 patients treated • Overall prevalence has declined with decreased use of this agent Phenytoin and Carbamazepine • Examples of drugs thought to induce aplastic anemia through toxic metabolites • Metabolites of these medications bind covalently to macromolecules in the cell, and cause cell death • Exert a direct toxic effect on the stem cell or • Cause the death of lymphocytes involved in regulating hematopoiesis Treatment of Drug-Induced Aplastic Anemia • Rapid diagnosis and immediate therapy initiation; high mortality rate with SAA and VSAA, with infections and bleeding being the major causes of death • Goals of therapy • Improve peripheral blood counts • Limit the requirement for transfusions • Minimize the risk for infections Treatment of Drug-Induced Aplastic Anemia 1. Remove the suspected offending agent; can allow for reversal of AA 2. Appropriate supportive care 1. Transfusion support with RBCs and platelets • Iron chelation therapy with drugs like deferoxamine (Desferal) or deferasirox (Jadenu) to avoid iron overload in those heavily transfused 2. Antimicrobial and antifungal prophylaxis only when neutrophils are < 500 cells/mm3 (0.5 x 109/L) • Prophylaxis for viruses or PJP are not recommended 3. If patient has febrile neutropenia, broad-spectrum IV antibiotics should be initiated • G-CSF does not improve outcomes and is not recommended, except when lifethreatening infections are present Treatment of Drug-Induced Aplastic Anemia 3. Allogeneic hematopoietic stem cell transplantation (HSCT) • Treatment of choice for healthy patients < 50 yo from an HLA-matched sibling donor • Can consider HLA-matched unrelated donor (MUD), but usually for those who fail prior immunosuppressive therapy • Complications like GVHD and graft rejection, need close monitoring 4. Immunosuppressive therapy • Treatment of choice for patients > 50 yo, not candidates for transplant due to comorbidities or no available match Immunosuppressive Therapy for AA • Cyclosporine + Antithymocyte globulin (ATG) • Combination reported to achieve 5 yr survival rates between 75-85% • Response is often delayed (3-4 months) • Monitor for adverse effects such as serum sickness, can occur 1 week after ATG begins • Corticosteroids are added to reduce adverse reactions associated with ATG administration (serum sickness) Cyclosporine • MOA: inhibits interleukin-2 production and release, and subsequent activation of resting T-cells • Dosing: varied, but most frequently reported initial dose is 5 mg/kg/day in 2 divided doses • Doses are titrated to a target blood concentration typically between 150-250 mcg/L • Should be continued at least 12 months after response, and then tapered slowly • Renal and liver function monitoring is required; hypertension and gingival hypertrophy are common side effects ATG • Composed of polyclonal immunoglobulin G (IgG) against human T lymphocytes derived from either horses or rabbits • Horse vs. rabbit product, the horse-derived ATG product resulted in significantly higher response rates (68% vs 37%) and 3 yr OS rates (96% vs 76%) • Greater depletion of CD4+ cells associated with the rabbit ATG may be associated with adverse outcomes • Horse ATG product is the preferred initial immunosuppressive treatment Other agents for Aplastic Anemia • Alemtuzumab or high dose cyclophosphamide for relapsed/refractory disease may achieve remission rate of 50% • Addition of G-CSF to cyclosporine + ATG à high response rates, but does not prolong survival • Eltrombopag, a thrombopoietin non-peptide agonist, has been used in treatment of SAA in combo with ATG and cyclosporine • Desmond et al. study showed response rate at 6 months was 85%; survival approached 90% • Starting dose is 50 mg once daily, titrated up based on platelet response Drug-Induced Agranulocytosis • A reduction in the total number of mature myeloid cells (granulocytes and immature granulocytes [bands]) to ≤ 500 cells/mm3 (0.5 x 109/L) • Older patients at greater risk due to increased medication use; occurs more frequently in women than men Clinical Presentation • Rare reaction • Increased infection risk with lack of WBCs • Symptoms include sore throat, fever, malaise, weakness, chills – may appear immediately or insidiously • Can develop 19-60 days after exposure of the offending drugs; typical onset is 1 month after drug initiation 2 Mechanisms of Drug-Induced Agranulocytosis 1. Direct toxicity • Due to the parent drug or toxic metabolite or byproduct • Associated with a slower decline in neutrophils (more insidious presentation) 2. Immune-mediated toxicity • Occurs within days to a few weeks after drug exposure, with rapid appearance of symptoms • Hapten mechanism; when drug or its metabolite binds to the membrane of neutrophils or myeloid precursors, which induces antibodies that destroy the cell • Immune-complex mechanism; when antibodies form complexes with the causative drug, complex adheres to the target cell, leading to cell destruction • Autoimmune mechanism; drug triggers the production of autoantibodies that react with neutrophils Drugs Associated with Agranulocytosis • Antipsychotics, antibiotics, antithyroid medications commonly implicated • Prophylthiouracil and methimazole (particularly long term, low doses) • Genetic variants associated - HLA alleles HLA-B*38:02 and HLA-DRB1*08:03 in ethnic Chinese and HLA-B*27:05 in white European adults • Ticlodipine • Causes neutropenia & agranulocytosis by inhibiting hematopoietic progenitor stem cells, occurs 1-3 months after drug initiation • Clozapine • Higher risk of agranulocytosis compared with other antipsychotic medications (BBW) • Only available through a REMS program that requires strict monitoring of WBC count • Phenothiazine class • Via immune-complex mechanism; bone marrow appears to have no cellularity (aplastic), but eventually becomes hyperplastic • Trimethoprim-sulfamethoxazole and β-lactam antibiotics • Via hapten mechanism or accumulation of drug to toxic concentrations in hypersensitive individuals Treatment of Drug-Induced Agranulocytosis 1. Removal of the drug; counts return to normal within 2-4 weeks 2. G-CSF 300 mcg/day subQ injection • Recommended in patients with an absolute neutrophil count < 100 cells/mm3 (0.1 x109/L), regardless of the presence of infection • Sargramostim (GM-CSF) and filgrastim (G-CSF) shorten duration of neutropenia, length of abx therapy, and hospital stay length 3. Supportive care and management of infection (i.e. initiation of IV abx) 4. Restarting drug is not recommended Drug-Induced Hemolytic Anemia • Normal RBCs survive for ~120 days, then are removed by phagocytic cells in the spleen & liver • Premature RBC destruction (hemolysis) occurs because of either defective RBCs or abnormal changes in the intravascular environment. Drugs can promote hemolysis by both processes. • Clinical presentation is variable, depends on the drug and mechanism • • • • • • Fatigue Malaise Pallor Shortness of breath Abdominal/lumbar pain Red urine Diagnosis of Drug-Induced Hemolytic Anemia • Direct Coombs test (or direct antiglobulin test) identifies foreign immunoglobulins either in the patient’s serum or on the RBCs themselves • Combines the patient’s RBCs with antiglobulin serum (Coombs reagent) • In a drug-induced process, the patient’s RBCs are coated with antibody or complement and the antibodies in the antiglobulin serum attach to the separate RBCs, creating a lattice formulation called agglutination • ‘Agglutination’ is considered positive for the presence of IgG or complement on the cell surfaces Mechanisms of Drug-Induced Hemolytic Anemia • Metabolic (oxidative) • Occurs in presence of G6PD deficiency • G6PD produces NADPH in RBCs, which keeps glutathione in a reduced state • Reduced glutathione is a substrate for glutathione perioxidase, which removes peroxide from RBCs, protecting them from oxidative stress • Without reduced glutathione (in the case of G6PD deficiency), oxidative drugs oxidize the sulfhydryl groups of hemoglobin, removing them prematurely from circulation (ie, causing hemolysis) Mechanisms of Drug-Induced Hemolytic Anemia • Immune • IgG, IgM, or both bind to antigens on the surface of RBCs and initiate their destruction through the complement and mononuclear phagocytic systems • Can either be drug-dependent (most common) or drugindependent • Drug-dependent • Involves the formation of antibodies directed against RBCs; antibodies are only present when the drug itself is present • 4 proposed mechanisms; similar to those in drug-induced agranulocytosis 4 Mechanisms of Drug-Dependent Hemolytic Anemia 1. Hapten mechanism • Haptens are drugs or molecules that cause an immune response when they bind to a protein in the body • When drug is administered again, an immune complex of drug-antidrug forms and attaches to RBCs, activating complement and leading to cell destruction 2. Immune complex • Drugs bind to an antibody to form an immune complex, which attaches to the RBC, activating complement and leading to intravascular hemolysis • The complex can detach and move onto other RBCs. RBCs are essentially victims or “innocent bystanders” of the immunologic reaction 4 Mechanisms of Drug-Dependent Hemolytic Anemia 3. Production of true RBC autoantibodies – 2 hypotheses • Drug or its metabolites act on the immune system and impair immune tolerance • Drug may bind to immature RBCs, altering the membrane antigens and inducing autoantibodies 4. Nonimmunologic protein adsorption to RBC membranes • Drugs can change the RBC membrane so that proteins attach to the cell, leading to a positive antiglobulin test Drugs Associated with Hemolytic Anemia • Over 130 drugs with evidence of causing hemolytic anemia • Piperacillin is the most commonly reported agent • Diclofenac • Fludarabine • Oxaliplatin • Cephalosporins • Patients should avoid all agents in the class; cross-reactivity may occur with the 2nd episode likely to be worse Treatment of Immune Hemolytic Anemia 1. Immediate removal of the offending agent • Hapten or autoimmune mechanism has slower onset and mild to moderate in severity • Immune complex mechanism has a sudden onset, can lead to severe hemolysis, and result in renal failure 2. Supportive care Treatment of Metabolic Hemolytic Anemia 1. Removal of the offending drug 2. Avoidance of medications capable of inducing hemolysis in those with G6PD deficiency (ex: dapsone and rasburicase) Drug-Induced Megaloblastic Anemia • When the development of RBC precursors called ‘megaloblasts’ in the bone marrow is abnormal • Caused by deficiencies in vitamin B12 or folate which impairs proliferation and maturation of hematopoietic cells, resulting in cell arrest and subsequent sequestration Diagnosis of Megaloblastic Anemia • Examination of peripheral blood shows an ↑ in the mean corpuscular hemoglobin concentration (MCHC) • Some can have normal appearing cell line, and diagnosis is made by vitamin B12 and folate levels • Megaloblastic changes are caused by direct or indirect effects of the drug on DNA synthesis, in any portion of the replication process. Drugs Associated with Megaloblastic Anemia • Antimetabolites like methotrexate • Because of its pharmacologic action on DNA replication, it’s an irreversible inhibitor of dihydrofolate reductase • Trimethoprim/sulfamethoxazole • Phenytoin and phenobarbital • Caused by either inhibiting folate absorption or by increasing folate catabolism à pt develops folate deficiency Treatment of Drug-Induced Megaloblastic Anemia • Supplementation of folic acid or vitamin B12 in adequate amounts is indicated • Trimethoprim/sulfamethoxazole à folinic acid 5-10 mg up to 4 times/day • Phenytoin or phenobarbital à folic acid 1 mg daily Drug-Induced Thrombocytopenia • Thrombocytopenia is defined as a platelet count < 100,000 cells/mm3 (100 × 109/L) or > 50% reduction from baseline values • More frequently seen in the elderly, critically ill and those exposed to TMPSMX, quinine, and GPIIb/IIIa inhibitors • Typically presents 1-2 weeks after a new drug is initiated, but can present immediately after a dose when it has been used intermittently in the past • May be associated with systemic drug concentration (ie, linezolid) • Can be misdiagnosed as idiopathic thrombocytopenic purpura (ITP) • Distinguished by severity of thrombocytopenia, timing in relation to medication administration, and the presence of bleeding which almost always accompanies drug-induced thrombocytopenia Heparin-Induced Thrombocytopenia (HIT) • Causes paradoxical increases in thrombotic rather than bleeding complications; 50% of pts with HIT develop thrombotic complications • Caused by the development of antibodies against platelet factor-4 (PF-4) and heparin complexes • Antibody formation is less common with LMWH than UFH because it doesn’t bind as well to PF-4 • Antibodies developed by pts receiving UFH react against LMWH, thus LMWH should not be used in pts with HIT Pathogenesis of HIT • IgG is the autoantibody against the heparinPF4 complex • Antibodies bind to complexes, platelet activation and aggregation occur, and subsequent release of more circulating PF-4 to interact with heparin • Platelets can bind to each other and become activated via the IgG-FC receptor interaction, the PF4-PF4 receptor interaction, or both àAggregation and thrombus formation may occur • IgG may bind to the endothelial cell-bound heparin-PF4 construct and cause vascular damage, which also provokes thrombus formation Types of Heparin-Induced Thrombocytopenia (HIT) • Type I • Most common, occurs in 10-20% of pts treated with heparin • Mild, reversible, nonimmune-mediated, usually occurs within first 2 days of therapy • Platelet count returns to baseline despite continued heparin therapy; not considered clinically significant • Type II • Presents with a low platelet count (<150k), or 50% or more decrease in platelet count from the highest platelet count value after initiation of heparin; thrombosis may be present • Platelet count declines 5-10 days after the start of heparin, but decline can occur hours after heparin if patient had recently received heparin (ie, within 100 days) • Occurs in 1 of every 5,000 hospitalized patients and in 1-3% of patients s/p cardiac surgery • Risk is higher in those receiving UFH as compared to LMWH Diagnosis of HIT • ‘4T’ scoring system • • • • Thrombocytopenia (magnitude) Timing of platelet count fall Thrombosis or other sequalae Other causes for thrombocytopenia • If high probability of HIT, lab tests like platelet activation assays, platelet aggregation studies and enzyme-linked immunosorbent assays should be done Treatment of Heparin-Induced Thrombocytopenia (HIT) • Goal of therapy: reduce the risk of clotting • D/C all forms of heparin (including flushes) • Start alternative anticoagulants, such as direct thrombin inhibitors— argatroban and bivalirudin are both IV direct thrombin inhibitors that are FDA approved for this indication • Argatroban is preferred in renal insufficiency; metabolized in the liver, doseadjust in significant hepatic impairment • Bivalirudin is preferred in hepatic impairment; renally metabolized, doseadjust for patients with renal impairment Treatment of Heparin-Induced Thrombocytopenia (HIT) • Both argatroban and bivalirudin affect PTT and INR, consider dosing protocols when transitioning to warfarin • Fondaparinux • Anticoagulant pentasaccharide that inhibits factor Xa, does not cause in vitro cross reactivity with HIT antibodies • Use in HIT is off-label, but is considered a primary treatment option • Subcutaneous administration • CHEST guidelines suggest it should be used in pts with history of HIT who presently have a clot and normal renal function Treatment of Heparin-Induced Thrombocytopenia (HIT) • DOACs such as apixaban and rivaroxaban are not currently FDA approved for treatment of HIT • Used in clinical practice since they do not react with PF4 or elicit recognition from HIT antibodies • Preliminary evidence supports use of DOACs in the management of HIT • Benefits: oral dosage form, rapid onset of action, avoidance of longterm vitamin K antagonist therapy Treatment of Heparin-Induced Thrombocytopenia (HIT) • Risk for thrombosis continues for days to weeks after heparin D/C and platelet recovery, therefore continued anticoagulation is essential during this time • Recovery begins 1-2 days after D/C of the offending drug and complete at 1 week • Antibodies to that drug may persist for years, so advised to avoid heparin indefinitely Mechanisms of Drug-Induced Thrombocytopenia • Nonimmune-mediated • Direct toxicity type reactions associated with medications that cause bone marrow suppression àsuppressed thrombopoiesis • Dose-dependent, takes weeks to manifest • Immune-mediated • • • • • Hapten-type reactions Drug-dependent antibody mechanism Platelet-specific autoantibody Immune complex-induced thrombocytopenia Drug specific autoantibody type reaction Drugs Associated with Thrombocytopenia • • • • • • • • • Carbamazepine Eptifibatide Ibuprofen Quinine Quinidine Oxaliplatin Rifampin Vancomycin Sulfamethoxazole-trimethoprim Treatment of Drug-Induced Thrombocytopenia 1. Removal of the offending drug 2. Corticosteroid therapy = controversial; useful in treating ITP 3. Consider IVIG, although data is limited 4. Platelet transfusions, if severe bleeding Questions?? Email: [email protected] Drugs Associated with Aplastic Anemia Observational Study Evidence Case report evidence (probable or definite causality rating) MedWatch postmarketing reports 2009-2017 Carbamazepine Furosemide Gold salts Mebendazole Methimazole NSAIDs Oxyphenbutazone Peniclliamine Phenobarbital Phenothiazines Phenytoin Propylthiouracil Sulfonamides Thiazides Tocainide Acetazolamide Aspirin Captopril Chloramphenicol Chloroquine Chlorothiazide Chlorpromazine Dapsone Felbamate Interferon alfa Lisinopril Lithium Nizatidine Pentoxifylline Quinidine Sulindac Ticlopidine Adalimumab Aliskirin Amlodipine Carvedilol Dantrolene Etanercept Oxcarbazepine Valsartan Drugs Associated with Agranulocytosis Direct Toxicity to Myeloid Cells Hapten mechanism Immune complex mechanism Autoimmune mechanism Chlorpromazine Procainamide Clozapine Dapsone Sulfonamides Carbamazepine Phenytoin Indomethacin Diclofenac Aminopyrine Penicillin Gold compounds Levisamole Quinine Quinidine Drugs Associated with Agranulocytosis Observational Study Evidence Case Report Evidence (probable or definite causality rating) Med Watch Postmarketing Reports 2009 -2017 Β-Lactam antibiotics Carbamazepine Carbimazole Clomipramine Digoxin Dipyridamole Ganciclovir Glyburide Gold salts Imipenem-cilastatin Indomethacin Macrolide antibiotics Methimazole Mirtazapine Phenobarbital Phenothiazines Prednisone Propranolol Spironolactone Sulfonamides Sulfonylureas Ticlopidine Valproic acid Zidovudine Acetaminophen Acetazolamide Ampicillin Captopril Carbenicillin Cefotaxime Cefuroxime Chloramphenicol Chlorpromazine Chlorpropamide Chlorpheniramine Clindamycin Clozapine Colchicine Doxepin Dapsone Desipramine Ethacrynic acid Ethosuximaide Flucytosine Gentamicin Griseofulvin Hydralazine Hydroxychlrorquine Imipenem-cilastin Imipramine Lamotrigine Amlodipine Aripiprazole Bocepravir Clozapine Deferasirox Fluoxetine Haloperidol Hydrochlorothiazide Iacosamide Leflunomide Levetiracetam Memantine Molindone Olanzapine Oxcarbazepine Paliperidone Pantoprazole Pimozide Propafenone Quetiapine Rifabutin Risperidone Sulfasalazine Thiothixene Trandolapril Ziprasidone Levodopa Meprobamate Methazolamide Methyldopa Metronidazole Nafcillin NSAIDs Olanzapine Oxacillin Penicillamine Penicillin G Pentazocine Phenytoin Primidone Procainamide Propylthiouracil Pyrimethamine Quinidine Quinine Rifampin Streptomycin Terbinafine Ticarcillin Tocainide Tolbutamide Vancomycin Drugs Associated with Immune Hemolytic Anemia Observational study Case report evidence (probable or definite MedWatch Postmarketing evidence causality rating) Phenobarbital Phenytoin Ribavirin Acetaminophen Angiotensin-converting enzyme inhibitors Β-lactam antibiotics Cephalosporins Ciprofloxacin Clavulanate Erythromycin Hydrochlorothiazide Indinavir Interferon alfa Ketoconazole Lansoprazole Levodopa Levofloxacin Methyldopa Minocycline NSAIDs Reports Omeprazole p-Aminosalicylic acid Phenazopyridine Probenecid Procainamide Quinidine Rifabutin Rifampin Streptomycin Sulbactam Sulfonamides Sulfonylureas Tacrolimus Tazobactam Teicoplanin Tolbutamide Tolmetin Triamterene Amlodipine Bevacizumab Chlorpropamide Pegademase Pioglitazone Rosiglitazone Drugs Associated with Hemolytic Anemia Hapten Mechanism Immune complex mechanism Red blood cell autoantibodies mechanism Nonimmunologic protein adsorption (NIPA) mechanism Cefotetan Pipercillin Minocyclne Tolbutamine Streptomycin Ceftriaxone Methyldopa Fludarabine Cladribine Beta-lactamase inhibitors Cisplatin Oxaliplatin Drugs Associated with Metabolic Hemolytic Anemia Observational study evidence Case report evidence (probable or definite causality rating) Dapsone Rasburicase Ascorbic acid Metformin Methylene blue Nalidixic acid Nitrofurantoin Phenazopyridine Primaquine Sulfacetamide Sulfamethoxazole Sulfanilamide Drugs Associated with Megaloblastic Anemia Case report evidence (probably or definite causality rating) Azathioprine Chloramphenicol Colchicine Cotrimoxazole Cytarabine 5-Fluorodeoxyuridine 5-Fluorouracil Hydroxyurea 6-Mercaptopurine Methotrexate Oral contraceptives P-Aminosalicylate Phenobarbital Phenytoin Primidone Pyrimethamine Sulfasalazine Tetracycline Vinblastine Drugs Associated with Thrombocytopenia Observational study evidence Case report evidence (probable or definite) Carbamazepine Oxaliplatin Phenobarbital Phenytoin Valproic Acid Abciximab Acetaminophen Acyclovir Albendazole Aminoglutethimide Aminosalicylic acid Amiodarone Amphotericin B Ampicillin Aspirin Atorvastatin Bevacizumab Bisoprolol Capecitabine Captopril Chlorothiazide Chlorpromazine Chlorpropamide Cimetidine Ciprofloxacin Clarithromycin Clopidogrel Dabigatran Danazol Deferoxamine Diazepam Diazoxide Diclofenac Diethylstilbestrol Digoxin Ethambutol Enzalutamide Felbamate Fenofibrate Fluconazole Gabapentin Gold salts Haloperidol Heparin HCTZ Ibuprofen Inamrinone Indinavir Indomethacin Interferon alfa-2b Isoniazid Isotretinoin Itraconazole Levamisole Levofloxacin Linezolid Lithium LMWH Lurasidone MMR vaccine Meclofenamate Mesalamine Methyldopa Minoxidil Morphine Moxifloxacin Nalidixic acid Naphazoline Naproxen Nitroglycerin Octreotide Olmesartan Oseltamivir Oxacillin p-Aminosalicylic acid Pantoprazole Drugs Associated with Thrombocytopenia Case report evidence (probable or definite) Medwatch postmarketing reports Penicillamine Pentamidine Pentoxifylline Piperacillin Primidone Procainamide Pyrazinamide Quinidine Quinine Ranitidine Recombinant Hep B vaccine Red Bush Tea Rifampin Rivaroxaban Acarbose Adalimumab Ado-trastuzumab Alfuzosin Amlodipine Benazapril Bocepravir Bortezomib Chlorambucil Cladribine Cotrimoxazole Dalteparin Dantrolene Deferasirox Didanosine Drotecogin alfa Efalizumab Eltrombopag Simvastatin Sirolimus Sulfasalazine Sulfonamides Sulindac Tacrolimus Tamoxifen Tolmetin Trastuzumab Trimethoprim Vancomycin Enoxaprin Epirubicin Epoprostenol Eptifibatide Ethionamid Filgrastim Fonaparinux Glimepiride Heparin HCTZ Indomethacin Iloprost Interferon beta 1a Leflunomide Losartan Montelukast Obinutuzumab Octreotide Oxcarbazepine Palivizumab Pamidronate Pemetrexed Pioglitazone Pomalidomide Propylthiouracil Quinine Raltegravir Rosiglitazone Rosuvastatin Spirinolactone Sunitinib Telmisartan Toresemide Trepostinil Ursodiol