INTRODUCTION — Hematologic abnormalities are common in systemic lupus erythematosus (SLE), both at the time of diagnosis and throughout the course of the disease. The major hematologic manifestations of SLE include anemia, leukopenia, thrombocytopenia, lymphadenopathy, and/or splenomegaly. These abnormalities may be a manifestation of SLE, related to another concomitant disease, and/or caused by an SLE treatment. 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.
This topic review will provide 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. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Overview of the management and prognosis of systemic lupus erythematosus in adults" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)
Anemia — Anemia is the most common hematologic abnormality in patients with systemic lupus erythematosus (SLE) and affects more than half of all patients [1-4].
Causes of anemia — Multiple mechanisms may contribute to the development of anemia in patients with SLE [1,2,5-11]:
●Nutritional Deficiency – Iron deficiency (eg, from gastrointestinal blood loss), vitamin B12 deficiency (malabsorption), folate deficiency (malnutrition or malabsorption)
●Autoimmune hemolysis (hemolytic anemia) or autoimmune destruction of hematopoietic cells in the bone marrow
●Impaired kidney function
●Acquired aplastic anemia with an autoimmune pathogenesis
●Hereditary hemolytic anemias such as thalassemia or sickle cell disease
These causes and their features in the setting of SLE are discussed in the sections below. These causes of anemia are not mutually exclusive (eg, a patient can have both chronic inflammation and iron deficiency, especially a menstruating female).
Other causes of anemia not specific to SLE that may be present (eg, nutritional deficiencies, inherited disorders, anemia of renal insufficiency) are discussed in more detail separately. (See "Diagnostic approach to anemia in adults".)
Anemia of chronic disease/anemia of inflammation — 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 . ACD/AI results from interleukin (IL)-6-mediated upregulation of the iron regulatory protein hepcidin, which disrupts iron trafficking and impedes iron incorporation into developing red blood cells (RBCs).
The anemia is typically mild, normocytic, and normochromic; the reticulocyte count is low; and iron stores are adequate. However, other than iron studies to determine whether iron stores are adequate, there are no specific laboratory tests for ACD/AI; it is a diagnosis of exclusion. Additional details of the evaluation for suspected ACD/AI and the pathologic mechanisms involved are presented separately. (See "Anemia of chronic disease/anemia of inflammation".)
In the absence of either symptoms attributable to anemia (eg, dyspnea on exertion, easy fatigability) or impaired kidney function, ACD/AI does not require specific treatment other than treatment of the underlying condition (ie, treatment of SLE). However, patients with symptoms due to anemia may require treatment with an erythropoiesis-stimulating agent (ESA). There are no clinical trials evaluating the use of ESAs in SLE patients, and ACD/AI is usually treated in a manner similar to adults without SLE (ie, by treating the underlying cause[s]) . (See "Anemia of chronic disease/anemia of inflammation", section on 'Management'.)
Iron deficiency anemia — Iron deficiency anemia is common in SLE, present in approximately one-third of patients [11,13]. Iron deficiency is usually caused by blood loss (eg, due to menorrhagia or gastrointestinal bleeding), and identifying and addressing the source of blood loss is an essential component of therapy.
The anemia of severe iron deficiency anemia is typically microcytic and hypochromic with an inappropriately low reticulocyte count; the serum ferritin and/or transferrin saturation (TSAT) are low; and the transferrin/total iron binding capacity is high (algorithm 1). However, many patients will initially present with a normochromic, normocytic anemia. In addition, because hepcidin impedes iron absorption from the gastrointestinal tract, prolonged ACD/AI may also contribute to iron deficiency through failure to absorb iron.
There are two important caveats about iron deficiency anemia in individuals with SLE [6,14]:
●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) . However, the ferritin will usually 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, but sTfR is not readily available and is rarely needed. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Patients with inconclusive initial testing or comorbidities'.)
●Patients may have concomitant iron deficiency and ACD/AI in SLE due to combined blood loss and chronic inflammation. Increased hepcidin levels in ACD/AI impede gastrointestinal iron absorption, predisposing to concomitant iron deficiency. Treatment of iron deficiency may be more challenging with concomitant ACD/AI because inflammation reduces absorption of oral iron; intravenous iron is often used. Specialist input may be required in challenging cases to assist with diagnosis and/or therapy. (See "Treatment of iron deficiency anemia in adults", section on 'Patient populations' and "Anemia of chronic disease/anemia of inflammation", section on 'Management'.)
Causes of blood loss may be similar to those observed in the general population. It is not known whether SLE confers an increased risk of peptic ulcer disease in addition to that of known risk factors (eg, nonsteroidal antiinflammatory drugs [NSAIDs], glucocorticoids, and/or Helicobacter pylori infection). Coadministration of glucocorticoids may exacerbate NSAID-induced peptic ulceration. Management of peptic ulcer disease and other sources of gastrointestinal blood loss is the same as that for patients without SLE. (See "Nonselective NSAIDs: Overview of adverse effects" and "Major side effects of systemic glucocorticoids", section on 'Gastrointestinal effects' and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)
Rarely, pulmonary hemorrhage can lead to iron deficiency in SLE. (See "Pulmonary manifestations of systemic lupus erythematosus in adults", section on 'Pulmonary hemorrhage'.)
Iron deficiency requires treatment, which includes identifying the source of bleeding and repleting iron stores. Iron may be administered orally or intravenously, as discussed separately. (See "Treatment of iron deficiency anemia in adults", section on 'Iron replacement products'.)
Megaloblastic anemia — Folate or vitamin B12 deficiency are relatively common in the general population and can also occur in patients with SLE. Malabsorption of vitamin B12 can be caused by autoimmune destruction of parietal cells (pernicious anemia) (see 'Pernicious anemia' below). In addition, malabsorption of folate, vitamin B12, and/or iron can all occur in the setting of celiac disease, another autoimmune disease. There is some evidence that celiac disease is more common in patients with SLE .
Medications — A number of medications used in SLE may cause anemia by a dose-dependent or an idiosyncratic (dose-independent) mechanism. Commonly implicated drugs and their mechanisms include the following:
●Cyclophosphamide – Bone marrow suppression
●Hydroxychloroquine – Bone marrow suppression, hemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency
●Mycophenolate – Bone marrow suppression
●NSAIDs – Gastrointestinal blood loss with iron deficiency, which can be exacerbated by concomitant use of glucocorticoids
●Azathioprine – Bone marrow suppression
Additional drugs implicated in causing immune hemolysis are discussed separately. (See "Drug-induced hemolytic anemia".)
Autoimmune destruction — Autoimmune destruction can affect mature RBCs, causing autoimmune hemolysis, or developing red cell precursors in the bone marrow, causing aplasia.
Autoimmune hemolytic anemia — The presentation of autoimmune hemolysis in SLE is the same as for those without SLE. Hemolysis causes an increased reticulocyte count, increased indirect bilirubin and lactate dehydrogenase (LDH), low haptoglobin, and positive direct antiglobulin (Coombs) test; spherocytes may be seen on the peripheral blood smear. Anemia is often present, but the hemoglobin may be normal if there is sufficient reticulocytosis to compensate for hemolysis. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Evaluation and diagnosis'.)
●Epidemiology and risk factors – Autoimmune hemolytic anemia has been reported in up to 10 percent of SLE patients [1,6-8,16].
Autoimmune hemolysis may be associated with other features of SLE, including kidney disease, neurologic disease (with seizures), serositis, and/or antiphospholipid antibodies [3,16]. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)
In a study of 1349 patients with SLE, the median time from the onset of SLE to the development of severe autoimmune hemolytic anemia (hemoglobin ≤ 7g/dL) was 111 days . Male sex was associated with a faster progression to severe autoimmune hemolytic anemia (hazard ratio [HR] 2.26).
●Classification – Autoantibodies to RBCs in SLE may be warm- or cold-reactive, leading to warm autoimmune hemolysis or cold agglutinin disease (see "Cold agglutinin disease", section on 'Diagnostic evaluation'). As in the general population, warm autoimmune hemolysis is more common than cold agglutinin disease among SLE patients.
●Associations – Autoimmune hemolysis may be a presenting feature of SLE; other features of SLE may not emerge for several years . Evans syndrome (ie, autoimmune hemolysis and immune thrombocytopenia) associated with SLE is rare and often precedes the onset of SLE [3,19]. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Evans syndrome'.)
Some individuals may have an autoantibody to RBCs that does not cause hemolysis. Thus, the presence of a positive direct antiglobulin test (direct Coombs test) 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 [5-8]. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Evaluation and diagnosis'.)
●Treatment – We typically use a high-dose glucocorticoid (eg, prednisone, 1 to 1.5 mg per kg daily), with the dose tapered once a sustained response is achieved [20,21]. For patients whose anemia is unresponsive to glucocorticoids, we suggest rituximab, which can treat other manifestations of SLE and may allow the patient to avoid splenectomy. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Rituximab' and "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Initial management'.)
Other immunosuppressive therapies such as the anti-CD20 monoclonal antibody ofatumumab, mycophenolate, cyclosporine, danazol, splenectomy, or intravenous immune globulin (IVIG) have also been used [3,21-33].
●We involve a hematologist if autoimmune hemolytic anemia is suspected. These approaches and the decision regarding which therapy to use are discussed separately. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Initial 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 (or against erythropoietin) interfere with the production of RBCs [9,10,34]. Patients typically present with severe anemia and a very low reticulocyte count.
Management is similar to that of individuals without SLE, typically with glucocorticoids, plus cyclophosphamide or cyclosporine if an autoimmune cause is considered likely [10,35]. Transfusions may be required. Hematologist involvement is suggested if PRCA is suspected. This subject is discussed in more detail separately. (See "Acquired pure red cell aplasia in adults".)
Microangiopathic hemolytic anemia — Microangiopathic hemolytic anemia (MAHA) refers to anemia with mechanical shearing of RBCs within the circulation, producing schistocytes on the peripheral blood smear (picture 1). This finding raises the possibility of a thrombotic microangiopathy, in which platelet microthrombi in small vessels are responsible for causing MAHA. These disorders are potentially life-threatening conditions that require immediate evaluation and intervention by a hematologist or other specialist with expertise in thrombotic microangiopathies to prevent organ damage from microthrombi.
Immediate specialist involvement should be sought if any of the following conditions is suspected:
●Thrombotic thrombocytopenic purpura (TTP) – (See "Diagnosis of immune TTP".)
●Drug-induced thrombotic microangiopathy (DITMA) – (See "Drug-induced thrombotic microangiopathy (DITMA)".)
●Disseminated intravascular coagulation (DIC) – (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)
●Catastrophic antiphospholipid syndrome (CAPS) – (See "Catastrophic antiphospholipid syndrome (CAPS)".)
Appropriate testing and interventions listed above (which are typically initiated before a specific diagnosis is confirmed) are similar to those for individuals without SLE and are discussed in more detail separately. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
Pernicious anemia — Pernicious anemia (vitamin B12 deficiency due to autoantibodies to gastric parietal cells or intrinsic factor) is a rare cause of anemia in individuals with SLE. The possibility of vitamin B12 deficiency should be evaluated when a patient develops macrocytic anemia, especially if accompanied by hypersegmented neutrophils. Other mild cytopenias may also be present. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)
The prevalence of vitamin B12 deficiency or pernicious anemia in SLE is unknown. 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 .
Evaluation of anemia — The evaluation of anemia in individuals with SLE should include the identification of potentially reversible causes, particularly bleeding. The urgency of the evaluation for anemia depends on its severity and acuity of development, the patient's clinical status, and the presence or absence of other cytopenias. The possibility of multifactorial anemia should be kept in mind.
●Isolated anemia, not acutely ill – For SLE patients with isolated anemia who are not acutely ill, the most common causes of anemia include anemia of chronic disease/anemia of inflammation, iron deficiency, and autoimmune hemolysis. The evaluation includes a thorough history for medications and concomitant conditions that may be associated with anemia, as well as laboratory testing that typically includes a complete blood count (CBC), reticulocyte count, and RBC indices.
Additional testing may be done sequentially or simultaneously for hemolysis, iron deficiency, kidney disease, and/or vitamin B12 and folate deficiencies as appropriate, depending on the history and preliminary laboratory results. Individuals with hemolysis may have an inappropriately low reticulocyte count if they have concomitant impairment of bone marrow function; deficiency of iron, vitamin B12, or folic acid; or anemia of chronic disease/anemia of inflammation. In such cases, other testing for hemolysis, including haptoglobin, lactate dehydrogenase, and indirect bilirubin, may be helpful. This evaluation is discussed in more detail separately. When anemia is severe, checking an erythropoietin level is recommended to make sure that erythropoietin response is appropriate. (See "Approach to the child with anemia" and "Diagnostic approach to anemia in adults".)
●Acutely ill, other cytopenias – Disorders to be considered in individuals who are acutely ill and/or have other cytopenias include megaloblastic anemia due to deficiency of vitamin B12 or folate deficiency or treatment with cytotoxic medications, a thrombotic microangiopathy, CAPS, severe infections, hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), and severe drug reactions. The patient should have a thorough history and physical examination; review of medications; and testing for hemolysis, coagulation abnormalities, renal and hepatic function, and other specific disorders as indicated from the initial evaluation. Hematology consultation is recommended.
Additional diagnostic testing for these disorders is presented separately. (See "Approach to the adult with pancytopenia" and "Catastrophic antiphospholipid syndrome (CAPS)" and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)
Management of anemia is directed to the underlying cause(s). (See 'Causes of anemia' above.)
If anemia is severe and/or symptomatic, RBC transfusion should be administered. 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, but transfusion should not be delayed if needed while awaiting the results of the laboratory evaluation. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult".)
Leukopenia — Reduced white blood cell (WBC) count (leukopenia) is common in SLE and often correlates with disease activity [7,37]. A WBC count of <4000 cells/microL has been observed in approximately 50 percent of patients with SLE, but only approximately 20 percent will have a WBC count of <1000 cells/microL .
Both the American College of Rheumatology (ACR) and the Systemic Lupus International Collaborating Clinics (SLICC) include leukopenia as classification criteria and define it as a WBC count of less than 4000 cells/microL in the absence of other known causes. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Classification criteria'.)
Since most WBCs are neutrophils, leukopenia typically reflects neutropenia, although it is also possible to have a selective reduction in lymphocytes (lymphocytopenia). (See "Approach to the adult with lymphocytosis or lymphocytopenia", section on 'Lymphocytopenia'.)
Neutropenia — Neutropenia is characterized by a decrease in the absolute neutrophil count (ANC) (calculator 1), which may correlate with a risk of serious infections, depending on the cause.
Causes of neutropenia in SLE may include the following [7,8,37,38]:
●Medications (eg, immunosuppressive medications)
●Vitamin B12 deficiency
Moderate to severe neutropenia (ANC <1000/microL) may be accompanied by infection (either as a cause or as a consequence of the neutropenia), other cytopenias (eg, anemia, thrombocytopenia), or a history of neuropsychiatric involvement . Neutrophil dysfunction has also been noted and is thought to be induced by immune abnormalities (eg, immune complexes, inhibition of complement-derived chemotactic factors) and/or medications (eg, cyclophosphamide, mycophenolate) [39-42]. An approach to the evaluation of neutropenia is presented in more detail separately. (See "Overview of neutropenia in children and adolescents" and "Approach to the adult with unexplained neutropenia".)
Some individuals have an ANC <1500/microL due to a normal variant in the ACKR1 gene, which encodes the Duffy antigen on RBCs. This is a normal variant with a different normal reference range, referred to as Duffy-null associated neutrophil count (DANC; previously called constitutional neutropenia or benign ethnic neutropenia). It should not be termed "neutropenia" as it is normal and is not associated with increased risk of infection. This is most commonly seen in individuals of African descent, Sephardic Jews, Yemenites, Greeks, Arabs, and West Indians. (See "Approach to the adult with unexplained neutropenia", section on 'Normal variants <1500/microL' and "Laboratory test reference ranges in adults", section on 'ANC (absolute neutrophil count)'.)
As neutropenia is common and usually mild, there are no guidelines for therapy, and expectant management is the rule . Therapies for neutropenia, such as myeloid growth factors, are generally reserved for severe life-threatening neutropenia (ANC <500/microL) and concomitant infection because of the potential risk of disease flare associated with the use of recombinant granulocyte-colony stimulating factor (G-CSF) in patients with SLE [12,43]. This possible risk was illustrated in a study involving nine patients with SLE who had neutropenia and refractory infections, in which treatment with G-CSF was associated with a disease flare in three (although this does not demonstrate causality) . Leukocytoclastic vasculitis has also developed in some patients; thus, the minimum dose of G-CSF should be used in order to maintain the peripheral neutrophil count ≥1000/microL [45,46]. (See "Management of the adult with non-chemotherapy-induced neutropenia".)
If neutropenia is severe or worsening and a medication is thought to be responsible, discontinuation (or dose reduction) of the implicated drug may be appropriate. These decisions are individualized based on the risks and benefits of the drug and the severity of neutropenia.
Lymphocytopenia — Lymphocytopenia (absolute lymphocyte count <1500/microL), especially involving regulatory T cells, has been observed in 20 to 75 percent of patients with SLE, particularly during active disease [5-7,47,48]. In vitro studies have suggested that lymphocytopenia may be due to autoantibodies to lymphocytes in some cases [49-51]. Autoantibodies against galectin-8 have also been correlated with lymphocytopenia . (See "Approach to the adult with lymphocytosis or lymphocytopenia", section on 'Lymphocytopenia'.)
Lymphopenia may be clinically silent or associated with increased risk of infections and/or active SLE .
The treatment of lymphocytopenia is mainly directed at treating the SLE. In rare cases with severe lymphocytopenia, 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 [3,53].
Causes of thrombocytopenia — Mild thrombocytopenia (platelet counts between 100,000 and 150,000/microL) has been noted in 25 to 50 percent of patients with SLE; platelet counts <50,000/microL occur in approximately 10 percent of SLE patients [5,7,8,37]. The most common cause of severe thrombocytopenia in SLE is ITP, in which the platelet count is reduced due to immune-mediated destruction of platelets and megakaryocytes. As noted above, this may occur in combination with autoimmune hemolysis. Evans syndrome refers to combined autoimmune hemolysis and ITP. (See 'Autoimmune hemolytic anemia' above.)
ITP may present prior to the development of SLE, as a chronic complication, or acutely during a disease flare . 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 go on to develop SLE . Severe bleeding from thrombocytopenia is only experienced by a minority of patients. 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 . The major mechanism implicated in immune SLE thrombocytopenia is immunoglobulin binding to platelets followed by phagocytosis in the spleen . Membrane glycoproteins (GP) are most often the target of such antibodies (eg, GP IIb/IIIa), but anti-human leukocyte antigen (anti-HLA) specificity also occurs [3,57]. There are no specific tests for ITP; the diagnosis is made clinically after excluding other causes of thrombocytopenia. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis" and "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis".)
Other causes of thrombocytopenia in SLE patients that should also be considered but are less common than ITP include the following:
●Drug-induced thrombocytopenia, which may be immune or nonimmune (eg, due to bone marrow suppression) (table 1). Heparin-induced thrombocytopenia is a 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'.)
●Platelet consumption in the setting of a thrombotic microangiopathic process. In this setting, thrombocytopenia is typically associated with microangiopathic hemolysis with schistocytes on the peripheral blood smear. (See 'Microangiopathic hemolytic anemia' above.)
●Platelet consumption in the setting of antiphospholipid syndrome (APS). APS is typically associated with thrombosis (venous or arterial) and/or pregnancy morbidity. (See 'Antiphospholipid antibodies and APS' below and "Clinical manifestations of antiphospholipid syndrome", section on 'Hematologic abnormalities'.)
These conditions and other causes of thrombocytopenia not specifically related to SLE are reviewed in more detail separately. (See "Approach to the child with unexplained thrombocytopenia" and "Diagnostic approach to thrombocytopenia in adults".)
Evaluation and initial management of thrombocytopenia — All individuals with SLE who develop thrombocytopenia should have an evaluation for potentially reversible causes. The urgency of the evaluation depends on the time course over which thrombocytopenia develops, the patient's clinical status, and the presence or absence of other cytopenias. (See 'Pancytopenia' below.)
●Isolated, mild thrombocytopenia – For patients with isolated, mild thrombocytopenia who are not acutely ill, the evaluation includes a thorough history for medications and other illnesses that may affect the platelet count, as well as review of the CBC. Additional testing may be done sequentially or simultaneously for vitamin B12 and folate deficiencies, liver disease, and coagulation abnormalities, especially antiphospholipid antibodies, as appropriate, based on the history and preliminary laboratory results. As noted above, ITP is a diagnosis of exclusion. Antiplatelet antibodies are not used to diagnose ITP, because they are neither sensitive nor specific. However, antibodies may be very useful in suspected drug-induced thrombocytopenia. This evaluation is discussed in more detail separately. (See "Approach to the child with unexplained thrombocytopenia" and "Diagnostic approach to thrombocytopenia in adults" and "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis" and "Drug-induced immune thrombocytopenia".)
●Acutely ill, severe thrombocytopenia, or other cytopenias – For patients who are acutely ill or have new onset of thrombocytopenia plus other cytopenias (eg, neutropenia, anemia), hematology consultation is recommended. The patient should have a thorough history and physical examination; review of medications; review of the blood smear for schistocytes or other abnormal cells, coagulation testing, and testing of renal and hepatic function. Disorders to be considered include ITP, thrombotic microangiopathies, CAPS, severe infections, HLH/MAS, and severe drug reactions. (See "Initial treatment of immune thrombocytopenia (ITP) in adults" and "Approach to the adult with pancytopenia" and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)
Management of thrombocytopenia is directed to the underlying cause. (See 'Causes of thrombocytopenia' above.)
Thrombocytopenia can be associated with petechiae, purpura, and bleeding, which can be severe. 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. Platelet transfusions are given for clinically significant bleeding, to prevent bleeding associated with certain invasive procedures, and/or for platelet counts <10,000 to 20,000/microL, but clinical features, including other features that increase bleeding risk, must also be taken into account. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Indications for platelet transfusion'.)
For ITP, the goal is to reduce the risk of bleeding rather than to normalize the platelet counts; thus, not all individuals require interventions. Glucocorticoids are typically used as first-line therapy for those who require treatment. 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 associated with an SLE flare, control of the flare may also contribute to improvement in the platelet count and may eliminate the need for more aggressive second-line therapies. (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 for ITP are generally initiated for platelet counts below 20,000 to 30,000/microL or clinically significant bleeding that does not improve with glucocorticoids and/or IVIG. 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 . 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 "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Approach to drug therapy'.)
For suspected thrombotic microangiopathies, the initial assessment is made to determine the most likely pathogenesis, and treatment is often initiated before the results of laboratory testing become available. Features that aid in this decision process are presented separately. Medications typically used in SLE generally have not been implicated in causing drug-induced thrombotic microangiopathy, although medications used for other conditions may be responsible. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
Causes of pancytopenia — Pancytopenia (reduction of RBCs, WBCs, and platelets) is less common than isolated cytopenias but may occur in SLE. There are many potential causes; 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 [59,60]. 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 :
●HLH/MAS is a life-threatening disorder in which immune dysregulation leads to massive activation of macrophages in the bone marrow and other tissues and is a rare complication of SLE. The designation MAS is used to refer to this syndrome when it occurs in the setting of a rheumatologic disorder. HLH/MAS presents with a number of clinical and laboratory abnormalities, which may include fever, hepatomegaly, lymphadenopathy, neurologic symptoms, rash, cytopenias, very high serum ferritin levels, and liver and coagulation abnormalities. Hemophagocytosis (engulfment of RBCs by macrophages) is often present in the bone marrow (picture 2) and/or other tissues, but it is neither necessary nor sufficient to make the diagnosis of HLH/MAS and is often absent in the early stages of the disease. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Rheumatologic disorders/MAS' and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Clinical features'.)
●Bone marrow toxicity may be caused by medications or infection. Sepsis or severe infections may be accompanied by DIC. (See "Approach to the adult with pancytopenia", section on 'Suspected medications' and "Overview of neutropenia in children and adolescents", section on 'Acquired neutropenias' and "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Approach to the adult with unexplained neutropenia", section on 'Causes of neutropenia'.)
●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. (See 'Lymphadenopathy, splenomegaly, and high blood cell counts' below.)
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 'Causes of thrombocytopenia' above.)
●Splenomegaly with hypersplenism and pooling of blood and blood cells in the spleen; this 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'.)
●Autoimmune myelofibrosis has been reported in a small number of patients with SLE . 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.
Evaluation and initial management of pancytopenia — Individuals with pancytopenia should have a thorough history, medication review, and physical examination. If any of the cytopenias are severe and/or associated with complications (eg, fever, bleeding) the patient should be hospitalized for evaluation and treatment.
The CBC should be reviewed, with attention to the RBC indices and review of the blood smear for the presence of infectious organisms, schistocytes, hypersegmented neutrophils, and immature WBCs (see "Evaluation of the peripheral blood smear"). Additional laboratory testing includes tests of liver and renal function and cultures of blood and urine if the patient is febrile. Coagulation testing is appropriate if thrombocytopenia is severe, if there are signs of bleeding, or if an invasive procedure is anticipated. Testing of vitamin B12 and folate levels and testing for hemolysis may also be appropriate. Testing for laboratory manifestations of HLH/MAS may be appropriate if the patient has suggestive clinical features; this testing is discussed separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Evaluation and diagnostic testing'.)
Many individuals with unexplained pancytopenia, including those with suspected HLH/MAS, will require a bone marrow aspirate and biopsy to determine the cause.
Exceptions for bone marrow biopsy may include the following:
●Patients who are septic and being treated with antibiotics may have a bone marrow evaluation deferred to see if the cytopenias respond to treatment of the infection, especially if the organism has been identified and the patient is improving clinically.
●Patients with mild pancytopenia thought to be due to liver disease, hypersplenism, or vitamin B12 or folate deficiency can have laboratory testing for these conditions, and, if these are diagnosed, the CBC can be monitored on therapy to document its recovery.
●Patients with mild pancytopenia (or reduction in two of the three blood cell lines) in the setting of an SLE flare may be treated and the CBC monitored while the flare is treated.
For those who do undergo bone marrow evaluation, it is extremely helpful to have this performed before glucocorticoids are administered, as glucocorticoids will rapidly alter the bone marrow findings in many conditions, making diagnosis especially difficult. Attempts should be made to obtain a hematologist evaluation prior to giving glucocorticoids if possible. However, if it is not possible to obtain a bone marrow evaluation promptly (eg, within one or two days) and/or if the patient is deteriorating clinically, glucocorticoids and other therapies should not be withheld in order to preserve bone marrow findings.
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 HLH/MAS. However, this treatment may also cause transient improvement when the cause of pancytopenia is a more severe condition that requires additional treatment, such as chemotherapy for lymphoma and/or some cases of HLH/MAS. In a 2017 series of 157 individuals with SLE who were admitted to the hospital with a febrile illness, approximately one-third to one-half were thought to have possible HLH/MAS, but mortality remained high (35 percent) despite immunosuppressive therapy . In another 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 . More aggressive therapies for those whose disease does not respond to glucocorticoids and SLE therapy alone are presented separately. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)
Antiphospholipid antibodies and APS — Antiphospholipid antibodies (aPL) are detected in approximately 30 to 40 percent of patients with systemic lupus erythematosus (SLE) [63,64]. Often these antibodies prolong the activated partial thromboplastin time (aPTT), termed a "lupus anticoagulant"; this is an in vitro artifact. These antibodies do not increase the risk of bleeding; they can, however, increase the risk of thrombosis (venous or arterial). Less commonly, the prothrombin time (PT) may also be prolonged and may be indicative of concomitant anti-prothrombin antibodies. Testing for aPL should be done routinely as part of the evaluation for SLE. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Evaluation'.)
When persistent aPL are associated with thromboembolism or pregnancy morbidity, the diagnosis of antiphospholipid syndrome (APS) may be made. This is discussed in detail separately. (See "Diagnosis of antiphospholipid syndrome".)
Other autoantibodies — Other autoantibodies can also be seen, in some cases leading to clinically significant cytopenias or bleeding disorders. Examples of the autoantigens and the complications include:
●Red blood cell (RBC) antigens – Autoimmune hemolytic anemia (AIHA). (See 'Autoimmune hemolytic anemia' above.)
●Platelet antigens – Immune thrombocytopenia (ITP). (See 'Thrombocytopenia' above and "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Terminology'.)
●White blood cell (WBC) antigens – Leukopenia. (See 'Leukopenia' above.)
●Clotting proteins – Acquired hemophilia A or other acquired factor inhibitor. (See "Acquired hemophilia A (and other acquired coagulation factor inhibitors)".)
LYMPHADENOPATHY, SPLENOMEGALY, AND HIGH BLOOD CELL COUNTS
Lymphadenopathy — Lymphadenopathy (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. Lymphadenopathy due to SLE responds quickly to low to moderate doses of glucocorticoids (eg, prednisone, 20 to 40 mg) with a marked decrease in the size of the lymph nodes, which is somewhat less true for lymphoma and highly unlikely for a metastasis or infection. In lymphadenopathy due to SLE, biopsies reveal areas of follicular hyperplasia and necrosis; the appearance of hematoxylin bodies is highly suggestive of SLE, although this finding is unusual [5,65]. Despite these observations, treatment with glucocorticoids as a means of determining the cause of lymphadenopathy and/or biopsy of the affected lymph nodes is not routinely done unless the lymphadenopathy continues to increase and/or cause vascular or other compromise.
Lymph node enlargement in individuals with SLE can also be due to infection (eg, mononucleosis) or a lymphoproliferative disease such as lymphoma or chronic lymphocytic leukemia (CLL). The risks of infections and lymphoproliferative disorders are more common in SLE than in the general population due to immune deficits and dysregulation. Various cohort series 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 [66-68]. The risk of Hodgkin lymphoma may also be increased . It is not clear whether immunosuppressive therapy increases this risk or is merely a marker of more active disease. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Prognosis'.)
There are no specific tests to distinguish between a lymphoid malignancy and reactive lymphadenopathy due to infection or SLE disease flare. 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 and/or tender lymphadenopathy are more consistent with infection. In cases in which the cause of lymphadenopathy is not clear and/or lymphoma is suspected, flow cytometry on peripheral blood may be helpful. Flow cytometry often detects the presence of a monoclonal population of lymphocytes, indicative of lymphoma, in cases of lymphoma associated with diffuse lymphadenopathy. (See "Differential diagnosis of a neck mass" and "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach" and "Evaluation of peripheral lymphadenopathy in adults".)
Prominent lymphadenopathy may also be a manifestation of angioimmunoblastic T-cell lymphoma. This lymphoma has overlapping features with SLE including arthritis, autoimmune hemolytic anemia, rash, and fever. (See "Clinical manifestations, pathologic features, and diagnosis of angioimmunoblastic T cell lymphoma".)
Splenomegaly — Splenomegaly (enlargement of the spleen) occurs in 10 to 46 percent of patients with 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 and blood cells. Biopsy is not used routinely, but if performed 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".)
Leukocytosis — Leukocytosis (increased numbers of white blood cells [WBCs]) can occur for a number of reasons in SLE, usually due to an infection or to high doses of glucocorticoids . Increases in the number of neutrophils can be seen with disease flare or infection. A shift of granulocytes to more immature forms (a "left" shift) suggests infection. Increased numbers of lymphocytes suggest a lymphoid malignancy, especially when accompanied by lymphadenopathy or splenomegaly. (See 'Lymphadenopathy' above and 'Splenomegaly' above.)
Other causes of leukocytosis in SLE besides infection and glucocorticoids may include disorders unrelated to SLE, which are discussed separately. (See "Approach to the patient with neutrophilia" and "Approach to the patient with neutrophilia", section on 'Causes of neutrophilia'.)
Thrombocytosis — Thrombocytosis (increase in the platelet count to ≥400,000 cells/microL) may occur in the setting of inflammation, infection, iron deficiency, or acute blood loss (eg, from gastrointestinal bleeding) . Another possible cause of thrombocytosis in SLE patients is hyposplenism (or autosplenectomy). In a cohort of 465 patients with SLE, 17 (3.7 percent) were found to have thrombocytosis (platelet ≥400,000 cells/microL) . Three of these patients had one or more of the following features of absent splenic function on the peripheral blood smear: Howell-Jolly bodies, spherocytes, and target cells. Ultrasound, computed tomography (CT), and liver-spleen scintigraphy failed to demonstrate a spleen. All three patients had aPL. These observations suggest that autosplenectomy may occur in patients with SLE, perhaps mediated by aPL.
Treatment is not required for reactive thrombocytosis due to loss of splenic function. However, if thrombocytosis is related to a myeloproliferative neoplasm, therapy to reduce the platelet count and/or prevent thromboembolic complications may be required. This subject is discussed separately. (See "Approach to the patient with thrombocytosis".)
Evaluation of lymphadenopathy, splenomegaly, and leukocytosis — The extent of the evaluation for lymphadenopathy with or without splenomegaly and/or leukocytosis is individualized and must balance the frequency of these findings in SLE with the increased risk of lymphoproliferative disorders.
Most lymphadenopathy related to disease activity in SLE resolves rapidly upon immunosuppressive therapy. 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, or if there are any other concerning features. (See "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach" and "Evaluation of peripheral lymphadenopathy in adults".)
Splenomegaly is evaluated using a focused 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".)
Evaluation of an increased neutrophil count should focus on the presence of infection. In an individual receiving glucocorticoids, the count typically normalizes with discontinuation. Other causes of neutrophilia and details of the evaluation are discussed separately. (See "Approach to the patient with neutrophilia" and "Approach to the patient with neutrophilia", section on 'Causes of neutrophilia'.)
Unexplained lymphocytosis may be evaluated using flow cytometry, which will show clonality in lymphoproliferative disorders such as CLL or lymphoma and will not show clonality in reactive processes such as viral infections. (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'.)
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 5th to 6th 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 10th to 12th 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
●Anemia – Anemia affects more than half of individuals with systemic lupus erythematosus (SLE); multiple causes may contribute, including chronic inflammation, iron deficiency, medications, autoimmune hemolysis, vitamin B12 deficiency, and thrombotic microangiopathies such as thrombotic thrombocytopenic purpura (TTP). For patients who are not acutely ill, the evaluation includes a thorough history and review of the complete blood count (CBC), reticulocyte count, and red blood cell (RBC) indices, with subsequent testing and treatment based on the results. (See 'Anemia' above.)
●Leukopenia – Leukopenia (reduced white blood cell [WBC] count) is also common in SLE and often correlates with disease activity. Neutropenia may be caused by immunosuppressive medications or hypersplenism, or it may be unrelated to SLE (due to viral infection or constitutional neutropenia). Lymphocytopenia may be caused by autoantibodies. Treatment is rarely needed but may involve titration of immunosuppressive medications and/or SLE therapies. (See 'Leukopenia' above.)
●Thrombocytopenia – Mild thrombocytopenia (platelet count 100,000 to 150,000/microL) is often seen in SLE, but platelet counts <50,000/microL are not common. Immune thrombocytopenia (ITP; due to autoimmune platelet destruction) is often the cause but is a diagnosis of exclusion; ITP may present prior to the development of SLE, as a chronic complication, or acutely during a disease flare. Other causes may include medications (table 1), splenomegaly, a thrombotic microangiopathy, or antiphospholipid syndrome (APS). Patients with isolated thrombocytopenia should have a history, examination, and review of the CBC, with additional testing such as vitamin B12 and folate levels, liver function testing, and/or coagulation testing as appropriate. (See 'Thrombocytopenia' above.)
●Pancytopenia – Pancytopenia (reduction of RBCs, WBCs, and platelets) is less common than individual cytopenias but may occur in SLE. There are many potential causes, some that can be evaluated as an outpatient and some requiring rapid hospitalization and intervention to prevent life-threatening complications (table 2). Possible life-threatening diagnoses include hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), as well as sepsis, bone marrow toxicity from drugs, thrombotic microangiopathies, vitamin B12 or folate deficiencies, and hematologic malignancies (table 3). Most patients will require a bone marrow evaluation. (See 'Pancytopenia' above.)
●Antiphospholipid antibodies – Antiphospholipid antibodies (aPL) are detected in approximately 30 to 40 percent of patients with SLE. These antibodies may prolong the activated partial thromboplastin time (aPTT) and less commonly may prolong the prothrombin time (PT) as a laboratory artifact. When persistent aPL are associated with thromboembolism or pregnancy morbidity, the diagnosis of APS can be made. (See 'Autoantibodies' above.)
●Lymphadenopathy and splenomegaly – Lymphadenopathy and splenomegaly are common in SLE, and when present, are usually associated with a disease flare. Additional causes of lymphadenopathy and splenomegaly, and the role of lymph node biopsy and other testing, are discussed above and in separate topic reviews. (See 'Lymphadenopathy, splenomegaly, and high blood cell counts' above.)
●Other clinical manifestations – Other clinical manifestations of SLE and our approach to diagnostic testing are presented separately. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟