The Antiphospholipid Antibody Syndrome

James P. Bolling, M.D.
James Bolling, M.D. is a Retina Specialist and Chair of the
Department of Ophthalmology at Mayo ClinicJacksonville .

Introduction

The antiphospholipid antibody syndrome (APAS) is condition associated with abnormal thromboses and the presence of Anticardiolipin Antibodies (aCL) or Lupus Anticoagulant (LA). The vascular events that are most associated with this syndrome are deep venous thrombosis of the legs, pulmonary embolus, and spontaneous fetal loss. Thromboses can be venous or arterial and may include many different vascular beds including cerebral veins and sinuses, the myocardium and the visceral vessels.1 The eye is frequently involved in APAS. According to one study 88% of patients with APAS had fundus findings.2

Laboratory Findings

The most common hematologic abnormality in APAS is thrombocytopenia. Platelet counts are usually in the low normal range but immune thrombocytopenic purpura can result in more significantly reduced platelet counts on occasion. Unfortunately the reduced platelet count does not protect against thrombosis. A positive combs is sometimes found but hemolytic anemia is rare. The PTT and APTT can be prolonged but this does not predispose to bleeding. These abnormal coagulation studies can make evaluating the effect of heparin complicated.

Patients with APAS may have lupus or other rheumatologic conditions. Therefore it is important to know the patient's sedimentation rate, antinuclear antibody test or other tests as indicated clinically. As with collagen vascular diseases the diagnosis requires clinical symptoms and is not based on lab findings alone.

Lupus Anticoagulant And Anticardiolipin Antibodies Are Related

It has been known for years that patients with connective tissue disease may sometimes have a biologic false positive syphilis test. Patients with a biologic false positive test for syphilis are know to be at risk for abnormal thromboses and subsequently have been found to have antibodies to phospholipids. These patients frequently have IgM antibodies to cardiolipin (aCL-IgM). More recently IgG-aCL have been reported. Both IgG-aCL and IgM-aCL are seen with increased tendency to thrombosis. It was initially thought that aCl assays would detect the same antibodies that LA assays. However it has been well documented that patients with APAS may be positive for aCL and not LA or positive for LA and not for aCL. A discussion as to why this is the case is beyond the scope of this review and is well-discussed elsewhere.3 Suffice it to say the LA and aCL may be discordant in up to 35% of patients. The implication is that a comprehensive evaluation would include aCL-IgM, aCL-IgG, and LA. LA has a stronger association with thrombosis than does aCL.

Ocular Findings

Retinal findings in APAS include venous tortuosity, cotton-wool spots, retinal vein occlusions, and retinal artery occlusions. Other fundus findings may include optic nerve edema, vitreous hemorrhage, choroidal vascular occlusions and RPE changes. Conjunctival telangectasia, episcleritis, and keratitis have also been reported. Visual acuity may be reduced and symptoms may include scintillating scotoma as seen in migraine. The signicance of migraine and blurred vision in patients with APAS is unknown. It is possible that these more protean symptoms are caused by the thombotic tendency of patients with APAS. Since migraine and blurred vision are relatively common, it is also possible that these symptoms occur in patients with APAS purely by coincidence.

Venous tortuosity is common, occurring in 70% of patients with APAS. Tortuosity is primarily found in the posterior pole. In over one half of cases venous tortuosity is associated with venous occlusions. Venous occlusive disease may take the form of central retinal vein occlusion, branch vein occlusion or venous stasis retinopathy. When venous occlusions occur in the retinal vessels they may differ from atherosclerotic branch vein occlusions in that they do not always occur at arterial/venous crossings. Retinal vein occlusions may occur with artery occlusions in the same distributions. These vascular occlusions may be multiple, even in the same eye.

Retinal artery occlusions may be central retinal artery occlusions or branch artery occlusions. The branch occlusions do not necessarily occur at bifurcations, as in embolic occlusions. Areas of the retina with vascular occlusions have a strong tendency to develop neovascularization of the retina. Patients respond to laser treatment to the affected area with resolution of the neovascularization in most cases. Vitreous hemorrhage is common in these patients and they may require vitrectomy in order to apply adequate laser treatment.

It is likely that in some cases, optic disc swelling may be due to ischemic optic neuropathy. The tendency toward thrombosis presumably increases the likelihood of an occlusion of a posterior ciliary artery. Elschnig's spots and a central serous type of appearance also occur with increased frequency.

Clinical Significance

Even though eye findings are common in APAS, most patients with retinal vascular disease do not have APAS.4 Since APAS is uncommon, it is an uncommon cause of retinal vascular disease. However, if patients do not have the usual risk factors for retinal vein and artery occlusive disease then the likelihood of having APAS is higher.5 It has been suggested that patients with retinal thrombosis who don't have hypertension, diabetes, hyperlipidemia, heart disease or atherosclerosis of the carotid arteries should be tested for APAS.

Should all patients who test positive for aCL and who have a retinal vascular occlusion be treated with anticoagulation? About two thirds of these patients may not have primary APS. Certainly in cases where other manifestations of thrombosis such as pulmonary embolus, deep venous thrombosis, and spontaneous abortion have occurred these patients should be considered at higher risk and may be considered for anticoagulation, at least until a second aCL test can be obtained in six weeks. The APAS is defined by an episode of arterial or venous thrombosis or spontaneous abortion and either a medium or high titer anticardiolipin antibody test (aCL) or the Lupus Anticoagulant (LA) on two occasions separated by at least 6 weeks.6

It is difficult to interpret the significance of one elevated aCL test. There are several reasons that one test result is not diagnostic. The aCL assay performed by the ELISA method is variable. Even the control group in this study had a 5% prevalence of medium or high aCL. It is also possible that aCL may be elevated in the period after an acute thrombosis. In other words, an elevated aCL may be a result of an episode of thrombosis and not the cause. Finally, the results of the aCL test are not normally distributed. The non-gaussian distribution of test result complicates setting the normal range for this test and has resulted in lack of agreement between laboratories.7

It is possible that some patients that have one elevated aCL level have a coagulopathy but not all the features of APAS. Leo-Kottler, et al have recently reported a group of patients who have one test positive for aCL; 50% have symptoms of either transient of permanent blurred vision. The significance of this finding is unknown.

Other findings that are of questionable significance include migraine, skin ulcerations, and livido reticularis. These findings are suggestive of vascular disease but are
not as strongly associated with APAS as deep venous thrombosis in the leg or a pulmonary embolus.

APAS is also complicated by the association with collagen vascular disease that can also cause microvascular complications as a result of inflammation in the arteries and veins and arteriolar narrowing. Therefore a vascular occlusion may be the result of vasculitis involving the arteries or veins and not abnormal coagulation or a combination of vasculitis and coagulopathy. This aspect can complicate treatment since the usual treatment for vasculitis would be anti-inflammatory treatment such as steroids. APAS on the other hand may be more appropriately treated with anticoagulation.

Summary

In summary, patients with APAS have thrombosis and an elevated aCL or LA titer on two occasions separated by 6 weeks. Many of the patients with APAS have eye findings and over half have retinal artery or vein occlusions. Some patients with APAS have migraine and blurred vision and these symptoms are of uncertain significance. Treatment with anticoagulation is usually recommended but patients must also be evaluated for lupus and other collagen vascular diseases that may alter therapy.

REFERENCES

  1. Petri M. Pathogenesis and treatment of the antiphospholipid antibody syndrome. Medical Clinics of North America: Advances in Rheumatology. 1977; 1:151-161.
  2. Castanon C, Amigo MC, Banales J, Nava A, Reyes PA. Ocular vaso-occlusive disease in primary antiphospholipid syndrome. Ophthalmology. 1995; 102:256-262.
  3. Petri M. Diagnosis of antiphospholipid antibodies. Rheumatic Disease Clinics of North America. 1994; 20:443-360.
  4. Glacet-bernard A, Bayani N, Chretien P, Cochard C, Lelong F, Coscas G. Antiphospholipid antibodies in retinal vascular occlusions. Arch Ophthalmol. 1994; 112:790-795.
  5. Cobo-soriano R, Sanchez-Ramon S, Aparicio MJ, et al. Aniphospohlipid antibodies and retinal thrombosis in patients without risk factors: a prospective case-control study. American J. Ophthalmol. 1999; 128:725-731.
  6. Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for defining antiphospholipid syndrome. Arthritis and Rheumatism. 1999; 42:1309-1311.
  7. Lockshin MD. Antiphospholipid antibody syndrome. Rheumatic Disease Clinics of North America. 1994; 20:46.
  8. Leo-Kottler B, Klein R, Berg PA, Zrenner E. Ocular symptoms in association with antiphospholipid antibodies. Graefe's Archive for Clinical and Experimental Ophthalmology. 1998; 236: 658-668.
September, 2000/ Jacksonville Medicine

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