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HIV患者中的贫血、白细胞减少和血小板减少症
Mehnaz Junagadhwalla M.D. Division of Hematology/Oncology, Department of Medicine SUNY Upstate Medical University Hospital 750 E. Adams St, Syracuse , NY 13210 Telephone: 315/464-4927
Thomas E. Coyle, M.D. Division of Hematology/Oncology, Department of Medicine SUNY Upstate Medical University Hospital 750 E. Adams St, Syracuse , NY 13210. Telephone: 315/464-4927 Email: CoyleT@upstate.edu
译 者： 朱祖懿 博士 中国协和医科大学 Email: zhuzuyi@tsinghua.org.cn
校对者： 李剑 博士 北京协和医院 血液科 北京市东城区帅府园1号 100730
INTRODUCTION Hematological abnormalities including anemia, leukopenia, and thrombocytopenia are common in patients with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). These are less common in the early stages of HIV infection, but increase in frequency and severity with progression of the acquired immunodeficiency syndrome. These cytopenias may be caused by the HIV infection directly, by complicating opportunistic infections or malignancies, by adverse effects of HIV related therapy, or by other coexisting diseases. There may be significant associated symptoms, and the development of cytopenias may be an important clue to complications of AIDS or progression of the disease. The challenge to the clinician is to efficiently discover the cause of the cytopenia, to provide appropriate supportive care and to provide specific treatment. The mechanism of cytopenias in HIV infected patients is most commonly decreased production, especially in the more advanced stages of the disease. However, increased destruction plays a major role in HIV related thrombocytopenia. 前言 血液学检查异常如贫血、白细胞减少、血小板减少在HIV病毒感染及获得性免疫缺陷综合征（AIDS）的患者中很常见。这些症状在HIV感染早期少见，但随着AIDS病情的进展其发生率和严重程度逐渐增加。血细胞减少的原因可能是由HIV病毒感染直接导致，或因为合并机会性感染或恶性肿瘤、HIV治疗相关的副作用，或合并其它疾病所致。血细胞减少可出现严重的症状，而出现血细胞减少症可能是出现AIDS并发症或其病情进展的重要线索。临床医生应尽可能明确血细胞减少的病因，给予恰当的对症支持治疗和特异性的对因治疗。HIV感染患者中血细胞减少最常见的机制是血细胞生成减少，尤其是在疾病晚期。然而血小板破坏增多亦是HIV相关性血小板减少症的重要发病机制。 Anemia Epidemiology Anemia is the most common hematological abnormality in HIV infection. Mild normocytic-normochromic anemia is seen in 15-30% of patients during early stages of the disease and the prevalence increases to 70-95% of patients in far advanced stages of the disease. The anemia becomes more severe in the advanced stages (237, 49, 107, 209, 135, 18). In an analysis of more than 32,000 HIV infected patients in the U.S., Sullivan et al., found the one year incidence of anemia, defined as a hemoglobin less than 10 gms/dl, to be 37% in patients with clinical AIDS, 12 % in patients with CD4+ cell counts of <200/mm3, and 3% in HIV infected individuals without clinical or immunologic AIDS (208). These authors found that anemia in HIV infected patients was associated with an increased risk of death and that recovery from anemia was associated with decreased risk of death. Similar findings were reported in a European study of more than 6,000 patients. Mild anemia, defined as a hemoglobin less than 14 gms/dl, was seen in 58% and severe anemia defined as a hemoglobin less than 8 gms/dL, was seen in 1.6%. Severe anemia was found to be associated with a faster rate of progression of AIDS, and anemia was a strong independent predictor of death (136). A number of observational studies have found that improvement of anemia is associated with prolonged survival and improvement in quality of life (1, 47, 69, 130, 141, 175, 205,139). The prevalence of anemia has decreased in the era of highly active antiretroviral therapy (HAART) (139). 贫血 流行病学 贫血是HIV感染中最常见的血液学异常。轻度正细胞正色素性贫血见于15～30％疾病早期患者，在疾病的晚期，这一比例增加至70～95％。晚期患者的贫血会更加严重(237, 49, 107, 209, 135, 18)。在一项对32，000多名美国HIV感染者的研究中，Sullivan等人发现贫血（血色素小于10g/dl）的年发病率在临床AIDS患者中为37％，CD4＋细胞计数<200/m3的患者中为12％，在没有AIDS临床表现或免疫学异常的HIV感染患者中为3％(208)。这些作者发现HIV患者的贫血与死亡率增加有关；贫血恢复后死亡的风险也有所下降。另一项纳入6000多名患者的欧洲研究也报道了类似的结果。<14g/dl的轻度贫血患病率为58%，<8g/dl的重度贫血为1.6%。重度贫血与AIDS的快速进展相关，贫血是死亡的独立预测因素(136)。许多观察性研究都报道贫血的改善与生存期延长和生活质量改善相关(1, 47, 69, 130, 141, 175, 205,139)。高效抗逆转录病毒治疗(HAART)时广泛使用后，贫血发病率有所下降(139)。 Differential Diagnosis The causes of anemia can be broadly categorized into anemia due to depressed erythropoiesis and anemia due to increased destruction (hemolytic anemia). The causes of anemia in HIV infection are summarized in Table 1 鉴别诊断 贫血的原因大致可以分为造血抑制和破坏增加（如溶血性贫血）。 表1总结了HIV感染中贫血的病因。 Risk Factors Anemia is correlated with more advanced stages of HIV infection, the presence of opportunistic infections, malignancies, liver disease, renal disease and drug therapy. 危险因素 贫血发生与HIV感染的晚期、合并机会性感染、恶性肿瘤、肝脏疾病、肾脏疾病和药物治疗相关。 Clinical Manifestations General The symptoms of anemia include fatigue, difficulty in mental concentration, decline in performance status, shortness of breath, and when anemia is severe, chest pain, heart failure, coma, and death. The symptoms of anemia significantly affect quality of life (223). Fatigue is the most common symptom and anemia may be a cause of fatigue in HIV infected patients that is independent of HIV viral load and CD 4 count, and HIV infected patients with fatigue should be assessed for causes other than anemia (206). Physical signs of anemia include skin and conjunctival pallor, tachycardia, and signs of congestive heart failure in very advanced anemia. 临床表现 概述 贫血的症状包括乏力、注意力不集中、体力下降、气短，贫血严重时会出现胸痛、心衰、昏迷甚至死亡。贫血症状可以严重影响生活质量(223)。乏力是最常见的表现，贫血可能是引起HIV患者乏力症状的原因中除HIV病毒载量和CD4细胞计数之外的独立因素，同时伴有乏力症状的HIV患者也应该寻找除贫血之外的其它原因(206)。贫血的体征包括皮肤结膜苍白，心动过速，长期的贫血会导致充血性心力衰竭。 Anemia of chronic disease Anemia in patients with AIDS most commonly has the characteristics of anemia of chronic disease. The mean hemoglobin in such patients is between 9 and 10 gm/dl (61, 62). The red cells are typically normochromic and normocytic, frequently with anisocytosis. In more advanced cases there may be hypochromia and microcytosis. There is decreased erythrocyte production and suppression of reticulocyte response. This is due to the suppression of the bone marrow from the HIV infection and due to the effects of opportunistic infections. Characteristic abnormalities of iron metabolism are seen, including low serum iron, decreased total iron binding capacity, low transferrin saturation, increased amount of storage iron in marrow macrophages, and a decreased percentage of sideroblasts in the bone marrow. Serum ferritin may be markedly elevated in AIDS patients (77, 173) and increased storage iron in bone marrow macrophages has been associated with a worse overall prognosis in AIDS patients (45, 187). Recently elevated hepcidin levels have been shown to be the mediator of the abnormal iron metabolism in anemia of chronic disease (66). There is a blunted response to erythropoietin in anemia of chronic disease. Inflammatory cytokines such as tumor necrosis factor and interleukin-1, which are elevated due to the HIV infection and opportunistic infections, play a central role in the etiology of anemia of chronic disease (187, 230). 慢性病性贫血 AIDS患者贫血最常表现出慢性病性贫血的特点。此类病人的平均血红蛋白值为9~10 g/dl(61, 62)。红细胞为典型的正细胞正色素性，常可出现大小不等。晚期患者中可能出现小细胞低色素性红细胞。并有红细胞生成减少，网织红细胞反应受抑制的现象。这是由于HIV感染所致的骨髓抑制以及机会性感染的影响。还可见到铁代谢异常的特征性表现，包括血清铁降低，总铁结合力降低，转铁蛋白饱和度降低，骨髓巨噬细胞中铁储备增多，骨髓中铁粒幼细胞比例减少。AIDS患者中血清铁蛋白可能会显著升高(77, 173)，骨髓巨噬细胞中铁储备的增加与AIDS患者整体预后差相关(45, 187)。铁调素（hepcidin，国内对此还没有一个明确的中文名字）水平的升高最近被证实是慢性病性贫血中铁代谢异常的介质(66)。慢性病贫血对促红细胞生成素的治疗有一些反应。HIV感染和机会性感染所造成的炎性因子如肿瘤坏死因子（TNF）和白介素1（IL-1）的增高在慢性病性贫血的发病机制中起重要作用(187, 230)。 Blood Loss and Iron Deficiency 失血和缺铁 Gastrointestinal bleeding causes both acute and chronic anemia with the latter being characterized by iron deficiency anemia. Such bleeding may result from intestinal lymphoma, gastrointestinal Kaposi sarcoma, and opportunistic infections especially CMV and Candidiasis. Acute blood loss anemia is generally normochromic, normocytic and the reticulocyte count may be elevated. Signs and symptoms of hypovolemia may be present. Iron deficiency causes microcytosis and hypochromia on peripheral smear, with a decreased reticulocyte count, low serum iron, elevated total iron binding capacity (TIBC), and low serum ferritin. These findings may be obscured by concomitant anemia of chronic disease or drug induced changes, and a bone marrow examination may be needed at times to assess iron stores. Non hematological manifestations of iron deficiency include glossitis, chelitis, pica, brittle nails, and restless leg syndrome. Acute gastrointestinal bleeding in AIDS patients associated with lymphoma, thrombocytopenia or two or more other concurrent major illness is associated with poor overall survival (30, 160). Women infected with HIV have a very high prevalence of concomitant iron deficiency anemia from menstrual blood loss. A higher prevalence of iron deficiency anemia was detected in female intravenous drug abusers who were HIV positive compared with those patients who were HIV negative (195). 消化道出血导致急性和慢性贫血，后者表现为缺铁性贫血。此类出血可能是肠道淋巴瘤，胃肠道卡波济肉瘤，机会性感染尤其是CMV和念珠菌感染所致。急性失血性贫血多为正细胞正色素性，网织红细胞计数升高。可表现出低血容量的症状和体征。铁缺乏后，外周血涂片呈现小细胞低色素的红细胞，网织红细胞计数降低，血清铁降低，总铁结合力（TIBC）升高，血清铁蛋白降低。这些表现可能会被并发的慢性病性贫血或药物导致的变化所掩盖，因此有时需要行骨穿以评估铁储备情况。缺铁的非血液系统表现包括舌炎，唇炎，异食癖，反匙甲和不宁腿综合征。AIDS患者中由于淋巴瘤、血小板减少或其它严重并发症导致的急性消化道出血与整体生存率差相关(30, 160)。HIV感染女性患者由于月经失血，缺铁性贫血的发生率很高。HIV阳性的女性静脉药物滥用者比阴性人群的缺铁性贫血发生率高(195)。 Myelophthisic Anemia Opportunistic infections cause anemia of chronic disease but may also cause anemia due to direct involvement of the bone marrow. Myelophthisic anemia is characterized by the presence of tear drop red cells, schistocytes, nucleated red blood cells, and early myeloid cells on peripheral blood smear. Anemia, fever, and weight loss in patients with advanced immunodeficiency (CD4+ lymphocytes less than <100/µl) should prompt an evaluation for mycobacterium avium complex (80). Severe anemia (hematocrit <26%) has been reported to be present in up to 76% of patients with disseminated mycobacterium avium complex (84). The anemia seen with mycobacterium avium complex infection is due to high levels of inflammatory cytokines, as well as a direct disturbance of bone marrow microenvironment by the mycobacteria. Anemia resulting from mycobacterium avium complex has been reported to be the most common type of anemia severe enough to require blood transfusion in AIDS patients, and prophylaxis for mycobacterium avium complex was shown to decrease the need for transfusions (106). Other opportunistic infections causing anemia include bacillary angiomatosis (137) and CMV infection. Myelophthisic anemia may also result from bone marrow involvement from non Hodgkin lymphoma, Hodgkin disease or other malignancy. Such patients may present with lymphadenopathy, weight loss or fever, but the hematological findings may predominate. The diagnosis may be confirmed by bone marrow biopsy. Multicentric Castleman’s disease is an uncommon syndrome of lymphadenopathy with a characteristic histology accompanied by fever, weight loss, hepatosplenomegaly, hypergammaglobulinemia, and edema. Anemia is seen in almost all patients with Castleman’s disease and approximately 35% have pancytopenia (158). 骨髓病性贫血 机会性感染导致慢性病性贫血，也可以导致由于骨髓直接受累所致的贫血。骨髓病性贫血特征性表现为外周血涂片中可见到泪滴形红细胞、破裂红细胞、有核红细胞和幼稚髓细胞。出现贫血，发热和体重下降的晚期免疫缺陷患者（CD4+淋巴细胞计数<100/µl）应该评价是否存在鸟分枝杆菌复合体感染(80)。78%的播散性鸟分枝杆菌复合体感染的患者可以出现重度贫血（红细胞压积<26%） (84)。鸟分枝杆菌复合体感染相关性贫血是由于高水平的炎症因子所致，同时伴有分枝杆菌对骨髓的直接破坏。鸟分枝杆菌复合体感染相关性贫血是AIDS患者中最常见的需要输血的严重贫血类型，预防鸟分枝杆菌复合体感染可以减少输血的处理(106)。 其它导致贫血的机会性感染包括杆菌性血管瘤病(137)和CMV感染。骨髓病性贫血也可以是非霍奇金淋巴瘤、霍奇金病或其它恶性肿瘤侵犯骨髓导致。这些患者可以表现为淋巴结肿大，体重下降或发热，但其主要表现为血液学改变。确诊需要骨髓活检。多中心型Castleman病是一种罕见的具有特征性组织学表现的淋巴结肿大综合征，可出现发热、体重下降、肝脾大、高球血症和水肿等症状。几乎所有Castleman病的患者都有贫血，其中约35%患有全血细胞减少症(158)。 Pure Red Cell Aplasia Chronic pure red cell aplasia can develop in HIV infected patients who are also infected with Parvovirus B-19 (60). This syndrome is characterized by chronic anemia with a very low reticulocyte count and an absence of erythroid precursors in the bone marrow along with the presence of giant pronormoblasts. There are low or absent levels of neutralizing IgM and IgG antibodies against parvovirus. High levels of parvovirus DNA are seen in the serum and marrow. Symptoms of acute viral illness from parvovirus infection similar to "fifth disease" are usually absent. Pure red cell aplasia has also been associated with zidovudine (36, 161). Lamivudine has also been implicated as a cause of pure red cell aplasia which reverses with drug cessation (206). 纯红细胞再生障碍性贫血 同时感染细小病毒B-19的HIV患者可以出现慢性纯红细胞再生障碍性贫血(60)。此综合征表现为伴有网织红细胞计数极低、骨髓中出现巨大原红细胞以及缺少红系前体的慢性贫血。（血清中）细小病毒的IgM和IgG抗体水平很低或没有。但血清和骨髓中可检测到高水平的细小病毒DNA（拷贝数）。由细小病毒感染导致的传染性红斑样的急性症状通常没有。纯红细胞再生障碍性贫血也与齐多夫定（Zidovudine）有关(36, 161)。拉米夫定也被证实可以导致纯红细胞再生障碍性贫血，停药后贫血可恢复(206)。 Drug Induced Anemia Hematopoietic suppression commonly occurs as an adverse effect of drug therapy for HIV and has been reported to be responsible for 20% of anemia in AIDS (208). Drugs causing hematologic adverse effects are summarized in Table 2. Hematological toxicity, chiefly macrocytic anemia, is the dose limiting toxicity of zidovudine. Macrocytosis develops within weeks following the initiation of zidovudine treatment in most patients and its presence can be used as marker of medication adherence. Zidovudine has been shown to suppress in vitro hematopoietic colony formation in dose dependant manner (42). Zidovudine induced anemia is also dose-dependent and less prevalent at the current doses of 200 mg three times a day as compared to earlier higher dose regimens. Didanosine and other nucleoside reverse transcriptase inhibitors are less myelosuppressive than zidovudine, but anemia may be seen with lamivudine and stavudine (12, 65). Patients with more advanced HIV infection with low CD4+ lymphocyte counts are more prone to drug induced cytopenia (65). Megaloblastic anemia has also been associated with trimethoprim-sulfamethoxazole (198) and pyrimethamine (34). Ribavirin and interferon, used for treatement of co-infection with hepatitis C, are also associated with drug induced cytopenias, particularly anemia with a hemolytic component. Treatment with erythropoietin alpha improves the associated anemia and permits continuation of ribarvirin and interferon treatment (5, 14). 药物导致的贫血 造血抑制是HIV药物治疗的一个常见副作用，与AIDS患者中20%的贫血有关(208)。表2总结了药物导致的血液学副作用。血液学毒性，特别是大细胞性贫血是齐多夫定的剂量限制性毒性。大多数患者在开始使用齐多夫定后数周内出现大红细胞症，大红细胞的出现可以作为用药依从性的标记。齐多夫定在体外已经被证实可以抑制造血干细胞集落形成，并具有剂量依赖性(42)。齐多夫定导致的贫血也呈现出剂量依赖性的，目前200mg，一天3次的剂量比早期更高剂量时的贫血发生率低。去羟肌苷和其它核苷逆转录酶抑制剂与齐多夫定相比骨髓抑制作用弱，但拉米夫定和司坦夫定也可导致贫血(12, 65)。晚期HIV感染患者，随着CD4+淋巴细胞计数的降低，更容易出现药物导致的血细胞减少(65)。巨幼细胞贫血还与甲氧苄啶-磺胺甲噁唑 (198) 和 乙胺嘧啶(34)有关。用于治疗丙型肝炎感染的利巴韦林和干扰素，也与药物导致的全血细胞减少尤其是溶血性贫血有关。使用促红细胞生成素alpha可以改善贫血并使利巴韦林和干扰素治疗可以继续下去(5, 14)。 Primaquine and Dapsone provokes oxidative hemolysis in patients with glucose-6-phosphate-dehydrogenase deficiency. These patients present with anemia occurring shortly after initiating the offending drug. Findings include an increased serum LDH, decreased serum haptoglobin, and positive Heinz body preparations. The diagnosis can be confirmed by specific assay of glucose-6-phosphate activity, but false negative assays can be seen if testing is performed immediately after an episode of hemolysis. Glucose-6-phosphate-dehydrogenase deficiency is an X -linked inherited disorder most common in those of African and Mediterranean descent. Febrile illnesses can also provoke hemolytic episodes in affected patients. Dapsone also directly causes dose-dependant hemolysis independent from glucose-6-phosphate- dehydrogenase deficiency (88), and may also rarely cause methhemoglobinemia (54), and the sulfone syndrome of anemia and hepatitis (33), and agranulocytosis (232). Hemolytic anemia has also rarely been associated with indinavir or pentamidine therapy (142, 211). 伯喹和氨苯砜可引起葡萄糖-6-磷酸脱氢酶（G-6PD）缺乏患者中的氧化性溶血。这些患者在开始用药后很快就会出现贫血。临床可以表现出血清LDH水平升高，血清结合珠蛋白减少以及Heinz小体阳性。确诊依靠特异性葡萄糖-6-磷酸酶活性检测，但是若在溶血发作后立刻检测会出现假阴性结果。G-6PD缺乏是X连锁的遗传性疾病，主要见于非洲和地中海地区。发热性疾病也会引起这些患者的溶血发作。氨苯砜也可以直接导致非G-6PD途径依赖性的剂量依赖性溶血(88)，也可导致少见的甲基血红蛋白血症(54)，表现为贫血和肝炎的氨苯砜综合征(33)或粒细胞缺乏(232)。溶血性贫血也偶见于茚地那韦和喷他脒治疗中(142, 211)。 Megaloblastic Anemia Decreased serum cobalamin (vitamin B12) levels have been reported in 10-30% of patients with AIDS (13, 27, 79, 82, 159). Low levels are more common in advanced AIDS, especially in those with diarrhea and malabsorption. Typical macrocytic anemia with hypersegmented neutrophils and frank megaloblastic changes in the bone marrow are not always seen in patients with early cobalamin deficiency states. Malabsorption of cobalamin may be demonstrated by a Schilling test, but low cobalamin levels may be seen in presence of a normal Schilling test. However, anemia in AIDS patients generally does not respond to cobalamin supplementation. Myelosuppression from zidovudine may be enhanced by concomitant vitamin B12 deficiency. Folate deficiency may also result in a megaloblastic anemia in AIDS patients (174, 214). One controlled trial failed to demonstrate any amelioration of myelosuppression when supplementation of cobalamin and folate was given to patients receiving zidovudine (56). 巨幼细胞贫血 10~30%的AIDS患者中血清钴胺（维生素B12）水平降低(13, 27, 79, 82, 159)。晚期AIDS患者更常见，尤其是伴腹泻和吸收不良的患者。早期钴胺缺乏的患者不一定有中性粒细胞分叶过多和骨髓巨幼细胞变的典型巨幼细胞贫血表现。钴胺吸收不良可以用Schilling试验检测，但是低钴胺水平也可见于Schilling 试验正常者。AIDS患者的贫血通常对补充钴胺反应不佳。伴发维生素B12缺乏可能会加重齐多夫定导致的骨髓抑制。叶酸缺乏也可以造成AIDS患者的巨幼细胞贫血(174, 214)。一项对照研究报道给使用齐多夫定的患者补充钴胺和叶酸后骨髓抑制没有明显改善(56)。 Autoimmune Hemolytic Anemia A positive direct antiglobin test (Coomb’s test) has been frequently reported in patients with AIDS. Its presence correlates with hypergammaglobulinemia, suggesting that the positive Coomb's test may be a part of the polyclonal hypergammaglobulinemia found in HIV patients (212, 78, 216). Despite high frequency of positive Coomb's test the actual incidence of autoimmune hemolytic anemia in AIDS is low. Autoimmune hemolytic anemia may be identified by anemia with an unusually high transfusion requirement, low serum haptoglobin, microspherocytes on peripheral smear, splenomegaly, indirect hyperbilirubinemia, elevated serum LDH, and bone marrow erythroid hyperplasia. Reticulocytosis may be lacking because of concomitant anemia of chronic disease. Cold agglutinins have been reported to be present in 20% of HIV infected patients but with no association to anemia, opportunistic infections or malignancy (35). 自身免疫性溶血性贫血 直接抗人球蛋白实验（Coombs试验）阳性常见于AIDS患者。这与高丙种球蛋白血症有关，提示Coombs试验阳性可能是HIV患者中多克隆高丙种球蛋白血症的一部分(212, 78, 216)。尽管Coomb’s试验阳性率很高，但是AIDS患者实际发生自身免疫性溶血的机率较低。自身免疫性溶血可以表现为异常高的输血需求，低血清结合珠蛋白，外周血涂片可见小球形红细胞，脾大，间接胆红素升高，血清LDH升高以及骨髓红系增生。伴发慢性病性贫血时可不出现网织红细胞增多。20%的HIV感染患者患有冷凝集病素阳性，但与贫血、机会性感染或恶性肿瘤无关(35)。 Hemophagocytic Syndrome Anemia, thrombocytopenia, leukopenia, fever, wasting, lymphadenopathy, hepatosplenomegaly, and cutaneous manifestations such as pannicultitis and purpura characterize the hemophagocytic syndrome, an uncommon complication of AIDS. The pathogenesis involves stimulation of histiocytes by cytokines. Prominent erythrophagocytosis and cytophagocytosis is seen in the bone marrow, and an elevated serum LDH and ferritin are frequently seen (203). The syndrome has been reported in the presence of opportunistic infections such as mycobacterium avium complex, histoplasmosis and pneumocystis (99, 100) as well as with CMV infection (185) and EBV infection (6, 43). 噬血细胞综合征 噬血细胞综合征是AIDS一个少见的并发症，主要表现为贫血，血小板减少，白细胞减少，发热，消瘦，淋巴结肿大，肝脾大，皮肤表现如脂膜炎和紫癜。病理机制包括细胞因子激活了组织细胞。骨髓中可见到明显的吞噬红细胞和吞噬其他细胞的现象，血清LDH和铁蛋白常升高(203)。噬血细胞综合征可见于机会性感染如鸟分枝杆菌复合体感染，组织胞浆菌病和肺孢子病(99, 100)，CMV感染(185)和EBV感染(6, 43)。 Microangiopathic Hemolytic Anemias Thrombotic thrombocytopenic purpura (TTP) (63, 146, 211) is an often fatal syndrome marked by the presence of neurologic signs and symptoms, fever, renal insufficiency, hemolytic anemia, and thrombocytopenia. Patients generally have a markedly elevated LDH and hyperbilrubinemia and mild to moderate azotemia. Waxing and waning changes in mental status, petechiae, and abdominal pain may be seen. The peripheral blood smear typically shows marked schistocytes, polychromasia, and nucleated red blood cells. Primary endothelial damage and abnormal platelet agglutination have been proposed as possible causes for HIV induced TTP (8, 52, 63, 210, 221). Recently deficiency of or the presence of an inhibitor antibody of a metaloprotease, ADAMTS-13, which cleaves high molecular weight multimers of von Willebrand factor, has been shown to be central to the pathogenesis of familial and idiopathic TTP respectively. The absence of ADAMTS-13 due to an inhibitor antibody has been reported in HIV associated TTP (183). Some patients have an underlying identifiable cause for thrombotic microangiopathy such as sepsis or acute pancreatitis, but the majority has no other cause than HIV infection. High dose valacyclovir (8 grams/day) has been associated with TTP in HIV patients (17). There is a single case report of TTP in a HIV patient being treated with lower doses of valacyclovir (177), however, it is unclear whether this is a causal relationship or an incidental finding. 微血管病性溶血性贫血 血栓性血小板减少性紫癜（TTP）(63, 146, 211)是一种死亡率较高的综合征，临床表现为神经系统症状和体征，发热，肾功能不全，溶血性贫血和血小板减少。患者常有显著升高的LDH和高胆红素血症，以及轻至中度的氮质血症。还可以见到神志状态的波动，瘀斑和腹痛。外周血涂片典型表现为破裂红细胞，嗜多色性细胞和有核红细胞增多。原发内皮损伤和异常血小板聚集被认为是HIV导致TTP的原因(8, 52, 63, 210, 221)。近期认为，缺乏裂解高分子量von Willebrand因子多聚体的金属蛋白酶ADAMTS-13、或存在该酶的抑制性抗体分别是导致家族性TTP和特发性TTP的主要病理机制。因抑制性抗体而导致ADAMTS-13缺乏可见于HIV相关性TTP (183)。虽然一些患者具有明确的血栓性微血管病的病因如败血症或急性胰腺炎，但是大多数患者除了HIV感染外无其它的原因。大剂量伐昔洛韦（8g/天）与HIV患者中的TTP有关(17)。也有个例使用低剂量伐昔洛韦治疗发生TTP的报道(177)，但尚不清楚这是病因关联还是巧合。 Early recognition and treatment of TTP are essential, as it is generally fatal without effective treatment. One report suggested that thrombotic microangiopathy may be responsible for as much as 3% of HIV related mortality (63). Advanced stages of AIDS, slow onset of TTP and delayed diagnosis and treatment are predictors of a poor outcome. 早期识别和治疗TTP是必要的，因为缺乏有效的治疗通常会致命。有一项研究报道血栓性微血管病占HIV相关死亡率的3%(63)。晚期AIDS，缓慢起病的TTP，延迟诊断和治疗是预后差的相关因素。 Hemolytic-Uremic Syndrome (HUS) is a related microangiopathic hemolytic anemia dominated by renal failure, hypertension, thrombocytopenia and schistocytosis, without prominent neurological symptoms or fever. There is not a deficiency of ADAMTS-13 in HUS. HUS in AIDS patients is usually seen in advanced stages of HIV infection, but can be the presenting feature (9). The prognosis of HUS has been noted to be poor, with a high mortality rate and requirement for dialysis (95). 溶血性尿毒症综合征（HUS）是另一种相关的微血管病性溶血性贫血，主要临床表现为肾功能衰竭、高血压、血小板减少和红细胞碎片，没有显著的神经系统症状或发热。HUS没有ADAMTS-3的缺乏。AIDS患者中的HUS常见于晚期HIV感染患者，但也可以是首发症状(9)。预后差，死亡率高和很多患者透析需要(95)。 Hypersplenism Hypersplenism from liver disease may cause hemolytic anemia, thrombocytopenia and leukopenia. Target cells may be seen on peripheral smear. Patients with HIV infection are commonly infected with chronic hepatitis B or hepatitis C infection and HIV infected patients have a more aggressive course of their hepatitis with early progression to cirrhosis (55). Such patients have stigmata of liver disease on physical examination, palpable splenomegaly, ascites, abnormal liver function tests, and coagulopathy of liver disease. 脾功能亢进 肝病继发的脾功能亢进可以导致溶血性贫血，血小板减少和白细胞减少。外周血涂片中可以看到靶细胞。HIV感染患者通常合并慢性乙型或丙型肝炎感染，而且合并HIV感染的患者其肝炎进展较快，更容易进展为肝硬化(55)。此类肝病患者体格检查可见到肝病患者特征性表现：脾大、腹水、肝功能异常及凝血功能异常。 Diagnosis The patient’s history should be reviewed with particular attention to manifestations of gastrointestinal bleeding, previous history of anemia, family history of anemia, history of liver disease or hepatitis, neurological symptoms, symptoms of opportunistic infections, including lymphadenopathy, fevers sweats, and weight loss. The patient’s volume status should be assessed and stools tested for occult blood. Previous blood counts, if available, should be reviewed to determine the rate of onset of the anemia. The stage of the patient’s HIV infection should be assessed. Patients with advanced immunodeficiency, high HIV viral loads, and low CD 4+ lymphocyte counts are more likely to have anemia from the marrow suppression due to the HIV virus and anemia of chronic disease. Such patients are more likely to have anemia due to opportunistic infections as well. 诊断 采集患者病史时要特别注意有无消化道出血的表现，贫血史，家族性贫血史，肝病或肝炎史，神经系统症状，机会性感染的症状，包括淋巴结肿大、发热、出汗及体重下降。评价患者的容量状态，查大便潜血。如果有之前的血细胞计数检查，应当复习之前的血象，以便评估出贫血发展的速度。评价患者HIV感染的分期。晚期免疫缺陷、高HIV病毒载量和低CD4+淋巴细胞计数的患者更容易出现HIV病毒抑制骨髓导致的贫血和慢性病性贫血。这类患者也容易出现机会性感染导致的贫血。 The medication profile should be reviewed including the temporal relationship of the initiation of the medication to the development of the anemia. 需要回顾患者的用药史，包括开始用药和贫血发生之间的时间关系。 The hemogram and peripheral smear should be carefully reviewed. Concomitant leukopenia and thrombocytopenia should be identified. A reticulocyte count, mean corpuscular volume (MCV), serum LDH, total and indirect bilirubin, total iron binding capacity (TIBC), and creatinine should be obtained. 需要认真检查血像和外周血涂片。识别出伴发的白细胞减少症和血小板减少症。检查网织红细胞计数、平均血红细胞体积（MCV）、血清LDH、总胆红素和间接胆红素，总铁结合力(TIBC)和肌酐。 Anemia with a low reticulocyte count suggests decreased red cell production. If the MCV is low, iron deficiency should be considered and the peripheral smear reviewed for the presence of hypochromia and microcytosis. A low serum iron, an elevated TIBC, and a decreased ferritin can confirm the diagnosis. Occasionally assessment of bone marrow iron stores may be needed to determine iron stores. 低网织红细胞计数的贫血提示红细胞生成减少。如果MCV小，应考虑缺铁性贫血，检查外周血涂片以便发现有无小细胞低色素性红细胞。血清铁降低，TIBC升高，铁蛋白降低可确诊。有时为测定机体铁储备需检测骨髓铁储备情况。 A low reticulocyte count and normal MCV with unremarkable red cell morphology on peripheral smear is consistent with anemia of chronic disease. The serum iron and TIBC are usually both decreased and the ferritin may be increased. Very low reticulocyte counts are seen in red cell aplasia due to parvovirus B-19 infection. Bone marrow aspiration and DNA studies for parvovirus may confirm the diagnosis. 网织红细胞计数低，MCV正常，外周血涂片红细胞形态无异常提示慢性病性贫血。血清铁和TIBC通常均降低，铁蛋白可能升高。极低的网织红细胞计数可见于细小病毒B-19感染所致的红细胞再生障碍性贫血。骨髓穿刺和细小病毒DNA检查可以确诊。 Marrow infiltration by infection or neoplasm (myelophthisic anemia) is often accompanied by a low reticulocyte count, tear drop cells on the peripheral smear, nucleated red blood cells and the presence of early myeloid cells in the peripheral blood. Thrombocytopenia often accompanies the anemia and diagnosis is established by bone marrow examination or by blood cultures in the case of opportunistic infection, such as mycobacterium avium complex. Other signs or symptoms of opportunistic infection or lymphoma such as fever, splenomegaly, lymphadenopathy and weight loss often are present. 感染或肿瘤的骨髓浸润（骨髓病性贫血）常伴低网织红细胞计数，外周血涂片出现泪滴形红细胞、有核红细胞和幼稚粒细胞。贫血常伴血小板减少，诊断依靠骨髓检查或机会性感染如鸟分枝杆菌复合体的血培养结果。其它机会性感染或淋巴瘤的症状或体征如发热、脾大、淋巴结肿大和体重下降也很常见。 An elevated MCV and low reticulocyte count may be seen in patients who are treated with zidovudine. Additionally, patients with liver disease and target cells may have an elevated MCV. An elevated MCV may be seen in patients with cobalamin or folate deficiency. Serum vitamin B-12 and folate levels should be obtained when megaloblastic anemia is suspected, and a Schilling test may occasionally be needed to assess cobalamin absorption. An elevated MCV may be artifactual in patients with rouleaux formation from hypergammaglobulinemia or in patients with cold agglutinins. In such patients, the red blood cell count and hematocrit may be spuriously decreased, but the hemoglobin determination is accurate. MCV增大、低网织红细胞计数可见于接受齐多夫定治疗的患者。此外，有肝病和靶型细胞的患者也可能会有MCV增大。MCV增大还见于钴胺或叶酸缺乏的患者。在怀疑巨幼细胞贫血时应测定血清维生素B-12和叶酸水平，为评价钴胺吸收情况有时还需要做Schilling试验。在高丙种球蛋白血症或冷凝集阳性的患者中，红细胞呈缗钱状排，MCV的增大可能是假象。在这些患者中，红细胞计数和红细胞压积可能会假性降低，但是血红蛋白数值是准确的。 Anemia with an elevated reticulocyte count suggests either hemolytic anemia or blood loss anemia. A low reticulocyte count secondary to coincidental anemia of chronic disease may sometimes be seen in patients with hemolytic anemia. Other findings in hemolytic anemia include an increased LDH, increased indirect bilirubin, and decreased serum haptoglobin. Autoimmune hemolytic anemia may give a decreased MCV with microspherocytes observed on peripheral smear. A positive direct antiglobulin test (Coomb’s test) accompanies this diagnosis. Oxidative hemolysis due to glucose-6-phosphate-dehydrogenase-deficiency occurs after exposure to certain drugs or other oxidative stress and may cause episodic hemolysis. The diagnosis can be confirmed by glucose-6-phosphate dehydrogenase assay. Microangiopathic hemolytic anemia (TTP/HUS) causes thrombocytopenia, and hemolytic anemia with prominent schistocytosis on smear, with markedly elevated LDH, renal insufficiency fever and neurological manifestations. Assays of ADAMTS-13 and its inhibitors may be confirmatory. Thrombocytopenia also accompanies the hemophagocytic syndrome, which causes hemolytic anemia accompanied by fever and cutaneous manifestations. An elevated MCV may accompany brisk reticulocytosis from hemolytic or blood loss anemia. 伴有高网织红细胞计数的贫血提示为溶血性贫血或失血性贫血。在溶血性贫血患者中也可以见到继发于慢性病性贫血的低网织红细胞计数。其他溶血性贫血的表现包括LDH升高，间接胆红素升高，血清结合珠蛋白下降。自身免疫性溶血性贫血可能会有MCV降低，外周血涂片可见到小球形红细胞。直接抗人球蛋白试验（Coombs试验）阳性有助于诊断。G-6PD缺乏的患者在接触某些药物或其他氧化性应激的情况下会发生氧化性溶血，有时导致阵发性溶血。通过G-6PD测定确诊。微血管病性溶血性贫血（TTP/HUS）可造成血小板减少、血涂片中可见大量的破碎红细胞、显著升高的LDH，肾功能不全，发热和神经系统表现。测定ADAMTS-13及其抑制物可确诊。血小板减少也可伴发于噬血细胞综合征，该综合征可导致伴发热和皮肤表现的溶血性贫血。MCV增大可见于因溶血性或失血性贫血所致的网织红细胞增多症。 Invasive tests The bone marrow aspirate and biopsy shows characteristic but non-specific changes in the HIV infected patient (40). The bone marrow cellularity can be normal, increased or hypocellular. Plasmacytosis and lymphoid aggregates are common and correlate to serum polyclonal hypergammaglobulinemia. Reticulin fibrosis is common, and therefore it can be difficult to obtain an aspirate. Poorly formed granulomas, serous atrophy, marrow necrosis, and hemophagocytosis have been reported. Myelodysplastic marrow changes with increased cellularity are common. These myelodysplastic changes do not progress to acute leukemia, however there are rare reports of acute leukemia in HIV (178, 90, 193). Megaloblastic changes are characteristic when patients are treated with zidovudine, but are also seen with trimethoprim-sufamethoxazole and Dapsone. 有创性检查 HIV感染患者的骨髓穿刺和活检可以发现出特征性但并非完全特异的改变(40)。骨髓细胞密度可以正常、增高或减少。浆细胞增多和淋巴细胞聚集常见，并与血清多克隆性高丙种球蛋白血症有关。网状纤维的纤维化常见，因此骨髓穿刺会有一定难度。也有形成不良的肉芽肿、浆液性萎缩（serous atrophy）、骨髓坏死和噬血细胞增多等表现的报道。骨髓增生活跃的骨髓异常增生样改变常见。这些骨髓异常增生性改变不会进展为急性白血病，但是的确有HIV感染者患急性白血病的罕见报道(178, 90, 193)。使用齐多夫定治疗时患者可有巨幼红细胞性贫血样的改变，也可见于使用甲氧苄啶-磺胺甲噁唑和氨苯砜治疗的患者。 The diagnostic yield of the bone marrow examination is highest in evaluating patients with pancytopenia, fever of unknown origin and for lymphoma staging. Patients with isolated anemia, or leukopenia generally are found to have the nonspecific changes associated with HIV infection, and those with isolated thrombocytopenia usually have findings consistent with HIV related thrombocytopenia (24) The bone marrow examination can be useful in the diagnosis of mycobacterial infections when blood cultures are negative, as well as in diagnosing other opportunistic infections such as disseminated histoplasmosis (25). Marrow examination may be diagnostic of pure red cell aplasia. Marrow examination can be used to define iron stores when serum tests are not definitive. 评价全血细胞减少、不明原因发热和淋巴瘤分期时，骨髓检查的诊断价值最大。患单纯性贫血或白细胞减少的患者（骨髓检查）通常具有HIV感染相关的非特异性改变，单纯性血小板减少者通常具有符合HIV相关性血小板减少症的表现(24)。骨髓检查在诊断血培养阴性的分枝杆菌感染以及时其他机会性感染如播散性组织胞浆菌病非常有用 (25)。骨髓检查是纯红细胞再生障碍性贫血的诊断性检查。骨髓检查还可以在血清学检查无法确诊时明确铁储备情况。 Management Whenever possible, management of anemia in the HIV infected patient should be directed at the underlying cause of the anemia. Any identified opportunistic infection or malignancy should be appropriately treated. In patients with anemia of chronic disease due to advanced HIV infection, effective antiretroviral therapy may correct the anemia and improve the quality of life (223). Anemic patients with advanced disease who were successfully treated with HAART were found to have an average increase in hemoglobin by 3 g/L (196). 治疗 无论如何，对HIV感染者的贫血治疗都应该针对于贫血病因。任何明确的机会性感染或恶性肿瘤都应该得到适当的治疗。对于晚期HIV感染者的慢性病性贫血，有效的抗逆转录病毒治疗可以纠正贫血并改善生活质量(223)。HIV感染晚期的贫血患者在成功接受HAART治疗后，其血红蛋白平均可以升高3g/L(196)。 When anemia is due to an adverse affect of a medication, a reassessment of the necessity of the offending medication and acceptable alternatives should be considered. If there are acceptable alternatives, or the treatment is not necessary, the drug should be withdrawn and response of the anemia to the drug withdrawal assessed. If the medication is necessary, and no acceptable alternatives are available, supportive care with growth factors or transfusion may be employed. 当贫血是药物的副作用时，应当重新评估当前药物的必要性并考虑其他可以替代的药物。如果有替代药物或者治疗不是必须的，应当停药并评估停药后贫血的改善情况。如果当前药物是必须的，并且没有可接受的替代疗法，可以采用生长因子或输血的支持治疗。 Iron deficiency and blood loss anemia are treated by identification and correction of the source of blood loss and with iron supplementation. Iron is generally given orally as Ferrous Sulfate at a dose of 325 mgs three times a day. Patients intolerant of oral iron may be given intravenous Iron Dextran, but this may cause hypersensitivity reactions. Newer formulations of parenteral iron such as ferrous sucrose (Venofer) are less likely to cause allergic reactions. Since increased iron levels in macrophages may be potentially associated with activation of HIV infection and progression of AIDS, caution should be used in repletion of iron in the absence of effective antiretroviral therapy (4, 187). 通过明确并纠正失血的病因以及补充铁可以治疗缺铁性和失血性贫血。补铁常用口服硫酸亚铁，剂量为325mg/次， 1天3次。无法耐受口服铁剂的患者可以给予静脉内输注右旋糖酐铁，但这可能会出现过敏反应。新的非口服铁制剂如蔗糖亚铁（Venofer）较少导致过敏反应。由于巨噬细胞中铁水平的增加可能与HIV感染激活和AIDS进展潜在相关，因此在未使用有效的抗逆转录病毒疗法时应谨慎补充铁剂(4, 187)。 Patients with cobalamin or folate deficiency should receive supplementation. Cobalamin supplementation is usually given parenterally at a dose of 1000 micrograms intramuscularly monthly and folate is given at a dose of 1 mg daily orally. One controlled trial failed to demonstrate any amelioration of myelosuppression when supplementation of cobalamin and folate was given to patients receiving zidovudine (56). 钴胺或叶酸缺乏的患者应该接受补充治疗。钴胺补充通常采用每月1000mg肌注的非口服方式，叶酸1mg/天口服补充。一项对照试验证实补充钴胺和叶酸无法改善接受齐多夫定治疗患者的骨髓抑制情况。(56)。 TTP in HIV infected individuals is treated with intensive plasma exchange or fresh frozen plasma infusions along with antiplatelet agents and corticosteroids similar to TTP in non HIV-infected patients (63, 146, 153, 221). Patients with hemolytic-uremic syndrome (HUS) may also be given trials of plasma exchange or plasma infusion, but the response rates are lower, and supportive care and dialysis are often needed. HIV感染患者TTP的治疗与非HIV感染者TTP治疗类似，使用强化血浆置换或新鲜冰冻血浆输注，并同时使用抗血小板药物和糖皮质激素(63, 146, 153, 221)。患溶血性尿毒症综合征（HUS）的患者也可试用血浆置换或者血浆输注，但是有效率较低，常需要支持治疗和透析。 Chronic pure red cell aplasia due to parvovirus infection responds to treatment with intravenous immunoglobulin (IVIG), which provides antibodies against the parvovirus. Re-treatment with IVIG may be required for relapse or as maintenance therapy (60, 101, 111, 112, 120). The recommended IVIG dose is 2 grams per kilogram divided over 2 days (1000 mg/Kg daily x 2). Typically patients with CD 4 counts less than 80 are more likely to relapse and mainentance therapy with IVIG at a dose of 0.4g/kg every 4 weeks is effective in preventing relapse (102). Treatment with HAART is also helpful in achieving and maintaining remission of pure red cell aplasia (145). 细小病毒感染导致的慢性纯红细胞再生障碍性贫血对静脉人免疫球蛋白（IVIG）反应较好，其中含有抗细小病毒的抗体。复发后需要再次使用IVIG，或者把IVIG作为维持治疗(60, 101, 111, 112, 120)。推荐剂量为2g/kg，分2天输注（1000mg/kg/天x 2）。CD4+ 细胞计数小于80的患者常会复发， 每4周一次的IVIG 0.4g/kg的维持疗法可以有效地预防复发(102)。HAART治疗也有助于获得并维持纯红细胞再生障碍性贫血的缓解 (145)。 Management of autoimmune hemolytic anemia includes glucocorticoids, IVIG, splenectomy, and zidovudine. Prednisone 1-2 mg/kg/day in divided doses or methylpredinsolone 30mg/kg /day should be initiated (103). Lower doses (Prednisone 0.6 mg/kg/day) may be considered in severely debilitated patient with concurrent severe infections. Response may take up to 3 weeks. The dose is then gradually tapered to the lowest level that controls the hemolysis. Splenectomy is indicated when there is failure to respond to corticosteroids, Prednisone dependence (requirement of doses greater than 10–20 mg/day to control hemolysis) or significant adverse effects from steroid treatment. However, in severely debilitated patients, maintenance doses of Prednisone 10 mg/day might be a better alternative than splenectomy given the surgical morbidity and mortality of a major abdominal operation in a debilitated patient. Another alternative includes IVIG at 400mg/kg/day for 5 days in selected patients (72). Patients may require long term maintenance with IVIG every 3 weeks. Judicious use of transfusion may be required depending on the patient’s cardiopulmonary status, but there appears to be a risk of disseminated intravascular coagulation and pulmonary embolism in HIV patients with auto-immune-hemolytic anemia (AIHA) who are transfused red blood cells (20, 184). Antiretroviral therapy with zidovudine has been reported to improve autoimmune hemolytic anemia (215). 自身免疫性溶血性贫血的治疗包括糖皮质激素、IVIG、脾切除和齐多夫定。初始剂量为强的松1-2mg/kg/天分次给予或甲基强的松龙30mg/kg/天(103)。伴有严重感染的重症患者可考虑给予更小的剂量（强的松0.6mg/kg/天）。最常3周可获得疗效。然后可以逐渐减量至控制溶血的最小剂量。对糖皮质激素治疗无效、强的松依赖（控制溶血需要的剂量大于10-20mg/天）或者有激素相关的严重副作用者可以行脾切除。但是在重症患者中，相比于脾切除这种腹部大手术所带来的手术风险发病率和死亡率而言，10mg/天的强的松维持可能是更好的选择。某些患者也可选择IVIG 400mg/kg/天x 5天(72)。患者可能需要每3周一次IVIG的长期维持治疗。根据患者心肺情况可能需要适当输血，但是在患有自身免疫性溶血性贫血（AIHA）的HIV感染者中，输注红细胞会有弥散性血管内凝血和肺栓塞的风险(20, 184)。包括齐多夫定的抗逆转录病毒疗法可改善自身免疫性溶血性贫血(215)。 Supportive Care Erythropoietin The availability of recombinant erythropoietin allows for treatment of anemia with depressed erythropoiesis caused by advanced HIV infection, zidovudine therapy, cancer chemotherapeutic agents and other drugs used in the treatment of HIV infected patients (10, 47, 77, 141, 164, 169, 175). Treatment with erythropoietin has been shown to increase hemoglobin levels, decrease transfusion requirements and to improve energy levels and quality of life in patients with AIDS (141). It has also been associated with reduced disease progression and mortality in observational studies (139). Erythropoietin therapy is generally well tolerated. In controlled trials, adverse reactions did not occur at higher frequency in erythropoietin treated patients than in those treated with placebo. 支持治疗 促红细胞生成素 重组促红细胞生成素可以用于治疗由于晚期HIV感染、齐多夫定疗法、肿瘤化疗药物和其他治疗HIV感染的药物导致的红细胞生成抑制性贫血(10, 47, 77, 141, 164, 169, 175)。促红细胞生成素治疗可以提高AIDS患者的血红蛋白水平，降低输血需求并改善生活质量(141)。一些观察性研究证实它还可以减缓疾病进展并降低死亡率(139)。促红细胞生成素治疗的耐受性一般很好。在对照研究中，促红细胞生成素治疗的副作用发生率并不比安慰剂高。 The initial recommended dose of erythropoetin was 100-200 IU/Kg subcutaneously given 3 times a week (40, 131). However, recent studies have illustrated that weekly epoetin alfa at doses of 40,000 IU to 60,000 IU were equally efficacious and may be more convenient. Weekly dosing demonstrated improvement in quality of life and increase in hemoglobin levels by approximately 2.5- 3 g/dl (76, 182). Treatment is continued until normalization of the hematocrit (> 36%) or until the maximum dose is reached. Treatment could then be given once a week or every other week with monitoring of the hematocrit to assure that the improvement is maintained. If the hematocrit rises to more than 40%, the erythropoietin is held until the hematocrit decreases to 36%, and it is then restarted at a lower dose. 促红细胞生成素的初始推荐剂量为100-200IU/kg皮下注射，每周3次(40, 131)。但是，近期研究表明每周1次注射40，000IU到60，000IU的epoetin alfa也同样有效并且更方便。每周一次给药可以改善生活质量并且提高血红蛋白水平近2.5-3g/dl(76, 182)。治疗持续到红细胞压积正常(> 36%)或达到最大剂量。然后在监测红细胞压积的情况下给予每周1次或隔周1次治疗以维持疗效。如果红细胞压积大于40%，就暂停促红细胞生成素直到红细胞压积降至36%，然后从低剂量重新开始。 Darbepoeitin alfa is another recombinant erythropoietic growth factor which has eight more sialic acids than epoetin alfa. The addition of the sialic acids increases the half-life threefold allowing administration every 2 to 3 weeks. Typically darbopoetin alfa can be given 200 mcg subcutaneous every 2 weeks or 300 mcg subcutenous every 2-3 weeks. These guidelines are based on studies involving patients with chemotherapy induced anemia and anemia of renal disease (58, 70). Darbepoeitin alfa 是另一种重组促红细胞生长因子，比epoetin alfa多8个唾液酸。增加唾液酸可以将半衰期延长3倍，因此可以每2到3周给药一次。Darbopoetin alfa 可以每2周200mcg 皮下注射一次或每2到3周300mcg皮下注射一次。 这些指南是以基于化疗药导致的贫血和肾病性贫血患者的研究为基础的(58, 70)。 Endogenous erythropoietin levels predict the response to recombinant erythropoietin. Patients with anemia due to zidovudine treated with erythropoietin with endogenous erythropoietin levels of 500 IU/L or higher do not respond well (81, 164). Functional iron deficiency is a major cause of inadequate response to erythropoietin treatment in patients with end stage renal disease, and oral or parenteral supplementation improves the response in that population, but there is less data in HIV infected patients (11). Those patients not responding to erythropoietin have been found to have down-regulation of erythropoietin response secondary to increased expression of cytokines such as TNF-alpha (108). 内源性促红细胞生成素水平可以预测重组促红细胞生成素治疗的疗效。齐多夫定治疗所致的贫血患者若其内源性促红细胞生成素在500IU/L以上，则对促红细胞生成素的疗效不佳(81, 164)。功能性铁缺乏是终末期肾病患者对促红细胞生成素治疗反应不佳的主要原因，口服或非口服补铁可以改善这些患者对EPO的反应，但在HIV感染者中尚缺乏足够资料(11)。继发于细胞因子如TNF-alpha高表达后的促红细胞生成素反应下调是这些患者对促红细胞生成素反应不佳的原因(108)。 Blood Transfusions The decision to initiate symptomatic treatment for anemia should be based on the patient’s symptoms and cardio-pulmonary status and not solely on any specific level of hemoglobin. Appropriate use of transfusions can greatly improve symptoms. However, there are a number of special concerns in the transfusion of the HIV positive patient beyond those associated with the transfusion of any patient. These concerns are mainly based upon retrospective and laboratory data, and there is, unfortunately, not sufficient controlled prospective clinical studies of many of these issues. 输血 是否开始贫血的对症治疗取决于患者的症状和心肺状态而不是只依据血红蛋白水平。适当输血可以明显改善症状。但是，HIV阳性患者有其他贫血患者没有的特殊问题。这些问题主要来源于回顾性和实验室研究，但针对对这些问题的对照前瞻性临床研究很少。 It has been suggested that there is decreased survival of AIDS patients who are given blood transfusion as compared to patients with similar degree of anemia and immunodeficiency who are not transfused (220). Modest increases in HIV viral loads several weeks following transfusions of packed red blood cells in patients with moderately advanced HIV infection have been reported (143). Stimulation of lymphocytes by exposure to exogenous antigen may be the cause. In vitro experiments by Busch et al (28) demonstrated that co-cultivation of lymphocytes from HIV infected patients with allogeneic peripheral blood mononuclear cells caused a dose related activation of HIV-1 expression. Co-cultivation with allogeneic leukocyte depleted plasma, red cells or platelets did not cause increased HIV expression. Interestingly, hemophiliacs with HIV infection have faster progression of immunodeficiency if they are transfused with intermediate-purity factor VIII concentrates containing multiple plasma proteins as opposed to patients transfused only with monoclonally-purified factor VIII concentrates containing only factor VIII and albumin (197). 有研究表明，输过血的AIDS患者比同等程度贫血和免疫缺陷但是没有输过血的患者有着更短的生存期(220)。有人发现中期的HIV感染者在输注压缩红细胞数周后的HIV病毒载量有轻度的升高(143)。原因可能是外源性抗原对淋巴细胞的刺激。Busch等人的体外实验(28)表明HIV感染者的淋巴细胞和异基因的外周血单个核细胞的共培养，可以出现剂量相关的HIV-1的激活。与异基因的去淋巴细胞的血浆、红细胞或血小板共同培养却不会造成HIV表达的增加。另外，输注中等纯度的含多种血浆蛋白的VIII因子浓缩物的感染HIV的血友病患者比仅输注单克隆纯化的只含VIII因子和白蛋白的VIII浓缩物者有着更快的免疫缺陷的进展 (197)。 Other concerns include transmission of blood borne viruses, especially the transmission of CMV to CMV negative recipients, as well as the activation of CMV by transfusion in patients who are CMV antibody positive. In a retrospective study, Sloand et al, described an increase in the incidence of CMV infections, bacterial infections, wasting syndrome and death in patients with CD4+ lymphocyte counts below 250/uL who received transfusions as compared to those who did not (201). However, one study done in HIV infected hemophiliacs did not demonstrate an increase in CMV related opportunistic infections or seroprevalence in transfused patients as compared to those who had not been transfused (171). The transfusion of blood products from CMV negative donors and the use of leukocyte depleted blood products are strategies to reduce CMV transmission (169). Other benefits of leukocyte reduction include decrease in the incidence of febrile transfusion reactions, a reduction in the incidence of platelet alloimmunization, and a decrease in the immunomodulation and stimulation of HIV replication caused by transfusions. 其他问题包括血液传播性病毒，尤其是传播CMV，或CMV抗体阳性的患者输注后出现CMV病毒的激活。Sloand等人的一项回顾性研究表明，在CD4+淋巴细胞计数小于250/ul的患者中，接受输血者比没有输血者的CMV感染、病毒感染、消耗综合征和死亡的发生率增加(201)。但是，一项针对感染HIV的血友病患者的研究没有证实输过血的患者比没有输血的患者增加了CMV相关的机会性感染或血清阳性率 (171)。输注CMV阴性供体的血制品以及使用去白细胞的血制品是减少CMV传播的策略(169)。去白细胞的其他益处包括降低发热性输血反应的发生率，降低血小板异体免疫的发生率，以及降低输血所致的对HIV复制的免疫调节和激活。 Gamma irradiation of blood products is routinely used in some centers to prevent transfusion-associated graft versus host disease. This is a rare, but highly fatal complication of transfusion of allogeneic lymphocytes to immunosuppressed patients, which is characterized by fever, rash, and pancytopenia. Interestingly, the syndrome has not been reported in HIV-infected patients. 在一些医疗中心使用经放射处理后的血制品以预防输血相关的移植物抗宿主病。这是一种给免疫抑制患者输注异基因白细胞时非常罕见的但死亡率很高的并发症，表现为发热、皮疹、和全血细胞减少。然而，这种综合症在HIV感染的患者中还没有报道。 Iron overload may occur in patients frequently transfused red blood cells. An autopsy series of HIV-infected patients showed hepatic iron overload in 32% of patients. The iron overload was associated with the number of transfusions and with the presence of mycobacterium avium intracellular infections (7). Transfusion associated iron overload in the HIV infected patient may be associated with the development of hepatic fibrosis, particularly in patients with coincident chronic hepatitis (71). It has been suggested that iron overload may increase progression of HIV infection through increased oxidative stress, and impairment of already compromised immune defenses (23). Additionally, it has been suggested that iron overload may have a prediliction for other infections in the HIV positive patient (228). Interestingly, one report indicated a relationship between prognosis and adequacy of iron chelation therapy in a group of transfusion dependant HIV infected thalassemia patients (38). These concerns do not prohibit appropriate transfusions for patients who require them, but unnecessary transfusions should be discouraged. 在频繁输注红细胞的患者中可能会出现铁过量。在对HIV感染患者的尸检中发现32%的患者都有肝脏的铁过量。铁过量与输血的次数和细胞内鸟分枝杆菌感染有关(7)。HIV患者中输血相关的铁过量可能与肝纤维化的发生有关，尤其是在同时患有慢性肝炎的患者中(71)。铁过量可以通过增加氧化性应激加速HIV感染的进展和加重已经受损的免疫防御系统(23)。此外，HIV阳性患者中的铁过量是其他感染的危险因素(228)。一项研究表明在一组有输血依赖性的感染HIV的地中海贫血患者中其充分的铁螯合治疗和预后相关(38)。这并不是禁止给需要输血的患者适当的输血，但是应当尽量避免不必要的输血。 Leukopenia Epidemiology Leukopenia is characteristic of AIDS. Lymphopenia is the most common abnormality, particularly decreases in the CD4+ helper T lymphocytes. Decreased monocyte counts and function are also seen (43, 113, 218, 236, 237). Neutropenia occurs in approximately 10% in asymptomatic HIV infected individual and in greater than 50% (up to 85% in certain series) of patients in advanced stages (87, 130, 134, 135, 237). 白细胞减少症 流行病学 白细胞减少是AIDS的特征性表现。淋巴细胞减少是最常见的白细胞异常，尤其是CD4+ T辅助细胞的减少。还可以见到单核细胞计数和功能的降低 (43, 113, 218, 236, 237)。中性粒细胞减少见于约10%无症状的HIV感染者，在晚期患者中达50%以上(某些研究中达85%)(87, 130, 134, 135, 237)。 Differential Diagnosis The differential diagnosis of leukopenia in HIV infected patients is summarized in Table 3. 鉴别诊断 表3总结了HIV感染者的白细胞减少的鉴别诊断。 Risk Factors Neutropenia from bone marrow suppression due to underlying HIV infection is seen in advanced HIV infection and is commonly accompanied by anemia and thrombocytopenia. Other etiologies include infiltration of the marrow by opportunistic infections or neoplasm such as lymphoma. Zidovudine causes neutropenia in up to 16% of patients. Zidovudine may rarely cause pancytopenia with a hypocellular marrow (68, 176). Ganciclovir is used for the treatment of CMV infections and frequently causes neutropenia via bone marrow suppression and may cause pancytopenia. Neutropenia from other medications is common and frequently complicates therapy with trimethoprim-sulfamethoxazole, pentamidine, pyrimethamine/sulfadiazine, flucytosine, rifabutin, and antineoplastic chemotherapy. Drugs causing hematological toxicity are summarized in Table 2. Hypersplenism from liver disease may also cause leukopenia. 危险因素 由于HIV感染所致的骨髓抑制性中性粒细胞减少可见于晚期HIV感染，并常伴发贫血和血小板减少。其他发病原因包括机会性感染或肿瘤如淋巴瘤的骨髓浸润。齐多夫定所致的中性粒细胞减少占16%。齐多夫定很少引起伴骨髓增生低下的全血细胞减少(68, 176)。更昔洛韦用于治疗CMV感染并经常通过骨髓抑制造成中性粒细胞减少以及全血细胞减少。其他药物导致的中性粒细胞减少也不少见，如甲氧苄啶-磺胺甲噁唑、喷他脒、乙胺嘧啶/磺胺嘧啶、氟胞嘧啶、利福布汀和肿瘤化疗。表2总结了引起血液学毒性的药物。肝病相关的脾功能亢进也可以导致白细胞减少。 Clinical Manifestations Symptoms of neutropenia may include fever, malaise, oral ulcerations, lymphadenopathy and infections. The incidence of bacterial and fungal infection patients is significantly higher in HIV infected patients with neutropenia than in those with normal neutrophil counts (94, 127). The risk of bacterial infection is increased almost two fold when absolute neutrophil count (ANC) is <1000 cells/µl and approximately eight fold when ANC<500 /µl (140). The risks of bacteremic infection are further increased by the presence of central venous catheters, antineoplastic chemotherapy and a low CD4 count (127, 128, 180). Neutropenic infections in patients receiving zidovudine may be more common when granulocyte count is less than 500 cell/µl, but neutropenia of lesser severity is better tolerated (199). The incidence of bacteremia and neutropenia appears to have lessened in the era of highly active retroviral therapy (219). 临床表现 中性粒细胞减少的临床表现包括发热，乏力，口腔溃疡，淋巴结肿大和感染。伴中性粒细胞减少的HIV患者的细菌和真菌感染的发生率显著高于正常中性粒细胞计数的患者(94, 127)。中性粒细胞绝对计数（ANC）小于1000/ml时细菌感染的风险几乎增加两倍，ANC小于500/ml时为8倍(140)。置入中心静脉导管，肿瘤化疗和低CD4细胞计数还会进一步增加细菌感染的风险 (127, 128, 180)。接受齐多夫定治疗的患者在粒细胞计数小于500/ml时更容易出现感染(199)。高效抗逆转录病毒治疗广泛应用后，菌血症和中性粒细胞减少症的发生率均有所降低(219)。 Infections associated with neutropenia in AIDS patients include bacteremia, fungemia, pulmonary aspergillosis, pyomyositis, malignant external otitis, neutropenic enterocolitis, and pseudomonas keratitis (41, 127, 147, 200, 213, 229). Staphylococcal infections are the most frequent bacterial infections. Other bacterial pathogens include Streptococcus pneumoniae, Pseudomonas aeruginosa, and Salmonella species. The most common fungal infections are Cryptococcus and Candida species. Aspergillosis is associated with neutropenia and with corticosteriod therapy (180). AIDS患者中性粒细胞减少相关的感染包括菌血症、真菌血症、肺曲霉菌病、化脓性肌炎、恶性外耳道炎、中性粒细胞减少性小肠结肠炎和假单胞菌性角膜炎(41, 127, 147, 200, 213, 229)。葡萄球菌感染是最常见的细菌感染。其他细菌病原体包括肺炎链球菌、绿脓杆菌和沙门菌属。最常见的真菌感染是隐球菌属和念珠菌属。曲霉菌病与中性粒细胞减少及糖皮质激素治疗有关(180)。 In addition to neutropenia, abnormal neutrophil function including decreased bactericidal capacity, impaired chemotaxis, phagocytosis, and decreased production of toxic oxygen species, has been described in patients infected with HIV (110). Neutrophils may be abnormally large, exhibit Pelger-Huet anomalies, and hyposegmentation (193) or hypersegmentation on peripheral smear. Large atypical monocytes and plasmacytoid lymphocytes have been described. 除了中性粒细胞减少，HIV感染者中还可以见到中性粒细胞功能异常，包括抗菌能力减低、趋化作用和吞噬作用受损以及氧毒性物生成减少(110)。在外周血涂片中，中性粒细胞可能是异常大的、有Pelger-Huet异常、以及分叶过少(193)或过多。也可见到不典型的大单核细胞和浆细胞样淋巴细胞。 Diagnosis A history of recurrent bacterial infections, fungal infections, oral ulcerations or fevers should be sought in patients with neutropenia. The patient should have an assessment of the stage of the HIV infection with HIV viral load and CD 4+ lymphocyte counts. Signs and symptoms of opportunistic infections or lymphoma should be noted. The medication profile should be reviewed carefully including the relationship of the initiation of the medication to the development of the leukopenia. The hemogram and peripheral smear should be carefully reviewed. Morphologic evidence of myelophthisic changes of the red cells and early myeloid cells in the peripheral blood suggest marrow infiltration. Concomitant anemia and thrombocytopenia should be identified. The patient should be evaluated for evidence of liver disease and hypersplenism. Severe megaloblastic anemia may cause leukopenia, and serum cobalamin and folate levels should be obtained if there are findings suggestive of this. It should be noted that healthy persons of African descent may have a lower baseline neutrophil count than Caucasians. 诊断 中性粒细胞减少的患者应仔细询问其反复细菌感染、真菌感染、口腔溃疡或发热的病史。应当根据HIV病毒载量和CD4+淋巴细胞计数评估患者的HIV感染的分期。要注意机会性感染或淋巴瘤的症状和体征。要仔细回顾用药史，包括药物开始使用到白细胞减少发生的关系。要认真复习血像和外周血涂片变化。外周血涂片中的红细胞骨髓病性改变以及幼稚髓细胞的形态学证据都提示骨髓浸润。要鉴别伴发的贫血和血小板减少症。应当评价患者有无肝病和脾功能亢进。严重的巨幼细胞贫血可以导致白细胞减少，提示巨幼细胞贫血时应测定血清钴胺和叶酸水平。通常非洲的健康人群白细胞基数水平比白人低。 The changes seen in the bone marrow in HIV infection are reviewed in the section on anemia above. A bone marrow aspirate and biopsy should be considered if there is coincident anemia or thrombocytopenia, or if there are signs or symptoms of opportunistic infection, lymphoma or bone marrow infiltration. HIV感染者的骨髓表现在上述贫血章节中已经详述。在伴发贫血或血小板减少，或者有机会性感染、淋巴瘤、骨髓浸润的症状或体征时应当进行骨髓穿刺和活检。 Management Neutropenia and bacteremia resulting from direct myelosuppressive effects of HIV infection often improves with effective antiretroviral treatment (83, 192, 219). 治疗 HIV感染的直接骨髓抑制作用造成的中性粒细胞减少症和菌血症在有效的抗逆转录病毒治疗后常会好转(83, 192, 219)。 If the patient is on a medication that is likely to be the cause of neutropenia, a reassessment of the necessity of the potentially offending medication and acceptable alternatives should be considered. If there are acceptable alternatives or the treatment is not necessary, the drug should be withdrawn and response of the neutropenia to the drug withdrawal assessed. If treatment is necessary, and no acceptable alternatives are available, supportive care with myeloid growth factors should be considered. 如果患者当前用的药很可能是导致中性粒细胞减少的原因时，应当考虑重新评估所用药物的必要性和其他替代药物。如果有替代药物或者治疗不是必须的，应当停用当前药物并评价停药后中性粒细胞减少的反应。如果治疗是必须的，并且没有可替代药物时，应当给予粒细胞生长因子的支持治疗。 A large number of studies have shown the beneficial effects treatment with myeloid growth factors in HIV infected patients with neutropenia (74, 97, 118, 131, 168). Treatment with myeloid growth factors has allowed the continuation of myelosuppressive medications such as zidovudine, ribavirin, interferon, ganciclovir and cytotoxic chemotherapy in neutropenic HIV infected patients, and lessens the duration of treatment interruptions due to neutropenia (5, 44, 75, 91, 109, 116, 189, 231). 大量研究表明中性粒细胞减少的HIV感染患者从粒细胞生长因子治疗中明显获益(74, 97, 118, 131, 168)。粒细胞生长因子的治疗可以容许中性粒细胞减少的HIV感染患者继续使用骨髓抑制性药物如齐多夫定、利巴韦林、干扰素、更昔洛韦和细胞毒性化疗药物，并缩短因中性粒细胞减少而中断治疗的时间(5, 44, 75, 91, 109, 116, 189, 231)。 Filgrastim (Neupogen, G-CSF) has been shown to increase neutrophil counts, prevent bacterial infection and decrease incidence and length of hospitalization in patients with HIV and neutropenia (134). Filgrastim also improves neutrophil function. It increases oxidative capacity of neutrophils, increases bacterial killing and reduces accelerated myeloid apoptosis in HIV infected individuals (15, 165, 166). Filgrastim treatment is usually well tolerated. The most common side effect is bone pain. Splenomegaly may also be seen with prolonged use. The peripheral blood may show an increase in early myeloid forms such as myelocytes and promyelocytes, and the serum LDH and alkaline phosphatase may be elevated. 非格司亭（Neupogen，G-CSF）被证实可增加中性粒细胞计数，预防细菌感染，以及减少中性粒细胞减少症HIV患者的住院机率和住院时间(134)。非格司亭还可以改善中性粒细胞的功能。它增加了HIV感染者的中性粒细胞的氧化能力，增强杀菌作用，减少加速了的骨髓凋亡 (15, 165, 166)。非格司亭治疗通常耐受的很好。最常见的副作用是骨痛，长时间应用也可以出现脾大。外周血表现为幼稚粒细胞如中幼粒细胞、早幼粒细胞的增加，血清LDH和ALP（碱性磷酸酶）也可以升高。 Sargramostim (GM-CSF) has also been shown to increase neutrophil number and to enhance neutrophil function (15). Sargramostim treatment has been associated with increased replication of certain HIV isolates, however sustained increase in viral load is not seen clinically (85, 105). However, Sargramostim also increases the efficacy of zidovudine by increasing its uptake and phosphorylation to its active tri-phosphate moiety (91, 162, 163). It is therefore recommended that Sargramostim be used concurrently with effective antiretroviral therapy. Sargramostim treatment is sometimes associated with fever, chills, myalgias and flulike syndrome. Filgrastim is more commonly used because of its better side effect profile. 沙格司亭（GM-CSF）也可以增加中性粒细胞数量及增强中性粒细胞功能(15)。沙格司亭治疗与某些HIV分离株复制的增加有关，但临床上并没有看到病毒载量的持续增加(85, 105)。沙格司亭还可以通过增加齐多夫定摄取和将其磷酸化为活性三磷酸结构的方式来提高齐多夫定的疗效(91, 162, 163)。因此推荐沙格司亭与有效的抗逆转录病毒治疗一起使用。沙格司亭治疗有时会出现发热、寒战、肌痛和流感样综合征。非格司亭由于其副作用较少使用更为广泛。 The usual indication for treatment with a myeloid growth factor in the treatment of HIV associated neutropenia is an absolute neutrophil count of less than 500/µl. Filgrastim is usually started at 5µ/kg/day given subcutaneously. The dose may be increased to 7.5µ/kg/day if an adequate response is not seen. In a responding patient, the dose should be reduced to lowest level that maintains the neutrophil count above 1000 /µL. Since Filgrastim is supplied in single use vials of 300µg or 480 µg, alternate day or less frequent dosing of Filgrastim may be employed. The starting dose of GM-CSF is also at 5µ/kg/day given subcutaneously in similar fashion. 用粒细胞生长因子治疗HIV相关性中性粒细胞减少的一般适应症为中性粒细胞绝对计数小于500/ul。起始剂量一般为非格司亭5u/kg/天皮下注射，如果疗效不足可以把剂量增加为7.5u/kg/天。对有疗效的患者，剂量应该降至能够维持中性粒细胞>1000/ul的最低水平。因为非格司亭的剂型为300ug或480ug，所以可以采用隔天或更低频率的给药。GM-CSF的起始剂量也是5u/kg/天皮下注射。 Lenograstim, a recombinant human granulocyte colony-stimulating factor (rHuG-CSF), has also been established in improving neutropenia secondary to ganciclovir. The recommended dose is 50 micrograms/m2/day and is overall well tolerated with few side effects (50). Currently, Lenograstim is only approved for use in Europe. 来格司亭，重组人粒细胞集落刺激因子（rHuG-CSF），也被用于改善继发于更昔洛韦的中性粒细胞减少症。推荐剂量是50ug/m2/天，耐受性很好，几乎没有副作用(50)。目前，来格司亭是欧洲唯一被批准使用的药品。 THROMBOCYTOPENIA Epidemology Thrombocytopenia is frequently seen during the course of HIV infection. It may be the initial sign of HIV infection (3, 188, 226), occur as a part of the acute retroviral syndrome (48, 98, 119), or be a manifestation of advanced immunodeficiency. Thrombocytopenia, defined as a platelet count <100,000/µL, occurs in 3-8% of asymptomatic seropositive HIV infected patients, and in up to 30-45% in advanced stages of immunodeficiency (2, 3, 93, 129, 144, 237). In approximately 30,000 HIV infected individuals who were evaluated for thrombocytopenia of less than 50,000 /µL, the one year incidence was 8.7% in patients with advanced stages of AIDS, approximately 3% in patients with CD4+ lymphocytes count <200, and 1.7% in asymptomatic HIV infected patients with higher CD4+ lymphocyte counts (207). 血小板减少症 流行病学 血小板减少症在HIV感染过程中非常常见。它可以是HIV感染后的首发表现(3, 188, 226)，可以为急性逆转录病毒综合征的一部分(48, 98, 119)，或者是晚期免疫缺陷的表现。血小板减少症，定义为血小板计数<100,000/ul,见于3-8%的无症状的血清学阳性的HIV感染者，在疾病晚期可增至30-45% (2, 3, 93, 129, 144, 237)。在约30，000位HIV感染者中，其血小板计数<50，000/ul的发生率在AIDS晚期患者中为8.7%， 在CD4+淋巴细胞计数<200的患者约为3%，在CD4+淋巴细胞计数较高的无症状HIV感染者中为1.7%(207)。 Differential Diagnosis The differential diagnosis of thrombocytopenia in HIV infected patients is shown in Table 4. 鉴别诊断 表4列出了HIV感染者中血小板减少症的鉴别诊断。 The mechanisms of HIV related thrombocytopenia include immune-mediated destruction of platelets and defects in platelet production. Increased destruction is more often seen in early stages of HIV infection, while defective production predominates as the disease progresses (48). The bone marrow usually shows megakaryocyte hyperplasia, though decreased megakaryocytes or myelodysplastic changes may also be seen (26). This dyplasia is likely to be a result of direct retroviral infection of megakaryocyte. Megakaryocytes have been demonstrated to be susceptible to HIV infection and viral RNA and proteins have been isolated from megakaryocytes of HIV infected individuals (16, 46, 48, 121, 151, 179, 186, 193, 233, 234, 238, 239). In a group of thrombocytopenic HIV infected patients, Cole et al found that platelet life span was decreased by two thirds and splenic sequestration was doubled. This was coupled with ineffective production of platelets, despite a thrombopoietin driven expansion of the megakaryocyte mass, presumably due to infection of the megakaryocytes by HIV (37). In vitro studies show megakaryocytes of infected patients express chemokine CCR5, CCR3, and CXCR4 which are implicated for entry of lymphotrophic HIV strains such as X4 and R5 (102, 224). It has been suggested that some strains of HIV, with distinct amino acid sequences in the V3 loop, are more likely to be associated with thrombocytopenia (225). HIV相关性血小板减少症的机制包括免疫介导的血小板破坏和血小板生成障碍。破坏增加多见于HIV感染的早期，随着疾病进展变为生成障碍为主(48)。骨髓一般表现为巨核细胞增生，不过也可以出现巨核细胞减少或骨髓异常增生样的改变(26)。这种异常增生可能是由于逆转录病毒直接感染巨核细胞的结果。巨核细胞很容易受到HIV感染的影响，并且可以从HIV感染者的巨核细胞中分离出病毒RNA和蛋白 (16, 46, 48, 121, 151, 179, 186, 193, 233, 234, 238, 239)。在一组血小板减少的HIV感染者中，Cole等人发现血小板的寿命减少了2/3以及脾破坏加倍。同时伴有血小板的无效生成，可能是因为HIV对巨核细胞的直接感染，尽管有更多的血小板生成素刺激着巨核细胞的扩增 (37)。体外试验证实感染者的巨核细胞表达与嗜淋巴细胞HIV株如X4和R5进入细胞内相关的趋化因子CCR5、CCR3和CCR4(102, 224)。有研究表明一些在V3环上有不同氨基酸序列的HIV株更容易出现血小板减少症(225)。 Increased platelet associated immunoglobulins and circulating immune compexes are present in patients with HIV related immune thrombocytopenia (227). The platelet associated immunoglobulins in HIV related thrombocytopenia react against normal platelets only in a small number of cases (26). The immune complexes contain anti-HIV gp120 and antibodies directed against the anti-HIV antibodies (92). Cross reactivity of antibodies against HIV gp120/gp160 with the platelet surface glycoprotein GP IIb/IIIa have been demonstrated (19). There is an increased proportion of CD5+ B cells in the blood of HIV- infected patients with immune mediated thombocytopenia (104). The CD5+ B cells are responsible for production of IgM rheumatoid factor directed against Fc portion of IgG. The IgM rheumatoid factor sequesters serum IgG antiplatelet (anti-GP IIIa) antibodies. These IgG antibodies facilitate the binding of platelet and immune complexes (209, 235). In vivo studies have demonstrated that blocking the IgM antiidiotype antibody against GPIIIa reverses thrombocytopenia (148). 在HIV相关的免疫性血小板减少症中存在血小板相关免疫球蛋白和循环免疫复合物的增多(227)。仅在少数情况下血小板相关免疫球蛋白对抗正常的血小板 (26)。免疫复合物包括抗HIV gp120、直接抗HIV抗体的抗体(92)。抗HIV gp120/gp160的抗体与血小板表面糖蛋白GP IIb/IIIa有交叉反应(19)。免疫性血小板减少症的HIV感染者血液中的CD5+ B细胞比例增加(104)。 CD5+ B细胞产生抗IgG Fc段的IgM类风湿因子。IgM类风湿因子俘获血清IgG抗血小板（抗 GP IIIa)抗体。这些IgG抗体促进了血小板和免疫复合物的结合(209, 235)。体内研究证实阻断IgM型抗GPIIIa的独特型抗体可逆转血小板减少症(148)。 Risk Factors Patients with more advanced immunodeficiency are more likely to have thrombocytopenia. Patients with older age, lymphoma, black race or history of injection drug use are also more likely to be thrombocytopenic (202, 207). The presence of anemia is correlated to the presence of thrombocytopenia, and thrombocytopenia has been correlated to an increased risk of death in some studies (207), but other studies have not demonstrated that severe thrombocytopenia confers an increased risk of progression to AIDS in HIV postive patients (64). 危险因素 免疫缺陷越严重的患者越容易出现血小板减少症。高龄、淋巴瘤、黑人或静脉注射毒品史的患者也更容易出现血小板减少(202, 207)。贫血与血小板减少相关，有些研究表明血小板减少症与死亡风险增加有关(207)，但是也有研究表明严重的血小板减少并不增加HIV阳性患者进展到AIDS的风险(64)。 Clinical manifestations Mucocutaneous bleeding is the usual manifestation of thrombocytopenia. Epistaxis, purpura, gum bleeding, easy bruising, menorrhagia, gastrointestinal bleeding, hematuria and central nervous system hemorrhage are the usual signs and symptoms. Spontaneous bleeding has been noted to be uncommon when platelet counts are above 50-30,000/µL (115, 181). Patients with platelet counts lower than 30,000 to 20,000/µL are at higher risk of abnormal bleeding and spontaneous hemorrhage is more likely with platelet counts below 10,000/µL. Patients with hemophilia or other coagulopathy are at higher risk for bleeding manifestations when platelet counts are lower than 50,000/µL (126, 173). Higher platelet counts, approximately 90-100,000/µL are needed to ensure surgical hemostasis. 临床表现 皮肤粘膜出血是血小板减少症的常见表现。鼻衄、紫癜、牙龈出血、容易擦伤出血、月经过多、胃肠道出血、血尿和中枢神经系统出血是常见的症状和体征。当血小板计数大于50-30，000/ul时自发性出血少见(115, 181)。血小板计数小于30，000到20，000/ul时异常出血的风险增高，小于10，000/ul时更容易发生自发性出血。血友病或其他凝血疾病的患者在血小板计数小于50，000/ul时即有较高的出血风险 (126, 173)。确保外科止血需要更高的血小板水平，大概90-100，000/ul。 Secondary causes of thrombocytopenia in HIV infected patients include hypersplenism due to coincident liver disease, marrow involvement by opportunistic infections such as histoplasmosis, cryptococcus, or bacillary angiomatosis, and marrow involvement by lymphoma or other neoplastic process. Drugs such as antineoplastic chemotherapy, Alfa-interferon, zidovudine, Didanosine, trimethoprim-sulfamethoxazole, pentamidine, pyrimethamine, ganciclovir, Fluconazole, Trimetrexate, Eflornithine, rifabutin, and Clarithromycin may cause thrombocytopenia in HIV-infected patients. Disseminated intravascular coagulation or severe bacteremic infection without disseminated intravascular coagulation may cause acute thrombocytopenia. HIV感染者中血小板减少的继发性原因包括肝病引起的脾功能亢进，机会性感染如组织胞浆菌病、隐球菌病或杆菌性血管瘤病造成的骨髓浸润，以及淋巴瘤或其他肿瘤造成的骨髓浸润。肿瘤化疗药物、alfa干扰素、齐多夫定、去羟肌苷、甲氧苄啶-磺胺甲噁唑、喷他脒、乙胺嘧啶、更昔洛韦、氟康唑、三甲曲沙、依氟鸟氨酸、利福布汀和克拉霉素可以导致HIV感染者的血小板减少。弥散性血管内凝血或不伴弥散性血管内凝血的严重细菌性感染也可以导致急性血小板减少症。 Thrombotic thrombocytopenic purpura, hemolytic uremic syndrome and hemophagocytic syndrome are very important in the differential diagnosis and are reviewed in the section on microangiopathic anemia. 血栓性血小板减少性紫癜、溶血性尿毒症综合征和噬血细胞综合征都是非常重要的鉴别诊断，在微血管病性贫血一节中已经详述。 Diagnostic Approach Symptoms of mucocutaneous bleeding including epistaxis, menorrhagia and gum bleeding should be sought. Additionally, the patient should be asked about a history of liver disease, chronic and recent alcohol intake and hepatitis exposure. Alcoholic binges may cause thrombocytopenia. The medication profile should be reviewed and any correlation of the onset of thrombocytopenia to the institution of any offending medication should be identified. Signs of liver disease, such as splenomegaly and ascites should be sought and the patient should be examined for purpura and petechiae. Staging of the HIV infection including HIV viral load and CD4+ lymphocyte counts should be performed. The patient should be evaluated for signs and symptoms of opportunistic infection and lymphoma, including the presence of fevers, chills, sweats, adenopathy and weight loss. The peripheral blood smear should be reviewed to exclude pseudothrombocytopenia due to platelet clumping. The smear should also be examined for the presence of schistocytes suggesting microangiopathic hemolytic anemia and for tear-drop cells suggesting marrow infiltration and myelophthisic anemia. The presence of giant platelets on the peripheral smear suggests destructive thrombocytopenia. Liver function tests, LDH and serum creatinine should be obtained. Blood cultures and a coagulation profile should be done to exclude bacteremic infection and disseminated intravascular coagulation. 诊断 应注意皮肤粘膜出血的症状包括鼻衄、月经过多和牙龈出血。另外，应询问患者的肝病史，慢性和近期饮酒史以及肝炎接触史。大量饮酒可以导致血小板减少。注意患者的用药史以及确定血小板减少发生和任何所用药物之间的关系。应检查肝病的体征如脾大和腹水，并检查患者有无紫癜和瘀斑。对HIV感染的分期检查包括测定HIV病毒载量和CD4+淋巴细胞计数。应当评价患者有无机会性感染和淋巴瘤的症状和体征，包括发热、寒战、出汗、淋巴结肿大和体重下降。检查外周血涂片以除外血小板聚集所致的假性血小板减少。还应检查涂片中有无提示微血管病性溶血性贫血的破碎红细胞以及提示骨髓浸润和骨髓病性贫血的泪滴样红细胞。外周血涂片出现巨血小板提示破坏性血小板减少。要测定肝功能、LDH和血肌酐。做血培养和凝血检查以除外菌血症和弥散性血管内凝血。 Patients with isolated thrombocytopenia are likely to have HIV related immune thrombocytopenia, and an immediate bone marrow examination is not mandatory in such patients. Patients with signs and symptoms of opportunistic infections, lymphoma or those with multiple cytopenias or signs of myelophthisic changes on peripheral blood smear should undergo bone marrow examinations. The bone marrow examination can help distinguish destructive thrombocytopenia, where megakaryocytes are increased, from hypoproliferative thrombocytopenia, where the megakaryocytes are decreased. 单纯血小板减少的患者更可能是HIV相关性免疫性血小板减少症，此类病人无须立刻行骨髓检查。有机会性感染、淋巴瘤症状和体征或多系血细胞减少或外周血涂片提示骨髓病性改变表现的患者应行骨髓检查。骨髓检查可以有助于区别破坏性血小板减少症与低增生性血小板减少症，前者的巨核细胞增多，而后者的巨核细胞减少。 Management Specific treatment of asymptomatic mild to moderate HIV-associated thrombocytopenia may not be necessary, as bleeding manifestations are rare unless the platelet count is below 50-30,000/µL. Treatment should be initiated in patients with lower platelet counts, those with other coagulopathies, those with bleeding manifestations and those requiring invasive procedures or surgery. 治疗 无症状的轻到中度HIV相关性血小板减少不需要特殊治疗，因为除非血小板低于50-30，000/ul，否则罕见出血表现。更低的血小板数目（小于50-30，000/ul）、伴其他凝血性疾病、有出血表现和需要有创性操作或手术的患者应给予治疗。 Anti-retroviral Therapy Therapy for HIV-associated immune thrombocytopenia with zidovudine has been extensively reported (126, 157, 172). The platelet count improves in 40-60% of patients and complete normalization is seen in approximately 20% thrombocytopenic HIV infected patients treated with zidovudine. The response is reported as durable and dose dependent in patients with both severe and moderate thrombocytopenia. Improvement generally begins within a week and maximum improvement is usually seen by four weeks. The response rate is higher at doses of 1000 mg/day or greater, but these high doses (113) are often accompanied by a higher incidence of anemia or leukopenia. 抗逆转录病毒治疗 使用齐多夫定治疗HIV相关性免疫性血小板减少症已经被广泛报道(126, 157, 172)。40-60%的HIV感染伴血小板减少的患者在使用齐多夫定后其血小板计数可以有改善，约20%患者可以完全正常。在重度和中度血小板减少的患者中，齐多夫定的疗效是持久的和剂量依赖的。血小板的改善通常出现在1周内，一般在4周后出现最大改善。1000mg/天或更大的剂量时的有效率更高，但是大的剂量(113)常伴随贫血或白细胞减少发生率的增加。 Antiretroviral therapy with Dideoxyinosine has also been shown to ameliorate thrombocytopenia (149, 167, 192). More recently, highly active antiretroviral therapy (HAART) with protease inhibitors such as Indinivir has been shown to significantly elevate the platelet counts in HIV infected patients (124, 217). Responses to antiretroviral therapy were reported to sustain platelet counts both above and below 50,000 and to be correlated to a response in HIV viral load. Responses were not correlated to baseline CD4+ lymphocyte counts (31). 双脱氧肌苷抗逆转录病毒治疗也可以改善血小板减少症(149, 167, 192)。最近，使用蛋白酶抑制剂如茚地那韦的高效抗逆转录病毒治疗（HAART）可显著提高HIV感染者的血小板水平(124, 217)。抗逆转录病毒治疗后血小板计数可以维持在50，000以上或以下，并与HIV病毒载量的反应有关。治疗反应与基础CD4+淋巴细胞计数无关(31)。 Glucocorticoids Glucocorticoids improve the platelet counts in HIV associated thrombocytopenia. Response rates of 79% to 94% have been reported (3, 226) and responses are generally prompt. The suggested starting dose of Prednisone is 1 mg/kg/day (0.25-0.5 mg/kg/day may provide comparable benefit). The dose is then tapered to the lowest dose that controls the thrombocytopenia. Unfortunately, responses to glucocorticoids are often not durable unless the steroids are continued, resulting in unacceptable side effects such as iatrogenic Cushing’s syndrome, increased immunosuppression and predisposition to opportunistic infections such as candidiasis and aspergillosis (67, 200). The maximum response is usually seen within 3-4 weeks. Thus, if remission is not sustained as the steroids are tapered, other treatment modalities should be initiated to avoid the adverse effects of long term glucocorticoids. 糖皮质激素 糖皮质激素对HIV相关性血小板减少症有效。报道有效率为79~94%(3, 226)，并且通常疗效迅速。强的松的推荐初始剂量为1mg/kg/天（0.25-0.5mg/kg/天也可能有类似效果）。然后逐渐减量至能够控制血小板减少症的最低值。不幸的是，除非持续使用激素，否则糖皮质激素的效果并不持久，这会造成较严重的副作用如医源性库欣综合征、加重免疫抑制和增加机会性感染如念珠菌病和曲霉菌病的机率增加(67, 200)。最大疗效一般在3-4周内出现。因此，如果在激素减量过程中疾病反复，则应开始其他的治疗方法，以避免出现长期使用糖皮质激素的副作用。 Splenectomy A number of series have reported that splenectomy resulted in a sustained remission of HIV related thrombocytopenia (3, 57, 96, 155, 156, 194). Splenectomy is not associated with more rapid course of HIV infection or increase progression to AIDS (114), but splenectomy spuriously increases the CD4+ lymphocyte count (39). Splenectomy increases the risk of sepsis from bacteremia with encapsulated organisms and patients should undergo vaccination against Streptococcus pneumoniae, meningiococcus and H. influenzae type b prior to splenectomy. Low dose splenic radiation has also been reported to raise the platelet count in HIV related thrombocytopenia, but the duration of response is short (22, 117, 150). 脾切除 很多报道HIV相关性血小板减少症通过脾切除获得了持久性缓解(3, 57, 96, 155, 156, 194)。脾切除与HIV感染进程加速或AIDS进展加快无关(114)，但是脾切除造成CD4+淋巴细胞计数的假性增多(39)。脾切除增加了带有荚膜的细菌造成败血症的机率，患者在脾切除前应当接种肺炎链球菌、脑膜炎球菌和B型流感嗜血杆菌的疫苗。低剂量脾放射也可以增加HIV相关性血小板减少症的血小板计数，但是持续时间短(22, 117, 150)。 Intravenous Gammaglobulin (IVIG) IVIG leads to a rapid but transient improvement in platelet counts in a high percentage of patients with HIV-related immune thrombocytopenia through reticuloendothelial blockade. IVIG may be used in previously splenectomized or unsplenectomized patients. The platelet count usually increases within 24 to 72 hours following treatment. Responses typically last several weeks (29, 86, 122). Treatment may be repeated every two to four weeks, if needed. The recommended IVIG dose is 2 grams per kilogram divided over 2 days (1000 mg/Kg daily x 2). The cost and availability of IVIG are significant issues, especially for long term treatment. However, the rapidity of response to IVIG makes it particularly useful for patients with severe thrombocytopenia and active bleeding, or for treatment of patients who require surgery or invasive procedures. Side effects include hypersensitivity reactions during the infusions, occasional acute renal failure and aseptic meningitis. 静脉输注人免疫球蛋白（IVIG） IVIG可以通过网状内皮封闭快速但短暂的改善大部分HIV相关性免疫性血小板减少症患者的血小板计数。IVIG可以用于脾切除前或非脾切除的患者。血小板计数通常在治疗后24-74小时内增多。效果一般可持续数周(29, 86, 122)。需要的话治疗可以每2-4周重复1次。IVIG推荐剂量为2g/kg，2天输注（1000mg/kg/天x 2）。IVIG的花费和可获得性是主要问题，尤其对于长期治疗者。不过，IVIG的快速有效性使其对于重症血小板减少、活动性出血、需要手术或有创性操作的患者特别有用。副作用包括输注过程中的过敏反应、偶发的急性肾功能衰竭和无菌性脑膜炎。 Anti-Rh (D) globulin Reticuloendothelial blockade may also be accomplished using intravenous anti-Rh (D) (Win-Rho) treatment in unsplenectomized, Rh positive patients. The anti-Rh immunoglobulin coats the red cell causing low-grade hemolysis. This destruction of red cells blocks the spleen from destroying platelets. This treatment may be associated with a fall in hemoglobin of up to 2.2 grams/dL. Responses have been reported in approximately 60 to 70% of patients with HIV associated thrombocytopenia (114, 154, 191). The anti-Rh (D) immunoglobulin is administered at 25mcg/kg IV given over 30 minutes for two days. Responses are transient, lasting 3 weeks in 50% of responding patients (191), but maintenance therapy may be given at a dose of 13 –25 mcg/kg IV administered after every 2 to 4 weeks. Intramuscular maintenance therapy at a dosage of 6-13ug/kg/week following intravenous induction was reported to maintain responses in 85% of patients with HIV related thrombocytopenia (73). Anti Rh (D) is less expensive than IVIG and is well tolerated. 抗Rh（D）球蛋白 未行脾切除且Rh阳性的患者还可以通过静脉滴注抗Rh（D）（Win-Rho）球蛋白实现网状内皮封闭。抗Rh免疫球蛋白包被在红细胞上并引起低度溶血。这种对红细胞的破坏可阻止脾破坏血小板。这种治疗会导致血红素下降2.2g/dl。HIV相关性血小板减少症患者中大约60-70%有疗效(114, 154, 191)。抗Rh（D）免疫球蛋白以25mcg/kg 的剂量大于30min静脉滴注共 2天。疗效是短暂的，约50%患者可持续3周(191)，维持剂量为每2-4周13-25mcg/kg静脉注射。静脉诱导后给予剂量为6-13ug/kg/周的肌肉注射维持疗法在85%的HIV相关性血小板减少症患者中有效(73)。抗Rh（D）球蛋白比IVIG便宜，耐受性好。 Alpha Interferon Alpha interferon at a dose of 3 x 106 units subcutaneously three times weekly has been reported in several series to improve the platelet counts in thrombocytopenic HIV infected patients (152, 222) including patients who previously failed zidovudine treatment (125). Responses were reported in over half the patients treated. The majority of responses were partial, but clinically significant. Alpha interferon was generally well tolerated. Alpha干扰素 一些研究中使用Alpha干扰素3 x 106 单位皮下注射每周3次治疗血小板减少的HIV患者以改善血小板计数(152, 222)，包括那些使用齐多夫定治疗无效的患者(125)。一半以上的患者有效。虽然多数是部分有效，但是临床效果显著。Alpha干扰素的耐受性通常很好。 Other Therapeutic Modalities Danazol, (156) Dapsone, (49) Prosorba columns, (204) and Vincristine (132) have also been tried in the management of HIV associated thrombocytopenia with varying success. 其他治疗方法 丹那唑、(156)氨苯砜、(49) Prosorba columns(204)和长春新碱(132)都曾用于HIV相关性血小板减少症的治疗，效果不一。 Platelet Transfusion Platelet transfusion is indicated for patients with active thrombocytopenic bleeding. Patients with decreased production respond better to platelet transfusions than patients with destructive thrombocytopenia. However, patients with destructive thrombocytopenia and severe or life threatening bleeding may derive benefit from transfusions. Patients with microangiopathic hemolytic anemia should generally not be given platelet transfusions. Patients with thrombocytopenia below 10,000/µL due to decreased production of a reversible/temporary cause are candidates for prophylactic platelet transfusions to prevent bleeding episodes. Thrombocytopenic patients needing surgery or invasive procedures should also be given platelet transfusions. 血小板输注 活动性出血的患者可以使用血小板输注。（血小板）生成减少的患者比破坏性血小板减少的对输血小板的反应好。然而破坏性血小板减少或严重甚至危及生命的出血仍可以从输注血小板中获益。微血管病性溶血性贫血的患者通常不应该输血小板。因可逆性/暂时性血小板生成减少使血小板计数小于10，000/ul的患者应预防性输注血小板以防止出血。需要手术或侵入性操作的血小板减少症患者应该（术前）输血小板。 A one hour post transfusion platelet count should be obtained. Generally, one unit of platelets per 10 Kg of body weight would raise the one-hour post transfusion platelet count by 50,000/µL. A normal transfusion yield would be considered to be at least 70% of this increment. The 20-hour increment is usually two thirds of the one-hour increment. The efficacy of platelet transfusions is diminished by the presence of hypersplenism, fever, infection, Amphotericin B therapy or immune-mediated destruction (immune complex, autoantibodies, or alloantibodies). Complications of platelet transfusions include febrile reactions, transmission of viral infections including CMV, bacterial contamination of platelets units, and alloimmunization of the recipient resulting in refractoriness to platelet transfusions. The use of leukocyte depleted platelet products may decrease the incidence of alloimmunization, febrile reactions, and CMV transmission. 输血小板后1小时检测血小板计数。一般情况下，1个单位血小板每10kg体重可使第1小时后血小板计数增加50，000/ul。正常的输注应该至少达到这个增量的70%。20小时后的增量通常是第1小时增量的2/3。如果存在脾功能亢进、发热、感染、两性霉素B治疗或免疫介导性破坏（免疫复合物、自身抗体或异种抗体）时血小板维持的时间会下降。血小板输注的并发症包括发热反应、传播病毒感染如CMV、细菌污染和受体的免疫反应导致的血小板输注无效。使用去白细胞的血小板制品可以降低异体免疫反应、发热反应和CMV传播的发生率。
Tables and Figures 表格和图表 Table 1. Causes of Anemia in HIV Infected Patients Table 2. Hematologic Toxicity from Drugs used in HIV/AIDS. Table 3. The Differential Diagnosis of Leukopenia in HIV Infected Patients Table 4. Causes of Thrombocytopenia in HIV Infected Patients
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