Anti-phospholipid syndrome Clinton Mitchell 5th year Haematology

Anti-phospholipid syndrome defined as a venous thromboembolic event or unexplained miscarriage, plus repeatably positive anticardiolipin antibodies and/or lupus anticoagulant that are repeatably positive at least 6 weeks later. Disorder due to the presence of auto- antibodies which bind proteins that act as co- factors for phospholipids Successful coagulation involves phospholipid-dependent coagulation factors β 2 -glycoprotein is thought to be one of the targets for these antibodies

Historical origins “It was clear from the beginning that, while the syndrome was associated with classical lupus, it was separable from it. For a distinct syndrome it most certainly is; it occurs in ANA-negative SLE patients, atypical lupus patients and, as expected, individuals with no lupus at all.” Graham Hughes (early 1980s)

Anti-phospholipid syndrome This quote would mark the origin of the primary anti-phospholipid syndrome APS can occur in patients without evidence of any definable associated disease (primary APS) It may also occur in association with SLE or another rheumatic or autoimmune disorder (secondary APS)

In APS, as noted may detect either anticardiolipin antibodies (ACA) or lupus anticoagulant (LAC) or both. Thought to be measuring same thing two different ways. Important to distinguish between the antibodies, detected as ACA or LAC, and the syndrome called Aps.

Epidemiology Antibodies can be found in as many as 50% of individuals with SLE and in 1-5% of the healthy population Anti-cardiolipin antibodies tends to occur more frequently in elderly individuals Actual frequency in the general population is unknown

Risk factors There is no defined racial predominance for primary APS higher incidence among Maori and Pacific populations of SLE may contribute to an increased risk Female predominance exists, particularly for secondary APS APS occurs more commonly in young to middle- aged adults Genetic predisposition (one study showed a 33% incidence rate)

Aetiology Autoimmune disorder of unknown cause Search for possible triggers has uncovered a wide array of associated rheumatic or autoimmune diseases SLE 25-50% rheumatoid arthritis 33% ITP 30% Infections (especially syphilis)

Pathophysiology An alteration of the homeostatic regulation of blood coagulation occurs Other mechanisms (which may or may not be dependent on β 2 GP1) include: activation of platelets to enhance endothelial adherence activation of vascular endothelium (facilitates the binding of platelets and monocytes)

Pathophysiology Other auto-antibody processes are thought to include: production of antibodies against other coagulation factors (prothrombin, protein C, and protein S) reaction of antibodies to LDL (predisposing to atherosclerosis and myocardial infarction)

Clinical presentation Clinical features include arterial and venous thromboses, recurrent miscarriages and thrombocytopaenia 20% of strokes occurring <45 years may be attributable to APS 27% of women with >2 miscarriages have APS Other features include VHD; cutaneous manifestations (livedo reticularis); chorea, migraine and epilepsy

Livedo reticularis Completely blanchable reticulated areas of erythema which may be red or blue depending upon the rate of blood flow through these vessels. In this case deep or incomplete obstruction of vessels is leading to impaired flow through the dermis, but this flow is sufficient to maintain the vascular integrity.

Investigations Anti-cardiolipin antibodies are diagnostic ANA are usually negative Haemolytic anaemia, thrombocytopaenia which is paradoxically associated with an increased risk of thrombosis Normal ESR Prolonged APTT Patients may have a false positive VDRL syphilis test

Management Prevention avoid smoking avoid oral contraceptives and HRT avoid any prolonged immobilisation lose weight exercise

Management Low dose aspirin can be used for mild cases and primary prevention Warfarin is used in more severe cases (aiming for an INR >3) Anti-platelet agents have not been extensively studied Hydroxychloroquine should be considered in patients with SLE consider fractionated heparin in pregnancy

Sequelae Sequelae are related primarily to the risk of thrombosis recurrent miscarriage (aPA decrease levels of annexin V, a protein with potent anticoagulant activity found in the placenta) CVA, MI, renal failure Pulmonary HTN

Prognosis Most individuals with primary APS lead normal healthy lives with appropriate medication and lifestyle modifications However, subsets of patients continue to have thrombotic events despite aggressive therapies Secondary APS carries a similar prognosis morbidity and mortality influenced by underlying autoimmune or rheumatic condition