Systemic lupus erythematosus: Hematologic manifestations

INTRODUCTION — 

Hematologic abnormalities are common in systemic lupus erythematosus (SLE), both at diagnosis and throughout the course of the disease. The major hematologic manifestations of SLE may include isolated or concurrent cytopenias (including anemia, leukopenia, and thrombocytopenia), lymphadenopathy, and/or splenomegaly. Cytopenias in patients with SLE may also be related to comorbid diseases (eg, anemia from chronic kidney disease) and/or treatments for SLE. In addition, alterations in hemostasis have also been observed in SLE patients and are likely associated with autoantibodies. Autoantibodies may be prothrombotic (eg, antiphospholipid antibodies [aPL]) or, conversely, may inhibit the function of clotting factors and increase the risk of serious bleeding. (See "Antiphospholipid syndrome: Pathogenesis" and "Clinical manifestations of antiphospholipid syndrome".)

This topic review provides an overview of the hematologic manifestations of SLE. The clinical manifestations, diagnosis, and an overview of the management of SLE in children and adults are discussed separately.

●Children, diagnosis (see "Childhood-onset systemic lupus erythematosus (cSLE): Clinical manifestations and diagnosis")

●Children, treatment

●Adults, diagnosis (see "Systemic lupus erythematosus in adults: Clinical manifestations and diagnosis")

●Adults, management (see "Systemic lupus erythematosus in adults: Overview of the management and prognosis")

WHEN TO EVALUATE URGENTLY/ADMIT TO HOSPITAL — 

Mild hematologic abnormalities are often detected in patients with systemic lupus erythematosus (SLE) as part of routine laboratory monitoring for disease activity and/or adverse drug effects and may cause mild to no symptoms. In such cases, further evaluation is done on an outpatient basis.

However, some patients with SLE who have evidence of hematologic abnormalities require expedited evaluation in an urgent care setting and/or an inpatient hospitalization, including the following scenarios:

●Acutely ill patients with a severe cytopenia and/or pancytopenia

●Febrile patients with neutropenia

●Patients with hemodynamically significant anemia and/or bleeding

●Patients with suspected thrombotic microangiopathy (TMA; eg, microangiopathic hemolytic anemia and thrombocytopenia)

●Patients with a suspected venous or arterial thrombus, including those with suspected catastrophic antiphospholipid antibody syndrome (CAPS; eg, multiorgan dysfunction and/or failure due to diffuse coagulopathy, venous and/or arterial thromboembolism)

●Patients with suspected macrophage activation syndrome (MAS; including cytopenias plus fever, hepatomegaly, extreme ferritin elevations, and transaminitis)

WHEN TO REFER TO HEMATOLOGY — 

The evaluation and management of many hematologic manifestations of systemic lupus erythematosus (SLE) can be guided by a rheumatologist. However, hematology referral may be helpful in the following scenarios:

●Hematologic abnormalities requiring urgent care or inpatient evaluation (see 'When to evaluate urgently/admit to hospital' above)

●A suspected or confirmed diagnosis of any of the following conditions:

•Autoimmune hemolytic anemia (AIHA) (see 'Autoimmune hemolytic anemia' below)

•Pure red cell aplasia (see 'Pure red cell aplasia' below)

•Microangiopathic hemolytic anemia (MAHA) and/or thrombotic microangiopathy (TMA) (see 'Thrombotic microangiopathies (eg, TTP)' below)

•Antiphospholipid syndrome (APS), including catastrophic APS (CAPS) (see 'Antiphospholipid antibodies and antiphospholipid syndrome' below)

•Hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS)

•Hematologic malignancy (see 'Pancytopenia' below and 'Lymphadenopathy' below)

ANEMIA

Prevalence — Anemia is the most common hematologic abnormality in systemic lupus erythematosus (SLE) and affects more than half of patients at some point in their disease course [1-4].

Symptoms — Symptoms of anemia depend on the severity; they may include fatigue, irritability, pallor, dyspnea, tachycardia, and, if severe, hemodynamic compromise. When anemia is related to hemolysis, patients can develop jaundice and/or dark urine. Certain causes of anemia are associated with other symptoms. (See 'Causes unrelated to SLE activity' below.)

Evaluation — Multiple mechanisms may contribute to the development of anemia in patients with SLE, which are summarized in the table (table 1). These causes of anemia are not mutually exclusive (eg, a patient can have both chronic inflammation and iron deficiency, especially a menstruating female). More information on causes of anemia in children and adults is described separately and is summarized in the context of SLE below. (See "Approach to the child with anemia" and "Diagnostic approach to anemia in adults".)

The evaluation of anemia in patients with SLE is similar to that in a patient without SLE and may differ depending on the severity and acuity of anemia, the patient's clinical status, and other cytopenias. The evaluation should include the identification of potentially reversible causes of anemia, particularly bleeding. The possibility of multifactorial anemia should be kept in mind. More detail on the approach to anemia in children and adults is provided separately and is summarized below in the context of SLE. (See "Approach to the child with anemia" and "Diagnostic approach to anemia in adults".)

●Acuity and severity of presentation – The most likely causes of anemia depend on the acuity of the illness and whether there are other cytopenias:

•Not acutely ill, isolated anemia – Types of anemia seen in patients with SLE who are not acutely ill and who do not have other cytopenias include anemia of chronic disease/anemia of inflammation (ACD/AI), iron deficiency, folate or vitamin B12 deficiencies (other mild cytopenias may be present), and autoimmune hemolytic anemia (AIHA). A general discussion of anemia evaluation is presented separately. (See "Diagnostic approach to anemia in adults".)

•Acutely ill, other cytopenias – Disorders to be considered in individuals who are acutely ill and/or who have additional cytopenias include effects of cytotoxic medications and other severe drug reactions, thrombotic microangiopathy (TMA), catastrophic antiphospholipid syndrome (CAPS), infections, and macrophage activation syndrome (MAS). A general discussion of pancytopenia evaluation is presented separately. (See "Approach to the adult with pancytopenia".)

●Initial evaluation – The initial evaluation of anemia in all patients with SLE should include the following elements:

•A thorough history and physical examination

•Review of medications that may cause anemia

•Review of the complete blood count (CBC), reticulocyte count, and red blood cell (RBC) indices

•Additional laboratory testing sequentially or simultaneously for other causes as appropriate, depending on the history and preliminary laboratory results:

-Kidney disease – Kidney function and, in patient with severe anemia and evidence of kidney dysfunction, erythropoietin

-Iron deficiency – Iron, ferritin, and total iron binding capacity (TIBC)

-Vitamin B12 or folate deficiency – Vitamin B12 and folate levels

-Inflammation – Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)

-Hemolysis – Indirect bilirubin, lactate dehydrogenase (LDH), haptoglobin, and direct antiglobulin (Coombs) test (DAT)

-Gammopathy – Serum protein electrophoresis (SPEP)

The RBC size (mean corpuscular volume [MCV]) can often help narrow the possible causes of anemia when the reticulocyte count is low.

The reticulocyte count may be inappropriately low in individuals with hemolysis who have concomitant impairment of bone marrow function; deficiency of iron, vitamin B12, or folic acid; or ACD/AI. In such cases, other laboratory tests provide a more accurate assessment for hemolysis (eg, indirect bilirubin, LDH, and haptoglobin) (table 2). (See "Diagnosis of hemolytic anemia in adults".)

●Additional testing for acutely ill patients with other cytopenias – Patients who are acutely ill and who have anemia with other cytopenias typically require evaluation in the urgent care or hospital setting and a hematology consult. In addition to the initial evaluation for all patients above, we order the following:

•Hemolysis testing – Indirect bilirubin, LDH, haptoglobin, and DAT

•Coagulation testing – Prothrombin time (PT) and activated partial thromboplastin time (aPTT)

•Liver function tests

•Morphologic evaluation – Peripheral smear, focusing on abnormal RBC morphologies such as spherocytes, bite cells, and schistocytes (see "Evaluation of the peripheral blood smear", section on 'RBC size and shape abnormalities')

In addition, some contributors would send testing for antiphospholipid antibodies (aPL), particularly if these assays have not been done in the past several months. Further diagnostic testing for disorders associated with anemia plus other cytopenias, which may be life-threatening, is presented separately:

•(See "Approach to the adult with pancytopenia".)

•(See "Catastrophic antiphospholipid syndrome (CAPS)".)

•(See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

•(See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

Causes associated with active SLE — Patients with SLE may develop anemia related to inflammation (ACD/AI) and/or autoimmunity (antibodies to RBCs) (table 1).

Anemia of chronic disease/anemia of inflammation — ACD/AI is the most common type of anemia in SLE patients, accounting for approximately a third of cases [5]. ACD/AI results from interleukin 6 (IL-6)-mediated upregulation of the iron regulatory protein hepcidin, disrupting iron trafficking and incorporation into developing RBCs (figure 1). Inflammation may be related to SLE disease activity, comorbid conditions (eg, chronic kidney disease), or infection in the setting of immunosuppression.

●Common findings – The anemia is typically normocytic and normochromic with a low reticulocyte count and adequate iron stores. Acute phase reactants (eg, ESR, CRP, and ferritin) are usually elevated, and the iron saturation is low, since hepcidin rapidly induces decreased serum iron. Additional details of the evaluation and the pathologic mechanisms involved are presented separately. (See "Anemia of chronic disease/anemia of inflammation", section on 'Clinical presentation'.)

●Management – In the absence of either symptoms attributable to anemia (eg, dyspnea on exertion, easy fatigability) or impaired kidney function, treatment involves treating the underlying cause (ie, active SLE) [6].

Patients with symptoms due to anemia may require treatment with an erythropoiesis-stimulating agent (ESA), although trials are lacking in SLE patients. Information on management in patients with chronic kidney disease is discussed separately. (See "Anemia of chronic disease/anemia of inflammation", section on 'Management' and "Treatment of anemia in nondialysis chronic kidney disease".)

Autoimmune hemolytic anemia — The presentation of autoimmune hemolysis in generally the same in patients with and without SLE, although it is a manifestation of active SLE and therefore may be accompanied by other disease manifestations. Autoantibodies to RBCs in SLE may be warm- or cold-reactive, leading to warm AIHA or cold agglutinin disease. As in the general population, AIHA is more common than cold agglutinin disease among SLE patients. More detail on the diagnosis of AIHA and cold agglutinin disease is provided elsewhere; manifestations of AIHA in the context of SLE are briefly summarized below. (See "Warm autoimmune hemolytic anemia (AIHA) in adults" and "Cold agglutinin disease".)

●Epidemiology and risk factors – AIHA has been reported in up to 10 percent of SLE patients [1,5,7-9]. Autoimmune hemolysis, including that related to Evans syndrome (ie, autoimmune hemolysis and immune thrombocytopenia [ITP]) may be a presenting feature of SLE; other features of SLE may not emerge for several years [3,10,11]. In general, severe AIHA seems to occur relatively early in the overall disease course for patients with SLE. In a longitudinal study of 1349 patients with SLE who were followed for a mean of 5.4 years, the median time from the onset of SLE to the development of severe AIHA (hemoglobin ≤7 g/dL) was 111 days [12]. Male sex was associated with a faster progression to severe autoimmune hemolytic anemia (hazard ratio [HR] 2.26). (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Epidemiology' and "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Evans syndrome'.)

AIHA is associated with active SLE and may be associated with specific features including aPL, kidney disease, neurologic disease (with seizures), and serositis [3,9,13]. In a systematic review including over 8200 patients with SLE, the presence of any aPL was associated with an increased risk of developing AIHA (odds ratio [OR] 2.83, 95% CI 2.12-3.79]).

●Common findings – Common laboratory findings in AIHA include an increased reticulocyte count, increased indirect bilirubin and LDH, low haptoglobin, and a positive DAT (table 2); spherocytes may be seen on the peripheral blood smear (picture 1 and picture 2) as the hemolysis takes place extravascularly in the spleen. Anemia is often present, but the hemoglobin may be normal if there is sufficient reticulocytosis to compensate for hemolysis.

Common patterns seen on direct antiglobulin testing are summarized in the table (table 3). Of note, some individuals may have an autoantibody to RBCs that does not cause hemolysis. Thus, the presence of a positive DAT does not necessarily imply that the individual has autoimmune hemolysis. Complement alone (eg, C3 and/or C4) on the RBC surface is almost always indicative of a cold-reactive antibody and is often not associated with hemolysis [5,7,8,14].

●Management

•Warm AIHA – In patients with suspected AIHA, a hematologist should be consulted. As with non-SLE-associated warm antibody-mediated hemolysis, warm AIHA related to SLE is treated with high-dose glucocorticoids (eg, prednisone, 1 to 1.5 mg/kg daily), with the dose tapered slowly once a sustained response is achieved [15,16]. For patients whose anemia is unresponsive to glucocorticoids, B-cell depletion (usually with rituximab) is often used as second-line therapy, which can treat other manifestations of SLE and may allow the patient to avoid splenectomy. This approach is generally consistent with the management of AIHA in patients without SLE, which is discussed in detail elsewhere. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Initial management' and "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Rituximab'.)

Other immunosuppressive therapies such as other agents that deplete B cells (eg, ofatumumab), mycophenolate, cyclosporine, danazol, splenectomy, or intravenous immune globulin (IVIG) have also been used [3,15,17-28].

•Cold agglutinin disease – The treatment of cold agglutinin-mediated hemolysis is discussed in detail separately. (See "Cold agglutinin disease", section on 'Management'.)

Pure red cell aplasia — Pure red cell aplasia (PRCA) is a rare form of bone marrow suppression in which autoantibodies directed against developing RBC precursors interfere with the production of RBCs [29-31]. Patients typically present with severe anemia and a very low reticulocyte count.

Management is similar to that of individuals without SLE transfusions may be required. Hematologist involvement is suggested if PRCA is suspected. This subject is discussed separately. (See "Acquired pure red cell aplasia in adults".)

Thrombotic microangiopathies (eg, TTP) — Thrombotic microangiopathies (TMAs) present with thrombocytopenia and microangiopathic hemolytic anemia (MAHA), with mechanical shearing of RBCs within the circulation, producing schistocytes on the peripheral blood smear (picture 3). A general approach to evaluation is presented separately. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

TMAs are more common among patients with SLE than in the general population, although they are still rare. Types of TMA include:

●Thrombotic thrombocytopenic purpura (TTP) – Risk factors for TTP in patients with SLE include active SLE flare and lymphocytopenia (absolute lymphocyte count [ALC] <1000/microL) [32-34]. (See "Diagnosis of immune TTP".)

●Catastrophic antiphospholipid syndrome (CAPS) – (See "Catastrophic antiphospholipid syndrome (CAPS)".)

●Drug-induced TMA – (See "Drug-induced thrombotic microangiopathy (DITMA)".)

TMAs are potentially life-threatening conditions that require immediate evaluation and intervention by a hematologist or other specialist with expertise in these disorders to prevent organ damage from microthrombi. The initial assessment is made to determine the most likely pathogenesis, but empiric treatment is often initiated before the results of laboratory testing become available. Features that aid in this decision process are presented separately. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

The diagnosis and management of TMAs in patients with SLE is similar to that in patients without SLE and is outlined in the respective disease topics. When TTP is diagnosed in patients with active SLE, immunosuppressive therapies, such as glucocorticoids and rituximab, are especially important additions to therapeutic plasma exchange. (See "Immune TTP: Initial treatment", section on 'Immunosuppression'.)

Medications used to treat SLE — A number of medications used in SLE may cause anemia by a dose-dependent or dose-independent mechanism. Commonly implicated drugs and their mechanisms include (table 1):

●Nonsteroidal antiinflammatory drugs (NSAIDs) – Gastrointestinal blood loss with iron deficiency, which can be exacerbated by concomitant use of glucocorticoids (see "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity")

●Hydroxychloroquine – Bone marrow suppression, hemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (see "Antimalarial drugs in the treatment of rheumatic disease", section on 'Other')

●Methotrexate – Bone marrow suppression (see "Major adverse effects of low-dose methotrexate", section on 'Myelosuppression')

●Azathioprine – Bone marrow suppression (see "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Bone marrow suppression')

●Mycophenolate – Bone marrow suppression (see "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Bone marrow suppression')

●Cyclosporine and other calcineurin inhibitors (tacrolimus and voclosporin) – Bone marrow suppression or drug-induced TMA (see "Drug-induced thrombotic microangiopathy (DITMA)")

●Cyclophosphamide – Bone marrow suppression (see "Cyclophosphamide in rheumatic diseases: General principles of use and toxicity", section on 'Cytopenias')

●Dapsone (used for cutaneous lupus) – Hemolytic anemia

Additional drugs that cause immune hemolysis are discussed separately. (See "Drug-induced hemolytic anemia".)

Causes unrelated to SLE activity — Patients with SLE may have anemia due to many other causes that unrelated to SLE disease activity or treatment. Causes of anemia in the general population include nutritional deficiencies (eg, iron, vitamin B12, folate), hereditary anemias (eg, thalassemia, sickle cell disease), and certain chronic conditions (eg, chronic kidney disease). Several of these causes are summarized in the table (table 1). Selected causes are briefly discussed below.

Iron deficiency anemia — Iron deficiency anemia is common in SLE, present in approximately one-third of patients [35,36]. It is described in more detail elsewhere and briefly summarized below in the setting of SLE.

●Children – (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Iron deficiency in infants and children <12 years: Treatment".)

●Adolescents – (See "Iron requirements and iron deficiency in adolescents".)

●Adults – (See "Diagnosis of iron deficiency and iron deficiency anemia in adults" and "Treatment of iron deficiency anemia in adults".)

●Causes – Iron deficiency is almost always a reflection of blood loss, even among patients with very low iron intake. Identifying and addressing the source of blood loss is essential in all patients with iron deficiency. Causes of blood loss in patients with SLE are similar to those observed in the general population. Patients with SLE often have multiple risk factors for peptic ulcer disease (eg, NSAIDs, glucocorticoids, and/or Helicobacter pylori infection). Rarely, pulmonary hemorrhage can lead to iron deficiency in SLE and should be considered in patients with respiratory symptoms. (See "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity" and "Major adverse effects of systemic glucocorticoids", section on 'Gastrointestinal effects' and "Pulmonary manifestations of systemic lupus erythematosus in adults", section on 'Pulmonary hemorrhage'.)

●Common findings

•Clinical symptoms – In addition to symptoms caused by anemia, patients with iron deficiency anemia may develop hair loss, headache, restless legs syndrome, and/or pica (desire to eat ice or non-food substances).

•Laboratory testing – The anemia caused by severe iron deficiency is typically microcytic and hypochromic with an inappropriately low reticulocyte count. The serum ferritin is uniformly low. The transferrin saturation (TSAT) is also usually low and the transferrin/total iron binding capacity is high (table 4). However, many patients will initially present with a normochromic, normocytic anemia. In addition, because hepcidin impedes iron absorption from the gastrointestinal tract, inflammation may also contribute to iron deficiency through failure to absorb iron. (See "Diagnosis of iron deficiency and iron deficiency anemia in adults".)

Ferritin is an acute phase reactant and may not accurately reflect iron stores in individuals with SLE (ie, ferritin may be within the reference range despite reduced iron stores) [7,36,37]. However, the ferritin will almost always be <100 ng/mL in iron deficiency, even if inflammation is present. In patients who do not have active inflammation at the time of testing, the ferritin is likely to be an accurate reflection of iron stores. Other testing, such as soluble transferrin receptor (sTfR), may be helpful in selected cases with indeterminant results or discordance between the clinical picture and initial laboratory testing; however, sTfR is not readily available and is rarely needed. (See "Diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Patients with inconclusive initial testing or comorbidities'.)

●Management – Iron deficiency requires treatment, which includes identifying the source of the deficiency and repleting iron stores. Patients with SLE may have concomitant iron deficiency and ACD/AI [7,37]; treatment of iron deficiency may be more challenging in this setting since increased hepcidin levels impede gastrointestinal iron absorption. (See "Diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation' and "Treatment of iron deficiency anemia in adults".)

Vitamin B12 or folate deficiency — Vitamin B12 and folate deficiencies can also occur in patients with SLE. Autoimmune causes of vitamin B12 deficiency may be more common in patients with SLE, although the prevalence is not known. Pernicious anemia is caused by abnormal destruction of parietal cells, leading to malabsorption of vitamin B12. In a case-control study involving 194 patients with SLE and 103 controls, antibodies to gastric parietal cells and endomysium were more common in the individuals with SLE, but these antibodies were not associated with vitamin B12 deficiency in all instances [38]. In addition, celiac disease can lead to malabsorption of folate, vitamin B12, and/or iron and may be more common in patients with SLE [39]. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Pernicious anemia' and "Diagnosis of celiac disease in adults", section on 'Extraintestinal signs/symptoms suggestive of celiac disease'.)

The clinical manifestations, diagnosis, and treatment of vitamin B12 or folate deficiency for patients with SLE is the same as that for those without SLE and is discussed elsewhere. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency" and "Treatment of vitamin B12 and folate deficiencies".)

Indications for blood transfusion — RBC transfusion may be indicated to treat severe anemia and/or certain related symptoms (eg, respiratory distress, hemodynamic compromise). Ideally, laboratory testing to determine the cause of the anemia is obtained prior to transfusion, as the results are best interpreted in the absence of transfused cells; however, transfusion should not be delayed if needed while awaiting laboratory evaluation. (See "Indications and hemoglobin thresholds for RBC transfusion in adults".)

LEUKOPENIA

Prevalence — Reduced white blood cell (WBC) count (leukopenia) is common in systemic lupus erythematosus (SLE) and often correlates with disease activity [8,40]. A WBC count of <4000 cells/microL has been observed in approximately 50 percent of patients with SLE, and approximately 20 percent have a WBC count of <1000 cells/microL [8].

WBC count <4000 cells/microL in the absence of other known causes, is a SLE classification criterion for clinical research and trials in both the 2019 European League against Rheumatism (EULAR)/American College of Rheumatology (ACR) and the 2012 Systemic Lupus International Collaborating Clinics (SLICC) SLE classification systems. It is also an indication of disease activity in measures such as the SLE Disease Activity Index (SLEDAI). (See "Systemic lupus erythematosus in adults: Clinical manifestations and diagnosis", section on 'Classification criteria' and "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Disease activity and damage indices'.)

Symptoms — Patients with mild leukopenia are characteristically asymptomatic. Patient with severe neutropenia may come to clinical attention when they develop infection. Importantly, the signs and symptoms of focal infections may be less obvious in severely leukopenic patients compared with immunocompetent patients. Clinical signs and symptoms that can be found in neutropenia (eg, fever, oral ulcers) are described in detail elsewhere. (See "Overview of neutropenia in children and adolescents" and "Approach to the adult with unexplained neutropenia".)

Lymphocytopenia — A selective reduction in lymphocytes (lymphocytopenia) is defined as an absolute lymphocyte count (ALC) <1500/microL and is common in SLE. Lymphocytopenia may be clinically silent or associated with increased risk of infections and/or active SLE [4]. The approach to evaluating lymphocytopenia is detailed elsewhere and summarized briefly below in the context of SLE. (See "Approach to the child with lymphocytosis or lymphocytopenia", section on 'Lymphocytopenia' and "Approach to the adult with lymphocytosis or lymphocytopenia", section on 'Lymphocytopenia'.)

●Epidemiology and pathogenesis – Lymphocytopenia affects 20 to 75 percent of patients with SLE and is more specific for active disease compared with other types of cytopenias [7,8,14,41,42]. In vitro studies have suggested that lymphocytopenia in SLE may be due to autoantibodies to lymphocytes in some cases [43-45].

Lymphocytopenia is also observed in patients receiving B-cell depleting therapies such as rituximab [46]. (See "Rituximab: Principles of use and adverse effects in rheumatologic disease", section on 'Effects on B cells, antibodies, and risk of infection'.)

●Management – The treatment of lymphocytopenia is mainly directed at treating the SLE. In rare cases with severe lymphocytopenia (eg, frequent viral infections), it may be appropriate to use prophylactic antibiotics against organisms such as Pneumocystis jirovecii, but there is a lack of high-quality data to support this approach [3,47].

Neutropenia — Since most WBCs are neutrophils, leukopenia typically reflects neutropenia, which is characterized by a decrease in the absolute neutrophil count (ANC) (calculator 1) to <1500/microL. Neutropenia may correlate with a risk of serious infections, depending on the cause. In addition to neutropenia, neutrophil dysfunction has been noted in patients with SLE and is thought to be induced by immune abnormalities (eg, immune complexes, inhibition of complement-derived chemotactic factors) and/or medications (eg, cyclophosphamide, mycophenolate) [48-51].

The evaluation of neutropenia in children and adults presented in more detail separately and neutropenia in the setting of SLE is briefly summarized below. (See "Overview of neutropenia in children and adolescents" and "Approach to the adult with unexplained neutropenia".)

●Causes – Causes of neutropenia in SLE may include the following [5,8,40,52]:

•Viral infections

•Medications (eg, immunosuppressive medications)

•Hypersplenism

•Vitamin B12 deficiency

•Autoimmune mechanisms (ie, autoantibodies against WBC antigens)

•Disease activity

Moderate to severe neutropenia (ANC <1000/microL) in patients with SLE may be accompanied by infection (either as a cause or as a consequence of the neutropenia), other cytopenias (eg, anemia, thrombocytopenia), and/or a history of neuropsychiatric involvement from SLE [52].

Baseline neutrophil counts can also be affected by a normal variant in the ACKR1 gene, which is more common in individuals with African, Sephardic or Yemeni Jewish, Greek, Arabic, and/or West Indian ancestry. These individuals tend to have a baseline ANC of <1500/microL and do not have an increased risk of infection; they are not considered to have neutropenia. (See "Approach to the adult with unexplained neutropenia", section on 'Normal variants <1500/microL'.)

●Evaluation – The urgency of evaluation in neutropenic patients with SLE depends on the severity of the clinical presentation and concern for concomitant infection. As examples, severely neutropenic patients (ie, ANC <500/microL) with fever require urgent inpatient evaluation, while those with asymptomatic mild to moderate neutropenia are typically evaluated in the outpatient setting (table 5). (See "Evaluation of children with non-chemotherapy-induced neutropenia and fever" and "Approach to the adult with unexplained neutropenia", section on 'Initial evaluation' and "Overview of neutropenic fever syndromes", section on 'Initial assessment'.)

●Management – Most patients with SLE and mild neutropenia without fever are treated expectantly, as mild neutropenia is common and there are no guidelines for therapy [4].

If neutropenia is severe or worsening and a medication is thought to be responsible, discontinuation (or dose reduction) of the implicated drug is often appropriate. These decisions are individualized based on the risks and benefits of the drug and the severity of neutropenia.

Neutropenia with fever is a medical emergency that requires rapid cultures and antibiotics. (See "Management of the adult with non-chemotherapy-induced neutropenia", section on 'Treatment of infection'.)

Therapies for neutropenia, such as recombinant granulocyte-colony stimulating factor (G-CSF), are generally reserved for severe life-threatening neutropenia (ANC <500/microL) with concomitant infection and are used at the lowest possible dose to maintain an ANC of ≥1000/microL [53,54]. This is due to the reported associations between G-CSF use and SLE flare [6,55,56] and leukocytoclastic vasculitis [54]. (See "Management of the adult with non-chemotherapy-induced neutropenia".)

Patients who have fever and neutropenia often need empiric antibiotics. (See "Management of children with non-chemotherapy-induced neutropenia and fever" and "Overview of neutropenic fever syndromes", section on 'Management'.)

THROMBOCYTOPENIA

Prevalence, causes, and risk factors — Thrombocytopenia (platelet count <150,000/microL) is relatively common in systemic lupus erythematosus (SLE). In a case-control study involving 50 patients with SLE who had thrombocytopenia and 100 controls with SLE and normal platelet counts, thrombocytopenia was associated with greater degrees of organ damage, likely reflecting more active disease [57].

Mild thrombocytopenia (platelet counts between 100,000 and 150,000/microL) has been noted in 25 to 50 percent of patients with SLE at some point in the disease course, usually with disease flares or as an adverse drug effect, while severe thrombocytopenia (platelet counts <50,000/microL) occurs in approximately 10 percent [5,8,14,40]. It is an indication of disease activity in certain disease activity measures, such as the SLE Disease Activity Index (SLEDAI). (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Disease activity and damage indices'.)

Severe thrombocytopenia (platelet count <50,000/microL) in SLE is most often due to immune thrombocytopenia (ITP; due to immune-mediated destruction of platelets). Evans syndrome refers to ITP plus autoimmune hemolysis [11,58]. (See 'Autoimmune hemolytic anemia' above.)

Causes of severe thrombocytopenia in SLE include the following:

●ITP – ITP is the most common cause of severe thrombocytopenia in SLE. ITP in patients with SLE may present prior to the development of SLE, as a chronic complication, or acutely during a disease flare [3]. When ITP precedes the diagnosis of SLE, it may do so by many years. It has been estimated that 3 to 15 percent of patients with apparently isolated ITP will later develop SLE [59]. More information on ITP in adults and children is provided separately. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis" and "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis".)

●Thrombotic microangiopathy (TMA) – TMA may cause thrombocytopenia and hemolytic anemia. It is typically associated with schistocytes on the peripheral blood smear. (See 'Thrombotic microangiopathies (eg, TTP)' above and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

●Drug-induced thrombocytopenia – Drug-induced thrombocytopenia may be immune due to bone marrow suppression. Heparin-induced thrombocytopenia is a potentially life-threatening form of drug-induced thrombocytopenia in which drug-dependent antibodies lead to platelet activation and may cause venous or arterial thromboses. (See "Drug-induced immune thrombocytopenia" and "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)

●Splenomegaly – The thrombocytopenia due to splenomegaly is typically mild to moderate (eg, platelet count between 60,000 and 150,000/microL) and may be accompanied by mild anemia and/or mild leukopenia. (See "Splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)

●Antiphospholipid syndrome (APS) – APS is typically associated with thrombosis (venous or arterial) and/or pregnancy morbidity. Thrombocytopenia may occur due to platelet consumption in thrombi. (See 'Antiphospholipid antibodies and antiphospholipid syndrome' below and "Clinical manifestations of antiphospholipid syndrome", section on 'Hematologic abnormalities'.)

Other causes of thrombocytopenia not specifically related to SLE are reviewed in more detail separately. (See "Causes of thrombocytopenia in children" and "Approach to the child with unexplained thrombocytopenia" and "Diagnostic approach to thrombocytopenia in adults".)

Symptoms — Patients with thrombocytopenia may be asymptomatic or develop bleeding, such as bruising, petechiae, purpura, epistaxis, and more serious bleeding.

Evaluation — The urgency of the evaluation depends on the platelet count, time course over which thrombocytopenia develops, patient's clinical status, and other cytopenias. (See 'Pancytopenia' below.)

All individuals with SLE who develop thrombocytopenia should have a thorough physical examination and an evaluation for potentially reversible causes, including medications and infection. Subsequent evaluation depends on whether the thrombocytopenia is isolated and mild or more severe:

●Not acutely ill with isolated, mild thrombocytopenia – For patients with isolated, mild thrombocytopenia who are not acutely ill, additional testing depends on the history and preliminary laboratory results. Generally it includes sequential or simultaneous testing for vitamin B12 and folate deficiencies, liver disease, coagulation abnormalities, and antiphospholipid antibodies (aPL). There are no specific tests for ITP since antiplatelet antibodies are neither sensitive nor specific; however, antibodies may be useful in suspected drug-induced thrombocytopenia.

●Acutely ill, severe thrombocytopenia, or other cytopenias – For patients who are acutely ill or have new onset of thrombocytopenia plus neutropenia and/or anemia, hematology consultation is recommended. Disorders to be considered include ITP, TMAs, catastrophic antiphospholipid syndrome (CAPS), severe infections, hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS), and severe drug reactions. Testing includes a blood smear for schistocytes or other abnormal cells, coagulation testing, aPL, and testing of kidney and liver function. (See 'Evaluation' above.)

The evaluation of specific causes of thrombocytopenia are discussed in more detail elsewhere:

●(See "Approach to the child with unexplained thrombocytopenia".)

●(See "Diagnostic approach to thrombocytopenia in adults".)

●(See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis".)

●(See "Drug-induced immune thrombocytopenia".)

Initial management — Management of thrombocytopenia is directed treatment of bleeding and of the underlying cause (eg, drug-induced ITP).

●Bleeding – Thrombocytopenia can be associated with petechiae, purpura, and bleeding, which can be severe. Platelet transfusions are given for clinically significant bleeding, to prevent bleeding associated with certain invasive procedures, and/or for very low platelet counts, but clinical features, including other features that increase bleeding risk, must also be taken into account. The absolute platelet count threshold for platelet transfusion to prevent spontaneous bleeding depends on the underlying cause of thrombocytopenia. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Indications for platelet transfusion' and "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Platelet transfusions'.)

The risk of clinically significant bleeding from thrombocytopenia depends on the platelet count and its underlying cause. Bleeding is unlikely with platelet counts above 50,000/microL in the absence of a hemostatic challenge such as surgery or trauma. For counts below 50,000/microL, the correlation between absolute platelet count and bleeding risk is weak.

●Treatment of the underlying cause – The approach to management of thrombocytopenia is based on the underlying cause, which is described in detail in the respective topics; management of ITP in patients with SLE is briefly summarized below.

When patients with SLE develop ITP, the goal is to reduce the risk of bleeding rather than to normalize the platelet count; thus, not all individuals require interventions. Glucocorticoids are typically used as first-line therapy for ITP in those who require treatment. intravenous immune globulin (IVIG) can also be used if there is a need to raise the platelet count more rapidly (eg, for surgery or an invasive procedure).

In cases of mild to moderate thrombocytopenia associated with increased SLE disease activity, control of the flare with immunosuppressants, rather than glucocorticoids, may improve the platelet count. IVIG may be used if a more rapid increase in platelet count is needed. Dosing and monitoring are the same as those used for patients without SLE. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Choice of glucocorticoid and dosing' and "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'IVIG dosing and administration'.)

Other therapies are generally initiated for patients with ITP if glucocorticoids and/or IVIG do not raise the platelet count above 20,000 to 30,000/microL or if there is clinically significant bleeding that does not improve with platelet transfusions. Many aspects of ITP treatment in SLE are the same as for individuals without SLE. An exception is that we are less likely to use splenectomy to treat ITP in the setting of SLE because of concerns that the response may be less durable. However, splenectomy has been demonstrated to be effective in a series of 25 adults with SLE, with an initial response of 88 percent and a long-term response of 64 percent at over six years, which is similar to the efficacy in non-SLE populations [60]. Rituximab is often preferred because it may also treat other manifestations of SLE. (See "Initial treatment of immune thrombocytopenia (ITP) in adults" and "Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults" and "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Approach to drug therapy'.)

PANCYTOPENIA

Causes — Pancytopenia (reduction of red blood cells [RBCs], white blood cells [WBCs], and platelets) may occur in systemic lupus erythematosus (SLE) but is less common than isolated cytopenias. There are many potential causes (eg, SLE complication, infection, malignancy, medications); some can be evaluated as an outpatient, while some require immediate hospitalization and intervention to prevent life-threatening complications.

In a series of patients with SLE who underwent bone marrow evaluation for pancytopenia, a variety of findings were documented, of which some were attributable to specific disorders and some not [61,62]. Hypocellularity and bone marrow necrosis were common, possibly attributable to immune mechanisms in active SLE.

Potentially life-threatening causes of pancytopenia, which are typically associated with severe cytopenias and/or other features of an acute illness, include the following [3]:

●Macrophage activation syndrome (MAS) – MAS is a rare but life-threatening disorder in which immune dysregulation leads to massive activation of macrophages in the bone marrow and other tissues. MAS is a subset of hemophagocytic lymphohistiocytosis (HLH) and is given that designation when it occurs in the setting of a rheumatologic disorder such as SLE. The distinction is important, since MAS usually responds to immunosuppression alone without the need for cytotoxic therapy, as is usually required with other forms of HLH. MAS is typically associated with a flare of SLE and may present with a number of clinical and laboratory abnormalities, including cytopenias, fever, hepatomegaly, lymphadenopathy, neurologic symptoms, rash, very high serum ferritin levels, and liver and coagulation abnormalities. Hemophagocytosis (engulfment of RBCs by macrophages) is often present in the bone marrow (picture 4) and/or other tissues, but it is neither necessary nor sufficient to make the diagnosis of MAS; it is often absent in the early stages of the disease. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Rheumatologic disorders' and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Clinical features'.)

●Infection – Bone marrow toxicity may be caused infection. Sepsis or severe infections may be accompanied by disseminated intravascular coagulation. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Approach to the adult with pancytopenia", section on 'Causes of pancytopenia'.)

●Medications – Medications can also cause bone marrow toxicity. (See "Approach to the adult with pancytopenia", section on 'Suspected medications'.)

●Hematologic malignancy – Hematologic malignancy, such as leukemia or lymphoma, often causes elevated WBC counts and lymphadenopathy/hepatosplenomegaly, but the initial presentation may be with pancytopenia. The presence of lymphoblasts or myeloblasts in the peripheral blood, or higher than normal blast counts in the bone marrow, should prompt immediate hematologist consultation.

Other causes of pancytopenia, typically with mild cytopenias, that may be evaluated in the outpatient setting include the following:

●Multiple autoimmune cytopenias such as Evans syndrome, which refers to autoimmune hemolysis and autoimmune thrombocytopenia. (See 'Autoimmune hemolytic anemia' above and 'Prevalence, causes, and risk factors' above.)

●Autoimmune myelofibrosis has been reported in a small number of patients with SLE [3]. Bone marrow findings may be difficult to distinguish from primary myelofibrosis, a myeloproliferative neoplasm (MPN), and additional testing for MPN-associated mutations may be warranted (see "Clinical manifestations and diagnosis of primary myelofibrosis"). Autoimmune myelofibrosis is reported to respond to glucocorticoids.

●Splenomegaly with hypersplenism and pooling of blood and blood cells in the spleen may be a consequence of liver disease or splenomegaly from another cause. (See "Hemostatic abnormalities in patients with liver disease" and "Splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)

●Other disorders that occur in the general population, such as vitamin B12 or folate deficiency, myelodysplastic syndrome, and infiltrative tumors. (See "Approach to the adult with pancytopenia", section on 'Causes of pancytopenia'.)

Evaluation — The urgency of evaluation depends on the presence of severe cytopenias (eg, absolute neutrophil count [ANC] <500/microL, hemoglobin ≤7g/dL, platelets <50,000/microL) and/or associated complications (eg, fever, bleeding). If these concerning features are present, the patient should be hospitalized for evaluation and treatment. The approach to evaluation of pancytopenia is discussed in detail separately. (See "Approach to the adult with pancytopenia".)

Initial management — Treatment of pancytopenia is highly dependent on the underlying etiology and is discussed in the appropriate treatment topics.

If the cause of pancytopenia is not obvious and the bone marrow is unavailable or uninterpretable, it may be appropriate to treat with glucocorticoids for presumptive autoimmune cytopenias, SLE flare, and/or MAS. Attempts should be made to obtain a hematologist evaluation prior to giving glucocorticoids if possible. Empiric treatment with glucocorticoids may cause transient improvement even when the cause of pancytopenia is a serious condition, such lymphoma or HLH/MAS.

Management of MAS in SLE often requires aggressive treatment with high-dose glucocorticoids (eg, intravenous methylprednisolone 1000 mg daily for three days) and institution of immunosuppressant medications, such as mycophenolate mofetil or cyclophosphamide. As an example, in a series of 12 patients with SLE admitted to the hospital with 15 episodes HLH/MAS, 12 had a response to glucocorticoids alone and two required cyclophosphamide [63]. More information on the treatment of HLH/MAS is presented separately. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

THROMBOTIC AND BLEEDING COMPLICATIONS

Antiphospholipid antibodies and antiphospholipid syndrome — Antiphospholipid antibodies (aPL) are present in approximately 30 to 40 percent of patients with systemic lupus erythematosus (SLE) [64,65]. Testing for aPL is routinely done as part of the evaluation for SLE. (See "Systemic lupus erythematosus in adults: Clinical manifestations and diagnosis", section on 'Evaluation'.)

Patients with SLE and aPL have an elevated risk of developing thrombocytopenia and autoimmune hemolytic anemia (AIHA) [13]. They may also develop antiphospholipid syndrome (APS), which is characterized by arterial and venous thromboses and a range of other manifestations.

Hematologic abnormalities in APS may include AIHA and/or moderate thrombocytopenia.

Patients with concern for a venous or arterial thromboemboli require immediate evaluation in the urgent care or hospital setting. The clinical manifestations, diagnosis, and treatment of APS and catastrophic APS (CAPS) are discussed in detail separately. (See "Clinical manifestations of antiphospholipid syndrome" and "Antiphospholipid syndrome: Diagnosis" and "Antiphospholipid syndrome: Management" and "Catastrophic antiphospholipid syndrome (CAPS)".)

Other autoantibodies — Other autoantibodies can also be seen, in some cases leading to clinically significant bleeding disorders. As an example, autoantibodies directed against clotting proteins such as factor VIII may lead to acquired hemophilia A. (See "Acquired hemophilia A (and other acquired coagulation factor inhibitors)".)

LYMPHADENOPATHY

●Causes – Enlargement of one or more lymph nodes occurs in approximately 50 percent of patients with systemic lupus erythematosus (SLE). The nodes are typically soft, nontender, discrete, varying in size from 0.5 to several centimeters, and usually detected in the cervical, axillary, and inguinal areas. Lymphadenopathy is more frequently noted at the onset of disease or in association with an exacerbation. In lymphadenopathy due to SLE, biopsies are not required but, if done, reveal areas of follicular hyperplasia and necrosis; the appearance of hematoxylin bodies (ie, collections of dense, basophilic material that contain immunoglobulins and nuclear deoxyribonucleic acid [DNA]) is highly suggestive of SLE, although this finding is unusual [14,66].

Other causes of lymphadenopathy in individuals with SLE include:

•Infection – Many patients with SLE are immunocompromised and more vulnerable to infections. Depending on the type of infection, lymphadenopathy may be localized (eg, viral upper respiratory tract infection) or generalized (eg, infectious mononucleosis). Lymphadenopathy from an infection is often tender. (See "Evaluation of peripheral lymphadenopathy in adults", section on 'Etiologies'.)

•Lymphoproliferative disease – The risk of lymphoproliferative disorders is higher in patients with SLE than in the general population. Cohort and case-control studies have demonstrated risks of non-Hodgkin lymphoma to be approximately three- to fourfold greater in SLE compared with the general population [67-69]. The risk of Hodgkin lymphoma may also be increased [69]. It is not clear whether immunosuppressive therapy increases this risk or is merely a marker of more active disease. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Prognosis'.)

Very rarely, prominent lymphadenopathy may be a manifestation of angioimmunoblastic T-cell lymphoma. This lymphoma has overlapping features with SLE including arthritis, autoimmune hemolytic anemia, rash, and fever. (See "T follicular helper cell lymphoma, angioimmunoblastic type (angioimmunoblastic T cell lymphoma): Clinical manifestations, pathologic features, and diagnosis".)

●Evaluation – There are no specific tests to distinguish between a lymphoid malignancy and reactive lymphadenopathy due to infection or SLE disease flare, but flow cytometry and lymph node biopsy can determine clonality. More information on the diagnostic approach to peripheral lymphadenopathy is described separately but may include the following elements (see "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach" and "Evaluation of peripheral lymphadenopathy in adults"):

•Complete blood count (CBC) with differential – We obtain a CBC with differential for all patients with SLE who have unexplained lymphadenopathy. Increased numbers of lymphocytes in the peripheral blood (mature or immature) suggest a lymphoid malignancy, but atypical lymphocytes may be present in viral infections. Increased neutrophils are more consistent with infection.

•Peripheral blood flow cytometry – In cases in which the cause of lymphadenopathy is not clear and/or lymphoma is suspected, flow cytometry on peripheral blood may be helpful. When lymphoma is associated with diffuse lymphadenopathy, flow cytometry often detects the presence of a monoclonal population of lymphocytes.

•Lymph node biopsy – A lymph node biopsy is warranted when the degree of lymphadenopathy is out of proportion to disease activity, when lymph node size increases despite therapy for SLE, and/or if there are any other concerning features (eg, vascular compromise).

●Treatment – Most lymphadenopathy related to disease activity in SLE resolves rapidly with immunosuppressive therapy. As an example, the size of lymph nodes may quickly decrease with the addition of low to moderate doses of glucocorticoids (eg, prednisone, 20 to 40 mg). However, it is important to establish a diagnosis prior to initiating therapy, as empiric use of glucocorticoids may interfere with further diagnostic testing. We only give glucocorticoids if the risk of infection and/or lymphoproliferative disease is low (eg, stable patient who is not acutely ill with no concerning features on diagnostic testing).

SPLENOMEGALY — 

Splenic enlargement occurs in 10 to 46 percent of patients with systemic lupus erythematosus (SLE), particularly during active disease. The mechanism is not well understood. Splenomegaly is not necessarily associated with cytopenias, although often mild cytopenias may be seen due to splenic pooling of blood cells. Biopsy is usually not performed, but if done it may show an onion skin appearance of the splenic arteries, a lesion that is thought to represent healed vasculitis. (See "Approach to the child with an enlarged spleen" and "Splenomegaly and other splenic disorders in adults".)

The evaluation of splenomegaly in patients with SLE is similar to that in patients without SLE, including a comprehensive history, examination for adenopathy and hepatomegaly, complete blood count (CBC), liver function testing, and, in some cases, imaging. (See "Approach to the child with an enlarged spleen" and "Splenomegaly and other splenic disorders in adults".)

LEUKOCYTOSIS — 

Increased white blood cells (WBCs) count can occur for a number of reasons in systemic lupus erythematosus (SLE), usually due to an infection or to high doses of glucocorticoids [70]. The most likely diagnoses and evaluation depends on the predominant type of WBC that is elevated:

●Neutrophilia – Neutrophilia, also known as neutrophilic leukocytosis, can be seen with high-dose glucocorticoids, infection (especially bacterial), and, less commonly, SLE flare. A shift of granulocytes to more immature forms ("left" shift) suggests infection more than SLE activity. In an individual receiving glucocorticoids, the neutrophil count typically normalizes with discontinuation. Patients with SLE may also develop neutrophilia from conditions that are unrelated to SLE, which are discussed separately. (See "Approach to the patient with neutrophilia", section on 'Causes of neutrophilia'.)

Evaluation of neutrophilia in patients with SLE is similar to that of patients without SLE and is discussed in detail elsewhere. (See "Approach to the patient with neutrophilia".)

●Lymphocytosis – Lymphocytosis is sometimes seen in response to infections, especially viruses. It may suggest a lymphoid malignancy, especially when accompanied by lymphadenopathy and/or splenomegaly.

Evaluation of unexplained lymphocytosis in patients with SLE is similar to that in patients without SLE and is described in detail elsewhere. (See "Approach to the child with lymphocytosis or lymphocytopenia", section on 'Evaluation of the child with lymphocytosis' and "Approach to the adult with lymphocytosis or lymphocytopenia", section on 'Evaluation'.)

THROMBOCYTOSIS — 

A platelet count ≥400,000/microL may occur with inflammation, infection, iron deficiency, and/or acute blood loss (eg, from gastrointestinal bleeding) [3].

Another possible cause of thrombocytosis in systemic lupus erythematosus (SLE) patients is hyposplenism (or autosplenectomy), which may be mediated by antiphospholipid antibodies (aPL). In a cohort of 465 patients with SLE, 17 (3.7 percent) were found to have a platelet ≥400,000/microL [71]. For three of these patients, the peripheral blood smear showed one or more features of absent splenic function (eg Howell-Jolly bodies) and imaging failed to demonstrate a spleen. All three patients had aPL. (See 'Antiphospholipid antibodies and antiphospholipid syndrome' above.)

The evaluation of persistent thrombocytosis (platelet count >450,000/microL on two separate tests) is presented in detail elsewhere. (See "Approach to the patient with thrombocytosis".)

Treatment is not required for reactive thrombocytosis due to loss of splenic function. However, if thrombocytosis is related to a myeloproliferative neoplasm (MPN), therapy to reduce the platelet count and/or prevent thromboembolic complications may be required. (See "Essential thrombocythemia: Clinical manifestations and diagnosis".)

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

SUMMARY AND RECOMMENDATIONS

●When to admit or refer – Outpatient evaluation is appropriate for patients with systemic lupus erythematosus (SLE) who have mild hematologic abnormalities that cause mild to no symptoms. Hematology input, with expedited evaluation or hospital admission, is required for acutely ill patients with a severe cytopenia and/or pancytopenia, suspected thrombotic microangiopathy (TMA), venous or arterial thrombosis, or macrophage activation syndrome [MAS]). (See 'When to evaluate urgently/admit to hospital' above and 'When to refer to hematology' above.)

●Anemia – Anemia affects more than half of individuals with SLE and may be multifactorial (table 1). (See 'Anemia' above.)

•Evaluation – Should include a thorough history and physical examination, review of medications, and laboratory testing. (See 'Evaluation' above.)

•Management – Management depends on the underlying cause. Red blood cell (RBC) transfusion may be indicated to treat severe anemia, respiratory distress, and/or hemodynamic compromise. (See 'Indications for blood transfusion' above and 'Causes associated with active SLE' above and 'Medications used to treat SLE' above and 'Causes unrelated to SLE activity' above.)

●Leukopenia – Leukopenia is an indicator of disease activity and can also be drug-induced. (See 'Leukopenia' above.)

•Lymphocytopenia – Lymphocytopenia is a common feature of SLE and can be autoimmune or more rarely related to medication toxicity. Lymphocytopenia is often clinically silent or may be associated with active SLE. Treatment is rarely needed but may involve increasing or decreasing SLE therapy. (See 'Lymphocytopenia' above.)

•Neutropenia – Potential causes include immunosuppressive medications, hypersplenism, or viral infection. Mild neutropenia is treated expectantly. Severe or worsening neutropenia and/or neutropenia with fever may require drug discontinuation (or dose reduction) and/or treatment with antibiotics. (See 'Neutropenia' above.)

●Thrombocytopenia – Platelet count 100,000 to 150,000/microL is common. SLE-related immune thrombocytopenia (ITP) is often the cause of thrombocytopenia but is a diagnosis of exclusion. Other causes may include medications, splenomegaly, thrombotic thrombocytopenic purpura (TTP), antiphospholipid syndrome (APS), or catastrophic APS (CAPS), as above. (See 'Thrombocytopenia' above.)

•Evaluation – All patients require a history, examination, and review of the complete blood count (CBC). Vitamin B12 and folate levels, liver function testing, and/or coagulation testing are performed as appropriate. (See 'Evaluation' above.)

•Management – Platelet transfusions are often given for clinically significant bleeding, to prevent bleeding associated with certain invasive procedures (platelet count threshold may be procedure-dependent), and/or for very low platelet counts. Additional therapy depends on the cause. (See 'Initial management' above.)

●Pancytopenia – Reduced RBCs, white blood cells (WBCs), and platelets is less common than individual cytopenias but may occur. Some causes require hospitalization and intervention to prevent life-threatening complications, especially if there are severe cytopenias, fever, or bleeding. (See 'Pancytopenia' above.)

●Antiphospholipid antibodies (aPL) – aPL are detected in approximately 30 to 40 percent of patients with SLE. The diagnosis of APS requires persistent aPL positivity plus thrombosis or pregnancy morbidity. (See 'Antiphospholipid antibodies and antiphospholipid syndrome' above and "Antiphospholipid syndrome: Diagnosis".)

●Lymphadenopathy – Lymphadenopathy affects approximately half of patients with SLE and is more frequently noted at disease onset or exacerbation. Evaluation focuses on distinguishing lymphoid malignancy from reactive lymphadenopathy due to infection or SLE flare. (See 'Lymphadenopathy' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Peter H Schur, MD, who contributed to earlier versions of this topic review.