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Offi cial reprint from UpToDatewww.uptodate.com ©2015 UpToDate

AuthorsPeter H Schur, MDNancy Berliner, MD

Section Editor David S Pisetsky, MD,PhD

Deputy Editor Monica Ramirez Curtis,MD, MPH

Hematologic manifestations of systemic lupus erythematosus in adults

All topics are updated as new evidence becomes available and our peer review process is complete.Literatur e review current through: Sep 2015. | This topic last updated: Aug 06, 2015.

INTRODUCTION — Abnormalities of the formed elements of the blood, and of the clotting, fibrinolytic, and related

systems, are very common in systemic lupus erythematosus (SLE). The major hematologic manifestations of SLE

are anemia, leukopenia, thrombocytopenia, and the antiphospholipid syndrome (APS). These hematologic

abnormalities may be a presenting manifestation of SLE, and can be a sign of disease activity if other possible

causes are excluded. This topic review will provide an overview of these problems.

ANEMIA — Anemia is a frequent occurrence in systemic lupus erythematosus (SLE), affecting most patients at

some time in the course of their disease. Multiple mechanisms contribute to the development of anemia, including

inflammation, renal insufficiency, blood loss, dietary insufficiency, medications, hemolysis, infection,

hypersplenism, myelofibrosis, myelodysplasia, and aplastic anemia that is suspected to have an autoimmunepathogenesis [1-8].

Anemia of chronic inflammation — A frequent cause of anemia in SLE is suppressed erythropoiesis from

chronic inflammation (anemia of chronic disease or anemia of chronic inflammation) [4]. The anemia is normocytic

and normochromic with a relatively low reticulocyte count. Although serum iron levels may be reduced, bone

marrow iron stores are adequate, and the serum ferritin concentration is elevated. The major mediator of the

anemia of chronic inflammation is hepcidin, a central regulator of iron homeostasis that inhibits the release of iron

from macrophages and iron absorption in the small intestine. This results in iron-limited hematopoiesis. The

mechanisms by which this anemia is produced by chronic inflammatory diseases are further discussed in detail

elsewhere. (See "Anemia of chronic disease/inflammation".)

As in other chronic illnesses, serum erythropoietin levels may be inappropriately low for the degree of anemia.

However, some of the apparent reduction in serum erythropoietin may be spurious; autoantibodies to erythropoietin

may interfere with commercial laboratory testing [9].

Recommendations — In the absence of either symptoms attributable to anemia (eg, dyspnea on exertion,

easy fatigability) or renal insufficiency (see 'Renal insufficiency' below), anemia of chronic inflammation does not

require specific treatment.

Patients with symptoms due to anemia of chronic inflammation and without another definite indication for

glucocorticoid or other immunosuppressive ther apy may be given a trial of an agent that promotes erythropoiesis.

Two such agents are available in the United States:

In one study that assessed the response to erythropoietin in patients with SLE and anemia of chronic

inflammation, 58 percent had an adequate response to erythropoietin supplementation [7].

Patients who are symptomatically anemic have signs of active inflammation, and do not respond to an agent that

®

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Epoetin alfa (recombinant human erythropoietin). Treatment should be started at 80 to 120 units/kg per week

(usually as two to three injections per week). The patient should be reassessed after one month, and the

dose should be increased monthly until the hemoglobin level is maintained at ≥11 g/dL.

Darbepoetin alfa, a unique molecule that stimulates erythropoiesis with a longer half-life than recombinant

human erythropoietin. A typical dose of darbepoetin alfa for adults is 0.45 mcg/kg once a week.

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promotes erythropoiesis, often improve when glucocorticoids are used in high doses (1 mg/kg per day of

prednisone or its equivalent in divided doses). If, after approximately one month of treatment, the response is

unsatisfactory (eg, hemoglobin still <11 g/dL), the dose of glucocorticoids should be rapidly reduced and

discontinued if there is no other indication for their use. If there is a response, the dose should be tapered as

rapidly as to possible to the lowest dose that maintains the improvement. Immunosuppressive agents also may

help, but carry a risk of further bone marrow suppression.

Renal insufficiency — An inappropriately low level of erythropoietin is a hallmark of anemia due to renal

insufficiency. The primary cause of anemia in this setting is typically deficient production of erythropoietin by the

diseased kidneys. In the patient with SLE, anemia, and renal insufficiency who does not have other evidence of

active inflammation, administration of erythropoiesis-stimulating agents may be indicated when the anemia is

causing symptoms or the hemoglobin concentration is <11 g/dL.

The rationale for treating anemia due to chronic renal disease prior to initiation of renal replacement therapy

(dialysis or transplantation) is discussed in detail separately. (See "Erythropoietin for the anemia of chronic kidney

disease among predialysis and peritoneal dialysis patients" and "Erythropoietin for the anemia of chronic kidney

disease in hemodialysis patients" and "Darbepoetin alfa for the management of anemia in chronic kidney

disease".)

Iron deficiency anemia — Anemia may reflect acute or chronic blood loss from the gastrointestinal tract, usually

secondary to medications (nonsteroidal antiinflammatory drugs [NSAIDs] or steroids), or may be due to excessivemenstrual bleeding (see "NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity"). Iron deficiency

anemia is not uncommon, especially among teenagers or young women. Long-term anemia of chronic

inflammation can also lead to iron deficiency, since, as mentioned earlier (see 'Anemia of chronic inflammation'

above), hepcidin, the key inducer of the anemia of chronic inflammation, inhibits iron absorption from the

gastrointestinal tract.

Pulmonary hemorrhage is a rare cause of anemia in SLE. Not all patients have hemoptysis. Other symptoms of

alveolar hemorrhage are dyspnea and cough. The presence of alveolar infiltrates on a chest radiograph or ground-

glass opacities on chest computed tomography (CT) are suggestive of alveolar hemorrhage. (See "Pulmonary

manifestations of systemic lupus erythematosus in adults".)

Red cell aplasia — Red cell aplasia, probably due to antibodies directed against either erythropoietin or bone

marrow erythroblasts, has been observed, although it is rare [ 5,6,10]. This form of anemia usually responds to

steroids, although cyclophosphamide and cyclosporine have been successfully employed. (See "Acquired pure red

cell aplasia in the adult".)

Even rarer are isolated case reports of aplastic anemia, presumably mediated by autoantibodies against bone

marrow precursors; immunosuppressive therapy also may be effective in this setting [11-13].

In addition, bone marrow suppression can also be induced by medications, including antimalarials and

immunosuppressive drugs.

Autoimmune hemolytic anemia — Overt autoimmune hemolytic anemia (AIHA), characterized by an elevated

reticulocyte count, low haptoglobin levels, increased indirect bilirubin concentration, increased levels of lactate

dehydrogenase (LDH), and a positive direct Coombs' test, has been noted in up to 10 percent of patients with SLE

[2-4,8,14]. The presence of hemolytic anemia may be associated with other manifestations of severe disease such

as renal disease, seizures, and serositis [14].

Other patients have a positive Coombs' test without evidence of overt hemolysis. The presence of both

immunoglobulin and complement on the red cell is usually associated with some degree of hemolysis, while the

presence of complement alone (eg, C3 and/or C4) is often not associated with hemolysis [1-4]. The antibodies are

"warm," IgG, and directed against Rh determinants (see "Pathogenesis of autoimmune hemolytic anemia: Warm

agglutinins and drugs"). IgM-mediated cold agglutinin hemolysis is uncommon.

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Recommendations — AIHA responds to steroids (1 mg/kg per day of prednisone or its equivalent in divided

doses) in 75 to 96 percent of patients [15,16]. Once the hematocrit begins to rise and the reticulocyte count falls,

steroids can be rapidly tapered. If there is no response, one can consider intermittent intravenous “pulses” of high-

dose steroids (eg, 1000 mg methylprednisolone intravenously daily for three days) [15], azathioprine (up to 2 mg/kg

per day) [17], cyclophosphamide (up to 2 mg/kg) [18], or splenectomy. Success rates for splenectomy as high as

60 percent have been reported [19], although others have found no benefit [20].

Other anecdotally described approaches to patients with refractory AIHA include intravenous immune globulin [18],

danazol (in doses of 600 to 800 mg/day) [21-23], mycophenolate mofetil [24], and rituximab [25].

Microangiopathic hemolytic anemia — Lupus has also been associated with a thrombotic microangiopathic

hemolytic anemia (TMA) [26], as manifested by a peripheral blood smear showing schistocytes and elevated

serum levels of LDH and bilirubin (picture 1). Many affected patients also have thrombocytopenia, kidney

involvement, fever, and neurologic symptoms. This pentad of features is compatible with a diagnosis of thrombotic

thrombocytopenic purpura (TTP). However, the pathogenesis of thrombotic microangiopathy in these patients is

likely heterogeneous, as it may reflect vasculitis or antiphospholipid syndrome as well [27,28].

Whether the occurrence of both SLE and TTP in an individual patient is a coincidence or represents a true

association is an unsettled question.

Other patients with microangiopathic red cell destruction do not have fever or neurologic disease, producing a

pattern of hemolytic-uremic syndrome. The pathogenesis of this syndrome is not completely understood. In one

report of four patients plus 24 others identified from a literature review, antiphospholipid antibodies (aPL) were

searched for in eight and found in five [26]. (See "Acquired TTP: Clinical manifestations and diagnosis".)

The presence of aPL in SLE patients with severe hemolytic anemia, renal dysfunction, and central nervous

system involvement has also been reported [31]. (See "Clinical manifestations of the antiphospholipid syndrome",

section on 'Hematologic manifestations'.)

Treatment — In a review of 28 reported patients, those treated with plasma infusions or plasma exchange,

glucocorticoids alone, or no therapy had mortality rates of 25, 50, and 100 percent, respectively [ 26]. However, inanother series of 15 patients with SLE and microangiopathic hemolytic anemia, all responded to treatment with

high-dose glucocorticoids, and none were treated with plasma exchange [32]. In a retrospective study cited above

[27] in which 70 percent of patients with SLE and TMA underwent plasma exchange, the response rate of 74

percent was comparable to that observed in patients with idiopathic TTP.

Recommendations — Patients with SLE, severe microangiopathic hemolytic anemia, and other major

organ dysfunction should be treated with plasma exchange as in other cases of thrombotic thrombocytopenic

purpura or the hemolytic-uremic syndrome. (See "Acquired TTP: Initial treatment".)

Available testing for ADAMTS13 activity has a turnaround time that is too long to be useful in initial treatment

In a 1998 review of the world literature, only 40 such cases were found [29].

A subsequent retrospective study of renal biopsies of 257 patients with SLE identified four cases with

compatible clinical features and histologic evidence of TTP [ 30].

A large study of patients with TMA in association with connective tissue disease examined clinical

parameters of the disease in the context of assessment of ADAMTS13 activity [ 27]. Most of the 127 patients

with TMA and a connective tissue disease had depressed ADAMTS13 activity. Severe deficiency (eg,

activity <10 percent), which is consistent with acquired (autoimmune) TTP, was found in only 16 percent of

those with associated connective tissue disease, as compared with 70 percent of the 64 patients with TTP in

the absence of connective tissue disease. Very low ADAMTS13 levels were associated with inhibitory

antibodies directed against the enzyme. Clinical response rates in patients with SLE were comparable to

other patients with acquired TTP.

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decision making. If the diagnosis of TTP is unclear, it may be appropriate to treat with plasma exchange while

awaiting ADAMSTS13 activity level results. (See "Approach to the patient with suspected TTP, HUS, or other

thrombotic microangiopathy (TMA)".)

LEUKOPENIA — Leukopenia is common in systemic lupus erythematosus (SLE) and usually reflects disease

activity. A white blood cell count of less than 4500/microL has been noted in approximately 50 percent of patients,

especially those with active disease [3,4], while lymphocytopenia occurs in approximately 20 percent [3]. In

comparison, a white blood cell count below 4000/microL (an American College of Rheumatology criterion for SLE)

occurs in only 15 to 20 percent of patients [ 3,33]. Neutropenia, lymphocytopenia, and decreased circulating

eosinophils and basophils may all contribute to leukopenia.

Neutropenia — Neutropenia in patients with SLE can result from immune mechanisms, medications (eg,

cyclophosphamide or azathioprine), bone marrow dysfunction, or hypersplenism [3,4,33,34]. Other clinical features

that may be associated with moderate to severe neutropenia (absolute neutrophils <1000/microL) include infection,

anemia, thrombocytopenia, and a history of neuropsychiatric involvement [34].

Functional defects of neutrophils have also been noted. They are thought to be induced by immune abnormalities

(eg, immune complexes, inhibition of complement-derived chemotactic factors) and/or medications (eg,

glucocorticoids) [35,36].

Lymphocytopenia — Lymphocytopenia (lymphocytes less than 1500/microL), especially involving suppressor T

cells, has been observed in 20 to 75 percent of patients, particularly during active disease [1-3,37,38]. This finding

is strongly associated with IgM, cold reactive, complement fixing, and presumably cytotoxic antilymphocyte

antibodies; such antibodies were noted in 26 of 29 patients with SLE, and the antibody titer correlated directly with

the degree of lymphopenia [39].

Another potential mechanism of lymphopenia is increased apoptosis as reflected by increased expression of Fas

antigen on T cells [40].

Decreased eosinophils and basophils — Steroid therapy may result in low absolute eosinophil and monocyte

counts [41].

The number of basophils may also be decreased in SLE, particularly during active disease [42]. Basophil

degranulation with release of platelet activating factor and other mediators may play a role in immune complex

deposition and vascular permeability.

Recommendations — Leukopenia in SLE rarely needs treatment. An exception is the patient with neutropenia

and recurrent pyogenic infections. One problem is the toxicity of the usual therapies. Prednisone (10 to 60 mg/day)

can raise the white blood cell count but can also result in an increased risk of infections; immunosuppressive

agents such as azathioprine or cyclophosphamide have the potential to cause worsening of the leukopenia via

bone marrow suppression [43].

Cautious use of azathioprine, with careful monitoring of the white blood cell count, may be considered in this

setting.

Therapies for leukopenia used in other settings may result in significant adverse results when applied to patients

with SLE. As an example, one study of nine patients with neutropenia and refractory infections found that

treatment with recombinant granulocyte colony-stimulating factor (G-CSF) increased the polymorphonuclear cell

count but also caused a disease flare in three patients [44]. Leukocytoclastic vasculitis has also developed in

some patients; thus, it is recommended that the minimum amount of G-CSF be used in order to maintain the

peripheral neutrophil count ≥1000/microL [45,46].

LEUKOCYTOSIS — Leukocytosis (mostly granulocytes) can occur in systemic lupus erythematosus (SLE).

When present, it is usually due to infection or the use of high doses of glucocorticoids [43], but it may occur during

acute exacerbations of SLE. A shift of granulocytes to more immature forms (a "left" shift) suggests infection.

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THROMBOCYTOPENIA — Mild thrombocytopenia (platelet counts between 100,000 and 150,000/microL) has

been noted in 25 to 50 percent of patients, while counts of less than 50,000/microL occur in only 10 percent

[1,3,4,33]. There are several potential causes of thrombocytopenia in patients with systemic lupus erythematosus

(SLE). Immune mediated platelet destruction is most often the cause, but platelet consumption may also occur in

association with microangiopathic hemolytic anemia (see 'Microangiopathic hemolytic anemia' above) or may be

due to impaired platelet production as a result of the use of cytotoxic, immunosuppressive, or other drugs (table 1).

Pathogenesis — The major mechanism is immunoglobulin binding to platelets followed by phagocytosis in the

spleen, as in immune thrombocytopenia (ITP) [47]. Membrane glycoproteins (GP) are most often the target of such

antibodies (eg, GP IIb/IIIa), but anti-HLA specificity also occurs [48].

Antigen-dependent B cell development in lymphoid tissues is influenced by binding of CD40 on B cells to CD40-

ligand on activated T cells (see "The humoral immune response"). The finding of autoantibodies to CD40-ligand in

patients with SLE, antiphospholipid syndrome (APS), and ITP, but not in the serum of healthy blood donors,

suggests that interference with T cell and B cell interaction may play a role in the development of

thrombocytopenia [49].

Other important mechanisms in selected patients include bone marrow suppression by immunosuppressive drugs

(other than glucocorticoids), increased consumption due to a thrombotic microangiopathy (thrombotic

thrombocytopenic purpura [TTP]) [26], the APS, or antibodies that block the thrombopoietin receptor on

megakaryocytes or their precursors. (See 'Antibodies to clotting factors and phospholipids' below and "Approach tothe adult with unexplained thrombocytopenia", section on 'Hematologist referral/consultation'.)

ITP may be the first sign of SLE, followed by other symptoms as distant as many years later. It has been

estimated that 3 to 15 percent of patients with apparently isolated ITP go on to develop SLE [ 50]. Evans syndrome

(ie, both autoimmune thrombocytopenia and autoimmune hemolytic anemia) also may precede the onset of SLE.

Severe bleeding from thrombocytopenia is only experienced by a minority of patients; however, SLE patients with

thrombocytopenia are more likely to have associated significant organ damage, such as that of the heart, the

kidneys, or the CNS [51].

Splenectomy in ITP was originally thought to predispose to the development of SLE [52]. However, this

hypothesis was refuted in subsequent studies [53].

Treatment — Platelet counts between 50,000/microL and 20,000/microL rarely cause symptoms or signs, while

counts of less than 20,000/microL may be associated with (and may account for) petechiae, purpura,

ecchymoses, epistaxis, gingival, and other clinical bleeding. (See "Immune thrombocytopenia (ITP) in adults:

Clinical manifestations and diagnosis".)

The indications for and the treatment of ITP in SLE are generally the same as that in patients without lupus, and

are discussed in detail elsewhere. (See "Immune thrombocytopenia (ITP) in adults: Initial treatment and prognosis"

and "Immune thrombocytopenia (ITP) in adults: Second-line and subsequent therapies".)

One practice difference is that physicians are less likely to use splenectomy in SLE patients due to concerns

about a less durable response to this therapeutic intervention. Instead, rituximab is often preferred because it may

also be used to treat other manifestations of SLE. However, using current surgical techniques, we consider

splenectomy to be a generally safe and a reasonable second-line therapeutic option for SLE patients with

refractory ITP. This view is supported by data from the largest observational series in which splenectomy was

performed in 25 patients with SLE seen from 1975 to 2001 at the Mayo Clinic [ 54]. After a median follow-up of 6.6

years, 16 patients had a complete or partial response; eight of these subsequently required medical therapy. Nine

patients relapsed, but five subsequently responded to medical therapy. After a median follow up of 9.5 years, 9 of

the 25 patients had died, with only one death being a result of bleeding complications.

THROMBOCYTOSIS — Thrombocytosis is a less frequent finding in those with systemic lupus erythematosus

(SLE). As an example, among 465 patients with SLE, 17 (3.7 percent) were found to have thrombocytosis (platelet

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≥400,000/mm ). Three of these patients had one or more of the following features on 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 antiphospholipid antibodies (aPL) [ 55]. These

observations suggest that autosplenectomy may occur in patients with SLE, perhaps mediated by aPL.

PANCYTOPENIA — Although peripheral destruction of red cells, leukocytes, and platelets may occur together

and lead to clinically significant pancytopenia, depression of all three cell lines also suggests bone marrow failure,

as in the case in aplastic anemia. Thus, bone marrow examination is the most important diagnostic test to

perform. (See "Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis".)

Causes of marrow failure include drugs and coincidental diseases including the acute leukemias, large granular

lymphocyte leukemia, the myelodysplastic syndromes, marrow replacement by fibrosis or tumor, severe

megaloblastic anemia, paroxysmal nocturnal hemoglobinuria (PNH), and overwhelming infection. In addition,

unexplained cytopenia can be associated with bone marrow necrosis, dysplasia, and distortion of the bone marrow

architecture [56,57]. (See "Clinical manifestations and diagnosis of primary myelofibrosis", section on 'Secondary

forms of myelofibrosis'.)

Among patients with systemic lupus erythematosus (SLE), an unusual cause of pancytopenia is the macrophage

activation syndrome. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on

'Rheumatologic disorders/MAS'.)

The clinical characteristics of 12 patients with SLE-associated macrophage activation syndrome included [ 58]:

The demonstration of hemophagocytosis in the bone marrow or in material obtained from peripheral lymph nodes is

a characteristic finding.

The few reported cases of macrophage activation syndrome in patients with SLE have usually responded to

treatment with glucocorticoids and immunosuppressive agents. Optimal treatment is uncertain. (See "Treatment

and prognosis of hemophagocytic lymphohistiocytosis", section on 'MAS/rheumatologic conditions'.)

LYMPHADENOPATHY AND SPLENOMEGALY — Enlargement of 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.

Biopsies reveal areas of follicular hyperplasia and necrosis; the appearance of hematoxylin bodies is highly

3

Fever – 100 percent

Weight loss – 80 percent

Arthritis – 50 percent

Pericarditis – 42 percent

Rash – 66 percent

Myocarditis – 33 percent

Nephritis – 33 percent

Splenomegaly – 27 percent

Hepatomegaly – 13 percent

Lymphadenopathy – 73 percent

Anemia – 100 percent

Leukopenia – 87 percent

Hyperferritinemia – 100 percent

Anti-DNA antibodies – 80 percent

Low C-reactive protein (CRP) (<30 mg/L) – 90 percent

Hypocomplementemia – 60 percent

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suggestive of SLE, although unusual [1].

Lymph node enlargement can also be due to infection or a lymphoproliferative disease in SLE. When infections are

present, the enlarged nodes are more likely to be tender.

Prominent lymphadenopathy may also be a manifestation of angioimmunoblastic T cell lymphoma. This disorder

has other clinical features (arthritis, Coombs-positive hemolytic anemia, skin rash, fever, and weight loss) that are

suggestive of systemic lupus erythematosus or systemic juvenile idiopathic arthritis (Still's disease). This type of

T cell lymphoma is discussed in detail elsewhere. (See "Clinical manifestations, pathologic features, and

diagnosis of angioimmunoblastic T cell lymphoma".)

Enlargement of the spleen occurs in 10 to 46 percent of patients, particularly during active disease. Splenomegaly

is not necessarily associated with a cytopenia. Pathologic examination of the spleen reveals an onion skin

appearance of the splenic arteries, a lesion that is thought to represent healed vasculitis.

In view of the frequent presence of lymphadenopathy and splenomegaly in SLE, the possibility of a

lymphoproliferative malignancy may be considered. The risk of non-Hodgkin lymphoma appears to be increased

four- to fivefold in patients with lupus. The studies that provide this estimate of the relative risk of lymphoma and

issues related to the risk of other malignancies are discussed in detail elsewhere. (See "Overview of the

management and prognosis of systemic lupus erythematosus in adults", section on 'Is cancer risk increased?' .)

Another group at risk for lymphoproliferative disorders is patients treated with prolonged oral cyclophosphamidetherapy (which is unusual in SLE) who are also at increased risk for bladder and other malignancies. Pulse

intravenous cyclophosphamide appears to have eliminated the risk of bladder cancer. The long-term risk of non-

bladder malignancy with intravenous pulse dosing is uncertain, but no association has yet been reported. (See

"General toxicity of cyclophosphamide in inflammatory diseases".)

A lymph node biopsy may be warranted when the degree of lymphadenopathy is out of proportion to the activity of

the lupus.

ANTIBODIES TO CLOTTING FACTORS AND PHOSPHOLIPIDS — Antibodies to a number of clotting factors,

including VIII, IX, XI, XII, and XIII, have been noted in patients with SLE [1,2,33]. These antibodies may not only

cause abnormalities of in vitro coagulation tests, but may also cause bleeding. (See "Acquired inhibitors of

coagulation".)

Much more common are antiphospholipid antibodies (aPL), the presence of which has been associated with a

prolongation of the partial thromboplastin time (lupus anticoagulant activity) and an increased risk of arterial and

venous thrombosis, thrombocytopenia, and fetal loss [59,60]. Antibodies to other phospholipids and to

phospholipid binding proteins (eg, anticardiolipin antibodies) in moderate or high levels may also be associated with

these clinical phenomena. When aPL occur in association with one or more of these clinical features in a patient

with SLE, it suggests the presence of the APS. A more detailed discussion of this disorder is presented

separately. (See "Clinical manifestations of the antiphospholipid syndrome".)

An increased prevalence of aPL in patients with SLE following treatment with cyclophosphamide was noted in a

single retrospective study that compared 177 cyclophosphamide-treated SLE patients with 203 SLE patients never treated with this alkylating agent [61]. Seroconversion occurred at a higher rate in the cyclophosphamide-treated

patients (19 versus 1 percent, respectively).

ERYTHROCYTE SEDIMENTATION RATE — Although acute phase reactants, such as the erythrocyte

sedimentation rate (ESR) and serum C-reactive protein levels, are less reliable markers of disease activity in lupus

than they are in many other inflammatory conditions, including rheumatoid arthritis and polymyalgia rheumatica

[62], elevated levels of the ESR may be associated with activity and accumulated damage [63].

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“patient info” and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS

th th

Basics topics (see "Patient information: Anemia of chronic disease (The Basics)")

Anemia is a frequent occurrence in systemic lupus erythematosus (SLE), affecting most patients at some

time in the course of their disease. Multiple mechanisms contribute to the development of anemia, including

inflammation, renal insufficiency, blood loss, dietary insufficiency, medications, hemolysis, infection,

hypersplenism, myelofibrosis, myelodysplasia, and aplastic anemia that is suspected to have an

autoimmune pathogenesis. Treatment of anemia differs depending upon the mechanism. (See 'Anemia of

chronic inflammation' above and 'Renal insufficiency' above and 'Iron deficiency anemia' above and 'Red cell

aplasia' above and 'Autoimmune hemolytic anemia' above and 'Microangiopathic hemolytic anemia' above.)

Leukopenia is common in SLE and usually reflects disease activity, although it may also result from certain

medications, particularly immunosuppressive drugs. Decreases in different cell lines may occur

independently of each other and may result from different mechanisms. Leukopenia in SLE rarely needs

treatment, except when neutropenia results in recurrent pyogenic infections. Leukocytosis (mostly

granulocytes) is usually due to infection or the use of high doses of glucocorticoids. (See 'Leukopenia' above

and 'Neutropenia' above and 'Lymphocytopenia' above and 'Decreased eosinophils and basophils' above and

'Recommendations' above and 'Leukocytosis' above.)

Mild thrombocytopenia is common in SLE; more severe thrombocytopenia occurs in only 10 percent. Immune

thrombocytopenia (ITP) may be the first sign of SLE, followed by other symptoms as distant as many years

later. Potential causes of thrombocytopenia in SLE include immune-mediated platelet destruction, which isthe most common, and platelet consumption, associated with microangiopathic hemolytic anemia or due to

impaired platelet production from medications (table 1). (See 'Thrombocytopenia' above and 'Pathogenesis'

above.)

Platelet counts between 50,000/microL and 20,000/microL rarely cause symptoms or signs, while counts of

less than 20,000/microL may be associated with (and may account for) petechiae, purpura, ecchymoses,

epistaxis, gingival, and other clinical bleeding. The indications for and the treatment of ITP in SLE are

generally the same as that in patients without lupus. (See 'Treatment' above.)

Pancytopenia may result either from peripheral destruction of red cells, leukocytes, and platelets together or

from bone marrow failure. Thus, in patients with pancytopenia, bone marrow examination is the most

important diagnostic test. There are a number of potential causes to consider such as drugs, various other

diseases, and bone marrow abnormalities; an uncommon cause is the macrophage activation syndrome.

(See 'Pancytopenia' above.)

Lymphadenopathy occurs in approximately 50 percent of patients with SLE, more frequently at the onset of

disease or in association with an exacerbation. Splenomegaly may also be present, particularly during active

disease. A lymph node biopsy may be warranted when the degree of lymphadenopathy is out of proportion to

the activity of the lupus. Other causes include infection or a lymphoproliferative disorder, such as non-

Hodgkin lymphoma or angioimmunoblastic T cell lymphoma (see 'Lymphadenopathy and splenomegaly'

above). Lymphadenopathy due to SLE does not require treatment, but enlarged nodes typically melt away on

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Topic 4670 Version 22.0

steroids. Lymphadenopathy in a patient on moderate or greater doses of glucocorticoids should increase

suspicion regarding infection or malignancy.

Antibodies to a number of clotting factors, including VIII, IX, XI, XII, and XIII, have been noted in rare

patients with SLE, which may cause abnormalities of in vitro coagulation tests and sometimes bleeding.

Much more common are antiphospholipid antibodies, the presence of which has been associated with a

prolongation of the partial thromboplastin time (lupus anticoagulant activity) and an increased risk of arterial

and venous thrombosis, thrombocytopenia, and fetal loss. (See 'Antibodies to clotting factors and

phospholipids' above.)

Elevated levels of the erythrocyte sedimentation rate (ESR) may be associated with disease activity, but the

ESR is a less reliable marker of disease activity in lupus than in many other inflammatory conditions. (See

'Erythrocyte sedimentation rate' above.)

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GRAPHICS

Peripheral smear in microangiopathic hemolytic

anemia showing presence of schistocytes

Peripheral blood smear from a patient with a microangiopathic

hemolytic anemia with marked red cell fragmentation. The smear

shows multiple helmet cells (small black arrows), other fragmented

red cells (large black arrow); microspherocytes are also seen (blue

arrows). The platelet number is reduced; the large platelet in the

center (red arrow) suggests that the thrombocytopenia is due to

enhanced destruction.

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 70851 Version 5.0

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow) can

also be seen. The red cells are of relatively uniform size and

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shape. The diameter of the normal red cell should approximate that

of the nucleus of the small lymphocyte; central pallor (red arrow)

should equal one-third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 59683 Version 2.0

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Drugs associated with isolated thrombocytopenia

Drug Mechanism(s)

Abciximab DITP

Acetaminophen DITP with antibodies to a drug metabolite; the antibodies do not

react with the unmodified parent compound

Alemtuzumab ITP-like syndrome*

Amiodarone DITP

Beta-lactam antibiotics

(eg, penicillins,

cephalosporins)

DITP

Carbamazepine DITP

Eptifibatide DITP

Ethambutol DITP

Furosemide DITP

Gold compounds Bone marrow suppression

Haloperidol DITP

Heparin Drug-dependent antibodies that also activate platelets and cause

endothelial injury

Ibuprofen DITP in some patients; in other patients only antibodies to a drug

metabolite that do not react with the unmodified parent

compound

Irinotecan DITP

Levofloxacin DITP

Linezolid Bone marrow suppression (dose-dependent)

Measles-mumps-rubella

(MMR) vaccine

ITP-like syndrome

Naproxen DITP with a antibodies to a drug metabolite; the antibodies do not

react with the unmodified parent compound

Oxaliplatin DITP

Phenytoin DITP

Piperacillin DITP

Quinidine DITP

Quinine DITP

Ranitidine DITP

Rifampin DITP

Simvastatin DITP

Sulfonamides DITP

¶

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Tirofiban DITP

Trimethoprim-

sulfamethoxazole

DITP

Valproic acid Bone marrow suppression (dose-dependent)

Vancomycin DITP

This table lists drugs with evidence for a causal association with isolated thrombocytopenia,

from clinical data in published case reports, identification of drug-dependent, platelet-reactiveantibodies, or both; it also lists their mechanisms. Drugs in bold are the most commonly

implicated in a causal relationship based on clinical criteria (eg, temporal relationship,

absence of an alternate explanation for thrombocytopenia). Drug-dependent antibodies have

been shown for all agents associated with DITP. Refer to other content in UpToDate on drugs

that can cause thrombotic microangiopathy (TMA).

DITP: drug-induced immune thrombocytopenia (ie, thrombocytopenia caused by drug-dependent

antibodies); ITP: immune thrombocytopenia, which is caused by an autoimmune mechanism that no

longer requires the presence of the drug; TMA: thrombotic microangiopathy, which is associated

with microangiopathic hemolytic anemia and thrombocytopenia, with an immune or dose-dependent

mechanism.

* A rare adverse reaction to alemtuzumab results in prolonged, severe thrombocytopenia that responds

to ITP therapy with sustained remission.

¶ Quinine can also cause a TMA.

Research leading to this compilation of drugs was originally published in Blood and has been modified for

use in this publication. Reese JA, Li X, Hauben M, et al. Identifying drugs that cause acute

thrombocytopenia: an analysis using 3 distinct methods. Blood 2010; 116:2127.

Graphic 73618 Version 9.0

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Disclosures: Peter H Schur, MD Nothing to disclose. Nancy Berliner, MD Nothing to disclose. David S

Pisetsky, MD, PhD Consultant/Advisory Boards: Merck [Autoimmunity (Xelganz, Enbrel)]; Lilly [Lupus];Celgene [Psoriatic arthritis (apremilast)]; Immunoarray [Lupus (SLE test)]. Monica Ramirez Curtis, MD,

MPH Nothing to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these areaddressed by vetting through a multi-level review process, and through requirements for references to be

provided to support the content. Appropriately referenced content is required of all authors and must

conform to UpToDate standards of evidence.

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Disclosures