Chapter 36 Hematologic and Coagulation Abnormalities of Systemic Lupus Erythematosus and the Antiphospholipid Syndrome

E. Nigel Harris, MD , Wendell A. Wilson, MD , Silvia S. Pierangeli, PhD

INTRODUCTION

Hematologic abnormalities such as anemia, leucopenia, thrombocytopenia, and clotting abnormalities are well recognized features of systemic lupus erythematosus (SLE). However, it is only within the past two decades that a group of autoantibodies, designated antiphospholipid (aPL) antibodies, has been shown to be intimately associated with these features of SLE.¹ APL antibodies are detected by the anticardiolipin (aCL) antibody² or lupus anticoagulant (LA) test.³ Although important, they are certainly not the sole autoantibodies associated with blood cell destruction in SLE, nor are they the sole reason for arterial or venous thrombosis (as discussed in material following). It should also be borne in mind that aPL antibodies and the hematologic and clotting abnormalities with which they are associated can occur independently of SLE [often manifested in the primary antiphospholipid syndrome (APS)]. This chapter discusses abnormalities of blood cells in SLE and examines the APS.

ANEMIA

There are a variety of causes of anemia in patients with SLE. These include anemia of chronic disease, iron deficiency anemia, autoimmune hemolytic anemia, pure red cell aplasia, and other causes. Anemia (less than 12 g/dl) of chronic disease is the most common cause of low hemoglobin in these patients.⁴

Iron deficiency anemia is not infrequent and doubtless relates to the frequency of women with menstrual abnormalities and consequent menorrhagia, which is not uncommon in women with chronic diseases such as SLE. Diagnosis depends on demonstrations of low serum iron and serum ferritin (<20 μg/dl) and high total iron binding capacity (TIBC).

Although anemia of chronic disease and iron deficiency anemia are rarely life threatening, the third cause of anemia in SLE (namely, autoimmune hemolytic) can cause severe morbidity and even mortality.⁵ It is recognized by a precipitous fall in hemoglobin (>3 g/dl), elevated reticulocyte count (>5%), a rise in bilirubin and invariably, a positive Coombs test. In the mid 1980s,⁶ an association of hemolytic anemia with elevated aCL antibodies was first recognized and this association was confirmed in many subsequent studies. Although IgG aCL antibodies (particularly at high levels⁶) are most frequently associated with the condition, IgM aCL antibodies (also at high levels) have been similarly associated.⁷^–⁹ There is speculation that aPL antibodies might bind phospholipid-protein complexes on red cell membranes, resulting in increased uptake and destruction by the reticulo-endothelial system.⁸

The presence of aPL antibodies in patients with autoimmune hemolytic anemia should prompt treating physicians to seek a history of thrombocytopenia, venous or arterial thrombosis, or recurrent pregnancy loss. In addition, they should be alert to the possibility that any of these events (manifestations of the APS ¹) may occur in the future.

A sizable percentage of patients with autoimmune haemolytic anemia are aCL antibody negative, suggesting that autoantibodies with specificities for a variety of red cell membrane antigens may also account for red cell destruction. Treatment of autoimmune hemolytic anemia relies acutely on high-dose corticosteroid. The dose is tapered as the hemoglobin level rises.^4,⁵ For patients unresponsive to corticosteroids, immunosuppressive drugs, danazol,¹⁰ and more recently introduced agents such as mycophenolate mofetil¹¹ may be effective.

Pure red cell aplasia is an uncommon cause of anemia in SLE, presumably secondary to auto antibodies targeting red cell precursors in the bone marrow.¹² Corticosteroid or immunosuppressive agents have proven useful in these circumstances.

THROMBOCYTOPENIA

The finding of a platelet count between 100,000/dl and 150,000/dl is not uncommon in SLE, occurring in 20 to 30% of patients.¹³ However, severe thrombocytopenia (platelet counts <50,000/dl) is less common, occurring in about 5% patients at some time in the course of their disease.⁵ A small number of patients may present first with immune thrombocytopenic purpura (ITP) and later develop other features of SLE.

A number of studies have demonstrated an association of thrombocytopenia with IgG and/or IgM aCL antibodies or the LA.^6,^7,^14,¹⁵ As noted previously, the presence of thrombocytopenia with aPL antibodies should trigger an examination of the patient’s previous history (or an anticipation in the future) for complications of APS.¹

The association of thrombocytopenia with aPL antibodies might be explained by autoantibodies interacting with phospholipid-protein antigens in platelet membranes, resulting in enhanced uptake and destruction. Absorption of aPL antibodies by platelet membranes has been demonstrated in one study.¹⁶ Of relevance, too, are studies showing that these antibodies in the presence of low doses of ADP, collagen, and thrombin can result in platelet activation.¹⁷ Studies from our group have shown that affinity purified aCL antibodies from patients with APS-enhanced activation of platelets treated with suboptimal doses of ADP, thrombin, or collagen.¹⁷ In another study, rabbit aCL antibodies were shown to enhance collagen-induced platelet activation.¹⁸

The platelet GPIIb/IIIa receptor mediates platelet aggregation induced by all physiologic agonists and is the receptor for fibrinogen and a marker of platelet activation. We have shown that aPL antibodies enhance the expression of platelet membrane glycoproteins, particularly GPIIb/IIIa and GPIIIa, when platelets are pretreated with suboptimal doses of TRAP (a thrombin receptor agonist peptide).¹⁹ In a recent study, the intracellular events resulting from activation of platelets by antiphospholipid antibodies and subthreshold doses of thrombin have been examined and involve the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK).²⁰

The nature of the receptor(s) for aPL antibodies in platelets has not been completely elucidated. Studies have shown that the exposure of phosphatidylserine is necessary for aPL antibodies to enhance activation/aggregation of platelets.¹⁶ Another publication indicated that a 70-kDa protein in the platelet membrane is a receptor for rabbit aCL antibodies.¹⁸ Recently, investigators suggested that dimers of β₂GPI (a putative target antigen for aPL antibodies) bind to the receptor for apolipoprotein E (aPOER2′) on the membrane of platelets and enhance the phosphorylation of p38MAPK and release of thromboxane B2 initiated by collagen.²¹

APL antibodies cannot be the only explanation for thrombocytopenia in SLE, in that antiplatelet antibodies have been demonstrated in patients who are aCL antibody negative. Treatment of patients with immune thrombocytopenia often relies on high-dose corticosteroids initially, with introduction of immunosuppressive agents such as cyclophosphamide if patients are unresponsive to corticosteriods. Newer agents such as mycophenolate mofetil (less toxic than cyclophosphamide) may be beneficial.²² In those unresponsive to all of these drugs, splenectomy is recommended. High-dose immunoglobulin therapy is often effective in the acute management of life-threatening thrombocytopenia, but its effect is short-lived and treatment is expensive. Hence, if such therapy is used the physician should have a longer-term management strategy.

THE ANTIPHOSPHOLIPID SYNDROME AND VASCULAR COMPLICATIONS OF SLE

Background

In 1952, Conley and Hartmann first recognized an unusual coagulation abnormality in two patients with SLE who presented with hemorrhage and prolonged clotting tests.²³ In the subsequent decade, other SLE patients with this disorder were described, but it became increasingly evident that bleeding abnormalities noted initially were uncommon (even when these patients underwent surgery). The clotting abnormality came to be called the “lupus anticoagulant (LA).” In 1963, Bowie and colleagues reported that patients with the LA were subject, paradoxically, to recurrent thrombosis.²⁴ By the early 1980s, the association with both venous and arterial thrombosis was confirmed in several studies. Affected women were also found subject to recurrent pregnancy losses, usually occurring in the second or third trimester of pregnancy.²⁵

As interest in the LA grew in the 1960s and 1970s, investigators demonstrated that this abnormality was due to an autoantibody that interrupts the conversion of prothrombin to thrombin, resulting in a prolonged clotting test. The prothrombin-thrombin conversion reaction is catalyzed by phospholipids and there was speculation that the LA autoantibody interacted with one or more of these phospholipids. This was based on the finding that addition of a phospholipid mixture (containing phosphatidylserine) corrected the clotting abnormality. Demonstration that a monoclonal antibody with LA activity reacted with phospholipids utilizing an Ouchterlony technique also suggested specificity for phospholipids.²⁶ In addition, patients with the LA often had a biologic false-positive test for syphilis (BFP-STS), attributed to the presence of autoantibodies reacting with the phospholipid antigen cardiolipin.

It was the association of the LA with the BFP-STS that led Harris and colleagues to develop a solid-phase immunoassay with cardiolipin as antigen ²⁷ to detect antibodies with “LA activity.” Once developed, the aCL test correlated with LA positivity and proved to be far more sensitive than the LA test. This test also correlated with recurrent venous or arterial thrombosis, pregnancy loss, and/or thrombocytopenia in a population of SLE patients.²⁷ Although this laboratory symptom complex was first largely detected in those with SLE, later studies showed that it could occur independently of SLE. In addition, it became evident that “aCL antibodies” cross-reacted with other negatively charged phospholipids and hence these antibodies were designated “aPL antibodies.” The disorder with which these antibodies were associated was called the APS.^28,²⁹

In the early 1990s there came another surprise, in that aPL antibodies were found to bind the serum protein β₂-glycoprotein I (β₂GPI).^30,³¹ β₂GPI binds negatively charged molecules, including phospholipids. About 60 to 80% of patients positive for the aCL test will bind β₂GPI presented on oxidized polystyrene plates.³² In some patients with aPL antibodies, binding to other serum proteins (including prothrombin) has been demonstrated.³³ Hence, antiphospholipid antibodies are best regarded as consisting of diverse subpopulations specific for β₂GPI, other serum proteins, negatively charged phospholipids, and protein-phospholipid complexes.

Clinical Features

Because patients with APS may be subject to thrombosis at any venous or arterial sites, involving vessels of any size, this disorder may present in many ways. In the venous system, deep-vein thrombosis is most frequent, but thrombosis of the inferior vena cava, hepatic, portal, renal, pulmonary, and sagital veins have all been described. In the arterial circulation, presentation with stroke is most frequent, but thrombosis of mesenteric, coronary, brachial, digital, and ocular arteries have all been reported. Hence, in addition to deep-vein thrombosis or stroke other presentations may include gangrene of the fingers, bowel infarction, loss of vision in an eye, myocardial infarction, and so on. Some patients have pulmonary hypertension, either secondary to pulmonary vascular thrombosis or multiple pulmonary emboli.

In most instances, thrombosis is episodic, but antibody levels are persistently present—suggesting that thrombosis is triggered by a site-specific vascular event in the presence of aPL antibodies. Some patients present with an aggressive thrombotic diathesis, where multiple sites are affected either simultaneously or over a period of weeks. This presentation has come to be known as the catastrophic antiphospholipid syndrome (CAPS).³⁴ Occlusion of small vessels appear to be most frequent, leading to ischemia of multiple organs such as the kidneys, bowels, lungs, heart, adrenal glands, and skin. This presentation is very similar to TTP or to disseminated intravascular coagulation (DIC).¹ The presence of a moderate to high positive aCL test and/or an unequivocally positive LA test would help clinch the diagnosis of CAPS.

Pregnancy loss is a frequent occurrence in women with the APS.³⁵ Although the earlier literature emphasized losses in the second and third trimester, this complication can occur at any time during pregnancy. In many but not all instances, placental infarction secondary to thrombosis of placental vessels is present. Some studies suggest that placental vascular thrombosis occurs because aPL antibodies displace annexin A5, a phospholipid binding protein in the placental trophoblast.³⁶ This results in “exposure” of the negatively charged phospholipid template of the placental vasculature, which serves as a catalytic surface for coagulation protein interactions, resulting in thrombosis.

There are a number of other clinical features associated with APS not attributable to thrombosis. The occurrence of thrombocytopenia (and less frequently hemolytic anemia) has already been discussed. Cardiac valvular abnormalities are also frequently observed. These include valvular vegetations (Libman-Sachs endocarditis), valvular thickening, valvular stenosis, and regurgitation. Whereas abnormalities of any of the four valves have been described, mitral involvement is most frequent, followed by the aortic valve.³⁷

These are a variety of non-thromobotic neurologic abnormalities described in APS. These include transverse myelopathy, chorea, Guillan-Barre syndrome, psychosis, and migraine headaches. Skin manifestations have also been described, including livedo reticularis and leg ulcers, often located in the pre-tibial or ankle areas.

Most of the non-thrombotic manifestations of APS described prevously (such as thrombocytopenia, hemolytic anemia, valvular abnormalities, neurologic, and skin manifestations) can occur in SLE in the absence of aCL or LA positivity. If these non-thrombotic complications are explained by autoimmunity, it suggests that APS and SLE share common autoantibodies that are not limited to aPL antibodies.

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