CASE REPORT

antiphospholipid amibody syndrome

The Antiphospholipid Antibody Syndrome in the Emergency Department Setting- Livedo Reticularis and Recurrent Venous Thrombosis From the Department of Emergency Medicine* and the Divison of

Samar Kester, DO* David L McCarty, MD*

Rheumatology, Immunology, and

Gale A McCarty, MD t

Allergy, t Oklahoma University Health Sciences Center, Oklahoma City. Receivedfor publication December26, 1990. Revision received July 1, 1991. Acceptedfor publication August 2, 1991.

We present the case of a 26-year-old man with an exacerbation of apparent chronic asthma with chronic peripheral vascular disease due to recurrent venous thrombosis. Localized livedo reticularis, new cutaneous infarctions, severe venous insufficiency, thrombocytopenia, renal failure, and cerebral supratentorial dysfunction were noted. During hospital admission, antibodies to phospholipids in high titer were present by three different testing methods. Renal biopsy demonstrated significant renal vasculature abnormalities characteristic of hemolytic endovasculopathy, and magnetic resonance imaging showed multiple cerebral infarctions. This case exemplifies the spectrum of presentations and management of the primary antiphospholipid antibody syndrome. The clue to its presence in this patient was the livedo reticularis rash, a cutaneous marker for this syndrome that was evident in the emergency department. [Kester S, McCarty DL, McCarty GA: The antiphospholipid antibody syndrome in the emergency department setting - Livedo reticularis and recurrent venous thrombosis. Ann Emerg Med February 1992;21:207-211.] INTRODUCTION The primary antiphospholipid antibody syndrome (APS) is an autoimmune symptom complex process that has been growing in recognition. 1-9 Previously healthy patients may present to the emergency department with venous or arterial thrombosis, thromboeytopenia, hemolytic anemia, livedo retieularis, or fetal loss. These features can also be indicative of systemic lupus erythematosus (SLE), which is also in the differential diagnosis of these symptoms. This case illustrates an example of a patient with APS with livedo reticularis as a primary feature of the ED presentation. Recognition of livedo retieularis is essential because it can be confused with the typical skin mottling of eyanosis, especially in the case of a patient in respiratory distress. In previously healthy patients without risk factors, the suspicion of the primary APS should be raised. I~

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CASE REPORT A 26-year-old man presented to the ED complaining of intermittent shortness of breath and wheezing for one month, with considerable worsening during the previous week. The patient interpreted these symptoms as an exacerbation of his chronic asthma. His medical history included chronic vascular insufficiency in the lower extremities since age 12 that was attributed to chronic trauma. The patient was a poor historian. The patient's mother reported that he had developed the "flu" about two months earlier and had intermittent episodes of wheezing since that time. The symptoms had worsened markedly approximately one week before presentation and had been associated with subtle mental status changes. A physician diagnosed an upper respiratory infection, and cephalexin was given. A "swollen tongue" developed

and was attributed to the cephalexin. Low-dose corticosteriods were prescribed, and the antibiotic was discontinued. Subsequently, his confusion and shortness of breath worsened. The patient denied abdominal pain, fever, or chest pain. A red-to-bluish mottling of small areas of skin on the chest, legs, and elbows was noted, and it progressively worsened. The patient had had asthma since childhood, requiring six hospitalizations. At age 12, he had a "blood clot" in the legs requiring heparinization, with a history suggesting a subsequent pulmonary embolism, but angiography was not performed because of an anaphylactic reaction to contrast material. An extensive coagulation battery was performed and reported as normal. The patient had been followed for chronic venous stasis ulcers in his lower extremities and treated with Unna boot applications.

The patient was adopted, thus no family history was available. He smoked two packs of cigarettes a day, consumed "a six-pack of beer" a day, and was employed as a waiter. Physical examination revealed an afebrile, welldeveloped young man in marked respiratory distress. Accessory muscle use with audible wheezing and perioral cyanosis was noted. Blood pressure was 86/58 mm Hg; pulse, 100; and respirations, 40. Jugular venous distension at 45 ° was present. Coarse wheezes and bibasilar rules were heard in all lung fields, precluding full cardiac auscultation. The liver spanned 12 cm and was not tender. Stool was hemoccult positive. The skin was mottled, cool, and dry; on the extremities and trunk, a diffuse bluish-purple mottling was noted (Figure 1). A similar, more intense reddish-blue mottling of the face was in a

malar distribution, and one alar wing of the nares was deeply cyanotic (Figure 2). Neurologie examination revealed the patient to be alert and oriented to person and place. He did not have complete insight into the situation and was not oriented to time. Platelet count was 40,000 cells/mm3. Hematocrit was 37.4% (.37 SI), and WBes were 10.9 x 103/mm 3 (10.9 x 109/L). Room air arterial blood gases were pH 7.40; PC02, 24 mm Hg; P02, 115 mm Hg; and HC03-,15 mEq/L. Prothrombin time (PT) was 17.9 seconds, and activated partial thromboplastin time (APTT) was 32 seconds (slightly prolonged). Potassium was 6.4 mEq/1; C02, 12 mEq/L; and glucose, 154 mg/dL. Other electrolytes were within normal range. A chest radiograph showed cardiomegaly with prominent vascularity consistent •

Figure 1.

Figure 2.

Infarcted skin lesion on patient's left elbow with livedo reticularis. Prominent livedo retieularis with skin mottling present in ED. Cutaneous infarction was present.

Infarcted nasal alar skin lesion with livedo reticularls on nasal bridge. The patient had livedo reticularis in a malar distribution in addition to an infarction where extrenw cyanosis had been present on the left nasal alar wing.

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with congestive heart failure. An ECG showed a normal sinus rhythm of 99, poor R wave progression, right axis deviation, and evidence of left atrial enlargement. Urinalysis showed occasional RBCs and no casts. Blood urea nitrogen was 102 mg/dL, and ereatinine was 5.4 mg/dL. Total protein was 5.3 g/dL (53 g/L); albumin, 2.5 g/L (25 g/L); calcium, 8.2 mg/dL; phosphorus, 9.3 mg/dL; and uric acid, 12.6 mg/dL. Lactic dehydrogenase was 668 units/L, and alkaline phosphatase was 274 units/L. Oxygen at 4 L by nasal prongs, 5 mg albuterol by hand-held nebulizer, 300 mg aminophylline by IV route, and 125 mg methylprednisolone by IV route were administered with moderate improvement in symptoms. Heart sounds were then audible, and an S3 gallop and occasional rub were noted. Calcium gluconate, insulin glucose, sodium bicarbonate, and sodium polystyrene were administered for hyperkalemia. Repeat vital signs showed blood pressure of 157/84 mm Hg; pulse, 100; and respirations, 18. The patient was much improved but remained short of breath, with rales now more audible. Blood pressure increased to 186/110 mm Hg. The patient was admitted to the 1CU and underwent diuresis, repeate dialysis, and plasmaphoresis. Computed tomography of the head and abdomen was unremarkable with no infarctions. An

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echoeardiogram showed dilated left and right ventricles with mild aortic regurgitation, secondary to thickening of aortic leaflets. A rheumatology consultation was obtained, and the skin lesions were defined as livedo reticularis. A biologic false-positive serologic test for syphilis (BFP-STS) was present. Elevated antiphospholipid antibody (aPL) by enzyme-linked immunosorbent assay (ELISA) was present in three isotopes: extremely high immunoglobulin fig)G, low IgM, and low IgA. Low C3 and low C4 were noted by protein determinations. Screening antinuclear antibody testing on HEp-2 cells was negative. The serum CH50 was 100 (normal, 100 to 300 CH50 units). The Westergren sedimentation rate was 97 ram/hr. Total protein was 5/3 g/dL, and albumin was 2.5 g/dL. The rheumatoid factor by Latex was negative. A direct Coombs' test was negative. The antinative DNA was negative, as was the antidenatured DNA. No precipitating autoantibodies were present by immunodiffusion with calf and rabbit thymus extract. Renal angiography showed marked delay in vascular flow to both kidneys with no other abnormality. Renal biopsy demonstrated only mild mesangial proliferation, but significant abnormalities of the renal vasculature suggested

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hemolytic endovasculopathy. No renal microthrombi were present. These findings were consistent with primary APS. The mottling of the skin was livedo reticularis, a cutaneous marker often associated with APE.l, 3-9 IV steroid therapy and administration of IV cyclophosphamide was initiated with marked improvement clinieally in renal, cardiae, and pulmonary functions. Platelet transfusions were given. The venous stasis ulcers improved markedly with IV steroid and cyelophosphamide therapy, plasmapheresis, and local whirlpool therapy, The infarct area of the nares and right elbow progressed to local necrosis after partial resolution of the livedo retieularis rash. Magnetic resonance imaging of the brain showed multiple old lacunar infarets seeondary to small-vessel disease and a healed infarction involving the left occipital lobe. The patient has done well; intermittent flares of the aPL syndrome have been responsive to steroids.

DISCUSSION Primary APE is an autoimmune process that has been growing in recognition since 1983, when the aPL ELISA was first perfected. 1-3 By criteria, the primary APE is defined as the presence of less than four clinical features within the SLE spectrum, by American College of Rheumatology criteria

for SLE, moderate or high levels of aPL, and at least two of the following clinical features: 1) recurrent venous and/or arterial thrombosis, 2) thrombocytopenia, 3) recurrent fetal loss, 4) livedo reticularis, and 5) hemolytic anemia.2,3,6,8,9 Thus, the primary APS is an entity distinct from SLE. However, patients with SLE can have a positive aPL. aPL occurs in patients with autoimmune diseases, infections, drug-induced malignancies, and other disorders and are reported most frequently in patients with SLE.3 There is an extremely low incidence of aPL (less than 5%) in normal individuals when the standard tests are performed.4. 8 There are three tests that define separate but related autoantibodies to negatively charged phospholipids: the BFP-STS, which uses reagin (a mixture of cholesterol, cardiolipin, and choline); the "lupus anti-coagulant" (LA), as detected by an (APTT) that does not correct with mixing with normal plasma; and aPL detected by the cardiolipin ELISA.2 A BFP-STS and an elevated APTY may be indicative of the presence of aPLs, and should prompt the physician to order the aPL ELISA. Patients with aPL may have BFP-STS. This result may be transient (usually the result of an intereurrent infection) or chronic (present for more than six months) and is commonly seen in autoimmune

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diseases. A negative result does not exclude the presence of aPLs as this test correlates poorly with the aPL ELISA. A positive result is useful in identifying patients who should be further evaluated by other tests for aPLs, as well as for other autoantibodies associated with connective tissue diseases2 Lupuslike anticoagulants are G or M immununoglobulins that prolong phospholipiddependent coagulation tests by interfering with calcium dependent binding of prothrombin (Factor II) and Factor Xa to phospholipids, thus inhibiting the generation of prothrombinase. This prevents conversion of prothrombin to thrombin, and leads to prolongation of the APTT with or without prolongation of the PT.1, lo In patients identified as having an LA by the APTT, 21% to 50% appear to have associated autoimmune disease.I, 11 The APTT should be performed with a mixing test to see if the abnormality eonrects with the addition of normal plasma: the true LA does not correct, whereas a clotting factor deficiency does correct. The IgG and IgM aPL isotopes also are associated with an increased risk of thrombosis. Clinical problems associated with aPL antibody are usually similar to those associated with LA. The incidences of thrombosis and fetal loss are generally related to the degree of elevation of the

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aPL antibody titer and are usually greater in patients with the IgG isotope of aPL antibodies.l-a32-14

the glomeruli of the kidney and the placenta may be affected. 3 Pulmonary hypertension may o c c u r . 6,15,16

Typical vascular lesions of SLE involve the small blood vessels (small arteries, small veins, arterioles, and venules) in a polyarteritis-type necrotizing vasculitis or, less often, a granulomatous vasculitis.2 In contrast, the vascular occlusive lesions of the antiphospholipid syndrome are usually thrombotic in nature and involve both large and small vessels. These lesions may occur anywhere in the vascular tree. No associated generalized abnormalities of the underlying endothelium or cellular infiltrates of vessel walls have been shown to be characteristic, but plasma cell perivascular infiltrates and predominant endothelial cell hyperplasia have been noted in the limited studies to date. 5,15 Patients have presented with deep or superficial venous thrombosis, pulmonary emboli, cerebrovascular accidents, transient ischemic attacks, myocardial infarctions, multi-infarct dementia, gangrenous extremities, or ischemic optic neuropathy.3, s Documented sites of venous thrombosis include superficial and deep veins of the leg, renal veins, hepatic veins, axillary veins, and the inferior vena eava. 2 Arterial sites have included intracranial/coronary, retinal, mesenteric, and peripheral arteries. Small vessels such as those of

Livedo reticularis is a geographically distributed dilatation of the superficial venous plexus of the skin, which is often seen over the thighs and arms and may also be seen on the face, extremities, or chest, as occurred with our patient. It is often provoked by exposure to cold. 3 It may also be seen in exacerbations of APS, and severe livedo changes are associated with increased antieardiolipin antibody titers to the extent that some investigators think that livedo retieularis is a marker rash for the presence of aPL. In one study, 40% of the patients had livedo skin rashes as the first signs of disease. The mother of our patient stated that he had had the livedo skin rash for many years, with periods of exacerbation and quiescence but that none of his physicians recognized it or commented on it. A precise single mechanism by which aPLs mediate thrombosis has not been elucidated, but the etiology is probably multifaetorial. Some proposed mechanisms are the inhibition of prostacyclin release from vascular endothelium; interactions with phospholipids in platelet membranes, resulting in platelet activation, aggregation, and thrombosis; or the induction of a relative deficiency of protein S or interference with f32-glycoprotein I, a naturally occurring anticoagulant.3,937-20

The role that aPLs play in producing thrombocytopenia is not clear, aPL antibodies could bind platelets, thus inducing platelet-enhaneed uptake and destruction by the reticuloendothelial system, or they could initiate thrombosis by binding and activating platelets.6 Female patients may present to the ED with fetal loss. Recurrent fetal loss may be the only manifestation of APS in otherwise "healthy" women. 19 Approximately 73% to 89% of women with LA who become pregnant have miscarriages.334 In one series of 24 patients with LA with 137 pregnancies with no treatment, less than 10% of pregnancies ended successfully.5 The mechanism of fetal death is not completely understood. Examination of placentae of aborted fetuses or neonates with severe intrauterine growth retardation often show multiple areas of thromboses and infarction. The degree of infarction has sometimes appeared to be insufficient to account for fetal death. 6 One suggested mechanism is a deficiency of prostacyclin production by placental vessels, causing increased platelet aggregation, reduced blood flow, and placental infarction.6 aPL also causes intrauterine growth retardation due to compromised placental blood flow. Other clinical features associated with APS may be aortic or mitral valve lesions

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(valvulitis; with or without associated embolic phenomena), chorea, neuropsyehiatric disorders, and, rarely arthralgias. 4

with steroid therapy in patients with SLE, LA activity, and a history of recurrent abortions.

There is a variety of effective treatments; however, the minimal morbidity and maximum efficacy of any one regimen have not been effectively compared in large populations.20-22 Some people have persistently elevated titers of aPLs yet have no clinical manifestations. In general, the risk for thromboses is considered to be proportional to the titer. It is generally thought that these patients should be observed, but recent data presented at the Fourth International aPL Symposium suggest that these patients are at risk for thrombotic events.2° Patients with a history of one mild thrombotic event and aPLs are usually managed with one

Primary APS is being increasingly recognized as a disease process. APS causes a localized or generalized vaseulopathy with protean clinical manifestations. The disease must be suspected in a patient who presents to the ED with livedo retieularis, otherwise unexplained occlusive thrombotic events, a history of recurrent fetal loss, a necrologic event (especially in a young patient without appropriate risk factors), or thrombocytopenia. A positive BFPSTS or elevated APTT in the ED may suggest APS in asymptomatie patients. Confirmation of the presence of aPLs should be done by a standard eardiolipin ELISA.

baby aspirin a day or aspirin plus prednisone. Patients with active thrombotic events should be heparinized, with subsequent conversion to warfarin therapy in some

Acute presentation of a patient with suspected APS demands immediate rheumatologie eonsuhation. The emergency physician should be aware of the existence of this syndrome

instances. Long-term treatment is probably indicated after recurrent thrombotic events in those who remain positive for aPL because the cessation of anticoagulants has been associated with recurrent thrombotic events. 9 Steroids have been shown to

and should know that effective treatments do exist and may be life saving. •

decrease both the LA titer and the aPL titer but at different time courses. Some studies have shown improved rates of successful pregnancies

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SUMMARY

REFERENCES 1. Bowles CA: Vascutopathyassociatedwith the antiphosphoiipid syndrome. Rheum Dis Cfin North Am 1990;16:471-490. 2. Lie JT: Vasculopathyin the antiphesphelipid syndrome:Thrombosisor vasculitis or both (editorial). J Rheum 1989;16:713-715. 3. Harris EN, Asherson RA, HughesGRA: Antiphosphelipid antibodies-Autoantibedies with a difference Annu Roy Med 1988;39:261-271. 4. Mackwerth-YoungCG, LoizouS, Walport, MJ: Primaryantiphespholipid syndrome: Features of patients with raised anticardiolipin antibodiesand no ether disorder. Ann Rheum Dis 1989;48:362-367. 5. Many A, Gitel S, PauznerR: The antiphosphelipid syndrome. Israefi J Med Sci 1989:25:674-677. 6. Bingely PH, Hoffbrand Bh Antiphospholipid antibody syndrome:A review. J t7 Soc Med 1987;80:445-448. 7. LovePE, Santero SA: Antiphospholipid antibodies: Anticardiolipin and the lupus anticoagulant in systemic lupus erythematesus(SLE}and non-SLEdisorder. Ann Intern Mefl 1990;112:682-698. 8. Harris EN, GharaviAE, HughesGRV: A@phospholipN antibodies. Ctin Rheum Dis 1985;11:591-609. 9. SammaritanoL, GharaviAE, Lockshin MD: Anticardielipin antibodies syndrome: Immunologicand clinical aspects. Sernin Arthritis Rbeum 1990:20:81-96. 10. FeinsteinDI, RapportSI: Acquired inhibitors of bleed coagulation,in SpeatTN (ed): Progress in Hemostasis and Thrombosis. New York, Grune & Stratton, 1972, p 75-95. 11. KornbergA, Silber L, Yona R, et ah Clinical manifestationsend laboratory findings in patients with lupus anticoagulants. Eur J Haematol 1989;42:90-95. 12. Triplett CA, BrandtJT, Mugrave KA, et ah The relationship between lupus anticoagulantsand antibodiesto phospholipid. JAMA 1988;259:550-554 13. DerksenRH, KaterL: Lupusanticoagulant: Revival of an old phenomenon.ClinExp Rheumatof 1985;3:349-357

14. Harris EN, ChanJKH, AshersonRA, et ai: Thrombosis, recurrentfetal loss, and thrombocytopenia: Predictivevalue of the anticardiolipin antibodytest. Arch Intern Med 1986;146:2153-2159. 15. SontheimerRD: The anticardiolipin syndrome: A new way to slice an old pie, or a new pie to slice? Arch Dermatot 1987;123:590-595. 16. Asherson RA, Mackworth-YoungCG, Boey ML, eLah Pufmenaryhypertension in systemic lupus erythematosus.BrMedJ 1983;287:1024-1025. 17. Harris EN, Ashersen RA, Gharavi AE, et ah Thrombocytopeniain SLEand related autoimmunedisordersassociatedwith anticardielipin antibodies. Br J Haematol 1985;59:231-234. 18. Asherson RA, KhamashtaMA: Sneddon's syndromeand primary antiphospholipid syndrome(PAPS)(letter).Br J Dermatel 1990;122:115-116 19. LubbeWE, Pattison N, Liggins GC: Antiphospholipid antibodies and pregnancy. N Engl J Med 1985:313:1350q351. 20. ParkeA, Weinstein R, Bona R, et al: Thrombotic diseasesassociatedwith aPL may be due to low levels of free protein S. Clin Exp Rheumato11990;8:210. 21. McCartyGa, Lister KA, Reichlin M, et al: Successful treatment ef three women with RFLand postpartum normafizationof aPL and placental studies. Arn J ReprodImrnunol 1990;221:81. 22. McCartyGA: Antiphospholipld Antibodies: Treatable Causes of Many Syndromes. OktahomaCity, University of Oklahoma Health ScienceCenterand Oklahoma Medical ResearchFoundation Publication, 1990.

Address for reprints: Gale A McCarty, MD, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, Oklahoma 73104.

The technical expertise of Carole Lash, Connie Little, and Sally Gilstrap in the preparation of this manuscript was greatly appreciated.

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