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Sirolimus-induced thrombocytopenia and leukopenia in renal transplant recipients: risk factors, incidence, progression, and management.

BACKGROUND: Our study assessed the factors that predispose renal transplant recipients to the occurrence of thrombocytopenia and leukopenia, as well as the severity and the time- and concentration-dependence of these side-effects, after administration of sirolimus (SRL) in combination with a cyclosporine (CsA) and prednisone (Pred) regimen. METHODS: The clinical courses of two cohorts of renal transplant recipients were compared over 1 year: 119 patients received SRL in addition to CsA and Pred, and 65 demographically similar, concurrent patients received only CsA and Pred. Using an analysis of variance, pretransplant laboratory values and SRL trough concentrations (C0) were correlated with the occurrence, severity, and persistence of drug-induced thrombocytopenia (platelet count <150x10(3) cell/mm3) and/or leukopenia (white blood cell count <5,000/mm3). RESULTS: Neither the ethnic background nor the pretransplant cytomegalovirus serological status was associated with the occurrence of hematological complications. Thrombocytopenia was usually observed during the first 4 weeks of treatment (P=0.004). The occurrence, but not the severity or the persistence, of both thrombocytopenia and leukopenia correlated significantly with SRL trough concentrations > or =16 ng/ml (P=0.001 and 0.0001, respectively). A significant correlation is evident between the occurrence of the two adverse effects (P=0.001). In 89% of patients, the first episode of either type of cytopenia resolved spontaneously. Among the remaining 11%, 7% responded to SRL dose reduction, and 4% to temporary suspension. No patient required permanent cessation of SRL therapy. Most patients experienced repeated, but self-limited, episodes of toxicity. CONCLUSION: Thrombocytopenia and leukopenia are not infrequent occurrences with SRL treatment, and they generally resolve spontaneously.

Adolescent↗

Evaluation of the mechanisms of antiepileptic drug-related chronic leukopenia.

Antiepileptic drug (AED)-related chronic leukopenia [white blood cell (WBC) count < 4,000/microliters] is a dilemma, especially when the AED is effective in controlling seizures. We evaluated the possible mechanisms of leukopenia in 7 patients. Mean WBC count was 3,000/microliters with a mean of 42% polymorphonuclear leukocytes (PMN). The AEDs were carbamazepine (CBZ) alone in 1 patient or CBZ combined with phenytoin (PHT), primidone (PRM), phenobarbital (PB) and/or valproate (VPA) in 5 patients; one patient was receiving PHT only. Bone marrow (BM) aspirates and PMN antibody studies using chemiluminescence were normal. Two liver-spleen scans showed mild relative splenomegaly. After exercise, WBC count (n = 7) increased by 54% (SEM 12%), while the WBC counts in controls (n = 5) increased by 52 +/- 16%. Antinuclear antibodies (Hep-2) were absent in 6 patients and positive (1:160) in 1. PMN adhesion to nylon wool was decreased (54 +/- 10% in patients vs. 80 +/- 5% in controls: n = 13, p < 0.005). Our data, particularly the appropriate WBC response to the stress of exercise, and normal BM examinations suggest that continuation of AED therapy when leukopenia is stable and the percentage of PMN is normal is probably safe. Caution should be used if the absolute PMN count is consistently < 1,000/microliters. BM examinations need not be performed routinely for every patient with neutropenia due to AEDs, especially if the leukopenia fluctuates in the range of 2,000-4,000 cells/microliters.

Adult↗

Effect of regional citrate anticoagulation on leukopenia, complement activation, and expression of leukocyte surface molecules during hemodialysis with unmodified cellulose membranes.

BACKGROUND: Dialysis with complement-activating membranes is associated with leukopenia, which is related to an increased expression of adhesion molecules on leukocytes. Citrate chelates calcium and has been claimed to attenuate leukopenia. METHODS: In this study, the effects of citrate anticoagulation on leukocyte and granulocyte counts, complement activation, and the expression of CD11b, CD11c, and CD45 on the surface of granulocytes were evaluated during hemodialysis with unmodified cellulose membranes. Standard heparin was compared to citrate in three different schedules: citrate was infused to obtain a concentration of either 7 or 10 mmol/l blood. CaCl(2) was administered into the dialyzer outlet at 8. 25 mmol Ca(2+)/h (citrate 10 mmol/l) or at 11 mmol Ca(2+)/h (citrate 7 and 10 mmol/l) to reconstitute the calcium levels in the blood returning to the patient. RESULTS: The use of citrate at a high concentration (10 mmol/l) was associated with a blunted upregulation of CD11b, both at the inlet and at the outlet bloodline; for CD11c a reduced upregulation was observed on granulocytes harvested from the inlet bloodline. No effects of citrate were observed on leukopenia, granulocytopenia, or complement activation. A positive correlation between the decrease in systemic ionized Ca(2+) concentration and the increase in CD11b and CD11c expression was found. CONCLUSION: Citrate/CaCl(2) administration affects leukocyte adhesion molecule expression in a dose-dependent way; however, no significant effect could be demonstrated on leukopenia and complement activation.

Adult↗

Frequency of leukopenia incidents following azathioprine therapy after kidney transplantation.

The frequency of leukopenia incidents and its dependence on the dose of azathioprine and kidney function were analyzed in 149 patients during the first 3 months after kidney transplantation. The results were compared with the data of 42 transplantation centers of the world. We found that the frequency of leukopenia increases significantly following azathioprine dosage exceeding 1.99 mg/kg body weight/day. The toxicity of the drug depends on the kidney function. Most of the leukopenia incidents were detected during the first 5 weeks after kidney transplantation. In 70% of the cases a first leukopenia incident is followed by a second. Low azathioprine dosage after the first episode diminishes the number of second incidents.

Azathioprine↗

Clopidogrel-associated leukopenia.

OBJECTIVE: To report a case of leukopenia in a patient receiving clopidogrel following intracoronary stent placement. CASE SUMMARY: A 58-year-old white man presented to the emergency department (ED) with fever and chills. Seven days prior to presentation, he underwent intracoronary stent placement and clopidogrel 75 mg once daily was initiated. In the ED, laboratory evaluation revealed leukopenia with negative blood and urine cultures. The patient was released but returned the following day with fever and sweating. Infectious complications were ruled out, and clopidogrel was discontinued. Leukopenia resolved within 7 days, and the patient has experienced no further hematologic complications. Based on the Naranjo probability scale, the leukopenia was rated as a probable reaction to clopidogrel. DISCUSSION: Ticlopidine and clopidogrel are the 2 commercially available thienopyridine antiplatelet agents. Risk of myelotoxicity with ticlopidine is well known and requires frequent hematologic monitoring. Clopidogrel is better tolerated, less toxic, and has more extensive indications, including use in acute coronary syndrome. These factors have resulted in the replacement of ticlopidine by clopidogrel. The 4 previously published reports of clopidogrel-associated white blood cell (WBC) toxicity are described. The mechanism of myelotoxicity with clopidogrel is not known. CONCLUSIONS: Better tolerability, reduced toxicity (particularly hematologic), and the convenience of once-daily dosing have resulted in the replacement of ticlopidine with clopidogrel. WBC toxicity associated with clopidogrel therapy is very infrequent and has occurred weeks to months following therapy initiation. Clinicians should be aware of the potential for this adverse effect.

Aged↗

Leukopenia with neutropenia associated with teicoplanin therapy.

The first case report of leukopenia with neutropenia due to the new glycopeptide antibiotic teicoplanin is described. The side effect occurred in a 73-year-old man hospitalized because of subacute bacterial endocarditis caused by Streptococcus faecalis. Leukopenia with neutropenia (white blood cells 2000/mm3, neutrophils 46%) developed after 20 days of teicoplanin therapy. After stopping teicoplanin white blood cell and neutrophil counts reverted to normal, but dropped again on rechallenge. A review of 1500 records of patients treated with teicoplanin alone or in combination with other drugs was also performed. Five cases were found in which leukopenia was possibly (four cases) or probably (one case) related to teicoplanin therapy. From these preliminary data the incidence of leukopenia related to teicoplanin seems to be low.

Aged↗

Pharmacodynamic activity (leukopoietic effect) of recombinant human granulocyte colony-stimulating factor (rhG-CSF) after rectal administration in rabbits with leukopenia induced by cyclophosphamide.

The pharmacodynamic activity (leukopoietic effect) and pharmacokinetics of recombinant human granulocyte colony-stimulating factor (rhG-CSF) administered in various doses as hollow-type suppositories were investigated in rabbits with leukopenia induced by cyclophosphamide (CPA-treated rabbits). We found that serum granulocyte colony-stimulating factor (G-CSF) concentration was increased following the rectal administration of rhG-CSF. Therefore, rhG-CSF could be absorbed from the rectal mucosa in leukopenic rabbits who received CPA at a dose of 30 mg/kg/d. When rhG-CSF of at least 300 micrograms/kg was administered rectally once a day for 3 d in CPA-treated rabbits 1 d after the induction of leukopenia (the total count of leukocytes in peripheral blood [total blood leukocyte count] was below 5000/microliter), decreased total blood leukocyte count returned to the normal physiological level and a maximum (7000-16000/microliter) was obtained 3 d after the start of the rhG-CSF multiple-dosing regimen. We report for the first time that rhG-CSF administered rectally induces leukopoiesis in CPA-treated rabbits and reduces the period of leukopenia induced by CPA. Thus, the rhG-CSF hollow-type suppository offers a promising means of reducing the risk of leukopenia, an adverse side effect of CPA therapy.

Administration, Rectal↗

Idiosyncratic rifabutin-induced leukopenia and SIADH: case report and review.

Rifabutin is increasingly critical for treatment of atypical mycobacterial infections. One of its serious adverse effects is leukopenia. When encountering rifabutin-induced leukopenia, clinicians are faced with the dilemma of whether to lower the dosage of rifabutin or discontinue it because existing literature does not indicate whether rifabutin-induced leukopenia is dose related or idiosyncratic. We report the first established case of idiosyncratic rifabutin-induced leukopenia in an immunocompetent man treated for pulmonary Mycobacterium avium complex infection. The patient also developed rifabutin-induced syndrome of inappropriate antidiuretic hormone (SIADH), which also has not been previously reported.

Aged↗

Species difference in susceptibility to phorbol myristate acetate-induced leukopenia and lung injury: rat vs. dog.

Phorbol myristate acetate (PMA) was administered intravenously in a single dose to rats (400 micrograms/kg) and in a single and repeated doses to dogs (40 micrograms/kg). Severe leukopenia was observed in both species. The leukopenia in rats was due to a decreased number of both lymphocytes and neutrophils while the leukopenia in dogs was mainly due to a decreased number of neutrophils. The rats recovered from leukopenia much faster than the dogs. The dog which received a single injection developed focal fibrosis in the lungs. Rats showed only slight localized hemorrhage in the lungs, although the rats received a ten-fold larger dose of PMA than the dogs. Lungs of dogs which received multiple injections revealed severe hemorrhagic lesions in most alveoli. Lung lesions induced by PMA are thought to be mediated by activated leukocytes. This suggests that the severity of lung lesion correlates with the degree and duration of neutropenia. In conclusion, intravenous administration of PMA caused lung damage in rats and dogs. However, rats show much less sensitivity to PMA than dogs, resulting from the different response of leukocytes to PMA.

Animals↗

A study on hemodialysis leukopenia using various dialyzers.

Hemodialysis leukopenia was studied using various dialyzers and membranes. We found that dialyzers with cellulosic membranes caused marked leukopenia, but in recently developed non cellulosic membranes, its occurrence was significantly less. Additionally, our results showed a newly developed cellulose acetate membrane to correlate well with the non cellulose membranes regarding leukopenia, in spite of it being a derivative of cellulose. The extent of white blood cell decrease seemed to correlate inversely with an increase in the ultrafiltration rate per membrane area of dialyzer. The relationship between leukopenia and hypoxemia was examined also. The results of this investigation are included, however, we feel that more research is necessary before any conclusions can be made.

Cellulose↗

Association of clinical complications with nutritional status and the prevalence of leukopenia among arsenic patients in Bangladesh.

This study conducted in Bangladesh reports the relationship of clinical complications with nutritional status and the prevalence of leukopenia among arsenic exposed patients living in the rural villages. A total of 115 exposed individuals diagnosed as arsenicosis patients were randomly selected from four known arsenic endemic villages, and age-matched 120 unexposed subjects were enrolled in the study program. The duration of arsenic exposure in about 37% of the patients was at least 10 yrs, while the population mean and range were 7.6 +/- 5.2 yrs, and 1 - 25 yrs, respectively. The mean arsenic concentrations in the drinking water for the exposed and unexposed (control) population were 218.1 microg/L and 11.3 microg/L, respectively. The spot urine sample of the arsenicosis patients contained an average of 234.6 microg/L arsenic. Although very few patients showed elevated WBC count, 16% had leukopenia (below normal count), and the whole population had significantly low WBC count than the control subjects. Prevalences of neutropenia and lymphocytosis were observed in patients with chronic exposure to high levels of arsenic in water. The body mass index was found to be lower than 18.5, the cut-off point for malnutrition (underweight), in about 28% of the arsenicosis cases compared to 15% of the controls. The monthly income and total calorie consumption per day showed the patients were underprivileged than the controls. Arsenical symptoms and complications were more severe in the nutritionally vulnerable (underweight) patients than the overweight ones. Also, the incidences of leukopenia and anaemia were more common in the female patients who were underweight. The findings of this research demonstrate that the poor nutritional status of patients increases the complications of chronic arsenic toxicity; suggest the possibility of other sources of arsenic contamination different from drinking water in the study area; and establish a higher prevalence of leukopenia and lymphocytosis in arsenicosis patients.

Adolescent↗

[Lishengsu promotes the recovery of chemotherapy-induced leukopenia in patients with malignant tumors].

In order to investigate the therapeutic effects of Lishengsu, a domestic preparation of recombinant human granulocyte colony stimulating factor, the recovery of leukopenia was observed in 58 patients with malignant tumors after chemotherapy. In these patients, 7 cases were in first cycle of chemotherapy and 51 were given in repeated cycles. When blood leukocyte level decreased to less than 3x10(9)/L, Lishengsu was subcutaneously injected for 3-5 days at a dose of 75 microgram or 150 microgram per day. The results showed that Lishengsu remarkably alleviated the degree of leukopenis and accelerated the leukocyte counts recovered to normal level. The promotive effects of Lishengsu to recovery of leukopenia were dependent on degree of leukopenia at start of administration of Lishengsu. The curative effect of Lishengsu to chemotherapy-induced leukopenia was reliable with slight side-effects

Adult↗

Colchicine-induced leukopenia in a patient with familial Mediterranean fever: the cause and a possible approach.

A young patient with familial Mediterranean fever (FMF) developed leukopenia each time she took colchicine. However, when she discontinued the drug the white cell and the platelets counts increased but she experienced FMF attacks. Later it was found that the patient also had concomitant cytomegalovirus (CMV) infection. This complex situation posed several diagnostic and therapeutic issues concerning the real cause for the leukopenia and the possible approach to take in such conditions. We propose that when an essential drug (such as colchicine for FMF) causes leukopenia, one should look for concurrent CMV or another viral infection. If there is no such infection, it is suggested that the mechanism leading to leukopenia be clarified. In the case of bone marrow suppression, colchicine should be continued with injections of G-CSF, whereas if the bone marrow is hypercellular it is suggested to use steroids and colchicine concomitantly.

Adult↗

[Curative effect of rhG-CSF on leukopenia induced by chemoradiotherapy in 140 cases of malignant tumors].

This study was to evaluate the effect of a Chinese genetic engineering product of rhG-CSF (Lishengsu) on leukopenia induced by chemoradiotherapy in patients with malignant solid tumors. One hundred and forty cases of leukopenia following chemoradiotherapy for malignant tumors were treated with Lishengsu. When the total leukocyte counts (WBC) less than 3.0 x 10(9)/L or the absolute neutrophil count (ANC) less than 2.0 x 10(9)/L, Lishengsu was given 75 micro g/day subantaneously and the administration was stopped when the WBC counts rose up to 4.0 x 10(9)/L or higher, or the ANC counts reached 2.5 x 10(9)/L or more. The results showed that peripheral leukocyte counts in all patients following the treatment with Lishengsu were recovered and the average time of its administration was 4.8 days. The rate of its efficaciousness was 96.4%. It is concluded that Lishengsu could elevate nadirs of leukopenia and significantly shortened time period of leukopenia below 4.0 x 10(9)/L with acceptable mild side effects, decrease complications of infection so that the chinese product of rhG-CSF facilitates chemoradiotherapy significantly.

Adult↗

[The effect of the primary and repeated use of dialyzers with different membranes on the degree of dialysis-induced leukopenia].

The degree of leukopenia that occurs during hemodialysis is one of the main parameters characterizing biocompatibility of the dialysis membranes. It has been demonstrated that the use of the DIP-03-02 dialyzer fitted with a membrane manufactured from Soviet polysulfone produces much less remarkable leukopenia as compared to the use of dialyzers fitted out with conventional cellulose membranes. It has also been shown that the repeated use of dialyzers brings about a decrease in leukopenia and that the method of washing off dialyzers influences the degree of leukopenia.

Adult↗

The use of lithium carbonate to correct leukopenia during cancer treatment.

Leukopenia is a common complication noted in patients receiving radiotherapy and/or chemotherapy but no effective method has been reported so far to correct this complication. In the field of psychiatry, lithium carbonate used in treating depression has been noted to have induced leukocytosis as a side effect. From July 1985 to December 1987, a total of 111 patients receiving radiotherapy and/or chemotherapy with leukopenia were included in this study. There were sixty nine patients who received lithium carbonate and the remaining forty two patients served as control group were allowed to stop their primary treatment temporarily without medication during their period of leukopenia. For the group given lithium carbonate, 79% of the patients were able to recover their white blood count (WBC) above 3,000/cu.mm. within 5 days and finished their primary treatment smoothly. For the control group, it took them on the average about 11.8 days of rest in order to recover their WBC level to 3,000/cu.mm. and above. Reports in the recent literature indicates that the average toxic level is around 1.5 mEq/l to 2.0 mEq/l. In our study, the average serum lithium level before administration is 0.44 mEq/l, it reached 0.59 mEq/l and 1.08 mEq/l after the fifth and the 10th day of intake respectively. From this laboratory data, obviously no patient reached the toxic level and no side effects were noted clinically. Based on these figures, we can see clearly that lithium carbonate can shorten the period of leukopenia in comparison to the control group which was not given any medication.

Adolescent↗

Leukopenia and hypoxemia. Unrelated effects of hemodialysis.

Hemodialysis-induced hypoxemia has been attributed to membrane-related complement activation leading to pulmonary leukostasis and to hypoventilation secondary to carbon dioxide losses via the dialyzer. We have separately assessed the role of membrane- and dialysis-related factors by using different dialyzers and sequential ultrafiltration and hemodialysis with first-use cellulose dialyzers produced both leukopenia and hypoxemia. With reused cellulose and polyacrylonitrile dialyzers, hypoxemia still occurred, but without leukopenia. Ultrafiltration produced leukopenia and no changes in Pao2; during the subsequent hemodialysis, hypoxemia developed as the leukocyte count increased by 50%. Our data indicate that leukopenia and hypoxemia are unrelated effects of hemodialysis, and favor hypoventilation as the major determinant of hypoxemia during hemodialysis.

Adult↗

Leukopenia prognosis by radiation therapy of patients with Hodgkin's disease.

The investigation goal of the present study is the possible utilization of early postradiation peripheral blood DNA content changes during radiotherapy (RT) of cancer patients for prognostic purposes related to the subsequent ascertaiment of leukopenia values. Twenty-three primary patients with II-III stage Hodgkin's disease were treated at the linear accelerator of 15 Mev electrons by usual fractionation to a total dose of 40 Gy. The blood DNA content was fluorometrically determined by 4',6-diamidino-2-phenylindole before treatment, 24 hrs after the first irradiated dose, in the middle and at the end of RT course. Retrospective analysis of obtained data demonstrated that the first patients' group with blood leukocyte level above 3 x 10(9) cells/l at the end of RT, revealed an average blood DNA concentration decrease only after half of the treatment course. The second group of patients, complaining at the end of RT severe leukopenia, showed a two-fold decrease of the DNA concentration after the first irradiation in 62% of cases. The biochemical changes were not accompanied by a proportional decrease of the leukocytes number. The early decrease of DNA content drop, at the middle and the end of RT course, was conditioned both by lymphocytes and granulocytes. These changes were not practically interfaced with plasma changes. Thus, given biochemical criteria may be used as a sensitive index for the prognosis of leukopenia values after the RT beginning. As confirmed by test-irradiation in vitro of blood specimens of primary patients with Hodgkin's disease. There was a significant correlation between the new index and the level of leukopenia during post-treatment course.

DNA, Neoplasm↗