Drug-associated disease: hematologic dysfunction

Hematologic dysfunction, including thrombocytopenia, anemia, neutropenia, thromboses, and coagulopathy, occur commonly during critical illnesses. A major challenge is to identify drug-induced causes of hematologic dysfunction. Given the wide variety of drug-induced hematologic effects, clinicians always should consider any concomitant drugs in the differential diagnosis of acquired hematologic dysfunction. The most severe effects include drug-induced aplastic anemia, heparin-induced thrombocytopenia, and drug-induced thrombotic microangiopathy. Certain drugs are associated with multiple hematologic effects. For example, cisplatin can cause hemolytic uremia syndrome and erythropoietin deficiency, and quinine can precipitate immune-mediated thrombocytopenia, immune-mediated thrombocytopenia, and thrombotic microangiopathy.     

Managing the hematologic side effects of antiviral therapy for chronic hepatitis C: anemia, neutropenia, and thrombocytopenia

Hematologic abnormalities such as anemia, neutropenia, and thrombocytopenia are common during combination therapy with pegylated (or standard) interferon and ribavirin for chronic hepatitis C. Ribavirin-induced hemolytic anemia is a common cause of dose reduction or discontinuation. Bone marrow suppression also contributes to the anemia and is the predominant mechanism for interferon-induced neutropenia and thrombocytopenia. Although dose reduction or discontinuation of combination therapy can reverse these abnormalities, they may reduce virologic response. Hematopoietic growth factors may provide a useful alternative for managing these hematologic side effects without reducing the optimal dose of the combination antiviral regimen. Treatment of anemia also may improve patients' health-related quality of life and their adherence to combination antiviral therapy. The impact of growth factors on sustained virologic response and their cost-effectiveness in patients with chronic hepatitis C need further assessment.     

Sunitinib-induced microangiopathic hemolytic anemia with fatal outcome

Sunitinib, a new vascular endothelial growth factor receptor inhibitor, has demonstrated activity in renal cell carcinoma and is now widely used in the palliative treatment of patients with metastatic renal cell carcinoma. It is generally well tolerated but has been associated with a low incidence of grade 3 and 4 toxicities including fatigue, diarrhea, anorexia, mucositis, skin toxicity, immune thrombocytopenic purpura, hypertension, hypothyroidism, cytopenias, and decreased cardiac ejection fraction. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is a rare condition that is severe and may be fatal. Several medications have been implicated in causing TTP-HUS including clopidogrel, mitomycin C, cisplatin. In this report, we describe a case of atypical HUS-microangiopathic hemolytic anemia during treatment with sunitinib in a patient with metastatic renal cell carcinoma. To our knowledge, this is the fourth case of microangiopathic hemolytic anemia associated with sunitinib described in the literature and the first case with fatal outcome despite treatment with plasmapheresis, dialysis, and withdrawal of sunitinib.     

Death from drug-induced hemolytic anemia

Fatal hemolytic anemia occurred in a 71-year-old man after trimethoprim-sulfamethoxazole was given for presumed cystitis. Administration of this combination has previously caused multiple hematologic reactions by affecting folic acid metabolism. Megaloblastic anemia and neutropenia have been produced by both of these agents, while sulfamethoxazole alone has induced acute hemolytic anemia in patients with hereditary deficiency of glucose-6-phosphate dehydrogenase. Although hematologic complications of trimethoprim-sulfamethoxazole treatment usually follow long-term or high-dose therapy, acute reactions apparently may occur at lower doses as well.     

Experience of therapy for sepsis in cancer patients with neutropenia

The paper generalizes experience gained in performing 5800 courses of multidrug therapy (MDT) in patients with malignant tumors at various sites, complicated in 68 cases of severe neutropenia (neutrophils less than 500 per microl). Sepsis was diagnosed in 22 cases. With the timely admission of patients with sepsis and neutropenia during complex intensive therapy, their mortality was 22.7%. Emphasis is laid on a role of colony-stimulating factors in the correction of agranulocytosis. Their use decreases the duration of neutropenia, antibiotic therapy, and the length of stay by 1.3 times, as well as the cost of treatment.     

Pulmonary aspergillosis and central nervous system hemorrhage as complications of autoimmune hemolytic anemia treated with corticosteroids

Warm, active antibody adult autoimmune hemolytic anemia is the most common form of hemolytic anemia not related to drug therapy. Mortality in adult autoimmune hemolytic anemia is related to the inability to successfully treat patients' underlying disease, or the infectious complications of splenectomy and prolonged steroid therapy. Predisposing factors for invasive aspergillosis are neutropenia and steroid therapy. We present a fatal case of aspergillosis complicating a nonneutropenic case of warm active antibody adult autoimmune hemolytic anemia treated with prolonged steroid therapy.     

Application of therapeutic plasma exchange in hematology

Therapeutic plasma exchange (TPE) was used in 146 patients with hematologic disorders: hyperviscosity syndrome, 74; cryoglobulinemia, 53; porphyria, 9; immune complex disease, 3; cold agglutinin disease, 1; hemolytic uremic syndrome, 1; autoimmune hemolytic anemia, 1; autoimmune thrombocytopenia, 1; autoimmune neutropenia, 1; Clq deficiency, 1; and secondary immunodeficiency, 1. It was shown that TPE applied in patients with hyperviscosity syndrome resulted in rapid reduction of paraprotein concentrations, and normalization or significant decrease of serum viscosity associated with marked clinical improvement (regression of neurologic, renal, hematologic, visual and other disturbances). Application of TPE in patients with cryoglobulinemia resulted in plasma cryoglobulin reduction and clear clinical effects (blood flow improvement, skin ulcer healing, reversal of impaired renal function and disappearance of purpura and other abnormalities). Very good results were obtained in patients with porphyria (decreased sensitivity to sunlight) and also in patients with Clq deficiency. Satisfactory clinical improvement and better laboratory findings were also seen in patients with immune complex disease, autoimmune hemolytic anemia, autoimmune thrombocytopenia and hemolytic uremic syndrome.     

抗CD20单克隆抗体治疗难治性自身免疫性溶血性贫血

本研究初步观察抗CD20单克隆抗体利妥昔（rituximab）用于治疗难治性自身免疫性溶血性贫血（AIHA）的疗效和安全性。对1例用糖皮质激素、脾切除治疗无效的AIHA患者,采用利妥昔单克隆抗体,375mg/m2,每周1次,共4次,观察溶血症状的改变并监测血红蛋白（Hb）水平及其它检验指标,同时观察有无不良反应发生。结果表明,首次治疗后11天乳酸脱氢酶（LDH）、总胆红素（TBIL）、直接胆红素（IBIL）逐渐下降,第45天降至正常范围;首剂治疗25天后Hb水平比治疗之前升高到95-100g/L以上。治疗后已4月余,患者仍处于缓解状态。治疗过程中未发生明显不良反应。结论：抗CD20单克隆抗体利妥昔用于治疗难治性自身免疫性溶血性贫血是有效而且安全的。     

Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis

Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.     

Managing hematologic toxicities in the oncology patient.

Myelosuppression associated with antineoplastic therapy may lead to neutropenia, anemia, or both, resulting in an increased risk for infection, fatigue, diminished quality of life, and reduced survival. Neutropenia can result in dose reductions and treatment delays. Hematopoietic growth factors have been used effectively as supportive therapy to reduce antineoplastic therapy-associated neutropenia and anemia. This article discusses management of neutropenia and anemia secondary to antineoplastic therapy, new medications, and nursing considerations.     

Diabetic microangiopathic hemolytic anemia: beneficial effect of an antiplatelet agent?

A 66-yr-old man with non-insulin-dependent diabetes mellitus complicated by retinopathy and nephropathy presented with shortened red cell survival associated with prominent fragmentation of erythrocytes and leading to severe hemolytic anemia. Neither abnormal carbohydrate tolerance per se nor renal failure was related to the red cell fragmentation syndrome. Also, a marked platelet hyperaggregability, which disappeared under treatment with ticlopidine, was demonstrated. Furthermore, during treatment with this potent platelet inhibitor, red cell survival normalized and all signs of hemolysis, as well as the schistocytes present in the peripheral blood smears, disappeared. Two weeks after stopping ticlopidine administration, microangiopathic hemolytic anemia relapsed. We suggest that the fragmentation hemolysis in this patient was related to diabetic microangiopathy, and that the beneficial effects of ticlopidine are related to its platelet-inhibiting activities. This case further reaffirms that antiplatelet agents may have a beneficial effect on the vascular disease of diabetes mellitus.     

Immune hemolytic anemia associated with teicoplanin

BACKGROUND: Several drugs can cause immune hemolytic anemia. Here a patient who developed hemolytic anemia after treatment with teicoplanin is described. CASE REPORT: Owing to a two-vessel disease, a 68-year-old white man underwent coronary artery bypass grafting. He was readmitted for superficial sternal wound infection and sternal instability. Rewiring was required and worsening anemia characterized the course after the reoperation. Drugs used in the second admission were gentamycin, teicoplanin, paracetamol, and codeine. They were considered as a possible cause of drug-induced hemolytic anemia. RESULTS: The DAT was positive for complement and IgG. Autoanti-e was identified in the patient's undiluted serum sample. The eluate was reactive with all RBCs tested only after adding teicoplanin; when diluted 1:4, anti-e specificity was observed in the presence of teicoplanin. CONCLUSION: To our knowledge, this is the first report of immune hemolytic anemia owing to teicoplanin.     

Intraperitoneal fluid neopterin,nitrate, and tryptophan after regional administration of interleukin-12

Activated monocytes-macrophages may be associated with antitumor activity, and activation of these cells by certain cytokines, primarily interferon gamma (IFN-gamma), can be indicated by alterations in the concentrations of neopterin, nitrate, or tryptophan. Specimens of peritoneal fluid were obtained from patients with intra-abdominal neoplasia who were undergoing treatment in a phase I trial of weekly intraperitoneal recombinant interleukin-12 (rhIL-12), an inducer of IFN-gamma. Concentrations of neopterin, nitrate, tryptophan, IFN-gamma, and tumor necrosis factor alpha (TNF-alpha) were determined at various times during the first 48 hours in 11 patients who received intraperitoneal rhIL-12 in doses ranging from 100 to 1,500 ng/kg. An increase in peritoneal fluid nitrate concentrations was observed in nine of these patients. Increased concentrations of TNF-alpha and IFN-gamma were detected in 3 of 9 and 8 of 11 patients, respectively. Increased peritoneal fluid neopterin concentrations were detected by 24 hours after the injection in all patients studied. A significant increase in the ascitic fluid neopterin level could still be detected after 1 or 2 weeks of treatment (mean +/- standard error, 7.8 +/- 1.5 nM vs. 4.6 +/- 0.3 nM; Wilcoxon test, p = 0.0019), which is consistent with monocyte-macrophage activation. In contrast, the tryptophan concentration was lower (4.7 +/- 1.1 microM vs. 6.1 +/- 1.2 microM; p = 0.0428) after 1 or 2 weeks of treatment. There was a significant correlation between the dose of rhIL-12 and posttreatment neopterin concentrations (r(s) = 0.559, p = 0.0102). The intraperitoneal delivery of rhIL-12 appears to be associated with an immediate, sustained, and dose-dependent increase in peritoneal fluid neopterin, associated in most patients by an increase in IFN-gamma and in certain patients by an increase in nitrate and a decrease in tryptophan concentrations.     

Fine structure of the spleen in autoimmune hemolytic anemia associated with systemic lupus erythematosus

The fine structures of the red pulp of the spleen and the liver of a patient with autoimmune hemolytic anemia, neutropenia and thrombocytopenia associated with systemic lupus erythematosus are described. The red blood cells were phagocytized in toto by the splenic macrophages. These also contained neutrophils and platelets in various stages of degradation. Sinus endothelial cells revealed occasional erythrophagocytosis. The Kupffer cells in the liver occasionally contained red cells and platelets. These morphological findings and marked improvement of hematological abnormalities following splenectomy suggested that the spleen was the major site of destruction of blood cells. Undulating tubules associated with the endoplasmic reticulum were present in the sinus endothelial cells of the spleen.     

rhIL-12对恒河猴造血系统辐射防护作用的初步研究

摘要本研究旨在初步观察重组人白介素-12（rhIL-12）对急性辐射损伤猴造血系统的防护和治疗作用,为同类型病人的临床救治提供实验依据。在体外实验中,观察了不同浓度rhIL-12（0、1、5、25、125和625ng/ml）对来自人和健康成年猴骨髓造血祖细胞集落形成能力的影响。在体内实验中,用11只经3．0Gy全身照射后90d活存猴再经致死剂量^60Coγ（6．0Gy）射线全身1次照射以建立重度骨髓型急性放射病动物模型。模型动物被随机分为照射对照组（n=4）、单次给药组（n=3）和分次给药组（n=4）。单次给药组于照射后2h皮下注射rhIL-124μg／kg,分次给药组分别于照射后2h和3、6、9d皮下注射rhIL-121μg/kg,对照组于皮下注射同样体积的PBS。观察照射后动物活存情况和外周血象变化。体外培养结果显示,不同浓度rhIL-12可明显促进正常猴和人骨髓单个核细胞形成各系造血祖细胞集落,特别是CFU-E和CFU-GM最为明显。照射对照组动物于照射后22d内全部死亡,死亡动物平均活存时间为（20．3±1．2）d;rhIL-12单次给药组3只动物全部存活,rhIL-12分次给药组1只动物于照射后17d因贫血死亡。与对照组比较,rhIL-12治疗能明显提高动物存活（P=0．018）,并促进外周血白细胞数、血红蛋白水平、血小板以及网织红细胞数的恢复（P〈0．05）。结论：rhIL-12可明显促进灵长类骨髓造血祖细胞体外集落形成,并明显促进重度骨髓型急性放射病猴的造血功能恢复,提高动物存活率。     

Direct antiglobulin test-negative autoimmune hemolytic anemia in a patient with β-thalassemia minor during pregnancy: A case report

BACKGROUNDSevere refractory anemia during pregnancy can cause serious maternal and fetal complications. If the cause cannot be identified in time and accurately, blind symptomatic support treatment may cause serious economic burden. Thalassemia minor pregnancy is commonly considered uneventful, and the condition of anemia rarely progresses during pregnancy. Autoimmune hemolytic anemia (AIHA) is rare during pregnancy with no exact incidence available. CASE SUMMARYWe report the case of a 30-year-old β-thalassemia minor multiparous patient experiencing severe refractory anemia throughout pregnancy. We monitored the patient closely, carried out a full differential diagnosis, made a diagnosis of direct antiglobulin test-negative AIHA, and treated her with prednisone and intravenous immunoglobulin. The patient gave birth to a healthy full-term baby.CONCLUSIONCoombs-negative AIHA should be suspected in cases of severe hemolytic anemia in pregnant patients with and without other hematological diseases.     

利妥昔单抗注射液治疗自身免疫性溶血性贫血患者的护理

目的探讨利妥昔单抗注射液治疗难治性自身免疫性溶血性贫血(autoimmune hemolytic anemia,AIHA)患者的护理方法。方法回顾性总结并分析2012年6月至2013年5月中国医学科学院血液病医院采用利妥昔单抗注射液治疗的6例复发/难治性AIHA患者的临床资料。结果经积极治疗,本组6例患者中,完全缓解3例、部分缓解3例、发生不良反应1例。结论利妥昔单抗注射液治疗难治性自身免疫性溶血性贫血具有一定的疗效,积极的护理干预可减少利妥昔单抗注射液引起的不良反应,有利于提高患者的生活质量。     

A high-titer,high-thermal-amplitude autoanti-B associated with acrocyanosis but no obvious hemolytic anemia

BACKGROUND: ABO autoantibodies are rare. Most reported examples have been antibodies with 4 degrees C titers not greater than 256 in patients without apparent hemolytic anemia. Most high-titer, high-thermal-amplitude, complement-activating cold agglutinins are associated with hemolytic anemia. STUDY DESIGN AND METHODS: A 52-year-old man presented with acrocyanosis and mild small-vessel brain disease, but no evidence of obvious hemolytic anemia. Regular plasmapheresis treatment was helpful in relieving the clinical symptoms associated with acrocyanosis. Serologic methods were used to study the patient's RBCs and sera. RESULTS: The patient's RBCs were strongly reactive with anti-C3 and anti-IgM and weakly reactive with anti-IgA. The patient's serum contained a high-titer, high-thermal-amplitude, IgMkappa autoanti-B, capable of activating complement in vitro. CONCLUSION: A patient with a powerful ABO autoantibody is described. This patient had acrocyanosis but did not appear to have an obvious hemolytic anemia. This case is a good example of the lack of correlation between in vitro serologic tests and in vivo reactions in individual patients.     

Deaths associated with inappropriate intravenous colchicine administration

Intravenous (IV) colchicine is occasionally prescribed for the treatment of acute gouty arthritis. The Food and Drug Administration (FDA) recently received a report of death in a patient that was associated with inappropriate IV dosing of colchicine. This report prompted further investigation of other deaths associated with IV colchicine use in the FDA Adverse Event Reporting System (AERS) and the medical literature. A total of 20 deaths were identified. Eight patients were females, 11 were males, and the gender was unknown in 1. In all cases, the recommended maximum cumulative dose of 2 to 4 mg during a course of therapy was exceeded. Dose reductions are recommended in patients with renal or hepatic disease and in the elderly. All reported adverse events were associated with colchicine toxicity, including thrombocytopenia, leukopenia, pancytopenia, agranulocytosis, aplastic anemia, acute renal failure, and disseminated intravascular coagulopathy. Death occurred within 1 to 40 days after drug administration. Therapeutic guidelines exist for use of IV colchicine and these guidelines should be followed to prevent serious toxicities and death.