**5. Clinical features**

Although any vasculature can be affected by thrombosis, stroke and transient ischemic attack are the most common presentations of arterial thrombosis, whereas deep vein thrombosis with or without pulmonary embolism is the most common presentation of venous thrombosis in APLS(George D 2009). Antiphospholipid antibodies can cause both arterial and venous thrombosis in the same patient. Reccurent thromboses tend to occur in the same vascular distribution(venous followed by venous and arterial followed by arterial). in some studies the incidence of venous thrombosis (70%) is greater than the incidence of arterial thrombosis.(Galli M 1997, Triplett DA 1995).

Superficial thrombophlebitis, superior vena cava syndrome, renal vein thrombosis, Budd Chiari syndrome, central retinal vein occlusion, pulmonary hypertension due to recurrent pulmonary embolism, and diffuse pulmonary hemorrhage due to microthrombosis are some of the thrombotic manifestations of APLS.

Of unselected patients with antiphospholipid antibody, 1% to 2.5% per year will develop thromboembolism(Galli M 2003, Finazzi G 1996),and 10% to 25% of patients with deep venous thrombosis will be found to have antiphospholipid antibodies(Ginsburg KS 1992).However, in a prospective population based study of 66140 individuals in Norway(Naess IA 2005), elevated anticardiolipin antibody levels were not a risk factor for

Antiphospholipd Syndrome and Venous Thrombosis 61

Treatment for venous thromboembolism with LMWH provides reliable anticoagulation levels when given subcutaneously on a weight-based dosing schedule. No laboratory monitoring of the intensity of anticoagulation is required for LMWH, except in special circumstances. Recent randomized controlled trials of the treatment of pulmonary embolism (PE) have shown LMWH to be as effective and safe as UFH. One randomized controlled trial of the treatment of venous thromboembolism (VTE) in 1,021 patients included 271 patients presenting with PE. In this study, there were no significant differences in outcomes following treatment with UFH versus LMWH. These studies used reviparin and tinzaparin. Two reviews agreed that LMWH may be efficacious in the treatment of PE, but cautioned that the LMWH products may not be equivalent to each other (Raskob 1999 ; Charland, 1998; Columbus Investigators, 1997; Simonneau, 1997). LMWH may not be appropriate for patients with renal insufficiency (creatinine clearance less than 30 mL/min). Studies have shown modestly delayed clearance in patients with chronic renal failure. The clinician should weigh this evidence when considering outpatient

A high-loading dose of warfarin (greater than 10 mg) is of no clinical use and should be discouraged. A 10 mg initial dose of warfarin has been associated with early overanticoagulation and, when compared to a 5 mg initial dose, was no more effective in achieving a therapeutic international normalized ratio (INR) by day four or five of therapy. A therapeutic range of anticoagulation to keep the INR at 2.5 (range 2.0-3.0) is recommended for patients with venous thromboembolism. Heparin and warfarin may be started at the same time. The anticoagulant effect of warfarin is delayed until clotting factors already circulating are cleared. Although Factor VII has a shorter half-life in the blood (six to seven hours), peak anticoagulant activity is delayed for up to 96 hours until factors with longer plasma half-lives (II, IX and X) have cleared . Heparin (UFH or LMWH) and warfarin may be started at the same time. Heparin (UFH or LMWH) and/or fondaparinux should be given for a minimum of five days. Patient should continue heparin until INR >=2.0 for two consecutive days. In patients with suspected hypercoagulable state (Protein C or Protein S deficiency), the patient should be adequately anticoagulated with heparin (UFH or LMWH) and/or fondaparinux before warfarin is started at a low dose (2-5 mg). This is to avoid

warfarin-induced skin necrosis or other transient hypercoagulable complications.

**6.2 Primary prophylaxis of thrombosis in patients with APL antibodies** 

dogma of a target INR of 3 to 4(high-intensity warfarin).

Recommendations for the management of thrombosis in the APLS have been based largely on retrospective case series. Recently, several clinical trials have been published on the management of thrombosis in APLS.These new clinical trials have challenged the previous

The therapeutic approach in asymptomatic carriers of APL without prior thrombotic events is still controversial. Present evidence-based knowledge does not support the widespread use of aspirin in all these aPL-positive patients. Annual thrombosis risk in asymptomatic APL-positive patients range from 0% to 3.8%( Finazzi G 1996, Shah NM 1998), being equivalent to that of major bleeding associated with the use of aspirin. The only randomized clinical trial (APLASA study) in which 98 asymptomatic persistently APL-positive individuals were randomized to recieve a daily dose of 81 mg of aspirin or placebo showed that these patients have a low overall annual incidence rate of acute

therapy.

predicting an initial venous thrombosis. Thrombosis is more frequent as the level of anticardiolipin antibody increases, and medium and high titers (>40 GPL and/or MPL units) are more frequently associated with thrombotic events. Although some investigators believe that elevated levels of IgG or IgA isotypes are more common than IgM in patients with thrombotic complications, this has not been clearly established. The lupus anticoagulant or increased levels of anticardiolipin antibody must be persistently present on more than one occasion at least 12 weeks apart because the incidence of thrombotic complications is almost the same in patients with transiently positive tests as in patients with negative tests at two different time intervals. The persistent presence of elevated levels of anticardiolipin antibody has been shown to be associated with indices of in-vivo coagulation activation. In a study of patients with SLE(Ginsberg JS 1993) who were persistently anticardiolipin antibody– positive versus patients who were transiently positive or persistently negative, anticardiolipin antibody–positive patients had a higher mean level of F1+2 and fibrinopeptide A than patients who were transiently positive, persistently negative, or on warfarin therapy. The differences remained significant even if patients with prior thromboembolism were excluded from the analysis. These results suggest that the presence of persistently elevated levels of anticardiolipin antibody in SLE patients is associated with an ongoing prothrombotic state.

Patients who are persistently positive for the lupus anticoagulant or who have persistently elevated levels of anticardiolipin antibody and suffer a thromboembolic event have a recurrence rate of approximately 50% within 2 years(Rosove MH 1992, Khamashta MA 1995). Recurrences tend to occur in most of the patients on the same side of the circulation as the initial event—venous recurrences after an initial venous event and arterial recurrences after an initial arterial event.
