Anemia, Leukopenia and Thrombocytopenia

in HIV Patients

Chinese Version 

Mehnaz Junagadhwalla M.D.,  Thomas E. Coyle, M.D.

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.

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).

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

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.

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. 

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). 

Blood Loss and Iron Deficiency

               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).

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).

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).

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).

            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).

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).

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).

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).

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.

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.

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).

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.

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.

               The medication profile should be reviewed including the temporal relationship of the initiation of the medication to the development of the anemia.

               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.

               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.

               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.

               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.

               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.

               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.  

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.

               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.

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).

              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.

               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).

               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).

                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.

               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).

               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).

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.

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. 

               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).

               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).

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.

               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).

               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.

               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.

               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.

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).

Differential Diagnosis

               The differential diagnosis of leukopenia in HIV infected patients is summarized in  Table 3.

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.

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). 

               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).

               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.

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.

               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.

Management

               Neutropenia and bacteremia resulting from direct myelosuppressive effects of HIV infection often improves with effective antiretroviral treatment (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.

               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). 

               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.

               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.

                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.

               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.

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).

Differential Diagnosis

            The differential diagnosis of thrombocytopenia in HIV infected patients is shown in Table 4.

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).

               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).             

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).     

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.

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.

               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.

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.

               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.

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.

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.

               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).

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.

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).

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.

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.

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.

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.

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.

               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.

Tables and Figures

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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