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Drug-Induced Blood Disorders

Rowa’ Al-Ramahi

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The five major types of drug-induced blood dyscrasias are:

(a) hemolytic anemia (b) thrombocytopenia (c) agranulocytosis or neutropenia (d) aplastic anemia (e) pure red cell aplasia

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Drug-Induced Hemolytic Anemia Drug-induced hemolysis refers to an

increased rate of red cell destruction, caused directly or indirectly by a drug. Destruction can occur within the blood vessels (intravascular hemolysis) or outside the vascular space (extravascular hemolysis). Anemia develops when the rate of hemolysis exceeds the rate that bone marrow is capable of replacing destroyed cells.

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More than 70 drugs are known to cause either positive direct antiglobulin tests (DAT) or immune hemolysis. Second- and third-generation cephalosporins, diclofenac, fludarabine, carboplatin, oxaliplatin, and β-lactamase inhibitors are among the drugs associated with severe or fatal hemolysis

Drug-Induced Immunologic Hemolytic Anemia High-affinity hapten-type reaction Drug binds tightly to RBC membrane surface;

immunoglobulins then form against the drug-membrane complex

Cephalosporins, penicillin, tetracycline

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Low-affinity hapten-type reaction or immune complex formation

Drug binds to either (a) low-affinity specific antigenic loci on the cell membrane or (b) to circulating proteins to form an immune complex that adheres loosely to RBC. Lysis via complement activation ensues

Acetaminophen, ASA, chlorpromazine, chlorpropamide, hydrochlorothiazide, INH, probenecid, quinidine, quinine, rifampin, sulfonamides

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Autoimmune reaction Drug stimulates production of anti-RBC

antibodies. Autoantibodies coat RBC and extravascular lysis occurs

Levodopa, mefenamic acid, methyldopa, procainamide, ceftriaxone, cefotetan

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Glucose-6-Phosphate Dehydrogenase Deficiency

F.S., a 55-year-old, Italian-American man, noted

suprapubic pain and burning on urination. Laboratory data included the following values: Hgb, 14.0 g/dL (normal, 12–16 g/dL); hematocrit (Hct), 43.6% (normal, 38%–48%); WBC count, 7,500/mm3 (normal, 4,000–11,000/mm3); reticulocyte count, 0.5% (normal, 0.2%–2.0%); and normal serum electrolytes, bilirubin, prothrombin time (PT), and activated partial thromboplastin time (aPPT). Urinalysis (UA) was notable for 20 to 50 WBC/per high-power field (HPF) and moderate bacteria. A tentative diagnosis of cystitis was attributed to prostatic hypertrophy. Urine was sent for culture, and F.S. was given a prescription for co-trimoxazole one double-strength tablet twice daily (BID).

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Four days later, F.S. returned to the clinic noting that, although his original symptoms had resolved, he was experiencing tiredness and that his urine had become dark. Current laboratory values are as follows: Hgb, 9.9 g/dL; Hct, 32.5%; WBC count, 9,100/mm3; corrected reticulocyte count, 11%; total bilirubin, 3.8 mg/dL (normal, <1.0 mg/dL); and direct bilirubin, 0.7 mg/dL (normal, <1.0 mg/dL). UA now reveals 0 to 5 WBC/HPF, no bacteria, and 4% blood. The urine also is positive for bilirubin and urobilinogen. Physical examination is unremarkable except for scleral icterus and a mild tachycardia.

How is the clinical picture of F.S. compatible with drug-induced hemolysis caused by G6PD deficiency?

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F.S.'s asymptomatic hemolysis began 1 to 4 days after the drug was begun. F.S.'s serum hemoglobin concentration began to fall and his urine became dark secondary to increased levels of urobilinogen. In severe cases, weakness and abdominal or back pain may occur and the urine may become nearly black. As F.S.'s levels of indirect bilirubin rise, the presence of scleral icterus is noted. Reticulocytosis is evident and could be attributed to the body's attempt to increase RBC production. A G6PD deficiency can be confirmed by assaying G6PD activity. In F.S.'s case, it is too early to determine with certainty the outcome if the drug were to be continued; the prudent course would be to discontinue the co-trimoxazole and substitute an appropriate nonoxidant agent. A cephalosporin or quinolone antibiotic is a possible alternative; at this point, culture results should be available and can be used to guide therapy.

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Why did F.S.'s urine test positive for blood when no RBC were present?

hemoglobin in the urine will result in a positive urine test for blood. In this case, a positive test for hemoglobin in the absence of RBC helps differentiate hemoglobinuria caused by hemolysis from true hematuria.

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F.S. expresses surprise when he is informed of this reaction to co-trimoxazole, because he has taken sulfa drugs in the past without difficulty. Do all sulfa drugs have the same potential for inducing hemolysis in patients with G6PD deficiency?

Drug-induced hemolysis in G6PD-deficient patients can be somewhat confusing. Sulfamethoxazole, alone or in combination as co-trimoxazole, causes hemolysis in class II deficiency, but class III-deficient patients may be at low risk if the daily dose is 3.2 g or less. Sulfisoxazole does not cause significant hemolysis at usually prescribed doses. Therefore, F.S.'s hemolytic response to sulfamethoxazole, but not to sulfisoxazole, is consistent with existing data.

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Drugs associated with significant hemolysis in patients with G6PDD. Sulfanilamide Primaquine Methylene blue Sulfapyridine Naphthalene Sulfacetamide Nitrofurantoin Sulfamethoxazole 

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How should F.S.'s G6PD deficiency be treated? Other than discontinuation and avoidance of drugs

and substances known to cause hemolysis, no specific therapy exists for G6PD deficiency. If hemolysis is severe, RBC transfusion may be necessary. The patient should be well hydrated to maintain a good urine flow to prevent or attenuate renal toxicity from hemoglobin. Vitamin E and oral selenium have been suggested as possible treatments for G6PD deficiency; however, neither has proved of value. F.S. should be cautioned regarding his G6PD deficiency and the deleterious effects of certain drugs.

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Nondrug inducers of hemolysis include infection, diabetic ketoacidosis, unknown factors during the neonatal period, and ingestion of fava beans. Fava beans (Vicia faba), also known as broad beans, are a common dietary staple in some parts of the world and can cause severe hemolysis in some G6PD-deficient patients.

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Drug-Induced Thrombocytopenia Thrombocytopenia is defined as a decrease in

platelet count to <100,000/mm3. Drugs can cause thrombocytopenia by three

primary mechanisms: (a) immune-mediated suppression or destruction of

platelets (b) decreased production of platelets through direct

suppression of thrombopoiesis (c)in the case of heparin, an apparently dose-

related, nonimmune direct effect on circulating platelets.

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Glycoprotein IIb/IIIa (GPIIb-IIIa) receptor antagonists (GPRA)

Quinine: drug-induced immune thrombocytopenia.

Vancomycin oxaliplatin, a new platinum derivative used in

colorectal cancer sulfamethoxazole and sulfisoxazole Heparin Ticlopidine and Clopidogrel: Thrombotic

Thrombocytopenic Purpura

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J.Y., a 56-year-old man with mild hypertension, started taking hydrochlorothiazide 25 mg/day. Routine blood work at this time showed an adequate platelet estimate (>150,000/mm3). The platelet estimate after 2 weeks of therapy was likewise normal. At a 1-month follow-up visit, however, J.Y.'s complete blood count (CBC) revealed a decreased platelet estimate, and a subsequent platelet count was 78,000/mm3. He reported no unusual bleeding, the physical examination was unremarkable, and the CBC was otherwise unchanged.

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Why should the differential diagnosis include hydrochlorothiazide as a possible cause of J.Y.'s thrombocytopenia?

Drugs should always be considered in evaluating blood dyscrasias. Thiazide diuretics as well as furosemide are known to be associated with thrombocytopenia.

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A bone marrow examination reveals only decreased megakaryocytes, and the initial workup fails to reveal other reasons for a low platelet count. Why is J.Y.'s clinical picture compatible with thiazide-induced thrombocytopenia?

J.Y.'s course to this point has been typical of thrombocytopenia caused by decreased thrombopoiesis. The onset of thrombocytopenia was delayed and gradual (rather than sudden) and, as usually the case

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the thrombocytopenia in J.Y. was not associated with fevers, rash, or other signs of immune reaction. The degree of platelet reduction frequently is mild (J.Y.'s platelets were 78,000/mm3) and, without other risk factors, bleeding is relatively uncommon unless thrombocytopenia is severe.

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How should J.Y. be treated and monitored? With discontinuation of hydrochlorothiazide, the

platelet count would be expected to return to normal within about 2 weeks in J.Y. The drug should be discontinued and the platelet count should be monitored to verify resolution of the thrombocytopenia. J.Y. also should be monitored for signs of bleeding until recovery. For treatment of his hypertension, a suitable alternative agent should be prescribed. As always, J.Y. should be advised to avoid this drug in the future and to inform future caregivers of this reaction.

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Drug-Induced Neutropenia Several terms are used to refer to abnormally

low numbers of WBC. The broadest description, leukopenia, simply denotes a total WBC count of <3,000/mm3. Granulocytopenia describes a granulocyte count of <1,500 granulocytes/mm3 (including eosinophils and basophils), whereas neutropenia refers to a neutrophil count (segmented polymorphonucleocytes and band forms) of <1,500/mm3. Agranulocytosis is defined as a severe form of neutropenia, with total granulocyte counts <500/mm3.

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J.K., a 34-year-old woman with schizophrenia, was found on routine blood testing to be moderately neutropenic. She started taking chlorpromazine 8 weeks ago when she began hearing voices warning her that she was being followed by the Central Intelligence Agency (CIA) and that her brain had been bugged. Her chlorpromazine dose was quickly titrated up to 400 mg/day, which she has been taking for 6 weeks with a good clinical response. J.K. has no medical problems and takes no other medications.

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How likely is it that J.K.'s chlorpromazine is the cause of her neutropenia?

Phenothiazines are one of the most common causes of drug-induced neutropenia, chlorpromazine being the model drug. These drugs induce neutropenia through toxic suppression of granulocyte production in the marrow of sensitive patients.

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How should J.K. be treated at this point?

No specific therapy is indicated at this time because J.K. is asymptomatic. Although it is possible that the neutropenia might resolve with a simple dose reduction of chlorpromazine, the most prudent course would be to withhold the drug completely until the WBC count returns to normal.

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Subsequently, the patient could be restarted at a lower dose with close hematologic monitoring, or an alternative neuroleptic agent with less propensity for marrow suppression could be substituted. A more potent phenothiazine or a nonphenothiazine neuroleptic would be preferable because the risk of agranulocytosis appears related to the absolute amount of phenothiazine taken.

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How quickly should J.K.'s WBC count return to normal once chlorpromazine has been discontinued?

A peripheral hematologic response following the discontinuation of chlorpromazine will be delayed by 4 to 6 days but will then improve rapidly. The neutrophil numbers and total WBC count then rapidly return to normal, sometimes with a WBC count “overshoot” into the 15,000 to 20,000/mm3 range. Recovery usually is complete within about 2 weeks.

How can the rate of WBC recovery be hastened?

Patients with drug-induced agranulocytosis or drug-induced neutropenia have been treated with the granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (GM-CSF; however, the overall impact of CSF on clinical outcomes is difficult to assess when based on anecdotal case reports

.Because J.K. currently is asymptomatic, use of CSF is not indicated.

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Why would it be reasonable (or unreasonable) to administer an atypical neuroleptic such as clozapine to treat J.K.'s schizophrenia subsequent to her recovery from chlorpromazine-induced neutropenia?

Clozapine, a dibenzodiazepine neuroleptic, initially appeared to have a favorable adverse effect profile; however, cases of clozapine-induced neutropenia soon were reported. When discovery of the neutropenia was delayed and clozapine was not promptly discontinued, eight fatalities resulted.

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As a result, when clozapine was approved for use in the United States for severely ill schizophrenic patients, who were refractory to standard antipsychotic drug treatment

J.K. is not at increased risk for clozapine-induced hematologic toxicity because there does not appear to be cross-reactivity between clozapine and other psychotropic agents, including chlorpromazine. Clozapine, however, is not indicated for J.K. because she is not refractory to more typical neuroleptic therapy.

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Drug-Induced Aplastic Anemia Aplastic anemia is defined as bicytopenia or

pancytopenia, with bone marrow biopsy evidence of decreased cellularity and absence of infiltration and significant fibrosis. The term pancytopenia is applied when anemia (Hgb <10 g/dL), neutropenia, and thrombocytopenia are present; and the term bicytopenia is applied when two of these three abnormalities are present.

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A number of commonly used drugs (e.g., NSAID, sulfonamides, antithyroid drugs, antiepileptics, psychotropics, cardiovascular drugs, gold, penicillamine, allopurinol) have been associated with pancytopenia or aplastic anemia.

Chloramphenicol Felbamate Linezolid Ticlopidine Interferon β-1α

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P.D., a 62-year-old man, notes gradually increasing tiredness and lack of energy over the past month. He seeks medical help after unsuccessful self-medication with stress-formula vitamins. His only other medical problem is osteoarthritis for which he has been taking diclofenac (Voltaren) 50 mg three times daily (TID) for the past 6 months, as well as aspirin 360 mg four to six times daily on an as needed basis.

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Physical examination is unremarkable except for pallor, several bruises on various parts of the body, and findings typical of osteoarthritis. A blood count, however, reveals an Hgb of 6.2 g/dL, a corrected reticulocyte count of 0.5%, a WBC count of 1,800/mm3 with 50% neutrophils, and a platelet count of 35,000/mm3. Diagnostic considerations include drug-induced aplastic anemia.

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A more complete history fails to reveal any additional pertinent information. Which of P.D.'s drugs is most likely to have caused this problem?

P.D.'s diclofenac has been associated with the development of aplastic anemia. The risk of aplastic anemia with diclofenac has been estimated to occur in about 1 in 150,000. Salicylates have also been linked with aplastic anemia in some, but not all, studies. Diclofenac is the most likely culprit among P.D.'s drugs, but aspirin cannot be ruled out.

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Further evaluation, including bone marrow biopsy, confirms the diagnosis of aplastic anemia. No causes other than drugs are identified. What interventions would facilitate P.D.'s recovery?

First and foremost, as is true in the treatment of most drug-induced diseases, all suspected causative agents should be discontinued. In this case, both diclofenac and aspirin should be stopped. In addition, supportive measures should be initiated as needed.

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The approach to treatment is based first on disease severity. Patients with mild aplastic anemia have a relatively benign short-term prognosis and can be treated conservatively. The two basic approaches to treating severe aplastic anemia are bone marrow transplant and immunosuppression.

Because P.D.'s disease is not severe, discontinuing the drugs and transfusing RBC are the only treatments indicated at this time. It is not possible to predict whether his blood counts will improve once the causative agents are discontinued.

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