Chapter 42 Clinical Aspects of the Antiphospholipid Syndrome

Introduction

The antiphospholipid syndrome (APS), an acquired thrombophilia, is characterized by vascular thrombosis and/or fetal loss in the presence of antiphospholipid antibodies (APLAs). APLAs are mainly directed against plasma proteins with an affinity for anionic phospholipids. Functional assays that measure the prolongation of phospholipid-dependent coagulation assays are used to detect the lupus anticoagulant (LA).¹ Solid-phase assays, such as enzyme-linked immunosorbent assays (ELISAs), detect anticardiolipin (aCL) and anti–beta 2 glycoprotein I (anti–β₂ GPI) antibodies.¹ This chapter focuses on current knowledge of the epidemiology, classification, pathogenesis, clinical features, diagnosis, and management of APS.

Epidemiology

APS is the most common form of acquired thrombophilia. In younger patients with stroke (under 50 years of age), APLAs are frequently present (one out of five patients), compared with older patients in whom other vascular risk factors may play more important roles.² APS accounts for 15% to 20% of all episodes of deep-vein thrombosis (DVT), with or without pulmonary embolism. The estimated prevalence of DVT in the general population is approximately 2% to 5%; consequently, APS may be responsible for DVT in 0.3% to 1% of the general population.³ ALPAs are present in 30% to 40% of patients with systemic lupus erythematosus (SLE), but only one third of them develop clinical manifestations of APS, highlighting the importance of non-APLA contributory factors.⁴ Recurrent pregnancy loss occurs in approximately 1% of women, and 10% to 15% of these women are diagnosed with APS.^5,⁶ In addition, APS is recognized to increase the risk of pregnancy complications such as preeclampsia, placental insufficiency, intrauterine growth restriction, and fetal loss.⁷

Classification Criteria

In 1999, an international consensus meeting formulated the first classification criteria—the “Sapporo criteria”—for patients with APS.⁸ These criteria were updated during the 11th International Congress on Antiphospholipid Antibodies in November 2004 in Sydney, Australia.¹ According to the original 1999 criteria, a definite classification of APS requires the presence of one of the two major clinical manifestations of APS (pregnancy morbidity or thrombosis) with either aCL or LA on at least two occasions, 6 weeks apart. The revised Sydney criteria (Box 42-1) included anti–β₂ GPI and increased the period for persistence to 12 weeks.

Box 42-1

Revised Classification Criteria for the Antiphospholipid Syndrome

Antiphospholipid antibody syndrome (APS) is defined as the presence of at least one of the following clinical criteria and one of the following laboratory criteria:

Clinical Criteria

1. Vascular thrombosis

• One or more clinical episodes of arterial, venous, or small-vessel thrombosis are present in any tissue or organ. Thrombosis must be confirmed by objective validated criteria (i.e., unequivocal findings of appropriate imaging studies or histopathologic examination). For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall.

2. Pregnancy morbidity

• One or more unexplained deaths of a morphologically normal fetus occurs at or beyond 10 weeks’ gestation with normal fetal morphologic features documented by ultrasound or by the direct examination of the fetus.

• One or more premature births of a morphologically normal neonate occurs before 34 weeks’ gestation because of either:

a. Eclampsia or severe preeclampsia, as defined according to standard definitions; or

b. Recognized features of placental insufficiency

• Three or more unexplained consecutive spontaneous abortions that occur before 10 weeks’ gestation with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded.

In studies of populations of patients who have had more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify the groups of patients according to one of the above criteria.

Laboratory Criteria

1. Lupus anticoagulant (LA)

• Is present in plasma on two or more occasions, at least 12 weeks apart, and detected according to the guidelines of the International Society on Thrombosis and Hemostasis (Scientific Subcommittee on LAs/phospholipid-dependent antibodies).

2. Anticardiolipin (aCL) antibodies

• IgG or IgM isotype or both are present in the serum or plasma in medium or high titer (i.e., >40 GPL or MPL, or greater than the 99th percentile), on two or more occasions, at least 12 weeks apart, and as measured by a standardized ELISA.

3. Anti–beta 2 glycoprotein I antibody

• IgG or IgM isotype in serum or plasma (in titer greater than the 99th percentile) or both are present on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA, according to recommended procedures.

ELISA, Enzyme-linked immunosorbent assay; GPL, IgG antiphospholipid units; MPL, IgM antiphospholipid units.

Reproduced with permission from Miyakis S, Lockshin MD, Atsumi T, et al: International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4(2):295-306, 2006.

Other noncriteria manifestations, such as thrombocytopenia, cardiac valvular disease, livedo reticularis, neurologic manifestations, and other APLAs, were also discussed during this meeting. It was concluded that although associated with APS, these features were not specific enough for inclusion in the classification criteria.¹

Pathogenesis

Despite the strong association between APLAs and the risk of thrombosis and fetal loss, the pathogenic processes have not been fully elucidated. Multiple mechanisms have been proposed, including interference with hemostatic reactions, cellular activation, and the activation of the complement system. These different pathways are likely contributory rather than mutually exclusive.

The binding of APLAs to negatively charged phospholipids can interfere with multiple hemostatic mechanisms. Reported effects include increased thrombin formation, an inhibition of protein C and S activity, interference with the annexin A5 anticoagulant shield, production of microparticles, and impaired fibrinolysis. The net effect shifts the equilibrium in favor of a prothrombotic state.^7,⁹^–¹²

The anti–β₂ GPI complex can also bind to and activate many cell types, including monocytes, endothelial cells, and platelets. Monocytes express increased numbers of adhesion molecules; both monocytes and endothelial cells upregulate the production of tissue factor. Platelets that are activated by the anti–β₂ GPI complex increase the synthesis of thromboxane and the expression of platelet-membrane glycoproteins (GPs), particularly GPIIb/IIIa and GPIIIa, contributing to the heightened thrombotic risk.^7,^9,¹⁰

Recently, complement activation has been found to play a significant role in an animal APLA model of thrombosis and pregnancy morbidity. In vitro studies have shown that APLAs induce complement activation, which generates split products that then attract inflammatory cells and initiate thrombosis and tissue injury.^13,¹⁴ Lower complement levels have been noted in patients with primary APS, compared with other systemic autoimmune diseases (excluding SLE) or healthy volunteers.¹⁵ The anti–β₂ GPI complexes preferentially target the placenta, activating complement via the classical pathway. The proinflammatory environment can result in trophoblast injury and pregnancy loss.¹⁶^–¹⁸ In addition, direct cytotoxic effects of APLAs on trophoblast cells may contribute to pregnancy morbidity.¹⁹

Contributory non-APLA factors serve as the “second hit” leading to thrombosis. Estrogen therapy, smoking, and certain genetic variants of clotting factors have been shown to increase the risk of myocardial infarction and stroke in women with positive APLAs.^7,²⁰

Clinical Features

The majority of clinical manifestations of APS are related to thrombosis, whereas immune mechanisms may contribute to some nonthrombotic manifestations.

Thrombotic Manifestations

In the Euro-Phospholipid project, 37% of the cohort participants had only venous thrombosis, 27% had arterial thrombosis, whereas 15% had both arterial and venous thrombosis.²¹ DVT is the most common type of venous thrombosis (~40%), followed by superficial leg vein thrombosis (~12%).²¹ Other reported organs include the kidneys (renal vein thrombosis), liver (Budd-Chiari syndrome), brain (cerebral venous thrombosis), and eye (retinal vein thrombosis).^21,²² Arterial thrombosis includes strokes, transient ischemic attacks (TIAs), and myocardial infarction. Digital and limb ischemia, as well as other organ infarctions, have been described.^21,²² Thrombotic events usually occur at single sites, except in catastrophic APS (CAPS), in which multiple sites can be involved simultaneously or in quick succession.²³

Neurologic Manifestations

Although most neurologic manifestations of APS are related to thromboembolism, local inflammation and neurotoxic effects of APLAs may contribute to some manifestations, including seizures, chorea, and myelitis.²⁴^–²⁸

Cerebrovascular events, strokes, and TIAs are the most frequent neurologic manifestation and are reported to be the initial presenting feature in 18% to 30% of patients with APS.^21,²⁹ Strokes may be recurrent and lead to multi-infarct dementia.³⁰ Multiple studies have found a strong association of APLAs (especially LA) with cerebrovascular events.^20,^24,^25,³¹ The risk of cerebrovascular events was higher in the presence of other concomitant vascular risk factors, such as smoking and the use of oral contraceptives.^20,³² Cardiac valvular lesions may be associated with cerebrovascular events in patients with APS.^33,³⁴ Although valvular thickening is the most common presentation, noninfective vegetations (e.g., Libman-Sack endocarditis) are also well reported. Cardiac echocardiography is recommended in APS patients with cerebrovascular events.³⁵

Although cerebrovascular disease is the only neurologic manifestation listed in the APS classification criteria, the linkage between epilepsy and APLAs has been documented by experimental and clinical studies.^26,^28,^36,³⁷ The prevalence of epilepsy in APS is reported to be approximately 8.6%, which is 20 times higher than in the general population.^21,^24,³⁸ Direct neurotoxicity of APLAs may play a significant role, in addition to ischemic insult from cerebral thrombosis.^24,³⁹

Headaches, including migraine, are a common complaint in APS, but any causative association with APLAs remains unproven. Most prospective studies have not found any association between APLAs and headache.^24,³⁹ An exception would be headache secondary to cerebral vein thrombosis. Movement disorders (e.g., chorea) have been associated with APLAs.²⁷ The prevalence has been reported to be 1.3% in the Euro-Phospholipid project and 1% to 4% in patients with SLE and APLAs.^21,⁴⁰ Demyelinating disorders, including myelitis and neuromyelitis optica (e.g., Devic disease), have been associated with APLAs.⁴¹^–⁴³

Ocular Manifestations

Occlusion of the central and branch retinal arteries and veins may lead to visual disturbances. Ischemic optic neuropathy, retinal vessel abnormalities, cilioretinal artery occlusion, and choroidal infarctions have been described.⁴⁴

Cardiovascular Manifestations

Ischemic heart disease is more common in patients with APS than the general population. In the Euro-Phospholipid project, myocardial infarction was noted in 5.5% of the cohort participants.²¹ The prevalence of myocardial ischemia was seven times higher in patients with APS.⁴⁵ Cardiac valvular lesions are more frequently reported in those with APS. Transthoracic and transesophageal echocardiographic studies reported prevalence rates of 35% to 82% in patients with APS.^35,^46,⁴⁷ The most common lesion is valvular thickening, although vegetations, stenosis, and regurgitation may also be present. The mitral valve is most commonly involved, followed by the aortic valve.^35,⁴⁷ The majority of the lesions are mild. Symptomatic valvular disease occurs in only 5% of the patients.^35,^46,⁴⁷ An association between cardiac valvular lesions and arterial thrombosis, including cerebrovascular events, has been described in APS and is likely linked by the higher embolic risk in patients with valvular lesions.³³^–³⁵

Dermatologic Manifestations

Livedo reticularis, a purplish discoloration of the skin with a netlike pattern, is the most common abnormality, noted in 16% to 25% of patients with APS.^48,⁴⁹ Livedo reticularis is reportedly more common in secondary APS and in women. It has been associated with positive immunoglobulin G (IgG) aCL, arterial thrombotic events, and cardiac valvular disease.^35,^49,⁵⁰ It may also occur in a variety of other disorders such as other autoimmune diseases, vasculitis, severe sepsis, cholesterol embolism, and even normal individuals (e.g., livedo rosacea). Livedo racemosa, an irregular branching pattern of finer and more widespread purplish discoloration and often with broken circles, has been associated with APLA-positive Sneddon syndrome.⁵¹

Cutaneous ulcerations are reported in 4% to 8% of patients with APS and range from ischemic to postphlebitic ulcers.⁵⁰ Ischemic ulcers are usually observed on the legs around the pretibial area and feet and are small and painful with central necrotic areas and sharp margins. They are often preceded by recurrent necrotizing purpura and leave whitish atrophic scars on healing. Occasionally, large solitary pyoderma gangrenosum–like ulcers, but without the undermined edges, have been reported in patients with APS.⁵⁰ Postphlebitic ulcers can occur in patients with long-standing venous thrombosis of the leg, leading to chronic edema, characteristic skin changes, and ulcerations.⁵⁰

Superficial thrombophlebitis, mainly on the limbs, is noted in a small percentage of patients. Thrombocytopenic purpura is uncommon but may occur when the platelet counts are below 20 × 10⁹/L. Digital gangrene and cutaneous gangrene are rare manifestations, usually preceded by digital cyanosis and extensive painful purpura, respectively.⁵⁰

Pulmonary Manifestations

The predominant pulmonary manifestation is pulmonary embolism in 14% to 40% of patients, with a majority of them having concomitant DVT.^21,⁵² A small percentage progress to chronic thromboembolic pulmonary hypertension.⁵²

Other Manifestations

Thrombocytopenia is a well-recognized feature of APS and is noted in up to 30% of patients in a large European study.²¹ It is generally mild, although moderate to severe cases have been described. Thrombocytopenia is more common in secondary APS associated with SLE than with primary APS.²¹ The pathogenesis is multifactorial but can include peripheral destruction of platelets, mediated by APLA binding and removal by the reticuloendothelial system. Antibodies directed against platelet GPs may also contribute to thrombocytopenia.¹ Occasionally, ethylenediaminetetraacetic acid (EDTA)–dependent APLAs and antiplatelet antibodies cause platelet clumping, leading to pseudothrombocytopenia.⁵³ Approximately 10% of patients with APS develop a Coombs-positive hemolytic anemia.²¹

Renal involvement usually takes the form of APS nephropathy with microvessel and glomerular thrombosis, although all levels of vasculature may be involved. Clinical manifestations include hypertension, proteinuria, and renal failure.⁵⁴ Rare intraabdominal manifestations include mesenteric ischemia and pancreatic and splenic infarctions.^21,⁵⁴ An association of APLAs with avascular necrosis of bone has been suggested but remains unproven.^48,⁵⁵

Pregnancy Complications

Pregnancy morbidity is one of the defining characteristics of APS. Both early and late losses occur with increased frequency—35% and 15%, respectively, in the European cohort. Increased rates of intrauterine growth restriction, preeclampsia, placental insufficiency, and preterm delivery have been reported.^21,⁵⁶ The pregnancy outcomes in patients with APS have significantly improved; successful pregnancy rates of 70% or more can be achieved with appropriate treatment.⁵⁷ Multiple pathogenic mechanisms likely contribute to pregnancy loss in APS. In the murine model of APLA-induced pregnancy loss, it has been shown that complement activation plays a causative role and complement inhibition can rescue the pregnancies.¹⁶ It has also been demonstrated that heparin inhibits activation of complement and, as a result, low prophylactic doses can prevent pregnancy loss.¹⁶ Other proposed mechanisms of APLA-induced pregnancy loss include inhibition of trophoblast function, interference with the prostaglandin balance at the endothelial cell level, and placental thrombosis.¹⁹