Thrombocytopenia azathioprine

Hematoiogic effects Severe leukopenia or thrombocytopenia, macrocytic anemia, severe bone marrow depression, and selective erythrocyte aplasia may occur in patients on azathioprine. Hematologic toxicities are dose-related, may occur late in the... 

The therapeutic use of azathioprine has been limited by the number and severity of adverse effects associated with its administration. Bone marrow suppression resulting in leukopenia, thrombocytopenia, or both may... 

Azathioprine is a cytotoxic inhibitor of purine synthesis effective for the control of tissue rejection in organ transplantation. It is also used in the treatment of autoimmune diseases. Its biologically active metabolite, mercaptopurine, is an inhibitor of DNA synthesis. Mercaptopurine undergoes further metabolism to the active antitumour and immunosuppressive thioinosinic acid. This inhibits the conversion of purines to the corresponding phosphoribosyl-5 phosphates and hypoxanthine to inosinic acid, leading to inhibition of cell division and this is the mechanism of the immunosuppression by azathioprine and mercaptopurine. Humans are more sensitive than other species to the toxic effects of the thiopurines, in particular those involving the haematopoietic system. The major limiting toxicity of the thiopurines is bone marrow suppression, with leucopenia and thrombocytopenia. Liver toxicity is another common toxic effect. 

The chief toxic effect of azathioprine and mercaptopurine is bone marrow suppression, usually manifested as leukopenia, although anemia and thrombocytopenia may occur. Skin rashes, fever, nausea and vomiting, and sometimes diarrhea occur, with the gastrointestinal symptoms seen mainly at higher dosages. Flepatic dysfunction, manifested by very high serum alkaline phosphatase levels and mild jaundice, occurs occasionally, particularly in patients with preexisting hepatic dysfunction. 

Fatal cerebral involvement in systemic aspergillosis has been described in a 25-year old woman with severe thrombocytopenia (platelet count 10 x 109/1) and mild intermittent leukopenia (granulocytes 0.375-3 x 109/1) who was taking prednisone 1-1.5 mg/kg/day and azathioprine 100-200 mg/day (344). 

Dose-related toxicities of azathioprine or 6-mercaptopurine include nausea, vomiting, bone marrow depression (leading to leukopenia, macrocytosis, anemia, or thrombocytopenia), and hepatic toxicity. Routine laboratory monitoring with complete blood count and liver function tests is required. Leukopenia or elevations in liver chemistries usually respond to medication dose reduction. Severe leukopenia may predispose to opportunistic infections leukopenia may respond to therapy with granulocyte stimulating factor. Hypersensitivity reactions to azathioprine or 6-mercaptopurine occur in 5% of patients. These include fever, rash, pancreatitis, diarrhea, and hepatitis. 

Potentially serious side-effects of azathioprine that are dose- and duration-dependent are haematological (leukopenia and thrombocytopenia) and gastrointestinal. Azathioprine is metabolized to 6-mercaptopurine, and both compounds are rapidly eliminated from blood and oxidized in red cells and liver. Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phosphoribosyl-transferase. 6-Mercaptopurine is inactivated by thiopurine S-methyltransferase and by xanthine oxidase. 

Hematological toxicity is the most commonly reported severe adverse effect of azathioprine, and is marked by predominant leukopenia, thrombocytopenia, and pancytopenia (SED-13, 1120). In a 27-year survey of 739 patients treated with azathioprine 2 mg/kg for inflammatory bowel disease, dosage reduction or withdrawal of the drug because of bone marrow toxicity was necessary in 37 patients (5%) (11). There was moderate or severe leukopenia in 3.8% of patients in three patients pancytopenia resulted in severe sepsis or death. 

In renal transplant patients, combining azathioprine with co-trimoxazole was followed by neutropenia and thrombocytopenia (92). 

Dose-limiting adverse effects of azathioprine are often hematologic (see Table 87-4). Leukopenia, anemia, and thrombocytopenia can occur within the first few weeks of therapy and can be managed by dose reduction or discontinuation of azathioprine. Other common adverse effects include nausea and vomiting, which can be minimized by taking azathioprine with food. Alopecia, hepatotoxicity and pancreatitis are less common adverse effects of azathioprine they generally are reversible on dose reduction or discontinuation. ... 

Azathioprine is indicated in renal homotransplantation (five-year patient survival rate of 35%) in rheumatoid arthritis (for patients with severe, active, and erosive disease not responding to conventional therapies) and in chronic ulcerative colitis, myasthenia gravis, and Behcet s syndrome (adverse effects may offset its limited value). As with other cytotoxic drugs, azathioprine can affect rapidly growing cells, resulting in leukopenia, thrombocytopenia, and gastrointestinal toxicity. In addition, hepatotoxicity (cholestasis) has been reported. Many of the general problems of immunosuppression, such as increased risk of infections, can also occur. 

Toxicity The major side effect of azathioprine is bone marrow suppression, including leukopenia (common), thrombocytopenia (less common), and/or anemia (uncommon). Other important adverse effects include increased susceptibility to infections (especially varicella and herpes simplex viruses), hepatotoxicity, alopecia, G1 toxicity, pancreatitis, and increased risk of neoplasia. 

Drug Interactions Xanthine oxidase, a key enzyme in the catabolism of azathioprine metabolites, is blocked by aUopurinol. If azathioprine and allopurinol are used concurrently, the azathioprine dose must be decreased to 25-33% of the usual dose it is best not to use these two drugs together. Adverse effects resulting from coadministration of azathioprine with other myelosuppres-sive agents or angiotensin-converting enzyme inhibitors include leukopenia, thrombocytopenia, and anemia as a result of myelosuppression. 

Azathioprine (Imuran) Converted to 6-mercaptopurine ribose phosphate which inhibits purine synthesis. Because DNA RNA synthesis requires proteins, all proliferating cells are inhibited (B-cells, T-cells, nonimmune cells). Prevention of organ transplant rejection. Gl distress, bone marrow depression, infections, mild leukopenia and thrombocytopenia. 

A number of other reports similarly describe reversible bone marrow toxicity associated with anaemia, pancytopenia, leucocytopenia and thrombocytopenia in patients given azathioprine with allopurinol, " and in one case a fatality occurred as a result of neutropenia and septicaemia. In a retrospective analysis of 24 patients who had received both azathioprine and allopurinol, 11 developed leucopenia, 7 developed moderate anaemia, and 5 developed thrombocytopenia. Only 14 of the patients had received a greater than two-thirds reduction in their azathioprine dose when allopurinol was started, but despite this, some of these patients still developed haematological toxicity." ... 

Azathioprine is firstly metabolised in the liver to mercaptopurine and then enzymatically oxidised in the liver and intestinal wall by xanthine oxidase to an inactive compound (6-thiouric acid), which is excreted. Allopurinol inhibits first-pass metabolism by xanthine oxidase so that mercaptopurine accumulates, blood levels rise and its toxic effects develop (leucopenia, thrombocytopenia, etc.). 

The observation that haematologieal toxieity often seemed to occur in renal transplant patients given azathioprine and co-trimoxazole, prompted a retrospective survey of the records of 40 patients. It was found that there was no difference in the incidence of thrombocytopenia and neutropenia in those given azathioprine, either alone, or with co-trimoxazole, (trimethoprim 160 to 320 mg and sulfamethoxazole 800 mg to 1.6 g daily) for a short time (6 to 16 days), but a significant increase occurred in the incidence and duration of thrombocytopenia and neutropenia if both drugs were given together for 22 days or more. ... 

TPMT genotype polymorphisms (TPMT 2, 3A, 3B, and 3C) have been studied in 108 patients with vascuhtis associated with positive antineutrophil cytoplasmic antibodies (ANCA), who were given azathioprine and followed for 47 months [144. Adverse reactions (leukopenia, anemia, thrombocytopenia, gastrointestinal adverse reactions including hepatitis, and hypersensitivity reactions) did not differ between patients who were heterozygous and those who were homozygous or between the ter-tiles of patients who were homozygous. 

Few studies have compared splenectomy with PSE in a randomized, prospective fashion. In a series by Mozes et al. [118], 53 patients who were to later undergo renal transplant with azathioprine immunosuppressive therapy (which causes leukopenia and thrombocytopenia) were randomly assigned to a splenectomy group (25 patients) or a PSE group (28 patients). For patients in the PSE group, a mean of... 

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