Advances in HematologyTo receive news and publication updates for Advances in Hematology, enter your email address in the box below. This is an open access article distributed under the Creative Commons Effexts Licensewhich permits unrestricted use, distribution, and reproduction in any medium, punishment for using steroids in baseball the original work is properly cited. Drugs can induce almost the entire spectrum hematological effects of steroids hematologic disorders, affecting white cells, red cells, platelets, and the hematological effects of steroids system. This paper aims to emphasize the broad range of drug-induced hematological syndromes and to highlight some of the newer drugs and syndromes. Medline literature on drug-induced hematologic syndromes was reviewed.
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This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Drugs can induce almost the entire spectrum of hematologic disorders, affecting white cells, red cells, platelets, and the coagulation system. This paper aims to emphasize the broad range of drug-induced hematological syndromes and to highlight some of the newer drugs and syndromes.
Medline literature on drug-induced hematologic syndromes was reviewed. Most reports and reviews focus on individual drugs or cytopenias. Drug-induced syndromes include hemolytic anemias, methemoglobinemia, red cell aplasia, sideroblastic anemia, megaloblastic anemia, polycythemia, aplastic anemia, leukocytosis, neutropenia, eosinophilia, immune thrombocytopenia, microangiopathic syndromes, hypercoagulability, hypoprothrombinemia, circulating anticoagulants, myelodysplasia, and acute leukemia.
Some of the classic drugs known to cause hematologic abnormalities have been replaced by newer drugs, including biologics, accompanied by their own syndromes and unintended side effects. Drugs can induce toxicities spanning many hematologic syndromes, mediated by a variety of mechanisms.
Physicians need to be alert to the potential for iatrogenic drug-induced hematologic complications. Hematological disorders arise through a variety of mechanisms and etiologies.
Drug-induced hematological disorders can span almost the entire spectrum of hematology, affecting red cells, white cells, platelets, and the coagulation system. Most recent reviews of drug-induced hematological disorders focused on specific drugs or cytopenias. The purpose of this review is to emphasize the broad range of drug-induced hematological syndromes and to highlight some of the newer drugs and syndromes described.
However, due to space limitations, this review is not meant to be comprehensive of all drug-induced hematological dyscrasias. Immune Hemolytic Anemia IHA is characterized by destruction of red cells by antibodies acting against antigens on the erythrocyte membrane. Mediated by either IgG or IgM antibodies, IHA may be idiopathic, or secondary to infections, autoimmune diseases, lymphoproliferative disorders, or drugs. Patients present with anemia, reticulocytosis, indirect hyperbilirubinemia, elevated LDH with a positive Coombs test.
Drug-induced IHA may be associated with either drug-dependent or drug-independent antibodies [ 1 ]. Other drugs may cause nonimmunologic protein adsorption onto drug-treated red cells. IHA has been described with cephalosporins, nonsteroidal anti-inflammatory agents, levaquin, oxaliplatin, and teicoplanin, amongst others [ 1 , 2 ]. However, severe hemolysis with renal insufficiency, disseminated intravascular coagulation, and death has been reported in a small number of cases [ 3 ].
Fludarabine, a purine nucleoside chemotherapeutic agent, has been reported to precipitate or exacerbate the auto-immune hemolytic anemia associated with chronic lymphocytic leukemia. However, combining fludarabine with rituximab and cyclophosphamide may reduce that risk [ 4 ]. G6PD deficiency is the most frequent red cell enzymopathy associated with hemolysis. Hemolysis may be precipitated by infection, fava beans, and drugs.
The sensitivity to various drugs depends on the inherited mutation and the associated degree of deficiency. In most cases, drug-induced hemolysis is self-limited. The deficiency is X-linked, so manifested more commonly and severely in males.
Primaquine, phenazopyridine, nitrofurantoin, and certain sulfas have been associated with hemolysis [ 5 ]. Ribavirin, used with peginterferon for treatment of hepatitis C, has been associated with anemia. Ribavirin concentrates within red blood cells, depletes ATP, and promotes hemolysis via oxidative membrane damage.
While the anemia will improve by stopping or dose-reducing ribavirin, such strategies may compromise the efficacy of the antiviral therapy. Erythropoietin has been reported to be helpful in moderating the anemia [ 6 ]. Most of this naturally occurring methemoglobin is reduced to hemoglobin through the methemoglobin reductase enzyme system. Methemoglobinemia, characterized by excess production of methemoglobin, causes impairment in the transport of oxygen.
Methemoglobinemia can be congenital due to defects in enzymatic reduction of hemoglobin or acquired.
Patients present with symptoms of anoxia, cyanosis, reduced oxygen saturation, and chocolate-brown arterial blood. Confirmation of the diagnosis is made by measurement of methemoglobin on arterial blood gas sampling. Drugs that induce methemoglobinemia either directly oxidize hemoglobin or are metabolically activated to an oxidizing species [ 7 ]. Phenazopyridine, used for relief of cystitis, can cause oxidative hemolysis [ 8 ].
Dapsone, used for leprosy, dermatitis herpetiformis, and prophylaxis for pneumocystis carinii, is metabolized to a hydroxylamine derivative [ 9 ].
It was the most common cause of methemoglobinemia in one recent series [ 10 ]. Primaquine and local anesthetics, such as topical or spray benzocaine used prior to upper endoscopic procedures and prilocaine, can cause methemoglobinemia [ 11 — 13 ].
Amyl nitrite and isobutyl nitrite have been implicated also [ 7 ]. Treatment includes cessation of the inducing agent, oxygen, and methylene blue. Megaloblastic anemias are characterized by the presence of a hypercellular bone marrow with large, abnormal hematopoetic progenitor cells megaloblasts. Leukopenia and thrombocytopenia also occur. Megaloblastic anemias can be congenital or acquired and most commonly are related to vitamin cobalamin and folic acid deficiencies. While they are usually a result of malnutrition or defective absorption, they can also be drug-induced.
Drugs that act by interfering with DNA synthesis, such as antimetabolites and alkylating agents, some antinucleosides used against HIV and other viruses [ 14 ], can all induce megaloblastic anemia. Trimethoprim in high, extended doses and pyrimethamine, which bind with greater affinity to bacterial than human dihydrofolate reductase, have been associated with megaloblastic anemia, primarily among patients already at risk for folic acid deficiency.
Antibiotics such as sulfasalazine and anticonvulsants such as phenytoin have been linked to folate-related changes which induce megaloblastic anemia, perhaps related to interference with absorption. Decreased cobalamin levels have been reported with term use of histamine 2-receptor antagonists and proton pump inhibitors e.
While protein bound B 12 absorption may be impaired by these agents, clinically significant deficiency seems rare despite widespread use. Sideroblastic anemias SAs are characterized by ringed sideroblasts erythroblasts containing iron-positive granules arranged around the nucleus in the bone marrow. Sideroblastic anemias, which can be inherited or acquired, exhibit impaired heme biosynthesis in erythroid progenitors.
Most sideroblastic anemias are acquired as clonal disorders of erythropoiesis. Additionally, ringed sideroblasts can be found in malnourished patients who abuse alcohol [ 17 ]. Drug-induced sideroblastic anemia has been associated with isoniazid [ 18 ]. The anemia is reversed by pyroxidine or by withdrawal of isoniazid.
Chloramphenicol, rarely used at present, causes a reversible suppression of erythropoiesis and produces ringed sideroblasts [ 17 ]. Myelodysplasias and secondary acute leukemias induced by chemotherapy, discussed below, may initially manifest as sideroblastic anemia [ 22 ].
Aplastic anemia AA , characterized by pancytopenia with a hypocellular bone marrow, can be inherited or acquired. Acquired aplastic anemia is most commonly idiopathic, but may be secondary to exposure to toxins, irradiation, viruses, and drugs.
AA can develop as a direct response to exposure, but can also develop indirectly, through immune-mediated mechanisms. Historically, drug-induced AA has not been easily distinguished from idiopathic forms of the disease since with rare case reports causality is difficult to establish [ 23 ]. From an immunological perspective, the absence of antibodies in aplastic anemia suggests that drugs do not serve as simple haptens in the initiation of aplastic marrow failure.
Drugs implicated in inducing AA include antirheumatic drugs, antithyroid medications, antituberculous drugs, NSAIDs, and anticonvulsants. Many drugs reported to cause aplastic anemia can also more commonly cause mild marrow suppression, suggesting that preliminary damage may occasionally perhaps related to host metabolism progress to more severe damage.
The treatment and prognosis of drug-induced aplastic anemia seem similar to idiopathic cases [ 23 ]. Pure red cell aplasia PRCA is characterized by normocytic anemia, reticulocytopenia, and absence of mature marrow erythroid progenitors. PRCA is distinguished from aplastic anemia by relatively normal leukocyte and platelet counts. It can be congenital or acquired. Acquired PRCA can be idiopathic or secondary, either an acute, self-limiting disorder or a persistent, chronic refractory anemia.
PRCA can arise in association with a thymoma, lymphoid cancer, parvovirus, rheumatoid arthritis, pregnancy, and drugs. PRCA can be acquired through exposure to a number of drugs, including immunosuppressants azathioprine, FK, antithymocyte globulin , antibacterials linezolide, isoniazid, rifampin, chloramphenicol , antivirals interferon-alpha, lamivudine, zidovudine , fludarabine, anticonvulsants diphenyldrantoin, carbamazepine, valporic acid , as well as chloroquine, allopurinol, ribavirin, and gold [ 28 , 29 ].
Additionally, PRCA has been reported to develop after prolonged exposure to recombinant human erythropoietin rHuEPO specifically the brand Eprex, predominately used in Europe [ 30 — 33 ]. Withdrawal of rHuEPO followed by treatment with immunosuppressives cyclosporine A for several months rendered patients anti-EPO antibody negative and transfusion independent. PRCA seemed to occur predominantly with subcutaneous administration in renal failure patients.
The frequency of this complication has reduced, seemingly as a result of changes in formulation and handling that may have decreased immunogenicity [ 33 ]. In immune thrombocytopenia purpura ITP , platelet destruction is caused as antibodies bind to platelets leading to their clearance by the reticuloendothelial system RES , as well as by some degree of decreased production.
ITP can be idiopathic, or related to viral infections, autoimmune disorders, lymphoproliferative disorders, or drugs [ 34 , 35 ]. Classical causes of drug-induced thrombocytopenia are the quinine and quinine-like drugs [ 36 ]. The thrombocytopenia is typically sudden, severe, and may be accompanied by bleeding.
Vancomycin can also be associated with marked thrombocytopenia and demonstrable drug-dependent antibodies in the serum [ 37 ]. Prolonged thrombocytopenia may occur in patients with renal insufficiency, likely due to delayed drug clearance.
Other drugs associated with immune thrombocytopenia include include antimicrobials sulfanomides, rifampin, linezolid , anti-inflammatory drugs, antineoplastics, antidepressants, benzodiazepines, anticonvulsants carbamazepine, phenytoin, valproic acid as well as cardiac and antihypertensive drugs [ 34 , 35 ].
Although the ITP generally develops rapidly, it usually resolves upon cessation of treatment and is drug-specific. Heparin is well known to be associated with thrombocytopenia, sometimes with arterial or venous thrombosis, which is generally a far greater threat than the risk of bleeding [ 38 , 39 ]. Heparin-induced immune thrombocytopenia is caused by antibodies against complex of heparin and platelet factor 4 PF4 , which can lead to platelet activation and the initiation of thromboses.
Although heparin can also induce a milder, nonimmune mediated thrombocytopenia, the immune version is potentially more severe. Heparin-induced thrombocytopenia follows exposure to both unfractionated and low molecular weight heparins, but is less common with the latter. There is usually a delay of 5—10 days for newly exposed patients, but thrombocytopenia can occur within hours in patients with a recent heparin exposure who still have PF4 antibodies, or within a few days for those with prior exposure who develop an anamnestic response.
Occasionally venous gangrene, skin necrosis, and acute anaphylactic-type reactions to heparin can occur. In the appropriate clinical setting, the diagnosis is supported by evidence of antiheparin antibodies, which can be detected by a number of assays. These include the more sensitive serologic assays e. In addition to cessation of heparin use, treatment involves anticoagulation to reduce the risk of thrombosis, typically with argatroban, bivalrudin, or lepirudin initially, with transition to warfarin.
Anticoagulation should be continued for several weeks even after the platelet count returns to normal due to the high risk of thrombosis during that time.