November 2005

Fig5.

Fig6.

Fig7.

Diagnosis: Antiphospholipid Syndrome

Histopathology:Two 4-mm punch biopsies were taken from the superior and inferior aspects of purpuric areas on the right superior and inferior thigh. Figs5-7 demonstrate vascular thrombi occluding some of the superficial to mid-reticular dermal blood vessels, along with congestion present in the remaining vessels. There is also notable extravasation of the erythrocytes and a paucicellular, perivascular, acute, inflammatory infiltrate with some nuclear debris. There was no vasculitis present. These findings were consistent with thrombosis secondary to anti-phospholipid syndrome. Tissue cultures obtained at the same time failed to grow bacteria, viruses, fungi, or mycobacteria.

Therapeutic & Clinical Course
It was postulated that she likely developed renal and cutaneous manifestations of antiphospholipid syndrome. However, the renal decompensation was also concerning for volume depletion and even possibly from a lupus flare. Her clinical status may have become acutely apparent from the recent infection and surgical debridement of her left lateral calf. Therefore, she was initiated on Solumedrol 1 gram IV every 24 hours, a heparin IV drip, Vancomycin 1 gram IV daily, and IV fluid hydration. For the severe pain, a morphine PCA pump was required. After 96 hours of the aforementioned therapy, her pain and renal status improved almost back to baseline. Therefore, the IV Solumedrol was exchanged for prednisone 60 mg daily, and she was started on long-term warfarin therapy. On hospital day 5, she also received a loading dose of Cytoxan 500mg/m2 IV. She was discharged on hospital day 6. The plan was for her to be followed closely by Rheumatology, and to continue the Cytoxan therapy as an outpatient. During the hospital course, the retiform, purpuric rash did not expand further or ulcerate.

Discussion
Antiphospholipid syndrome (APS) is characterized by the occurrence of arterial or venous thromoboses, as well as recurrent miscarriages, in the setting of antiphospholipid antibodies: lupus anticoagulant and anticardiolipin antibodies (1). The presence of antiphospholipid antibodies (aPL) without any clinical thrombotic complications, does not constitute a diagnosis of APS, as long-term, asymptomatic, aPL-positive patients do exist. In fact, the prevalence is 2-4%, and they are more commonly found in the elderly. If APS is diagnosed in patients with autoimmune disorders, most commonly systemic lupus erythematosus (SLE) (23-47%), then it is called secondary APS. In healthy patients, it is called primary APS. Catastrophic antiphospholipid syndrome (CAPS) is a severe, life-threatening form of APS, which occurs when multiple, small-vessel thrombosis occurs in several distinct organs, by which multisystem failure is seen in a short period of time. Mortality from CAPS has been reported up to 50%, even despite therapy (2).

The Sapporo criteria are used to diagnose antiphospholipid syndrome. In order to be diagnosed with APS, one laboratory criterion of either a positive anticardiolipin or lupus anticoagulant must be present, and one clinical criterion of vascular thromobosis or pregnancy complication (1 or more fetal deaths >10 weeks, 3 or more spontaneous abortions <10 weeks, or 1 or more premature births) must be present (2).

The pathogenesis of APS has not been fully elucidated. However, it is thought that antiphospholipid antibodies may disrupt the normal balance between procoagulation and anticoagulation, which occurs on cell membranes. In vivo, thombosis appears to occur. However, in vitro, prolongation of clotting times occurs (3). Studies have demonstrated the ability of aPL to inhibit protein C, protein S, and thrombomodulin, which are all normal anticoagulants produced within the body. These antibodies can also inhibit naturally occurring fibrinolysis. They may also stimulate cells to secrete various molecules to promote coagulation, including increased platelet activation and aggregation (1). In an aPL-positive patient, additional prothrombotic events may serve as a trigger for APS, including tobacco use, oral contraceptives, surgical procedures, prolonged immobilization, pregnancy, malignancies, and infection (4).

Clinical manifestations are varied and include arterial thrombosis, such as cerebral vascular accident and TIA, extremity gangrene, and aortic occlusion. Venous thromboses also commonly occur, including deep vein thrombosis, which is the most common manifestation of APS. Other manifestations of venous thromboses include pulmonary embolism, as well as mesenteric, hepatic, and renal vein thromboses. Complications arise from the multi-system thromboses. Obstetric complications include recurrent fetal loss, pre-eclampsia, and intrauterine growth retardation. Hematologic complications commonly seen include thrombocytopenia, hemolytic anemia, and microangiopathy. Neurologic complications reported include seizures, multi-infarct dementia, chorea, migrane headaches, transeverse myelitis, amaurosis fugax, and a multiple sclerosis-like syndrome (5). Cardiac complications include mitral and/or aortic valvular insufficiency, intracardiac thrombosis, and coronary artery thrombosis. Pulmonary complications include pulmonary hypertension, adult respiratory distress syndrome, and intra-alveolar hemorrhage (6). Thromboses can manifest at any area within the renal vasculature. Therefore, renal complications seen include nephropathy with glomerular thrombosis, cortical necrosis, and renal infarction. Moreover, avascular necrosis can occur from APS, independent of corticosteroid use.

There have been many cutaneous manifestations of antiphospholipid syndrome reported. Livedo reticularis is the most common. Others include noninflammatory, nonblanchable, and nonpalpable reticulated purpura, cutaneous necrosis, splinter hemorrhages, anteoderma, and even digital gangrene.

Histological evaluation of cutaneous specimens from patients with antiphospholipid syndrome may demonstrate dermal edema and hemorrhage. Thrombi may be seen in both arteries and veins. Although there may be a mild lymphocytic perivascular infiltrate, there is no vasculitis seen by definition (7).

Therapy directed at asymptomatic, aPL-positive patients is yet controversial, as there have been no prospective therapeutic data to support anticoagulant use. However, the current recommendations have been to use low-dose (81 mg/day) aspirin, along with educating the patient on avoidance of procoagulant states (smoking, oral contraceptives, immobility, etc). In patients with APS, retrospective studies have demonstrated that long-term, high dose warfarin (INR 3-4) was most effective in reducing recurrent, thrombotic events. However, controversy still exists about the therapeutic INR, and more recent data demonstrate an INR of 2-3 is acceptable. Standard therapies for pregnant women with aPL include low-dose, subcutaneous heparin or low-molecular weight heparin (LMWH), with low-dose aspirin. For catastrophic APS, anticoagulation, corticosteroids, and plasmapheresis or IVIG have demonstrated improved survival rates (2).

This patient will likely require life-long anticoagulation, improved control of her systemic lupus erythematosus with Cytoxan to preserve her kidneys, and close monitoring for future infections in order to prevent future antiphospholipid syndrome sequela.

This case was presented by Maria J Canizares, MD and Beatriz Tapia, MD,

References
1) Espinosa G, Cervera R, Font J, Schoenfeld Y. Antiphospholipid syndrome: pathogenic mechanisms. Autoimmun Rev. 2003; 2(2): 86-93.
2) Sammaritano L. Antiphospholipid Syndrome: Review. Southern Medical Journal. 2005; 98(6): 617-623.
3) DeGroot PG, Derksen RHMW. The antiphospholipid syndrome: clinical characteristics, laboratory features and pathogenesis. Curr Opin Infect Dis. 2005; 18: 205-210.
4) Erkan D, Lockshin MD. What is antiphospholipid syndrome? Curr Rheum Rep. 2004; 6: 451-457.
5) Asherson RA, Cervera R. Unusual manifestations of the antiphospholipid syndrome. Clin Rev Allergy Immunol. 2003;25(1): 61-78.
6) Marai I, Zandmann-Goddard G, Shoenfeld Y. The systemic nature of the antiphospholipid syndrome. Scand J Rheumatol. 2004; 33: 365-372.
7) Weedon D. Skin Pathology (2nd ed). Churchill-Livingstone. 2002.