CHAPTER 128 LUPUS ANTICOAGULANTS AND RELATED DISORDERS
CHAPTER 128 LUPUS ANTICOAGULANTS AND RELATED DISORDERS
JACOB H. RAND
Definition and History
Etiology and Pathogenesis
Systemic Vascular Thrombosis
Lupus and Other Autoimmune Conditions
Stroke and Other Neurologic Conditions
Catastrophic APL Syndrome
Pregnancy Losses, Obstetrical Complications, and Infertility
Coronary Artery Disease
Valvular Heart Disease
Peripheral Vascular Disease
“Seronegative” APL Syndrome
APL and AIDS
APL Syndrome in Children
Therapy, Course, and Prognosis
The antiphospholipid (aPL) syndrome is an acquired disorder in which patients have thrombotic manifestations together with laboratory evidence for autoantibodies which recognize anionic phospholipid-protein complexes. The disorder is considered to be secondary when it occurs in the presence of systemic lupus erythematosus (SLE) or other major autoimmune conditions and primary in their absence. The aPL syndrome usually manifests clinically as vascular thrombosis or embolism or as recurrent spontaneous pregnancy losses. While the deep veins of the lower extremities are the most frequent sites of thrombosis, thromboembolism can involve virtually any portion of the arterial or venous circulations. Additional reported manifestations of the aPL syndrome include immune thrombocytopenia, livedo reticularis, stroke, atherosclerosis, pulmonary hypertension, and sensorineural hearing loss. Rare patients will present with a catastrophic form of the aPL syndrome caused by disseminated large- and small-vessel thrombi with accompanying multiorgan ischemia and infarction. This form of the disorder may also mimic the presentation of thrombotic thrombocytopenic purpura or disseminated intravascular coagulation.
The antigenic targets for the antibodies generated in this condition appear to be epitopes on phospholipid-binding proteins such as b2 glycoprotein I (b2GPI) rather than the phospholipid itself. The syndrome is recognized by laboratory evidence for the presence of antibodies against these phospholipid-protein cofactor complexes by ELISA assays (anticardiolopin, antiphosphatidyl serine, or anti-b2GPI assays) or by coagulation assays (“lupus anticoagulants”) which paradoxically report the inhibition of phospholipid-dependent coagulation reactions. Several conditions are associated with increased levels of antibodies directed against anionic phospholipids themselves but not against protein cofactors. These are not associated with an increased risk of thrombosis and include infections such as syphilis and Lyme disease, hepatitis C and alcoholic liver injury, HIV infection, and multiple sclerosis.
Patients with spontaneous vascular thrombosis and the aPL syndrome should be treated with oral anticoagulant therapy. Hydroxychloroquine may be a useful adjunct for prevention of thrombosis. The catastrophic aPL syndrome may require additional therapy with high-dose anticoaguclants, plasmapheresis, and immunosuppressive agents. Patients with recurrent spontaneous pregnancy losses and the aPL syndrome require treatment with aspirin and heparin for the major portion of their pregnancies and may need additional prophylaxis against deep vein thrombosis during the postpartum period. Since aPL tests may be abnormal in conditions other than the aPL syndrome, patients should not be committed to antithrombotic therapy on the basis of laboratory tests alone. The clinician should have documented evidence-or at least a very high suspicion—for thromboembolism or pregnancy losses before treating. In patients who are treated with warfarin, care should be taken to confirm that coagulation tests for monitoring oral anticoagulant therapy reflect true reductions in the levels of coagulation proteins and that these are not artifactually affected by lupus anticoagulants.
Acronyms and abbreviations that appear in this chapter include: aCL, anticardiolipin; APC, activated protein C; aPS, antibodies to phosphatidyl serine; aPL, antiphospholipid; BFP syphilis test, biological false-positive serological test for syphilis; dRVVT, dilute Russell viper venom time; GP, glycoprotein; IVF, in vitro fertilization; LA, lupus anticoagulant; LMWH, low-molecular-weight heparins; PAI-1, plasminogen activator inhibitor 1; RVV, Russell viper venom; SLE, systemic lupus erythematosus; SNAP, seronegative aPL syndrome.
DEFINITION AND HISTORY
The aPL antibody syndrome is a disorder in which vascular thrombosis or recurrent pregnancy losses occur in patients who have laboratory evidence for antibodies against phospholipids or phospholipid-binding protein cofactors. The presence of these antibodies is detectable with immunoassays using solid phase phospholipids (the structures of several relevant phospholipids are shown in Fig. 128-1) and protein cofactors as antigenic targets, or with coagulation assays that demonstrate the inhibition of phospholipid-dependent coagulation reactions known as the lupus anticoagulant (LA) phenomenon. The syndrome was first proposed to be a distinct entity, the anticardiolipin (aCL) syndrome, in 19851 and was soon renamed the aPL syndrome.2 The disorder is classified as primary if no other autoimmune condition such as systemic lupus erythematosus is concurrent, and secondary in the presence of such disorders (Fig. 128-2). There appears to be no difference in the clinical presentations or in the courses of thrombosis of patients with the primary and secondary disorders.3,4 In view of the apparent multiplicity of antigens recognized by the antibodies (see “Antigenic Specificities” below) and the ambiguous pathophysiology, other names for the condition, such as the aPL/cofactor syndrome,5 the antibody-mediated thrombosis syndrome,6,7 or the eponym Hughes syndrome8 have been proposed.
FIGURE 128-1 Phospholipid structures. (Reprinted with permission from Obstet Gynecol Surv.154)
FIGURE 128-2 The conceptual distribution of patients having antibodies against phospholipid and of patients with the aPL syndrome. The large thick-walled circle includes all patients having antibodies against phospholipid. Within this group are patients with the aPL syndrome (primary, secondary, and asymptomatic) and patients having antibodies but lacking the syndrome. Outside the circle are patients with seronegative aPL syndrome (“SNAP”) and patients with SLE lacking aPL antibodies.
In retrospect, the first serologic evidence for the disorder was the observation of the biological false-positive serological test for syphilis (BFP syphilis test), described by Moore and Mohr in 1952.9 This laboratory anomaly was found to often be associated with SLE10 and with an anticoagulant phenomenon,11 but its clinical significance was not known. In the early 1950s, the development of coagulation tests which used a phospholipid extract of animal brain (cephalin) to accelerate coagulation reactions12 led to the recognition of abnormalities that were attributed to the presence of an anticoagulant in patients with systemic lupus eythematosus—frequently together with BFP syphilis tests. This phenomenon was named the “lupus anticoagulant.13 Although the first report of patients with these anticoagulants described bleeding manifestations,14 it became evident that these in vitro anticoagulants were associated with bleeding problems in vivo only if there were other hemostatic defects present, such as hypoprothrombinemia, thrombocytopenia, platelet function abnormalities, or specific inhibitors of blood coagulation factors.11 It was surprising when these anticoagulants were found to be associated with thrombotic and embolic manifestations15 and with recurrent pregnancy loss.16 A major step leading to the identification of the aPL syndrome occurred in 1983 when a quantitative test was developed to assay antibodies against the anionic phospholipid known as cardiolipin (diphosphatidyl glycerol), which is the primary antigen in the syphilis test reagent.17
As shown in Fig. 128-2, individuals having aPL antibodies include those with aPL syndrome (whether primary or secondary) and those without the clinical syndrome. The latter include completely asymptomatic normal healthy people, patients with infections that induce antibodies recognizing anionic phospholipids directly, and patients on medications such as chlorpromazine or procainamide. In the asymptomatic normal healthy population there are some individuals who are at high risk but have not yet developed the disorder (pre-aPL syndrome). There are also patients who are suspected to have a seronegative form of the disorder (SNAP—seronegative aPL syndrome).
ETIOLOGY AND PATHOGENESIS
The genesis of the antibodies in this disorder and even their antigenic specificities are not yet understood. The disorder is generally considered to fall into the category of autoimmune conditions. While antibodies against anionic phospholipid moeities arise during the course of infections such as syphilis and Lyme disease, those antibodies are distinct from antibodies generated by patients with the syndrome, because they recognize phospholipid epitopes directly (i.e., they are not cofactor dependent) and are not associated with the clinical manifestations of the syndrome. In contrast (as described below in “Antigenic Specificities”), the antibodies generated in patients with the syndrome recognize epitopes which include protein cofactors, primarily b2GPI, and thus are often referred to as being cofactor-dependent.
GENETIC PREDISPOSITION HLA Linkages
Familial clustering of raised aPL antibody levels18 along with HLA-linkages19,20,21 and 22 indicate that the antibodies probably occur in response to some antigenic challenge in a genetically susceptible host. One study suggested that the aPL responses in SLE and in primary aPL syndrome are immunogenetically distinct from SLE itself. The strongest association with aPL was the HLA-DR53 haplotypes, some of which include DQ7, whereas the HLA-B8, DR17, DQ2 haplotypes closely associated with SLE were significantly decreased in patients with primary and secondary aPL syndrome.20
POSSIBLE ETIOLOGIC AGENTS
There have been intriguing reports of the aPL syndrome arising in patients with infections (in contrast to patients having antibodies against phospholipid alone without the syndrome, whose relationship to infection has been well established). aPL antibodies have been reported in patients with postvaricella purpura fulminans23 or venous thrombosis24, in patients with varicella pneumonia and spontaneous tibial artery thrombosis25 and in patients with hepatitis C.26 An association of aPL and mesenteric and femoropopliteal thrombosis in a patient with cytomegalovirus infection has also been reported.27 Also, b2GPI cofactor dependent antibodies against cardiolipin, phosphatidyl serine and phosphatidyl ethanolamine have been identified in sera from patients with parvovirus B19.28 Anticardiolipin antibodies having b2GPI-dependence and lupus anticoagulant activity have been generated in rabbits immunized with lipid A and lipoteichoic acid, suggesting that some bacteria might contribute to the production of pathogenic aPL antibodies.29 It has been proposed that cellular apoptosis, with the resulting exposure of anionic phospholipids on the cell surface, triggers the generation of aPL antibodies.30,31 and 32
The pathophysiologic mechanisms of this syndrome have remained obscure. In part, this is because of the apparent multiplicity of antigenic determinants recognized by the antibodies. Also, a large number of effects have been described for the antibodies in vitro and in cell culture systems, and it is difficult to determine which of these are clinically relevant. Many of these effects, including the paradoxical lupus anticoagulant (LA) phenomenon, are a consequence of the multiple roles involving phospholipids in the hemostatic system and in biologic processes in general.
RELATIONSHIP OF ANTIBODIES TO CLINICAL MANIFESTATIONS-EVIDENCE FROM ANIMAL STUDIES
Although there had been much debate about the relationship of the aPL antibodies to the disease process—i.e., whether cause, effect, or epiphenomenon—convincing evidence has accumulated from experimental animal models of the aPL syndrome to indicate that aPL antibodies can play a causal role in the development of thrombosis and pregnancy loss. Mice immunized against b2GPI develop aPL antibodies and pregnancy wastage.33 Mice that have been passively or actively immunized with aPL antibodies develop fetal wastage.34,35 and 36 Also, mice infused with the aPL antibodies developed significantly larger thrombi in femoral veins after experimental vascular injury than mice infused with control antibodies.37,38 Importantly, a monoclonal human anticardiolipin antibody derived from a patient with the aPL syndrome promoted thrombosis in mice.39 Also, atherosclerosis in a susceptible mouse model (the LDL-receptor knockout mouse) was accelerated by immunization with human anticardiolipin antibodies from an aPL syndrome patient, suggesting that these antibodies may play a role in the development of atherosclerosis in patients with the aPL syndrome.40
A direct causal relationship between aPL antibodies and thrombotic manifestations or pregnancy losses in humans has not yet been proved. While it is clear that there are patients with aPL antibodies who manifest thrombosis and pregnancy loss, the fact that elevated levels of antibodies are detectable in a significant proportion of asymptomatic individuals41,42,43 and 44 has raised questions about their predictive value.
While there is evidence that some aPL antibodies may recognize phospholipids directly without protein cofactors,45 purified aPL antibodies generally do not bind directly to purified cardiolipin in the absence of a source of serum proteins.46,47 aPL antibodies from patients with the syndrome are usually “dependent” upon a serum phospholipid-binding protein, that is known as b2GPI or apolipoprotein H, for recognition of the phospholipid in ELISAs. In contrast, antibodies against phospholipid that arise in the course of the immunologic response to syphilis infection are not cofactor-dependent and recognize the anionic phospholipid epitopes directly.48
b2GPI is a highly glycosylated single-chain plasma protein composed of 326 amino acids with a molecular weight of 50 kDa (Fig. 128-3) that appears to be the major, but not the only, cofactor for the recognition of anionic phospholipid by aPL antibodies.49 The protein is a member of the complement control protein or short consensus repeat superfamily.50 There is evidence that b2GPI itself may be one of the major epitopes for aPL antibodies or may, in complex with phospholipids, form an antigenic site. aPL antibodies can recognize b2GPI directly (i.e., in the absence of phospholipid) if the protein antigen is present on microtiter plates at a sufficient density.51,52 The protein has repeating motifs or domains that structurally resemble multiple loops (“sushi domains”). The physiologic function of b2GPI has not yet been established, but it has been proposed that the protein may play a scavenging role for exposed anionic phospholipid following apoptosis.53 Work with deletional mutants demonstrated that the phospholipid recognition and an antibody recognition site are present at the protein’s highly cationic fifth sushi domain.54,55 and 56 The relationship between antibody recognition of b2GPI and thrombosis is not yet clear; however, there is also evidence that aPL antibody recognition of the fourth sushi domain plays a role.57
FIGURE 128-3 Amino acid sequence and location of disulfide bonds in human b2GPI. (Reprinted with permission from Hughes et al.8)
Following the discovery of the cofactor role for b2GPI, additional candidate cofactors and antigenic targets were identified.58 These include prothrombin (coagulation factor II), coagulation factor V, protein C, protein S, annexin-V, high-molecular-weight kininogen, and low-molecular-weight kininogen. Interestingly, protein C can be a target of aCL in the presence of cardiolipin and b2GPI, leading to protein C dysfunction.59 Also, antibodies of some aPL patients have been found to cross-react with heparin and inhibit the formation of antithrombin III-thrombin complexes.60
It has been proposed that phosphatidyl-ethanolamine reactivity is associated with thrombosis in autoimmune diseases, since a high proportion of patients with aPL syndrome also have antibodies reactive with this zwitterionic phospholipid.61 Antibody recognition of phosphatidyl-ethanolamine appears to require kininogen or kininogen-associated proteins as cofactor.62
The oxidation of phosphospholipids may be necessary for aPL antibody recognition.63,64 The epitopes for some aPL antibodies appear to be adducts of oxidized phospholipid and protein such as b2GPI.65 Thus, some affinity-purified cardiolipin-binding antibodies in sera from patients with systemic lupus erythematosus appear to cross-react with oxidized LDL.66 Elevated levels of the latter antibodies have been proposed to be markers for arterial thrombosis,67 but there is controversy on this point.68
Antimitochondrial M5 type antibodies have been reported to be a serological marker for the aPL syndrome distinct from anticardiolipin and anti-b2GPI antibodies. These antibodies, unlike aCL and anti-b2GPI IgG antibodies, are not significantly associated with thrombosis, but they are associated with thrombocytopenia and recurrent fetal loss.69
PROPOSED PATHOGENIC MECHANISMS
Since virtually any of the many biologic processes that involve or require phospholipids may be affected by the presence of antibodies which bind to the phospholipids (either directly or via cofactors), any proposed aPL-mediated effects that are based on in vitro studies must be evaluated for in vivo relevance. Also, any plausible explanation for the aPL syndrome needs to account for the paradox of the LA phenomenon. The current hypotheses for pathogenic mechanisms in the aPL syndrome are summarized in Table 128-1. It is possible that several of these effects could act in concert to cause the clinical manifestations.
TABLE 128-1 MECHANISMS PROPOSED FOR THE aPL SYNDROME
aPL Antibody-mediated Disruption of the Annexin-V Anticoagulant Shield Annexin-V (placental anticoagulant protein-I, vascular anticoagulant a) has potent anticoagulant properties in vitro that are based on its high affinity for anionic phospholipids and its capacity to displace coagulation factors from phospholipid surfaces.70 Thus far, more than 20 annexin proteins have been identified in both animal and plant cells.71,72 These are very similar in structure, with most of the members consisting of 4 highly homologous cassette domains of about 70 amino acids each. The uniqueness of each of the proteins is believed to reside in the structure of its amino-terminal sequences.
Annexin-V significantly prolongs phospholipid-dependent coagulation reactions by forming two-dimensional clusters that displace coagulation proteins from phospholipid surfaces.70 This clustering property is likely to be of functional importance, since it permits the formation of a protective shield of annexin-V over the phospholipid surface, blocking the phospholipids from availability for coagulation reactions.
There is evidence to suggest that annexin-V plays an antithrombotic role in physiologic conditions. Phosphatidyl serine is present on the apical membranes of syncytialized trophoblasts, where it is covered by a binding layer of annexin-V.73,74 and 75 Treatment of a pregnant animal model with anti–annexin-V antibodies results in placental necrosis, fibrosis, and pregnancy loss.76 Dissociation of annexin-V from the surface of human placental trophoblasts and human umbilical vein endothelial cells accelerates the coagulation of plasma exposed to those cells.77 Thus, annexin-V may play a thrombomodulatory role on the surfaces of cells lining the placental and systemic vasculatures.
aPL antibodies may promote thrombosis by displacing annexin-V from phospholipid membrane surfaces.78 There is a marked reduction of annexin-V on the apical membranes of human placentas of women with aPL antibodies as compared to placentas of women with uncomplicated term deliveries, non-aPL-related pregnancy losses and elective pregnancy-terminations.79,80 Moreover, IgG fractions from aPL syndrome patients reduce the quantity of annexin-V on cultured trophoblasts and endothelial cells and also accelerate the coagulation of plasma exposed to these cells.77 Similarly, a monoclonal antiphosphatidyl serine antibody reduces the level of annexin-V on a syncytialized trophoblast cell line and increases the binding of prothrombin to these cells.75
While the displacement of annexin-V occurs via aPL antibodies, some investigators have identified patients with antibodies that recognize annexin-V directly.81,82 Anti–annexin-V antibodies from patients with the aPL syndrome can induce apoptosis in cultured human umbilical vein endothelial cells.83
Effects of aPL Antibodies on Platelets and on Eicosanoid Metabolism Some investigators have demonstrated that aPL antibodies stimulate platelet aggregation.84,85 Also, circulating activated (CD62-positive) platelets were detected by flow cytometry in the majority of primary aPL syndrome patients with neurological disease, suggesting the existence of a relationship among activated platelet, aCL, and the neurological disorders.86
aPL antibodies may alter the balance of eicosanoid synthesis toward prothrombotic moieties as indicated by the presence of an increased quantity of thromboxane metabolites in the urine of aPL patients compared to controls.87,88 However, other studies have not found aPL antibodies to affect eicosanoid metabolism.89,90
Effects of aPL Antibodies on Vascular Endothelial Cells aPL antibodies have been found to recognize, injure, and/or activate cultured vascular endothelial cells.91,92,93 and 94 Cultured endothelial cells incubated with aPL express increased levels of cell adhesion molecules,95 an effect that may be mediated by b2GPI96 and may increase the adhesion of leukocytes to the vascular wall and promote inflammation and thrombosis. Not all studies have been able, however, to demonstrate such an effect.97 It has also been demonstrated that incubation of cultured endothelial cells with aPL results in the increased expression of tissue factor.98,99 Significantly increased plasma levels of endothelin-1, which is thought to play a role in arterial tone, vasospasm, and thrombotic arterial occlusion, were found in aPL syndrome patients with arterial thrombosis.100 Human monoclonal aCL-induced prepro-endothelin-1 mRNA levels significantly more than control monoclonal antibody.
Immune Complexes The IgG2 subtype of aPL is most closely associated with thrombosis95; it has therefore been postulated that complement-fixation plays an important role in aPL-mediated thrombosis. High-titer anticardiolipin IgG antibodies have been shown to bind complement C5b-9, as demonstrated by a monoclonal antibody.101 Also, it has been found that the concentration and avidity of aPL antibodies were higher in fractions which were enriched for circulating immune complexes.102
Induction of Tissue Factor Activity by Leukocytes In addition to the expression of tissue factor by cultured endothelial cells mentioned above,98 aPL antibodies have also been reported to promote tissue factor synthesis by leukocytes.103 In one study, the ability of IgG to stimulate monocyte tissue factor expression was associated with the presence of decreased free protein S and increased prethrombotic markers.104
Interference with the Components of the Protein C Pathway The protein C pathway, one of the important endogenous antithrombotic mechanisms (see Chap. 113), is initiated when thrombin binds to thrombomodulin on endothelial cells. This binding modifies the substrate specificity of thrombin; the enzyme loses its procoagulant specificities and cleaves protein C to activated protein C (APC). In the presence of the free form of protein S, APC proteolyzes coagulation factors Va and VIIIa. aPL antibodies can interfere with the protein C system by: (1) inhibiting the formation of thrombin; (2) decreasing the activation of protein C by the thrombomodulin-thrombin complex; (3) inhibiting the assembly of the protein C complex; (4) inhibiting the activity of protein C, directly or via its cofactor protein S, and (5) binding to factors Va and VIIIa in a manner that protects them from proteolysis by APC.105 In addition, patients with aPL syndrome have been found to have protein S deficiency.106,107
Inhibition of the Antithrombin-III Pathway Antithrombin-III is a member of the serine protease inhibitors family. Individuals with inherited deficiencies of antithrombin III are at increased risk for deep vein thrombosis (see Chap. 127). The antithrombotic activity of this protein is markedly accelerated by the presence of heparin. In vivo, heparan sulfate proteoglycans may exert a thrombomodulatory effect. It has been demonstrated that at least some aPL antibodies cross-react with heparin and heparinoid molecules (which are highly polyanionic) and inhibit the acceleration of antithrombin-III activity.60
Additional Effects aPL antibodies may show cross-reactivity against oxidized-LDL63,64,66 and may thereby be associated with an increased risk of atherosclerosis.108 Also, it has been suggested that fibrinolysis may be impaired in the aPL syndrome, since females with the disorder have been described to have elevated plasminogen activator inhibitor 1 (PAI-1) levels.106 Fibrinolysis may also be impaired via anti-b2GPI-mediated inhibition of the autoactivation of factor XII109 and the ensuing reductions of kallikrein and urokinase.
Although aPL antibodies are unquestionably associated with thrombosis, it is also clear that there are a significant number of individuals with positive aPL screening tests who are asymptomatic. At present, it is not possible to distinguish those asymptomatic individuals who are at increased risk for future thromboembolic events and pregnancy losses (pre-aPL syndrome) from false positives (Fig. 128-2). The current available data from animal models support a causal role for the antibodies in the development of thrombosis. However, it remains possible that the primary pathogenic process might be the exposure of thrombogenic anionic phospholipids through some other process and that the development of aPL could be the effect of autoimmune reactivity to anionic phospholipids in susceptible individuals. For example, the surfaces of apoptotic cells promote procoagulant activity,110 and aPL antibodies have been shown to bind to phospholipid exposed by apoptotic thymocytes.31 Thus, it is possible that aPL antibodies may be both an effect and a cause of thrombosis. Anionic phospholipids, exposed during blood clotting, could trigger immunological recognition and formation of aPL antibodies which could then promote a vicious cycle through their thrombogenic properties. Finally, it is still possible that the aPL could be an epiphenomenon or a surrogate marker and not directly involved in the cause-effect relationships of this disease process.
Patients generally present with thrombotic manifestations-i.e., evidence for vaso-occlusion or end-organ ischemia or infarction—and/or pregnancy losses and complications. The usual age of patients at the time of presentation with thrombosis is about 35 to 45,111 with the disease rarely presenting past the age of 60.112 Men and women are equally susceptible.111 The thrombotic manifestations may occur in the setting of a concurrent autoimmune condition such as SLE (secondary aPL syndrome) or as an independent autoimmune disorder (primary aPL syndrome). No differences have been observed between the arterial and venous distributions of thromboses of primary and secondary aPL patients.113
TABLE 128-2 CLINICAL MANIFESTATIONS OF THE aPL SYNDROME
SYSTEMIC VASCULAR THROMBOSIS
Patients may present with spontaneous venous and/or arterial thrombosis or embolism which may involve any site in the vasculature. The syndrome should be especially suspected when unusual sites are involved or when a patient experiences recurrent thromboses with no other cause.114 Nevertheless, most patients will present with deep vein thrombosis of the lower extremities, similar to most patients with venous thromboembolism and to patients with other thrombophilias.115 In one study of patients with radiologic evidence of thrombosis, 59 percent had thrombi limited to the venous circulation, 28 percent had solely arterial thromboses, and 13 percent had both types of events.114 Deep vein thrombosis of the legs was the most common finding, occurring in about half of the patients; other sites of venous thrombotic events included pulmonary embolism, thoracic veins (superior vena cava, subclavian vein, or jugular vein), and abdominal or pelvic veins.114 Patients may also present with stroke, cerebral venous infarction, upper extremity venous thrombosis,115 myocardial infarction, adrenal infarction, acalculous gall bladder infarction, aortic thrombosis with renal infarction,116 and mesenteric artery thrombosis.117
Thrombosis may occur spontaneously or in the presence of a predisposing factor such as estrogen hormone replacement therapy, oral contraceptives,113,118 vascular stasis, surgery, or trauma. Women are at particularly high risk for venous thrombosis during pregnancy and in the postpartum period.113 Some patients with venous thrombosis—but generally not with arterial thrombosis119—will also have concurrent genetic thrombophilic conditions such as heterozygosity for the factor V Leiden polymorphism.119,120,121 and 122 Having a history for a previous thromboembolic event is a major risk factor for future thromboembolism. The risk of recurrence doubles to about 30 percent in patients with a first episode of venous thromboembolism who also have aCL antibodies.123 The risk of recurrence correlates with the titer of antibodies.123
A 4-year prospective study of 360 patients with aPL antibodies reported that previous thrombosis and aCL titer higher than 40 U are independent predictors of thrombosis.124 Remarkably, other than thrombosis, hematological malignancies including non-Hodgkin lymphoma were the major causes of death in this group of patients.
LUPUS AND OTHER AUTOIMMUNE CONDITIONS
The aPL syndrome is classified within the category of autoimmune disorders. Patients may have concurrent features of other autoimmune conditions such as SLE. About 30 to 40 percent of SLE patients have elevated aPL antibodies. In one study of 47 patients with SLE and aPL antibodies who were diagnosed for the aPL syndrome, about half had thrombosis, about half had thrombocytopenia, and about 40 percent had neuropsychiatric manifestations, consisting mainly of cerebrovascular ischemic disease.125 Immune thrombocytopenia is probably the most common concurrent condition in patients with the aPL syndrome. aPL syndrome has also been associated with myasthenia gravis,126 Budd-Chiari syndrome in the setting of SLE,127 Graves’ disease,128 autoimmune hemolytic anemia, progressive systemic sclerosis,129 Evan’s syndrome,130 and secondary Sjogren’s syndrome in the presence of SLE.131 There does not appear to be a direct association between relapsing polychondritis and the aPL syndrome.132 Rather, the elevated aPL antibodies in patients with this disorder appear to occur in patients who also have SLE. Although patients with vaso-occlusive disease and aPL antibodies generally have thrombosis,133 elevated aPL antibodies have also been observed in vasculitis. aCL antibodies are present early in the course of giant cell arteritis and disappear within a few weeks of initiation of corticosteroid therapy.134 Takayasu arteritis135 and polyarteritis nodosa136 have also been associated with the aPL syndrome.
STROKE AND OTHER NEUROLOGIC CONDITIONS
Prospective analysis for the presence of aPL antibodies in stroke patients in the AntiPhospholipid Antibody Stroke Study (APASS) demonstrated that elevated levels of anticardiolipin antibodies are associated with increased risk for developing stroke but not with subsequent thromboembolic events.137 The aPL syndrome should be suspected in young patients with transient ischemic attacks or stroke, particularly when the usual risk factors for cerebrovascular disease are absent.138 aPL-associated stroke has also been reported with other medical conditions such as Crohn’s disease139 and liver transplantation.140 Most aPL patients presenting with stroke appear to have arterial thromboembolic strokes that are clinically indistinguishable from general patients with arteriosclerotic strokes; however, a significant proportion of patients have cerebral venous infarction.141 aPL antibodies may be an important factor contributing to development of cerebral venous thrombosis even in the presence of other potential etiologies or risk factors. The onset of cerebral venous thrombosis in the presence of aPL antibodies occurs at a relatively young age and with relatively more extensive involvement of the superficial and deep cerebral venous system.141 In one series of 40 cases of cerebral venous thrombosis, three patients (8 percent) had elevated aPL antibodies, and two of these three also had factor V Leiden mutation.142 Superior sagittal sinus thrombosis has been associated with the primary aPL syndrome.143
Additional neurologic abnormalities which have been associated with aPL antibodies include seizures, chorea, migraines, Guillain-Burré syndrome, transient global amnesia, dementia, diabetic peripheral neuropathy, and orthostatic hypotention.144 Recurrent acute transverse myelopathy has been described with aPL syndrome145,146,147,148 and 149; however, in one study of 315 SLE patients, including 10 with a history of transverse myelopathy, the disorder was not associated with aPL antibodies.150 There is a high incidence of elevated aCL antibodies in patients with multiple sclerosis (in one series 9 percent had IgG antibodies and 44 percent had IgM antibodies).151 However, no clinical distinction has been observed betwen aPL-positive and aPL-negative multiple sclerosis patients. An increased prevalence of LA and aCL antibodies in psychotic patients, even in the absence of taking chlorpromazine or other antipsychotic drugs, has been reported.152 In this study, 32 percent (11/34) of the unmedicated psychotic patients had laboratory evidence for aPL antibodies.152
CATASTROPHIC aPL SYNDROME
Rarely, patients present with a catastrophic form of the aPL syndrome, which is characterized by severe widespread vascular occlusions, sometimes leading to death. These patients present with evidence for severe multiorgan ischemia/infarction, usually with concurrent microvascular thrombosis. Patients with catastrophic aPL syndrome can present with massive venous thromboembolism, along with respiratory failure, stroke, abnormal liver enzymes, renal impairment, adrenal insufficiency and areas of cutaneous infarction. The respiratory failure is usually due to acute respiratory distress syndrome and diffuse alveolar hemorrhage. Laboratory evidence for disseminated intravascular coagulation is frequently present. A review of 50 patients with catastrophic aPL syndrome153 showed that two-thirds were females, with a mean age in the late thirties, but ranging from childhood to old age. Most had primary aPL syndrome, while the minority had SLE and other autoimmune conditions including Sjogren syndrome, scleroderma and rheumatoid arthritis. Precipitating factors were thought to contribute to the development of catastrophic aPL syndrome in some of the patients. These included infections, drugs (sulfur-containing diuretics, captopril, and oral contraceptives), surgical procedures, and cessation of prior anticoagulant therapy. The patients usually presented with multiple organ failure developing over a very short period of time. Most patients manifested evidence of microangiopathy affecting predominantly small vessels of the kidney, lungs, brain, heart, and liver. Only a minority of patients experienced large-vessel occlusions. Death occurred in about half of the patients.
PREGNANCY LOSSES, OBSTETRICAL COMPLICATIONS, AND INFERTILITY
For a comprehensive review, the reader is referred to Lockwood and Rand.154 Most studies have estimated the prevalence of aPL antibodies among general obstetric populations at about 5 percent or less; most of these patients are not clinically affected.155 Among obstetrical patients with recurrent fetal losses, about 16 to 38 percent of patients are found to have aPL antibodies.
Female patients with the aPL syndrome often present with a history of recurrent (usually defined as three or more) pregnancy losses. Pregnancies occurring in women with aPL antibodies are at significantly increased risk of miscarriage, prematurity, intrauterine growth retardation, and preeclampsia.156 Although pregnancy losses occurring in the middle trimester or later in pregnancy—even stillbirth-are most striking, it has been estimated that approximately half of the patients with this condition experience first-trimester losses. Pregnant patients with the aPL syndrome are also more prone to develop deep vein thrombosis during pregnancy or the puerperium. Rarely, pregnant patients develop the catastrophic form of the aPL syndrome, described above.157,158 The best predictor for pregnancy loss in a patient testing positive for aPL antibodies is not the degree of laboratory abnormality but whether the patient has a history of previous pregnancy loss or thrombosis.124,159
There is evidence for increased activation of coagulation mechanisms in pregnant women with the aPL syndrome. Prothrombin activation fragment F1.2, a marker for thrombin generation, is increased in pregnant patients with aPL antibodies and a previous history of pregnancy losses, compared to control healthy non-aPL pregnant women.160 Histologic abnormalities were found in many, but not all, placentas of aPL patients. One study did not define a morphologic lesion specific for the aPL syndrome but did describe a higher frequency of decreased vasculo-syncytial membranes, the presence of villous fibrosis, hypovascular villi, increased syncytial knots, and evidence of thrombosis or infarction.161 Studies of placental pathology in patients with aPL antibodies but without a prior history of fetal loss showed that about half had uteroplacental vascular pathology, about half had evidence of thrombotic occlusion, and about one-third had chronic villitis and/or decidual plasma cell infiltrates.162,163
The thrombotic occlusions and vascular pathology may be due to the marked decrease of the placental anticoagulant protein annexin-V which has been described on the apical membranes of aPL placental syncytiotrophoblasts.79 It has been proposed that the reduction of this protein, which normally lines the interface between the maternal and fetal circulations, may disrupt a constitutive antithrombotic mechanism within the intervillous blood circulation.74,76 This would accelerate coagulation within the maternal side of the maternal-fetal interface.
There is controversy about whether aPL syndrome is a cause of reproductive failure (i.e., infertility) in patients undergoing in vitro fertilization (IVF). In one study of women undergoing this procedure, aPL antibodies were detected in 22 percent of women with implantation failure compared with 5 percent of controls.164 It was noted that most of these antibodies reacted with phospholipids other than cardiolipin. Nevertheless, other investigators are not convinced that aPL antibodies play a role in infertility and IVF-failure.165,166
A minority of patients with the aPL syndrome exhibit a bleeding tendency. In these patients, the presence of a concurrent coagulopathy needs to be excluded. Severe bleeding due to acquired hypoprothrombinemia has been reported.167,168 This diagnosis may be missed when coagulation abnormalities are attributed only to the LA effect, and thus a specific assay for prothrombin should be performed when the prothrombin time is prolonged. Other associated bleeding causes in the aPL syndrome include acquired thrombocytopathies, thrombocytopenia (usually immune-mediated), and acquired inhibitors against specific coagulation factors, e.g., factor VIII.
Cutaneous manifestations may occur as the first sign of aPL syndrome.169 Noninflammatory vascular thrombosis is the most frequent histopathologic feature observed. These include livedo reticularis (occasionally, a necrosing form170), necrotizing vasculitis, livedoid vasculitis, thrombophlebitis, cutaneous ulceration and necrosis, erythematous macules, purpura, ecchymoses, painful skin nodules, and subungual splinter hemorrhages. Rarely, the aPL syndrome may also be associated with anetoderma (macular atrophy), discoid lupus erythematosus, cutaneous T-cell lymphoma, or disorders that closely resemble Sneddon or Degos syndromes. Patients with systemic sclerosis who are aCL-positive have more widespread skin and visceral involvement than those who are aCL-negative with this disorder.171
CORONARY ARTERY DISEASE
aPL antibodies have been associated with increased susceptibility to coronary artery disease—particularly premature atherosclerosis.172 Antiprothrombin antibodies were reported to be a predictor of myocardial infarction in middle-aged men, and one study found that the joint effect of antiprothrombin antibodies with other known risk factors were multiplicative.173 Coronary artery disease also appears to be associated with antibodies against oxidized LDL. The aPL sydrome should be considered in patients who lack the usual risk factors for coronary artery disease or who have evidence for thrombotic or embolic coronary occlusion without angiographic evidence of atherosclerotic disease. aPL antibodies also appear to be a risk factor for restenosis after percutaneous transluminal coronary angioplasty, where restenosis with recurrent ischaemia appears to occur earlier and more frequently.174,175
VALVULAR HEART DISEASE
Approximately 35 percent of patients with primary aPL syndrome have valvular abnormalities detected by echocardiography.176 Also, about 20 percent of cardiac patients with valvular heart disease have evidence for aPL antibodies compared with about 10 percent of matched control subjects.177 Valvular abnormalities occur in about half of patients with SLE and aPL antibodies. Valvulopathy includes leaflet thickening, vegetations, regurgitation, and stenosis.178 The aPL syndrome valvular lesion consists mainly of superficial or intravalvular fibrin deposits in association with variable degrees of vascular proliferation, fibroblast influx, fibrosis, and calcification. This results in valve thickening, fusion, and rigidity, sometimes leading to functional abnormalities. Inflammation is not a prominent feature of this lesion.179 Deposits of immunoglobulins including aCL antibodies, and of complement components, are common in the affected valves of patients with primary and secondary aPL syndrome.180 One study of patients with SLE, progressive systemic sclerosis, rheumatoid arthritis, and primary aPL syndrome, however, did not find a relationship between increased aCL antibodies and valvular abnormalities.181
PERIPHERAL VASCULAR DISEASE
One prospective study found that about one-third of patients with peripheral arterial disease undergoing bypass grafting procedures had elevated aPL antibody levels (mostly aCL antibodies). Although these patients did not appear to be at increased risk for reocclusion, this may have been due to the higher frequency of anticoagulant therapy given in these patients.182 An unusual pattern of premature aortoiliac atherosclerosis has been reported in women under the age of 50, which appears to be associated with the presence of aPL antibodies in about 40 percent of the patients. Intraarterial thromboembolic events are common at presentation and complicate surgical management.183
In addition to pulmonary thromboembolism, patients with the aPL syndrome may present with in situ thrombosis in pulmonary vessels. aPL antibodies have been described in pulmonary hypertension.184,185 and 186 In one prospective trial of 38 consecutive patients with precapillary pulmonary hypertension, about 30 percent had aPL antibodies with various phospholipid specificities.185 aPL antibody syndrome has been diagnosed in patients presenting with refractory noninflammatory pulmonary vasculopathy.187,188 The majority of patients with catastrophic aPL syndrome have dyspnea, and most of these individuals have acute respiratory distress syndrome.153
Gastrointestinal manifestations of aPL syndrome include Budd-Chiari syndrome, hepatic infarction, esophageal necrosis with perforation, intestinal ischemia and infarction, pancreatitis, and colonic ulceration. Also, primary biliary cirrhosis,189 acute acalculous cholecystitis with gall bladder necrosis,190,191 and giant gastric ulceration have been associated with aPL antibody syndrome.192 There have been case reports of the primary aPL syndrome associated with mesenteric inflammatory venoocclusive disease,193 and with mesenteric and portal venous obstruction.194
About 20 to 40 percent of patients with the aPL syndrome have varying degrees of thrombocytopenia. This is usually mild or moderate and is rarely significant enough to cause bleeding complications or to affect anticoagulant therapy.195,196 Most cases appear to be immune-mediated. It is not yet clear whether aPL antibodies themselves can directly reduce platelet counts or whether these reflect a common autoimmune background but are mediated by different antibody populations. Antibodies directed against major platelet membrane glycoproteins may play a role in the thrombocytopenia. The majority of patients with the aPL syndrome and thrombocytopenia have antibodies against glycoprotein (GP) IIb/IIIa complex and/or GP Ib/IX complex according to one study.197 However, in another study no correlation was found between the presence of antibodies against platelet GPIIb/IIIa, GPIb/IX, and thrombocytopenia, and the eluted platelet antibodies did not have any LA activity.198 It thus appears that platelet antibodies may represent an independent marker for autoimmunity in these patients. Conversely, aPL antibodies and antibodies against platelet membrane glycoprotein were present simultaneously in about 70 percent of patients with immune-mediated thrombocytopenia.199
The diagnosis of aPL antibody retinopathy should be suspected in patients with diffuse retinal vasoocclusion, particularly when characterized by involvement of both arteries and veins, neovascularization at presentation, and symptoms of systemic rheumatologic disease.200 aPL antibodies were present in 5 to 33 percent of patients with retinal vein occlusion.201,202 Cilioretinal artery occlusion203 and optic neuropathy204 have also been described with the aPL syndrome.
aPL antibodies are frequently elevated in patients with chronic liver disease of various causes. In one prospective study of patients with liver disease, about half of patients with alcoholic liver disease and one-third of patients with chronic hepatitis C virus hepatitis had elevated aPL antibodies; the frequency was even higher in patients with more severe cirrhosis.205 In another study, aCL antibodies were found in 22 percent of patients with chronic hepatitis C.26 Since hepatitis C infection has been associated with other autoimmune disorders such as rheumatoid arthritis, SLE, polymyositis, and thyroid disease,206 it is possible that the the aPL antibodies in this condition may also be autoimmune in origin.
“SERONEGATIVE” aPL SYNDROME
Some patients present with the clinical picture of this syndrome but without laboratory evidence of aPL in their serum at the time of initial presentation and are found to develop laboratory evidence for the antibodies several months later.207
APL AND AIDS
While patients with HIV-1 infection frequently have elevated aPL antibodies, they rarely have thrombotic manifestations. In one series, 64 percent of HIV-1 patients had elevated aCL antibodies.208 However, most of these positive patients also had antibodies against phosphatidyl choline, and very few had antibodies to b2GPI, antiprothrombin antibodies, LA, biological false positive test for syphilis, or thrombosis.208
APL SYNDROME IN CHILDREN
aPL syndrome has been reported among pediatric patients in whom diverse clinical features are common as in adults.184 aPL-related thrombosis seems to constitute a significant proportion of childhood thromboses. About one-third of children suffering a thrombotic event have circulating aPL antibodies, and more than two-thirds of children with idiopathic cerebral ischemia have evidence for elevated aPL antibodies.209 One study reported a high prevalence of aCL antibodies in children (7/10) who suffered acute cerebral infarction.210 Also, a variety of neurological disorders, including migraine, benign intracranial hypertension, or unilateral movement disorders such as hemichorea and hemidystonia other than stroke have been associated with aPL antibodies in childhood.211 The catastrophic form of the syndrome is rare in children.212
Acute adrenal failure secondary to bilateral infarction of the adrenal glands has been reported as the first manifestation of primary aPL syndrome.213 Adrenal hemorrhage has also been reported.214,215 and 216 aPL antibodies has also been associated with bone marrow necrosis.217 Sudden acute sensorineural hearing loss in patients with systemic lupus erythematosus or lupus-like syndromes may be a manifestation of the aPL syndrome.218
The diagnosis of the aPL syndrome requires the presence of antibodies against phospholipids and/or relevant protein cofactors. This is most commonly obtained through immunoassays that detect aCL, antiphosphatidyl serine, anti-b2GPI, or antiprothrombin antibodies or through evidence for interference with phospholipid-dependent coagulation assays (lupus anticoagulant phenomenon) (Table 128-3). Definitive guidelines and criteria for laboratory testing are not yet available, and thus the laboratory diagnosis of the aPL syndrome is frequently problematic. At present, no single test is sufficient for diagnosing this disorder. It is therefore recommended that when the disorder is suspected, a panel of tests, including syphilis testing, antibodies against cardiolipin, phosphatidyl serine, and b2GPI and coagulation tests for lupus anticoagulant, should be performed.
TABLE 128-3 DIAGNOSTIC TESTS FOR THE aPL SYNDROME
ANTIPHOSPHOLIPID ANTIBODY AND COFACTOR ASSAYS
Most patients with the condition are identified by elevated levels of aCL antibodies. The precursor of this assay, the biologic false-positive VDRL test for syphilis, in which cardiolipin is the primary antigen, is itself a crude aPL test. High levels of aCL antibodies are predictive for an increased risk of thrombosis. During a 10-year follow-up on patients who presented with raised levels of aCL antibodies, about 50 percent of patients who presented with elevated antibodies but without clinical manifestations of the syndrome, went on to develop the syndrome.219 Also, the presence of elevated titers of anticardiolipin antibodies 6 months after an episode of venous thromboembolism is a predictor for an increased risk of recurrence and of death.123 Women with IgM antibodies, IgG aCL antibodies lower than 20 IgG binding units, and without a LA do not appear to be at risk for aPL-syndrome.220 In contrast, women with an IgG aCL titer greater than 20 binding units or a positive LA were found to be more likely to develop complications.220
As mentioned previously, most patients with elevated aCL antibodies do not have the aPL syndrome. The prevalence of positive tests in the asymptomatic “normal” population has generally ranged from about 3 to 10 percent. In a prospective study of 2132 consecutive Spanish patients with venous thromboembolism, 4.1 percent were found to have elevated aCL antibodies (i.e., about the same prevalence as in the asymptomatic healthy population).221 It should be borne in mind, however, that many individuals have antibodies which are elevated in response to microbial infections and are not associated with thrombotic complications. Patients with syphilis, Lyme disease, and other infections may be misdiagnosed for the aPL syndrome on the basis of elevated aCL antibodies when concurrent stroke or arterial thrombosis are present, and these must always be ruled out in susceptible patients. Also, the aCL ELISA test will be artifactually abnormal in patients with hypergammaglobulinemias unless the results of parallel assays, done on microtiterplates that are not coated with cardiolipin, are subtracted.222
aPL syndrome has been described primarily with elevated aCL IgG antibodies but also occurs with elevated IgM antibodies. aCL antibody isotype distributions may vary in different ethnic groups.223 While all four IgG subclasses are found in autoimmune aCL, the presence of IgG2 is significantly associated with thrombotic complications.224 There is controversy about whether a polymorphism in the Fc gamma receptor IIA expressed on platelets, monocytes, and endothelial cells efficiently recognizing IgG2 may be a genetic marker for the aPL syndrome.225,226
There have been some reports of patients with elevated IgA aCL antibodies with aPL syndrome. However, the determination of IgA aCL antibodies does not appear to be helpful in diagnosing the aPL syndrome or in explaining thrombotic events or fetal loss since the prevalence of true positivity to IgA anticardiolipin antibodies is extremely low; for example in one study of 795 patients, IgA aPL were found in only two patients, both of whom were also positive to IgG aPL.227
About 20 percent of patients taking procainamide have moderate to high levels of aCL antibodies.228 In these patients, the antibodies are associated with anti-b2GPI specificity. However, the predictive significance of procainamide-induced aPL is not known. Treatment with chlorpromazine is frequently associated with the development of aCL antibodies; these are rarely associated with thrombosis,229 and it is not clear whether these are cofactor dependent.
ANTIPHOSPHATIDYL SERINE ANTIBODY ASSAY
Since cardiolipin is present in intracellular membranes and does not become exposed to coagulation proteins in vivo, it was hypothesized that tests for antibodies against phosphatidyl serine, which is normally present in the inner leaflet of the plasma membrane, may be more relevant pathophysiologically. Phosphatidyl serine is also exposed on syncytialized cells, on apoptotic cells and on activated platelets. Antibodies to phosphatidyl serine (aPS) appear to correlate more specifically with aPL syndrome than aCL antibodies.230,231,232 and 233
ASSAYS FOR ANTIBODIES AGAINST OTHER PHOSPHOLIPIDS
Antibodies against the zwitterionic phospholipid, phosphatidyl ethanolamine, have been associated with thrombosis and with activated protein C resistance.234 Some studies have suggested that antiphosphatidyl ethanolamine antibodies can occur in the aPL syndrome in the absence of antibodies against cardiolipin or other anionic phosphoipids.235 Some investigators have advocated testing for antibodies against a panel of phospholipids other than cardiolipin,235,236,237 and 238 while others have disagreed,239 and one group recommends that a mixture of anionic and zwitterionic phospholipids be used for testing for antibodies.240
ANTI-b2GPI ANTIBODY ASSAY
b2GPI is believed to be the major protein cofactor for the aPL antibodies. ELISAs for anti-b2GPI antibodies are considered to be more specific but less sensitive for the aPL syndrome than aCL assays.241 While these antibodies are usually seen in patients with abnormal aCL and aPS antibodies, some patients with the aPL syndrome, whether primary or secondary, may present with antibodies to b2GPI but without antibodies detectable in standard aPL assays.242,243 Despite their higher specificity for the aPL syndrome (98 percent) and high positive predictive value (about 90 percent), b2GPI antibodies cannot be relied upon alone for the diagnosis because of their low sensitivity (40 to 50 percent).244,245 Concurrent testing for aCL and aPS antibodies and LA is therefore advised. The presence of elevated levels of anti-b2GPI antibodies correlates well with thrombosis. In one study, elevated levels of antibodies against b2GPI were found in 49 percent of a group of SLE patients and were significantly associated with deep venous thrombosis. Testing of antibodies against b2GPI and prothrombin seem to be clinically useful for evaluating the risk of thrombosis.246
ANTIPROTHROMBIN ANTIBODY ASSAY
Prothrombin is the second major cofactor for aPL antibodies. Antiprothrombin antibodies occur in 30 percent of patients with SLE and have been significantly associated with thrombosis.246,247 and 248 The presence of these antibodies also correlates with hypoprothrombinemia and with thrombocytopenia.249
One of the most perplexing features of the aPL syndrome is the frequent presence of the LA phenomenon in vitro.250,251 Although commonly used, the term LA is a misnomer, since it is not restricted to patients with systemic lupus erythematosus. LAs appear to act by limiting the quantity of phospholipid available to support coagulation reactions (listed in Table 128-4), thus prolonging the coagulation times. A number of different methods have been devised to detect the LA phenomenon including modifications of the aPTT test with LA-sensitive and -insensitive reagents, the kaolin clotting time, the dilute Russell viper venom time (dRVVT), the tissue thromboplastin inhibition time, the hexagonal phase array test, and the platelet neutralization procedure. The common denominator for the various LA tests is that they detect the inhibition of the phospholipid-dependent blood coagulation reactions.11
TABLE 128-4 PHOSPHOLIPID-DEPENDENT COAGULATION REACTIONS
The results of LA tests can be so variable that even specialized laboratories may frequently disagree. For example, three surveys in the United Kingdom have shown that while most laboratories can agree in their identification of plasmas containing strong positive LA activity, there is frequent disagreement about plasmas that are known to have weak LA activity (these are missed in about half the cases) and frequent misdiagnosis of factor-IX-deficient LA-negative plasmas as being LA-positive.252
Paradoxically, the presence of the LA activity is more predictive and more specific for the occurrence of thrombosis or pregnancy loss than the aCL ELISA assays,44,253,254,255 and 256 the anti-b2GPI assay, or the antiprothrombin assay.254 The LA appears to be more predictive for venous thromboembolism than aCL antibodies even when only high titers of aCL are considered.257 Thus, in a meta-analysis of the risk for aPL-associated venous thromboembolism in individuals with aPL antibodies without underlying autoimmune disease or previous thrombosis for a 15-year period, the mean odds ratios were: for aCL antibodies-1.6; for high titres of aCL -3.2, and for LA -11.0.257 The presence of LA also appears to be a significant risk factor for arterial thrombosis.256,258
In addition to their role in immunoassays for aPL antibodies, protein cofactors also play a role in the LA activity.8,259 In the case of b2GPI, the LA activity of anti-b2GPI antibodies appears to depend on their epitope specificity. Anti-b2GPI mAbs directed against the third and fourth domains of b2GPI have a LA effect, whereas anti-b2GPI mAbs directed against the fifth domain and the carboxy-terminal region of the fourth sushi domain show no LA-like activity.260 While LA can be due to antiprothrombin antibodies, removal of antiprothrombin antibodies does not eliminate LA activity in the majority of plasmas.8
It is not clear why the LA, a test for in vitro anticoagulant activity, is the marker which correlates best with in vivo thrombosis in the aPL syndrome. Conceivably, the LA effect “reports” aPL antibody-phospholipid/cofactor complexes having the highest affinities and avidities for the antigens and the most potent ability to displace endogenous phospholipid-binding anticoagulant proteins which shield anionic phospholipids from participating in coagulation reactions.78 This explanation for the LA phenomenon and a “lupus procoagulant” mechanism has been described in detail by the author.78 A model is presented in Fig. 128-4.
FIGURE 128-4 A model for the mechanisms of the “lupus anticoagulant effect” and for a “lupus procoagulant effect”:
(A) Anionic phospholipids (negative charges), when exposed on the apical surface of the cell membrane bilayer, serve as potent cofactors for the assembly of three different coagulation complexes: the tissue factor (TF)-VIIa complex, the IXa-VIIIa complex, and the Xa-Va complex, and thereby accelerate blood coagulation. The TF complexes yield either factor IXa or factor Xa, the IXa complex yields factor Xa, and the Xa formed from both of these reactions is the active enzyme in the prothrombinase complex which yields factor IIa (thrombin), which in turn cleaves fibrinogen to form fibrin.
(B) Annexin-V, in the absence of aPL antibodies, serves as a potent anticoagulant by forming clusters which bind that high affinity to the anionic phospholipid surface and shield the surface from the assembly of the phospholipid-dependent coagulation complexes.
(C) In the absence of annexin-V, aPL antibodies can prolong the coagulation times, compared to control antibodies, by reducing the access of coagulation factors to anionic phospholipids. This may result in a “lupus anticoagulant” effect. Lupus anticoagulant tests can be designed to be sensitive by limiting the quantities of phospholipids.
(D) In the presence of annexin-V, antiphospholipid antibodies, either directly or via interaction with protein-phospholipid cofactors, disrupt the the ability of annexin-V to cluster on the phospholipid surface. This results in a net increase of the amount of anionic phospholipid available for promoting coagulation reactions. The aPL-cofactor complexes expose significantly more phospholipids by disrupting the annexin-V shield than they block by direct binding. This manifests in the net acceleration of coagulation in vitro and in thrombophilia in vivo. (Reprinted with permission from Rand and coworkers.78)
DILUTE RUSSELL VIPER VENOM TIME
DRVVT is considered to be one of the most sensitive of the LA tests. The test is performed by using Russell viper venom (RVV) in a system containing limiting quantities of diluted rabbit brain phospholipid. The RVV directly activates coagulation factor X, leading to the formation of fibrin clot. LA will prolong the dRVVT by interfering with the assembly of the prothrombinase complex. To ensure that prolongation of the clotting time is not due to a factor deficiency, the method uses mixtures of patient and control plasmas. The presence of the LA may be confirmed by addition of an excess of phospholipid which will correct the prolongation.
Prolongation of the aPTT will detect some LAs, and, in the general population, LAs are the most frequent cause of prolonged aPTT tests.261 The various reagents available for performing aPTTs vary widely in their sensitivity to LAs, and thus it is important to know which reagents are used. The aPTT reflects the contact activation coagulation pathway. When the aPTT of a particular plasma sample is prolonged, and not “correctable” by mixture with normal plasma, the presence of an “anticoagulant” or “inhibitor” should be suspected. The LA needs to be differentiated from inhibitors of specific coagulation factors and from anticoagulants such as heparin. Besides specific assays to exclude the latter two possibilities, the clinician should check whether the aPTT is normalized when an LA-insensitive aPTT reagent is used or when the assay is done using frozen washed platelets as the source of phospholipid—also referred to as the platelet neutralization procedure. Also, the effects of incubation with normal plasma may be helpful in differentiating LAs from coagulation factor inhibitors. aPTTs done on mixtures of normal plasma and plasma containing a factor VIII inhibitor may show no prolongation immediately after mixing but marked prolongation with incubation at 37°C, whereas LA-containing plasmas will usually markedly prolong the aPTT immediately after mixing with normal plasmas and show no further prolongation with incubation. However, both types of anticoagulants—LA and specific coagulation factor inhibitors—may coexist in rare patients. Specific coagulation factor inhibitor assays should clarify this issue. It should also be recognized that LAs may result in artifactual decreases in coagulation factor levels using the standard assays, since they are based on aPTT. These patients can be misdiagnosed as having multiple coagulation factor deficiencies. This problem can usually be avoided by using an aPTT reagent which is insensitive to LA for the specific factor assays or by repeating the coagulation factor assays following dilution of the plasma samples. The latter will result in improved coagulation factor levels with progressive dilution.
KAOLIN CLOTTING TIME
This assay depends upon the ability of aPL antibodies to block the availability of trace quantities of phospholipid present in centrifuged plasma from participation in coagulation reactions. Some authors maintain that the kaolin clotting time–LA test reflects dependence on prothrombin as a cofactor and is less likely to be associated with thrombosis than the dRVV test, which appears to be more dependent on b2GPI.249,262
TISSUE THROMBOPLASTIN INHIBITION TEST
This test is a prothrombin time assay done with diluted tissue factor-phospholipid complex. It can be performed with standard and recombinant tissue factor.263,264 The results are expressed as a ratio of the patient:control clotting times.
HEXAGONAL PHASE ARRAY TEST
aPL antibodies can recognize phosphatidyl ethanolamine in the hexagonal phase array configuration but not in the lamellar phase. The principle of this test is that incubation of plasma with the hexagonal phase phosphatidyl ethanolamine should absorb the LA antibodies, if these are present, and therefore normalize a prolonged aPTT due to LA.
This test depends on the different coagulation mechanisms initiated by two snake venoms—Textarin activates prothrombin via a phospholipid dependent pathway, and Ecarin activates prothrombin even in the absence of phospholipid.264
Patients with the aPL syndrome usually present with vascular occlusion, recurrent pregnancy losses, or abnormal coagulation screening tests. When vascular occlusion occurs in the setting of a known autoimmune disorder such as SLE, then the possibility of vasculitis must be considered. Patients with the catastrophic aPL syndrome may appear to have other multisystem vasoocclusive disorders such as thrombotic thrombocytopenic purpura or disseminated vasculitis and may present with laboratory findings of disseminated intravascular coagulation.
The differential diagnosis of a prolonged aPTT includes hereditary and acquired coagulation factor deficiencies, antibody inhibitors to coagulation proteins (e.g., acquired hemophilias), and the presence of heparin or hirudin in the sample. The diagnosis of a LA will be clarified through plasma mixing studies and specific factor assays. A positive aPL ELISA will help to confirm the diagnosis.
When an elevated level of an antiphospholipid antibody is detected, the clinician must consider the possibility that the patient may have an infectious etiology for the antibodies. These will occur frequently in syphilis, Lyme disease, HIV-1, and hepatitis C. Also, elevated antibodies may be artifactual and due to increased immunoglobulin levels222 or in association with antipsychotic or other medication. Here, diagnosis will be aided by specific tests for suspected infection, quantitative measurement of serum immunoglobulins, and subtraction of background controls using uncoated microtiter wells.
THERAPY, COURSE, AND PROGNOSIS
A recent survey of physicians treating patients with the aPL syndrome265 found opinions concerning treatment to vary widely and emphasized the need for prospective studies to examine the utility of specific anticoagulant regimens in the prophylaxis of recurrent thromboembolism in patients with aPL antibodies. Overall, there is general agreement that patients with recurrent spontaneous thrombosis require long-term, and perhaps life-long, anticoagulant therapy and that patients with recurrent spontaneous pregnancy losses require antithrombotic therapy for most of the period of gestation. Differences arise in the approach to the treatment of patients with single thrombotic events, with significant thrombotic events in the distant past, and with thrombotic events that were not spontaneous. Opinions also vary widely on the treatment of asymptomatic pregnant women with aPL antibodies, especially if they are in an older age category or have difficulties with fertility.
There is no evidence that the acute treatment for patients presenting with thrombosis in the aPL syndrome should be any different from that of patients with other thrombotic etiologies. For patients treated with intravenous unfractionated heparin, care must be taken to determine whether the patient might have a preexisting LA that can interfere with the aPTT monitoring of heparin levels by aPTT. If so, then the heparin concentration can be estimated with one of the LA-insensitive aPTT reagents, with a specific heparin assay, or with the activated coagulation time test, which is usually insensitive to LAs.
Patients who have experienced spontaneous thromboembolism and have evidence for the aPL syndrome should be treated with long-term oral anticoagulant therapy. Studies have yielded varying results as to the recommended intensity of anticoagulant therapy. For example, a prospective study on the treatment of venous thromboembolism concluded that an INR in the range of 2.0 to 3.0 will prevent recurrences.44,123 A retrospective study of a variety of patients with the aPL syndrome showed that a higher intensity (INR greater than 3.0) was necessary for preventing recurrences.266 In one retrospective study, 6 out of 16 patients (37 percent) followed over 6 to 42 months developed deep venous thrombosis in spite of oral anticoagulation (INR 1.5 to 3.0).267 Another study of secondary aPL syndrome concluded that conventional management of thromboembolic manifestations with heparin and/or oral anticoagulants prevented neither recurrent thromboses nor fatal outcomes.125 At the time of writing a large prospective randomized trial, the Warfarin in Antiphospholipid Syndrome (WAPS) Study,268 is in progress to study optimal treatment.
The following is recommended until the treatment is further resolved by clinical trial. Patients with venous thromboembolism should be anticoagulated to an INR of approximately 3.0. Patients with arterial thromboembolism should have their warfarin doses adjusted to achieve a target INR of 3.0 to 3.5 where possible. Patients should not be treated with concurrent aspirin.269 A high titer of aCL (greater than 30 U/ml) is not sufficient to justify prophylactic anticoagulation therapy in asymptomatic patients,267 and the same conclusion can probably be applied to patients with LAs who have not experienced thrombotic or embolic events.
An important practical consequence of the LA effect is that prothrombin time and INR results have been reported to be falsely elevated in a significant proportion of patients with the aPL syndrome and LAs treated with warfarin anticoagulant therapy.270 As with the aPTT, there may be differences in the prothrombin time reagent with regard to their sensitivity to LAs, and different LAs vary significantly in their effects on the prothrombin time.271 It has been suggested that alternative tests, such as specific chromogenic coagulation factor assays for vitamin K–dependent proteins or the prothrombin and proconvertin time, would be useful to confirm the appropriate warfarin effect in these patients.270
There have also been case reports of fibrinolytic treatment in primary aPL syndrome for extensive thrombosis of the common femoral and iliac veins extending to the lower vena cava,272 acute ischemic stroke,273 and acute myocardial infarction.274 Treatment with the antimalarial drug hydroxychloroquine appears to have an antithrombotic effect in patients with the aPL syndrome and SLE.275,276 The potential effectiveness of this treatment has also been supported by animal studies.277
Patients with the catastrophic aPL syndrome may be refractory to therapy with anticoagulation alone. A review of 50 cases showed that 70 percent of the patients recovered following management with the combination of anticoagulation, steroids, and plasmapheresis or intravenous gammaglobulins.278
Experimental therapies of the aPL syndrome include specific anti-idiotypic or anti-CD4 antibodies, IL-3, ciprofloxacin or bromocriptine, and bone-marrow transplantation.279
Women with a history of three or more spontaneous pregnancy losses and evidence of aPL antibodies should be treated with a combination of low dose aspirin (75 to 81 mg daily) and unfractionated heparin (5000 units subcutaneously every 12 h).280,281 and 282 Treatment should be started as soon as pregnancy is documented, and both medications can be stopped 1 month prior to term if there are no complications (e.g., thromboembolism, intrauterine growth retardation, oligoamnion, or fetal distress). Some practitioners extend treatment with aspirin until about 1 week before term, and some extend it until labor. For complicated pregnancies, anticoagulant therapy may be warranted until just before delivery, and in especially high risk situations, induction of early delivery may be necessary. Prophylactic doses of heparin (i.e., 5000 units every 12 h subcutaneous) should be started about 4 to 6 h after delivery, if significant bleeding has ceased, and continued until the patient is fully ambulatory. For patients who have experienced systemic thromboembolism, oral anticoagulant therapy is warranted for at least 6 weeks after delivery. Treatment with low-molecular-weight heparins (LMWH) has been described,283,284,285 and 286 but at the time of writing these drugs have not been approved in the United States for use during pregnancy. The potential benefits of LMWH include once-daily injections, a decreased rate of allergic reactions, and the possibility of decreased bone loss compared to unfractionated heparins.
The presence of aPL antibodies during pregnancy, without any history of clinical problems, does not require treatment. A prospective study of an untreated general obstetric population found that 2 to 3 percent of nonpregnant patients had low-titer aCL antibodies and that there was a live birth rate of about 60 percent among these patients. The organizing group of the aPL Antibody Treatment Trial287 randomly assigned 19 women with one or no prior spontaneous abortion and without a history of thrombosis or thrombocytopenia to low-dose aspirin or no treatment and found that both groups were at such a low risk for pregnancy losses that prophylactic therapy seemed unwarranted.
While prednisone also improves the outcomes of pregnant patients with the aPL syndrome,34,287,288 this benefit comes along with significant toxicity.287 Thus, both corticosteroids and intravenous IgG (see below) should probably be considered only for patients who are refractory to anticoagulant therapy or who have a severe immune thrombocytopenia or a contraindication to heparin therapy. The results of one study cast doubt on the benefit of prednisone in autoimmune-associated pregnancy losses.289 Treatment with the combination of prednisone and heparin should be avoided, when possible, since this combination will markedly increase the risk of osteopenia and of vertebral fractures.290 There have been preliminary reports of treatment of aPL-associated recurrent first-trimester pregnancy losses with intravenous immunoglobulin,291 but randomized placebo-controlled trials are necessary to confirm the efficacy of this treatment.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn