APL Cas clinique Une jeune femme de 35 ans se présente avec une histoire de fièvre, fatigue et amaigrissement significatif depuis 3 semaines. Elle présente de puis dix ans un lupus systémique, des ménométrorragies et une thrombophlébite des membres inférieurs au cours de l'année passée. A l'examen clinique, on observe de grandes lésions purpuriques, aux contours mal définis, non papuleux sur le sein gauche et la cuisse gauche qui se sont développés dans les dernières 24 heurs. Il existe un œdème papillaire bilatéral au fond d'œil et la patiente est en tachycardie sinusale. Le reste de l'examen clinique est sans particularité. CASE REPORT Les examens biologiques initiaux sont les suivants: wbc=3.3, hgb=7.4, hct=24.6, mcv=71.1, mch=20.9, plts=176, bands=3, segs=59, lymphs=36, mono=1, aPTT= 39.2, PT=2.3, INR=1.2, Na=137, K=3.7, Cl=100, C02=21, BUN=7, Cr=0.9, Gluc=102 Ca=8.4, AST=70, ALT=82, Total Bili=0.7, P=60, LDH=370 (nl 90-275 IU/L). Further labs revealed an elevated ANA =1:240 with homogenous pattern (nl<320), anti-ssDNA=382 (nl=0-19 EU), and anti-dsDNA= 92. Complement levels of C4 < 10 (nls=12-51mg/dL), C3=54.2 (70-163 mg/dL), and CH50 =61 (125-200 U/ml). Anti-la, Anti-ro, Anti-ribonucleotide, and Anti-Sm were all negative. However, aPL were positive for anticardiolipin IgG=79 (nl=0-13), and the lupus anticoagulant was elevated at 14.8 (nl < 3.37). Protein C=136 (nl>70%), free protein S=77 (nl=56-124%), total protein S=100 (nl=56-124%). The patient was treated with high dose systemic methylprednisolone, anticoagulated with heparin and warfarin, maintaining the INR at >3, and later, treated with IVIg immunotherapy. In the ensuing days, new purpuric lesions developed over both breasts, anterior thighs, and left flank region with progression to full thickness cutaneous necrotic lesions. A skin punch biopsy of one of the lesions was histopathologically consistent with aPL syndrome: a noninflammatory, microvascular thrombosis. After approximately three days, the cutaneous lesions stabilized; however her stay was further complicated by the development of thrombocytopenia, gram negative bacteremia, empyema, and pericardial effusion. She was subsequently treated with appropriate antibiotics, and a pericardial window was placed. Twenty-four days after her admission, the patient was discharged home on enoxaparin sodium (70 mg SC BID), methylprednisolone (24 mg po BID), hydroxychloroquine sulfate (200 mg PO BID), and metoprolol tartrate (50 mg PO BID). Follow-up appointments were made with hematology, plastic surgery, rheumatology, opthomology, and cardiology.

DISCUSSION The antiphospholipid antibody (aPL) syndrome is an acquired multisystem disorder of hypercoagulation. The aPL syndrome may be primary or secondary to an underlying disease, most commonly systemic lupus erythematosus (SLE). Clinically, aPL syndrome is characterized by venous and/or arterial thrombosis, recurrent fetal loss, and thrombocytopenia. The two serologic markers of antiphospholipid syndrome are lupus anticoagulant and anticardiolipin antibody. Although skin lesions are not necessary for the diagnosis of aPL syndrome, various cutaneous abnormalities have been associated (1), and as in this case, may be presenting signs. Although not common, widespread cutaneous necrosis (WCN) can be a manifestation of the aPL syndrome secondary to dermal microvascular thrombosis (2,3). The exact mechanism of this hypercoagulable state is not fully understood, however, many theories have been postulated. These can be divided into four major groups: dysfunction of the thrombomodulin-protein C-protein S anticoagulant system, aPL-platelet interactions, endothelial dysfunction, and annexin-V. Dysfunction of the thrombomodulin-protein C-protein S anticoagulant system has been demonstrated in patients with aPL syndrome (2). However in this patient, both protein C and S levels were within normal limits. The mechanism of this dysfunction most likely involves beta2GPI, a phospholipid-binding plasma protein (4). Beta2GPI is a 50 kD glycoprotein, originally discovered in 1990 when it was shown that IgG anticardiolipin antibodies that had been purified from patient sera, lost their affinity to solid-phase cardiolipin and cardiolipin liposomes in serum free assays (5,6). However, addition of normal serum restored antibody binding. This serum component was identified as Beta2GPI, which has since been shown to enhance the binding of anticardiolipin autoantibodies to cardiolipin (7,8,9). The exact physiological role of Beta2GPI is still unclear; however, it has been shown to inhibit ADP-dependent platelet aggregation (10) and protein C activation (4). These data support the theory that aPL interferes with the antithrombotic effects of B2-GP1, thereby leading to a hypercoagulable state. APL-platelet interaction requires prior activation or damage to the platelets, which results in exposure of the anionic inner leaflet of the platelet membrane. This leads to an increased hypercoagulable state. Endothelial cell damage can occur secondary to antiendothelial cell antibodies (11, 12, 13) including antibodies to endothelial cell surface proteins, such as thrombomodulin and vascular heparin sulfate proteoglycan (14, 15). Interestingly, vessel wall heparin sulfate is required for the activation of antithrombin III. It has been postulated that binding of various aPL antibodies to endothelial cells can result in a decrease in endothelial prostacyclin production (16). Annexin-V is an anionic phospholipid-binding protein, which under physiologic conditions prevents anionic phospholipids from formingcomplexes with coagulation proteins in circulating blood. The aPL syndrome disrupts the annexin shield increasing the exposure of thrombogenic phospholipids (17). Adding to the thrombogenic potential of the aPL syndrome is Beta2-GP1, which when added to cultured trophoblasts and endothelial cells in vitro were shown to displace annexin-V from phosphatidyl serine/phophatidyl choline phospholipid bilatyers (18). The exact mechanism of hypercoagulability in this patient remains unclear. However, in patients with pre-existing antibody disease, acute conditions that exacerbate an inflammatory response are speculated to increase the risk of hypercoagulability (2). This patient presented with a three-week history of fevers and was harvesting a gram-negative bacteremia. Laboratory studies were also consistent with an exacerbation of her SLE. The causative relationship of these finding remains speculative. However, they should be kept in mind for patients who present with a similar picture. The diagnostic work-up for this patient included routine blood work as given above. Screening tests include the modified Russell viper venom time and the sensitive PTT. In addition, a mixing test and a hypercoagulability work-up should be done to rule out a factor deficiency or genetic predisposition, respectively. Specific blood work for lupus anticoagulant and anticardiolipin antibody should also be ordered.
Initial treatment for this patient included anticoagulation with heparin followed by high dose warfarin, with an INR goal of greater than 3. Pulse high dose solumedrol (2g/day IV x 3 days) was also initiated. Other treatment options include cyclophosphamide and intravenous immunoglobulin. Long term treatment includes anticoagulation with warfarin. Patients need to be carefully followed on an outpatient basis, with prothrombin times checked at least every 2 weeks after achieving a stable dose.

Prognosis for recurrent thrombotic events is based on limited data. The largest retrospective trial is that of Khamashta et al (19). in which a total of 147 patients were included. In this study, recurrent thrombosis occurred in 69% of the study group, within a median time frame of 12 months.