Causes of anemia in patients with cancer

INTRODUCTION — Anemia frequently complicates the course of cancer. While anemia may be a presenting sign of malignancy, it may also be a consequence of a patient's antineoplastic therapy or progressive disease.

Fatigue ranks as the most common symptom affecting cancer patients and limiting their daily activity. Since anemia is a frequent cause of fatigue, recognizing anemia and its causes is important for identifying appropriate interventions that may improve the cancer patient’s quality of life.

This review will discuss those causes of anemia that are of specific relevance in patients with neoplastic disease.

A general discussion of anemia and its treatment in patients with malignancy are presented separately:

●Anemia evaluation – (See "Diagnostic approach to anemia in adults".)

●Treatment of cancer-related anemia – (See "Cancer-related fatigue: Treatment", section on 'Anemic patients' and "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer".)

●Perioperative optimization – (See "Perioperative blood management: Strategies to minimize transfusions".)

OVERVIEW

Mechanisms — As with anemias in general, three broad categories should be considered when assessing causes of anemia in patients with malignancies. (See "Diagnostic approach to anemia in adults".)

●Red blood cell (RBC) losses from the body (blood loss anemia)

●Increased RBC destruction (hemolytic anemia)

●Decreased RBC production (hypoproliferative anemia)

Anemia may be "apparent" rather than real in patients with a normal RBC mass but an expanded plasma volume. This may be the result of fluid retention or volume expansion or the expanded plasma volume seen in patients with splenomegaly due to one of the myeloproliferative neoplasms. (See "Diagnostic approach to anemia in adults".)

Myelophthisis refers to displacement of hematopoietic cells by other cells or proteins not normally present in the bone marrow, such as tumor cells, fibrosis, or granulomas. It may be associated with leukoerythroblastic changes (teardrop cells and immature white blood cells) on the peripheral blood film. (See "Evaluation of the peripheral blood smear", section on 'Leukoerythroblastic smear'.)

Causes — Anemia caused by one or more of these three mechanisms (see 'Mechanisms' above) can develop in the setting of cancer in three different ways:

●A direct effect of the neoplasm (eg, bleeding from the tumor, bone marrow replacement).

●An effect of a product of the neoplasm (eg, autoantibodies, microangiopathy, amyloid production, cytokine inhibition of erythropoiesis, paraneoplastic pure red cell aplasia).

●An effect of treatment directed against the neoplasm (eg, suppression of erythropoiesis by radiation therapy and/or systemic antineoplastic agents).

Presence of multiple causes of anemia — Multiple factors may contribute to the development of anemia in the cancer patient. In determining which factors may be contributory, it is important to correlate patients' clinical histories and physical exam findings with laboratory observations, realizing that more than one contributor may underlie the development of anemia. (See "Diagnostic approach to anemia in adults".)

As an example, a large prospective observational study evaluated multiple factors leading to the development of anemia in 888 patients with cancer, prior to the initiation of any cancer treatment. Observations included the following [1]:

●Sixty-three percent of the patients in this study were anemic, with the incidence of anemia increasing with increasing cancer stage and decreasing Karnofsky performance status (table 1).

●Hemoglobin concentration was inversely correlated with the levels of inflammatory markers, hepcidin, ferritin, erythropoietin, reactive oxygen species, and the modified Glasgow Prognostic Score [2], and positively correlated with leptin, albumin, cholesterol, and antioxidant enzymes.

It was concluded that cancer-related anemia is a multifactorial problem, with immune, nutritional, and metabolic components affecting its severity.

WHO and NCI CTCAE gradings of anemia — According to the World Health Organization (WHO) and National Cancer Institute (NCI), normal values for hemoglobin are 12 to 16 g/dL in adult females and 14 to 18 g/dL in adult males; the National Comprehensive Cancer Network (NCCN) suggests evaluation of anemia if the hemoglobin is ≤11 g/dL or if there is a decrease of ≥2 g/dL below the individual's baseline [3].

For anemia that arises as a treatment-related toxicity, NCI common terminology criteria for adverse events (CTCAE) criteria for grading anemia are used (table 2). (See "Common terminology criteria for adverse events", section on 'Hematologic'.)

ANEMIA FROM DIRECT EFFECTS OF NEOPLASMS

Intraluminal bleeding — Intraluminal neoplasms arising from or metastatic to the gastrointestinal or genitourinary tract may bleed, producing blood loss anemia. Accordingly, when evaluating cancer patients who have anemia, stool and urine samples should be examined for the presence of blood, which may be occult. (See "Evaluation of occult gastrointestinal bleeding".)

While the patient's hemoglobin, hematocrit, and red blood cell (RBC) indices may be normal in the early stages of blood loss, persistent bleeding will ultimately result in iron deficiency when the patient's iron stores become depleted. This usually occurs in males when total blood loss exceeds 1200 mL and in females at approximately 600 mL. (See "Diagnostic approach to anemia in adults" and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)

Decreased concentrations of serum ferritin, reflecting deficient stores of iron, may be present. In addition, microcytic, hypochromic RBCs may be evident on review of peripheral blood smears (picture 1). A progressive decrease over time in RBC mean corpuscular volume (MCV) and/or mean corpuscular hemoglobin (MCH) and/or mena corpuscular hemoglobin concentration (MCHC) is another clue that iron deficiency may be developing.

Intratumoral hemorrhage/rupture — Occasionally, acute anemia may occur due to spontaneous bleeding into the body of the tumor or rupture of the tumor into the peritoneum/retroperitoneum. Approximately 10 percent of hepatocellular cancers spontaneously rupture. The clinical picture is that of acute abdominal pain and distension, hypotension, and an acute drop in the hematocrit, and spontaneous liver rupture can occur with catastrophic consequences [4,5].

Malignancies associated with hemorrhage into the tumor or rupture with risk of massive internal bleeding include:

●Hepatocellular cancer [4,5]. (See "Clinical features and diagnosis of hepatocellular carcinoma", section on 'Other clinical presentations'.)

●Gastrointestinal stromal tumors, particularly those involving the stomach. (See "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors".)

●Malignant hepatic epithelioid hemangioendothelioma [4,6]. (See "Pathology of malignant liver tumors".)

●Liver metastases, especially from cutaneous or ocular melanomas [7].

●Splenic hemangiosarcomas [8].

●Stromal ovarian tumors or cancers metastatic to the ovary [9,10]. (See "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults".)

●Retroperitoneal tumors with retroperitoneal hemorrhage [11-14].

Generalized bleeding — In addition to bleeding from the tumor itself, effects of the malignancy on platelets and clotting factors can cause generalized bleeding. The following possible effects should be kept in mind [15]:

●Thrombocytopenia-associated bleeding from treatment-associated bone marrow suppression. (See 'Anemia from effects of cancer treatment' below.)

●Tumor-associated immune thrombocytopenia. (See "Overview of the complications of chronic lymphocytic leukemia", section on 'Thrombocytopenia'.)

●Disseminated intravascular coagulation with coagulopathy-associated bleeding, which is especially common in pancreatic cancer and acute promyelocytic leukemia. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

●Acquired autoantibodies inhibiting coagulation factors (eg, acquired von Willebrand disease, acquired factor VIII deficiency). Malignancy (in particular, lymphoproliferative disorders) is a risk factor for these acquired inhibitors [16,17]. (See "Acquired von Willebrand syndrome" and "Acquired hemophilia A (and other acquired coagulation factor inhibitors)", section on 'Evaluation'.)

Not all bleeding episodes will be related to direct effects of the patient's malignancy. Preexisting bleeding disorders (eg, von Willebrand disease), bleeding lesions (eg, peptic ulcer disease), or use of anticoagulation may also contribute. Hemostatic testing (platelet count, coagulation studies, fibrinogen) may reveal these conditions. (See "Approach to the adult with a suspected bleeding disorder".)

Iron, vitamin B12, and folate deficiencies — While iron deficiency most commonly arises from bleeding, it may occasionally result from impaired iron absorption. (See "Regulation of iron balance", section on 'Intestinal iron absorption'.)

Iron malabsorption should be considered in patients with iron deficiency who do not respond to treatment with oral iron and/or whose malignancies involve the mucosa of the duodenum and/or upper jejunum, the sites of maximal iron absorption. This effect can be direct, as in gastrointestinal lymphoma [18], or indirect, as in amyloidosis from multiple myeloma [19].

Folate deficiency is rare except in individuals with an extremely limited diet. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Inadequate dietary intake'.)

Intestinal involvement by neoplasms is unlikely to result in vitamin B12 deficiency, as body stores of vitamin B12 in the liver may be extensive, and vitamin B12 deficiency due to malabsorption generally takes years to develop. Vitamin B12 deficiency due to surgery for gastrointestinal tract cancer is discussed below. (See 'Nutritional deficiencies after surgery for a GI tract malignancy' below.)

Hemophagocytosis — Hemophagocytosis is characterized by ingestion of RBCs by macrophages or cancer cells. While the hemophagocytic syndrome (hemophagocytic lymphohistiocytosis [HLH]) is most commonly seen in association with infection, particularly Epstein-Barr virus (EBV) infection, this disorder can complicate certain malignancies, producing anemia in the absence of documented infection [20]. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Malignancy'.)

Leukemias and lymphomas are the most common cancers associated with HLH. The latter are usually of T cell lineage, although NK cell, B cell, and myeloid proliferations causing hemophagocytosis have also been described [21-24]. (See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma", section on 'Clinical presentation' and "Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type", section on 'Clinical features'.)

Interferon-gamma and monocyte-colony stimulating factor (M-CSF) levels may be elevated [22]. Rarely, solid tumors demonstrate hemophagocytosis [24-26].

Detection of hemophagocytosis is generally made by bone marrow aspiration and biopsy, which reveals macrophages or cancer cells with ingested whole RBCs. (See "Evaluation of bone marrow aspirate smears", section on 'Macrophages (histiocytes) with ingested cells or debris'.)

Bone marrow infiltration — Leukemias, lymphomas, and plasma cell dyscrasias commonly involve bone marrow, supplanting normal hematopoiesis and resulting in a process known as myelophthisis (see 'Mechanisms' above), causing anemia and other cytopenias. Solid tumors can also produce anemia by involvement of the bone marrow space with metastases.

Disruption of the bone marrow microenvironment produces a leukoerythroblastic blood picture. This process is defined by the appearance of immature granulocytes, tear drop RBCs, and nucleated RBCs in peripheral blood (picture 2A-B). Detection of this finding on review of a patient's peripheral blood smear should alert the clinician to the possibility of myelophthisic disease.

While leukoerythroblastosis can arise from hematopoietic malignancies [27], it is more commonly seen in patients with tumors metastatic to bone marrow (picture 3) [28]. In this instance, myelofibrosis and hepatosplenic extramedullary hematopoiesis appear to be important to the pathogenesis of the leukoerythroblastosis [29,30].

●The myeloproliferative neoplasms are commonly associated with a leukoerythroblastic blood picture (eg, post-polycythemia myelofibrosis, post-essential thrombocythemia myelofibrosis, and primary myelofibrosis). (See "Clinical manifestations and diagnosis of primary myelofibrosis", section on 'Evaluation and diagnosis'.)

●Solid tumor types most commonly resulting in this disorder are prostatic, breast, and gastric carcinomas [29,31-35]. (See "Clinical manifestations and diagnosis of primary myelofibrosis", section on 'Non-hematologic conditions'.)

ANEMIA FROM PRODUCTS OF THE NEOPLASM (INDIRECT EFFECTS)

Amyloid — Amyloid, either primary (AL) or secondary (AA), may deposit in a variety of organs including bone. While large bone deposits of amyloid (amyloidomas) may be seen, producing osteolytic lesions and pathologic fractures [36], extensive replacement of bone marrow by amyloid is rare. Hence, anemia and other cytopenias are not a prominent feature of amyloidosis unless renal failure or coagulopathy is present. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Systemic presentations'.)

While disorders causing secondary (AA) amyloid are chiefly chronic inflammatory and infectious diseases, malignant diseases giving rise to AA amyloid have been reported, including Hodgkin lymphoma, non-Hodgkin lymphoma, Waldenstrom macroglobulinemia, renal cell carcinoma, and rarely, hepatocellular carcinoma [37-44]. (See "Overview of amyloidosis", section on 'Hematologic abnormalities'.)

Hemolysis — Hemolysis, defined here as a shortening of RBC survival to less than 100 days, may occur in various malignancies. Two different mechanisms may be involved:

●Production of autoantibodies that recognize red cell membrane antigens and cause an autoimmune hemolytic anemia

●Microangiopathic hemolysis

Autoimmune hemolytic anemia — Autoimmune hemolytic anemia (AIHA) is usually associated with the presence of immunoglobulin (IgG) or complement (C3d) on the surface of circulating RBCs, as detected by the direct antiglobulin (Coombs) test. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Direct antiglobulin (Coombs) testing'.)

The presence of spherocytic RBCs on the peripheral smear, along with increased serum concentrations of indirect bilirubin and lactate dehydrogenase (LDH) and reduced concentrations of haptoglobin are the hallmark findings (picture 4). While cancer-associated AIHA is most frequently noted in patients with chronic lymphocytic leukemia (CLL), other associated tumors include non-Hodgkin lymphoma, Hodgkin lymphoma, carcinomas, multiple myeloma, Waldenström macroglobulinemia, acute myeloid leukemia, angioimmunoblastic T cell lymphoma (formerly termed angioimmunoblastic lymphadenopathy with dysproteinemia), acute lymphoblastic leukemia, and myelodysplasia. (See "Diagnosis of hemolytic anemia in adults".)

While the majority of AIHAs are due to warm-reacting antibodies, certain malignancies may be associated with cold-reacting antibodies. These include CLL, Waldenström macroglobulinemia, and the lymphomas. (See "Cold agglutinin disease".)

AIHA may be exacerbated by fludarabine and other purine nucleoside analogs used in the treatment of certain indolent lymphoproliferative disorders such as CLL and follicular lymphoma [45-47]. The mechanism is unclear, but may be related to altered T cell immunity and dysregulation of B cells, since fludarabine induces a decline in CD4 cells [48]. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Direct antiglobulin (Coombs) testing'.)

Microangiopathic hemolysis — In microangiopathic hemolytic anemia (MAHA), Coombs testing is negative, and schistocytes (RBC fragments) are the hallmark peripheral blood smear finding (picture 5). MAHA with thrombocytopenia in malignancy may be a consequence of cancer-associated vascular endothelial injury (secondary thrombotic microangiopathy [TMA]) or disseminated intravascular coagulation (DIC).

Most patients with cancer-related MAHA have already been diagnosed with cancer, although it can occasionally be a presenting sign of malignancy [49]. However, many disorders other than cancer may trigger MAHA, particularly chemotherapy and other drugs, infection-associated sepsis, and DIC [50]. Hence, implicating cancer as the cause of MAHA requires exclusion of these other causes. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Differential diagnosis'.)

Both solid tumors and hematologic malignancies may give rise to MAHA [51]. However, in contrast to leukemia-associated MAHA, which is generally due to DIC with risk of hemorrhage from consumptive coagulopathy (as in acute promyelocytic leukemia), solid tumor-associated MAHA is generally thrombotic, with an increased risk for thrombotic complications and renal failure. The solid tumors most commonly associated with MAHA are mucinous adenocarcinomas (eg, gastric, breast, pancreas, prostate, lung) [52-54].

DIC — In DIC, the primary findings are those of depletion of coagulation factors along with increases in fibrin degradation products and D-dimer (table 3). Peripheral blood schistocytes are generally few in number, whereas in TTP they are often plentiful and readily detectable on review of peripheral blood smears. Accordingly, serum LDH levels due to hemolysis and tissue ischemia are generally more strikingly elevated in TTP than in DIC, often reaching levels higher than 1000 international units/L [55].

Similarly, peripheral blood nucleated RBCs due to stress erythropoiesis are more common with TMA than with DIC. An exception might be DIC in association with leukoerythroblastosis from myelophthisis, which could cause nucleated RBCs on the blood smear. (See 'Mechanisms' above and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

Mechanisms responsible for cancer-triggered DIC are uncertain. For example, tissue factor, the activator of factor VII, has been shown to be expressed on the surface of certain tumor cells [56] as well as on circulating procoagulant microparticles in patients with malignancy [57,58]. In addition, tumor necrosis factor and interleukin-6, proinflammatory cytokines associated with the malignant state, may dysregulate anticoagulant and antifibrinolytic mechanisms [59,60]. (See "Cancer-associated hypercoagulable state: Causes and mechanisms", section on 'Procoagulant proteins'.)

Cancer procoagulant (CP) is a calcium-dependent cysteine protease, which has been found in malignant and fetal tissue, but not normally differentiated tissue. It activates factor X directly, independent of the tissue factor/factor VIIa complex. CP is present in extracts of cells obtained from patients with acute promyelocytic leukemia (APL), malignant melanoma, and cancers of the colon, breast, lung, and kidney. (See "Cancer-associated hypercoagulable state: Causes and mechanisms", section on 'Procoagulant proteins'.)

APL is associated with a particularly high risk for DIC. The mechanism by which APL leads to DIC, which is often accompanied by secondary fibrinolysis, is incompletely understood. Three tumor cell procoagulants may be of primary importance (see "Cancer-associated hypercoagulable state: Causes and mechanisms" and "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults", section on 'Coagulopathy and APL'). These are:

●Tissue factor, which forms a complex with factor VII to activate factors X and IX.

●Cancer procoagulant, which activates factor X independent of factor VII.

●Increased annexin II receptor expression on the surface of the leukemic promyelocytes [61]. Annexin II receptor binds plasminogen and its activator, tissue plasminogen activator, increasing plasmin formation by a factor of 60.

The induction of tumor cell differentiation with retinoic acid or arsenic trioxide can lead to rapid improvement in the coagulopathy and reduces the incidence of severe DIC in this disorder [61,62]. (See "Initial treatment of acute promyelocytic leukemia in adults", section on 'Control of coagulopathy'.)

Other TMAs — Patients with TMAs other than DIC present with thrombocytopenia and a microangiopathic blood smear. Since primary TMAs primarily cause platelet consumption rather than clotting factor consumption (in particular, fibrinogen), levels of the coagulation components are usually normal, and there is little or no prolongation of the prothrombin time (PT) or activated partial thromboplastin time (aPTT). Measurement of fibrinogen and D-dimer also helps to clarify the situation, since these tests are generally normal in TMAs and abnormal in DIC. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'DIC versus other TMAs'.)

Secondary TMA in malignancy may be systemic, affecting numerous organs, or organ confined, as in hemolytic uremic syndrome (HUS), which primarily affects the kidney.

Mechanisms of cancer-associated TMAs are less certain. It is presumed that direct endothelial injury is the initiating event in these settings [63,64]. However, the onset of clinically evident disease may be delayed, frequently occurring months after chemotherapy has been discontinued or hematopoietic cell transplantation (HCT) has been performed [65-67]. Affected patients typically present with slowly progressive renal failure, hypertension, and a relatively bland urine sediment, which may occur in the absence of clinically apparent tumor. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)".)

Alternatively, certain drugs used to treat the malignancy or HCT may incite TMA (referred to as drug-induced TMA [DITMA]) [35,68]. DITMA may be due to an immune or a non-immune mechanism. The implicated drugs, mechanism, presentation, and management are discussed in detail separately. (See "Drug-induced thrombotic microangiopathy (DITMA)".)

Anemia of chronic disease/anemia of inflammation (ACD/AI) — Certain cytokines (eg, interferon-alpha, interferon-beta, interferon-gamma, TNF-alpha, TGF-beta, IL-1, IL-6), produced in vivo in response to malignancy, may result in anemia by mediating a block in iron utilization, inhibiting erythropoietin mRNA synthesis, and exerting other ill-defined suppressive effects on erythropoiesis [69-73]. IL-1, IL-6, and TNF-alpha induce increased levels of the iron-regulatory hormone hepcidin, which sequesters iron in macrophages, shunting iron away from erythropoiesis. In the case of Waldenström macroglobulinemia (WM), the lymphoplasmacytic cells of WM produce hepcidin [74]. Variously known as the "anemia of chronic disease" (ACD) or "anemia of (chronic) inflammation," anemia due to inflammatory cytokines should be diagnosed after excluding other causes of anemia. (See "Anemia of chronic disease/anemia of inflammation", section on 'Pathogenesis'.)

While the anemia in ACD/AI is most often normocytic and normochromic, close review of peripheral blood smears will often reveal a small population of hypochromic, microcytic RBCs. Other findings include the following:

●Abundant iron stores in bone marrow macrophages (unless concomitant blood loss has occurred) with decreased, if not absent, numbers of sideroblasts

●Serum erythropoietin (EPO) levels that are inappropriately low given the degree of anemia and intact renal function

●Low plasma concentrations of iron and transferrin (measured as total iron binding capacity [TIBC]) in the presence of normal or increased plasma ferritin concentrations. A low ratio of the soluble transferrin receptor (sTfR) to the serum ferritin may help to distinguish ACD from iron deficiency.

These findings and the diagnostic evaluation are presented separately. (See "Anemia of chronic disease/anemia of inflammation", section on 'Diagnostic evaluation'.)

Pure red cell aplasia — Along with cancer, numerous drugs, chemicals, and non-malignant conditions may be responsible for the development of acquired pure red cell aplasia (PRCA). PRCA is a profound hypoproliferative anemia, characterized by markedly decreased or absent erythroid progenitors in the bone marrow, marked reticulocytopenia, and normal leukocyte and platelet counts. (See "Acquired pure red cell aplasia in adults".)

Thymoma — In older series, thymomas accounted for as many as 50 percent of PRCA cases, with the incidence of PRCA in patients with thymomas ranging from 5 to 15 percent [75-77]. Subsequent series, however, implicate thymomas less frequently [78]. (See "Clinical presentation and management of thymoma and thymic carcinoma", section on 'Paraneoplastic disorders'.)

Hematologic malignancy — Of the hematologic malignancies reported in association with PRCA, chronic lymphocytic leukemia (CLL) is one of the most frequently cited, with as many as 6 percent of CLL patients developing PRCA [79]. Of these, two-thirds have B cell CLL and one-third have T cell CLL. However, in a Mayo Clinic series of 47 adults with acquired pure red blood cell aplasia, large granular lymphocyte (LGL) leukemia was the most common underlying cause [80]. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia", section on 'Autoimmune disorders' and "Acquired pure red cell aplasia in adults", section on 'Secondary PRCA'.)

Other hematologic malignancies reported in association with PRCA include non-Hodgkin lymphomas, Hodgkin lymphoma, acute lymphoblastic leukemia, chronic myeloid leukemia, and multiple myeloma [81,82]. While non-hematologic solid tumors have also been reported in association with PRCA, a cause-and-effect relationship between the patient's solid tumor and their PRCA has not been established in most cases [82].

Mechanisms causing cancer-associated PRCA include [77,83-87]:

●Immunoglobulin inhibitors of erythropoietin responsive cells

●Immunoglobulin-mediated cytotoxicity directed against erythroblasts

●T cell inhibition of erythropoietin-responsive cells

Immunoglobulin inhibitors of erythropoietin have also been described; however, this mechanism as a cause of cancer-associated PRCA is much less common than mechanisms involving immunoglobulins directed against marrow erythroid cells [88]. In PRCA associated with CLL, serum inhibitors of erythropoiesis have not been typically found. Rather, T lymphocytes appear to suppress erythroid growth in these patients, including those with B cell as well as T cell CLL [89,90]. (See "Pure red cell aplasia (PRCA) due to anti-erythropoiesis-stimulating agent antibodies", section on 'Etiology and pathogenesis'.)

Parvovirus B19 infection — While not an indirect effect of the neoplasm, it is important to keep in mind possible parvovirus B19 infection as a cause of PRCA, particularly in immunocompromised hosts. Parvovirus B19 selectively invades erythroid progenitors and can cause profound erythroid hypoplasia with erythroid maturation arrest, particularly with protracted infections arising in patients with altered immunity [91]. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Chronic infection in immunosuppressed hosts'.)

Since patients with cancer are often immunosuppressed, either primarily by their malignancy or secondarily by therapy for their disease, parvovirus B19 infection must be considered as a possible cause of hypoproliferative anemia in such patients [92]. In addition to profound erythroid hypoplasia with erythroid maturation arrest, a characteristic bone marrow finding in patients infected with parvovirus B19 is the presence of giant pronormoblasts with prominent eosinophilic intranuclear viral inclusions. Bone marrow biopsy can be highly informative in evaluating these patients (picture 6). (See "Acquired pure red cell aplasia in adults", section on 'Clinical features'.)

ANEMIA FROM EFFECTS OF CANCER TREATMENT

Bone marrow suppression from chemotherapy or radiation therapy — Most commonly, anemia in patients with cancer is the consequence of cancer therapy. Ionizing radiation encompassing sites of marrow hematopoiesis results in depletion of hematopoietic stem cells. However, systemic antineoplastic therapy is a more common cause of anemia than radiotherapy [93,94].

●Stem cell death with long-term myelosuppression can occur following chemotherapy with non-cell-cycle-dependent drugs such as alkylators (mitomycin, melphalan), often in a dose-dependent fashion.

●Long-term myelodysplasia, often leading to acute myeloid leukemia, may be a consequence of the use of alkylating agents and inhibitors of topoisomerase II [94-96]. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)

●Non-myeloablative doses of chemotherapy agents (myelotoxic doses that do not require stem cell rescue) such as cytarabine, methotrexate, anthracyclines, etoposide, and hydroxyurea can cause actively proliferating committed progenitor cells to die, invariably yielding early short-term myelosuppression. Although usually short term, treatment-related myelosuppression may worsen in duration and severity as the number of treatment courses increases.

Other mechanisms by which chemotherapy causes anemia include:

●Suppression of hematopoietic growth factor synthesis, especially erythropoietin [97].

●Oxidant damage to mature hematopoietic cells [98].

●Induction of immune-mediated hematopoietic cell destruction (eg, cisplatin, oxaliplatin) (table 4) [98-101]. (See "Drug-induced hemolytic anemia", section on 'Immune-mediated'.)

●Exacerbation of an underlying autoimmune hemolytic anemia associated with the patient's malignancy, as in fludarabine treatment of chronic lymphocytic leukemia [45]. (See 'Autoimmune hemolytic anemia' above.)

●Induction of microangiopathic hemolytic anemia, as in chemotherapy-induced thrombotic microangiopathy [102]. (See "Drug-induced thrombotic microangiopathy (DITMA)".)

●Acute bone marrow stromal damage with intramedullary serofibrinous exudate and hemorrhage, particularly from high dose chemotherapy. (See "Evaluation of bone marrow aspirate smears", section on 'Bone marrow necrosis'.)

Management of symptomatic anemia from chemotherapy-induced myelosuppression may include transfusion of packed red blood cells (RBCs) and/or administration of an erythropoiesis-stimulating agent. (See "Cancer-related fatigue: Treatment", section on 'Transfusions versus ESAs' and "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer".)

Nutritional deficiencies after surgery for a GI tract malignancy

Iron deficiency — Iron malabsorption may also arise in patients who have had certain surgical operations involving the gastrointestinal (GI) tract, such as partial or total gastrectomy resulting in achlorhydria, gastric dumping, or afferent (blind) loop syndromes with or without bacterial overgrowth [103-105]. If iron deficiency anemia is present and bleeding as a source of iron loss is not evident, disorders of impaired iron absorption should be considered. In such cases, an oral iron absorption test may be helpful [18,106]. Intravenous iron may be required in such circumstances. (See "Treatment of iron deficiency anemia in adults", section on 'Intravenous iron'.)

Vitamin B12 deficiency — Surgical removal of tumors involving the stomach (the source of intrinsic factor) or terminal ileum (the site of vitamin B12 absorption) may result in vitamin B12 deficiency. However, because body stores of vitamin B12 in the liver may be extensive, vitamin B12 deficiency may take years to develop following such surgery. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Causes of vitamin B12 deficiency'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anemia in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics link (see "Patient education: Anemia of inflammation (anemia of chronic disease) (The Basics)")

SUMMARY

●Causes – Multiple factors may contribute to anemia in the cancer patient. It is important to correlate patients' clinical histories and physical examination findings with laboratory observations, since more than one contributing factor may be present. (See 'Overview' above.)

●Mechanisms – There are three general mechanisms for the development of anemia in any patient. One or more of these may be present in the anemic cancer patient:

•Blood loss, both local and generalized

•Increased red blood cell destruction (hemolysis)

•Decreased red blood cell production (bone marrow suppression)

●Mediators – Anemia caused by one of these mechanisms can develop in the setting of cancer in several ways:

•A direct effect of the neoplasm (eg, bleeding from the tumor, bone marrow replacement). (See 'Anemia from direct effects of neoplasms' above.)

•A factor produced by the cancer cells (eg, autoantibodies, amyloid, cytokines that inhibit erythropoiesis, paraneoplastic phenomena that cause pure red cell aplasia [PRCA]). (See 'Anemia from products of the neoplasm (indirect effects)' above.)

•An effect of cancer treatment (eg, suppression of erythropoiesis by radiation therapy and/or chemotherapeutic agents). (See 'Anemia from effects of cancer treatment' above.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic review and was a founding Editor-in-Chief for UpToDate in Hematology.