Antiphospholipid Syndrome Hussein Halaby MBBS, ABIM , FRCPC.

Definition Etiology and Pathogenesis Clinical features Laboratory tests Treatment Prognosis

APS is a disorder of recurrent arterial or venous thromboses, or pregnancy loss associated with persistently positive result of anticardiolipin or lupus anticoagulant tests. The disorder may be primary or associated with other autoimmune diseases especially SLE. The antibodies are directed against either phospholipid or plasma proteins bound to anionic phospholipid.

Four types of AP antibodies have been characterized. Antibodies resulting in false positive serologic test for syphilis. Lupus anticoagulant. Anticardiolipin antibodies. Anti-B2 glycoprotein antibodies.

Criteria for diagnosis Clinical Vascular Thrombosis (one or more clinical episodes of arterial,venous,or small vessel thrombosis in any tissue or organ.) Pregnancy Morbidity 1- One or more unexplained death of a morphologically normal neonate at or beyond the 10th week of gestation or 2- One or more premature birth at or before 34th week of gestation because of severe preeclampsia or eclampsia or severe placental insufficiency or 3- Three or more unexplained consecutive spontaneous abortion before the 10th week of gestation.

Laboratory Criteria. ACL antibody of IgG and/ or IgM isotype in blood present in medium or high titer, on 2 or more occasions, at least 6 weeks apart. Lupus anticoagulant present in plasma, on 2 or more occasions, at least 6 weeks apart Definite APL syndrome is considered to be present if at least one of the clinical and one of the lab. Criteria are met.

Both ACL and LAC tests should be ordered for patients suspected of having APS, since one test can be positive without the other. Always check the titer since high titer is more suggestive for the diagnosis. Many conditions could give transient elevation of APL antibodies especially infections, those usually IgM type. Patients positive for APL antibodies should have platlets count, ANA,urine analysis,ESR, with further evaluation for lupus if abnormalities are found

Clinical Manifestation Thrombosis (venous, arterial, small vessel) Venous thromboses are more common than arterial thromboses in the APS. The most common site of deep vein thrombosis is the calf, but the renal, hepatic, axillary, subclavian, and retinal veins or the vena cava may be involved. The most common site of arterial thrombosis is the cerebral vessels, but coronary, renal, and mesenteric arteries and arterial bypass graft occlusions have also been noted. Recurrent events are common in APS. An interesting observation is that initial arterial thrombosis tend to be followed by an arterial event and initial venous thrombosis by a venous event. The factors that determine the predilection for the venous or arterial circulation are not known.

CNS Various neurologic disorders have occurred in association with antiphospholipid antibodies. Some, such as stroke, epilepsy, dementia, transverse myelopathy, and amaurosis fugax are suspected to to be due to thrombosis or embolization. This may occur from valvular lesions as in Libman Sacks endocarditis. Other central nervous system diseases, including Guillain-Barré syndrome, transient global amnesia, motor neuron disease, depression, movement disorders (chorea and hemibalismus), and pseudotumor do not have a clear pathogenetic mechanism to link them to antiphospholipid antibodies.

Pulmonary Diseases Multiple pulmonary complications can occur in patients with SLE and the APS including:- Pulmonary embolism and infarction, which occur in approximately one-third of patients with recurrent deep venous thrombosis. Thromboembolic and perhaps nonthromboembolic pulmonary hypertension, possibly leading to right-sided heart failure. Pulmonary arterial thrombosis. Pulmonary microthrombosis. Adult respiratory distress syndrome. Intraalveolar pulmonary hemorrhage. Fibrosing alveolitis. A postpartum syndrome, characterized by spiking fever, pleuritic chest pain, dyspnea, and findings of pleural effusion and patchy infiltrates on chest radiograph.

Cardiovascular Patients with antiphospholipid antibodies commonly have cardiac disease, including valvular thickening and the development of vegetations due to unclear mechanisms. The mitral and aortic valves are most commonly affected, possibly leading to valvular insufficiency and rarely stenosis. Antiphospholipid antibodies have also been incriminated in intracardiac thrombi, pericardial effusion, cardiomyopathy, emboli in those with or without infective endocarditis, premature restenosis of vein grafts for coronary bypass, and peripheral vascular disease.

Hematological Thrombocytopenia and thrombotic thrombocytopenic purpura (thrombotic microangiopathy) have both been reported in the APS. A review of 13 studies of 869 patients with SLE (and/or SLE-like diseases) found that thrombocytopenia was more common in those with antiphospholipid antibodies (37 percent), the lupus anticoagulant (55 percent), and anticardiolipin antibodies (29 percent) than in those without these antibodies. Conversely, patients with thrombocytopenia frequently have antiphospholipid antibodies. These antibodies have been found in 70 to 82 percent of patients with SLE and thrombocytopenia, and approximately 30 to 40 percent of those with idiopathic immune thrombocytopenia (ITP). Hemolytic anemia present in 10 percent of 1000 patients at some time during a mean of 7 years of observation.

Renal The incidence of renal disease in the APS is unclear. Approximately three percent of patients with APS had some renal manifestation in one large multicenter series. When present, thrombi are observed in the glomerulus and small arteries, similar to the lesions found in the hemolytic-uremic syndrome. The clinical signs of thrombi in the glomeruli and small arteries are variable. Some patients have only asymptomatic mild proteinuria (less than 2 g/day) with normal renal function, while others develop acute or subacute renal failure with proteinuria, an active urine sediment (that can include red cell casts), and often marked hypertension. Prominent unilateral or bilateral flank pain and severe hypertension can occur in patients with renal infarcts. As with the other manifestations of the APS, there is no predictable association between antiphospholipid antibodies and renal disease.

Gastrointestinal Patients with antiphospholipid antibodies may have ischemia involving the esophagus, stomach, duodenum, jejunum, ileum, or colon resulting in gastrointestinal bleeding, abdominal pain, an acute abdomen, esophageal necrosis with perforation, or giant gastric or atypical duodenal ulceration. Spleenic or pancreatic infarction may also occur.

Cutaneous Antiphospholipid antibodies have been associated with many cutaneous abnormalities including livedo reticularis, livedoid vasculitis, cutaneous necrosis and infarctions, thrombophlebitis, gangrene of digits, skin ulcerations, lesions resembling vasculitis (nodules, macules), subungual splinter hemorrhages, and Degos' disease (malignant atrophic papulosis).

Other Rheumatological Manifestations Anticardiolipin antibodies (aCL) have been reported in approximately 20 percent of patients with polymyalgia rheumatica or giant cell arteritis. In one prospective study of 284 patients, the presence of antiphospholipid antibodies was associated with an increased risk of giant cell arteritis, suggesting that antibody development resulted from endothelial activation and inflammation. The presence of anticardiolipin antibodies was not associated with an enhanced risk of thrombosis in these patients.

Primary versus secondary APS Both groups have similar clinical and lab manifestations. Patients with APL secondary to lupus are more likely to have autoimmune hemolytic anemia, neutropenia, and low C4 level. No evolution of primary APS in to SLE.

Who should be checked for AP antibodies? Unexplained arterial or venous thrombosis. Thrombotic involvement of unusual sites. Thrombosis in patients younger than 50y old. Recurrent thrombotic events. Patient with SLE especially if they have hemolytic anemia or thrombocytopenia. Women with recurrent pregnancy losses especially 2nd or 3rd trimester or early preeclampsia <20 weeks.

Treatment Standard therapy of thrombosis in patients with APS commonly consists of Heparin, followed by warfarin. ASA alone has no benefit. Low intensity warfarin (INR<2.6) offered some protection (23% of patient per year) High dose warfarin (INR>3) markedly reduces the incidence of new thrombotic episode to 1.3% of patient per year. INR maintained between 3 and 4 was associated with bleeding episode and severe bleeding (7.1 and 1.7% of patient per year) this was much lower than the absolute benefit of thrombosis prevention.

Patient with APS should be on life long anticoagulation,having said that patient with one episode of mild venous thrombosis may not require prolonged therapy,although life long ASA is usually administered. Patients who develop thrombotic event despite being on anticoagulation should have their warfarin dose increased or that ASA be added. Corticosteroids cytotoxic drugs, and IVIG are of no proven utility in patients with APS. Nevertheless the use of these drugs may be used in special situations.

Prophylactic therapy for asymptomatic individuals is not recommended. However in patient with high level of LA or ACL and other risk factors such as SLE many authors recommend giving one baby ASA/day.

Prognosis The risk of thrombosis in women who have a history only of pregnancy losses and in patients with ACL or LAG who have no clinical symptoms are unknown. Patients with catastrophic APS have the worse prognosis.

References Kelly’s Textbook of Rheumatology Primer on the rheumatic diseases Medical secrets of rheumatology Mechanisms in rheumatology Up-To-Date.