Antiphospholipid Syndrome

Prakarn.T, M.D.

Outline
l Terminology l Pathogenesis l Epidemiology l Clinical

manifestations l Classification criteria and risk stratification l Management of thrombosis l Pregnancy management l Future therapies

antiphospholipid syndrome
systemic autoimmune disorder characterised by arterial and venous thrombosis, adverse outcomes in pregnancy l raised titres of antiphospholipid antibodies. l occurs in isolation (primary antiphospholipid syndrome) in more than 50% of patients l can be associated with other autoimmune diseases. l 20-35% of patients with SLE develop secondary antiphospholipid syndrome.
l

Pathogenesis
l endothelial

cells, monocytes, platelets, and complement induction of thrombosis and fetal death l procoagulant state is induced mainly mediated by the increased tissue factor and thromboxane A2 l Activation of the complement cascade might close the loop and provoke thrombosis

Epidemiology
l 40%

of patients with SLE have antiphospholipid antibodies but < 40% of them have thrombotic events l general population, antiphospholipid antibodies can be detected in about 1/5 stroke patients less than 50 years of age l 1015% of women with recurrent miscarriage are diagnosed with antiphospholipid syndrome

Epidemiology
l Pregnant

women with a previous diagnosis of antiphospholipid syndrome are at increased risk for developing preeclampsia or placental insufficiency l antiphospholipid antibodies are detected in 1129% of women with pre-eclampsia l 25% of women delivering growth restricted fetuses had antiphospholipid antibodies

Clinical manifestations
l Thromboses

are one of the hallmarks and venous thrombosis, or embolism, is the most frequent l CNS is most affected,
l stroke

or transient ischaemic attacks l venous sinus thrombosis, myelopathy, chorea l migraine, and epilepsy.

Clinical manifestations
anticardiolipin antibodies linked with cognitive impairment in SLE l cardiac valvular regurgitation disease, with the mitral valve or aortic valve is more common l Renal involvement
l
l l l l l

Thrombotic microangiopathy fibrous intimal hyperplasia, focal cortical atrophy Hypertension with proteinuria (often subnephrotic) renal insufficiency Renal artery stenosis

Clinical manifestations
l thrombocytopenia,

haemolytic anaemia, skin ulcers, avascular bone necrosis, adrenal insufficiency l Livedo reticularis present a quarter of patients with antiphospholipid syndrome
l marker

of patients at a high risk for arterial thrombosis

Obstetric complications
most common is recurrent miscarriage, l defined as three or more consecutive before the mid-second trimester, l most losses occurring before the 10th week of gestation l one or more fetal deaths at or beyond the 10th week of gestation l severe pre-eclampsia, or placental insufficiency l prompting delivery at more than 34 weeks gestation
l

Obstetric complications
l positivity

for antiphospholipid antibodies increased the risk for both pre-eclampsia and placental insufficiency

Classification criteria and risk stratification

l In

1998, the preliminary classification criteria were proposed at Sapporo l In 2006, classification criteria were updated

sensitivity and specificity

l The

sensitivity and specificity of

l anti-2-GPI

were 57.1 and 79.2%, l IgG aCL were 25.7 and 94.8%, l IgM aCL were 5.7 and 98.7%, l LAC were 44.8 and 77.3%, l the combination of anti-2-GPI and IgG aCL tests was the best for the diagnosis of APS in Thai SLE patients.

Classification criteria and risk stratification

l Lupus

anticoagulant is the most powerful predictor of thrombosis l Both IgG and IgM anticardiolipins are associated with an increased risk of miscarriage l triple positivity for lupus anticoagulant, anticardiolipin, and anti-2- glycoprotein 1 are at the highest risk for venous and arterial thrombosis and for obstetric

Limitations
l Several

classic APS have been reported that aPL became negative at the time of thrombosis but reappeared shortly after the thrombotic events l positive aPL test can be associated with infections (usually lowtiter aPL ELISA) or anticoagulation (positive LA test)

Management of thrombosis
l Prevention
l primary

of thrombosis is a major goal

thromboprophylaxis l secondary thromboprophylaxis

l patients

with lupus and antiphospholipid antibodies will develop thrombosis at a yearly rate of about 34%

secondary thromboprophylaxis

secondary thromboprophylaxis
l recommended

to less intense or extended antithrombotic regimens, especially in the setting of reversible triggers

primary thromboprophylaxis

primary thromboprophylaxis
l low

potential for toxic effects, many experts recommend

l low-dose

aspirin (combined with hydroxychloroquine) as primary thromboprophylaxis in patients with SLE having lupus anticoagulant or persistently positive anticardiolipin, or both.

Pregnancy management
complete profile of antiphospholipid antibodies should be available before planning of pregnancy l frequent prenatal visits, at least every 24 weeks before mid-gestation and every 12 weeks thereafter. l objectives of prenatal care in the second and third trimesters are close observation for maternal hypertension, proteinuria and other features of preeclampsia,
l

Pregnancy management
obstetric ultrasound to assess fetal growth and amniotic fluid volume, and appropriate fetal surveillance testing. l Surveillance testing should begin at 32 weeks gestation every week until delivery. l Uterine and umbilical artery Doppler widely used in Europe to assess the risk for preeclampsia, placental insufficiency, and fetal growth restriction after the 20th week
l

Pregnancy management
Regular and coordinated medical consultation every 24 weeks, especially in women with systemic lupus erythematosus l goals of treatment in pregnant women with antiphospholipid syndrome are to improve maternal and fetal-neonatal outcomes including
l
l l l

maternal thrombosis, fetal loss, preeclampsia, placental insufficiency fetal growth restriction

Pregnancy management
l Heparin

and low-dose aspirin are the treatments of choice for antiphospholipid syndrome in pregnancy. l Heparin is usually started in the early first trimester after presence of a live embryo is shown by ultrasonography. l recommend preconceptional aspirin because of its possible beneficial effect on early stages of implantation

Pregnancy management
l from

meta-analysis shown a significant reduction of pregnancy complications in high risk for pre-eclampsia who were given antiplatelet agents (mostly aspirin) l Cochrane analysis concluded that intravenous immunoglobulins were associated with an increased risk of pregnancy loss or premature birth

Pregnancy management
l pregnant

women with antiphospholipid syndrome who have had a previous thrombotic event
l low-dose

aspirin and therapeutic dose heparin or low-molecularweight heparin anticoagulation are recommended

Pregnancy management
l Vitamin

K antagonists are teratogenic and should be avoided between 6 and 12 weeks of gestation. l Because of the risk of fetal bleeding thereafter, warfarin after 12 weeks gestation should be given only in exceptional circumstances

Pregnancy management
l Antithrombotic

coverage of the postpartum period is recommended in all women with antiphospholipid syndrome l women with previous thrombosis will need long-term anticoagulation, prefer switching to warfarin, as soon as the patient is clinically stable after delivery

Pregnancy management
l patients

with no previous thrombosis, the recommendation is prophylactic dose heparin or low-molecular-weight heparin therapy for 46 weeks after delivery l Both heparin and warfarin are safe for breastfeeding mothers.

Future therapies

Future therapies
l oral

antifactor Xa and antifactor IIa drugs have not been done in patients with antiphospholipid syndrome l B-cell depletion therapy with rituximab has been tested in severe forms of antiphospholipid syndrome. limited to case reports

Future therapies
l Statins

inhibit NFB and in addition to cholesterollowering effects, could have antithrombotic properties in patients with antiphospholipid syndrome. l Hydroxychloroquine
l antithrombotic

effect l dose-dependent reduction of platelet activation and clotting induced by antiphospholipid antibodies

Future therapies
l absence

of any adverse effects on the fetus-neonate, and absence of associated bleeding

l hydroxychloroquine

should be considered for an adjuvant antithrombotic in patients with systemic lupus erythematosus who are positive for antiphospholipid antibodies or have a high-risk profile for major haemorrhage

catastrophic antiphospholipid syndrome

l rare

life threatening condition l characterised by

l rapid

development of multiple microthrombi in various organ systems, typically the brain, kidneys, lungs, and skin. l Thrombocytopenia, haemolysis, schistocytes and activation of the coagulation system l results in widespread thrombotic microangiopathy and multiple organ failure

catastrophic antiphospholipid syndrome

catastrophic antiphospholipid syndrome

l differential

diagnoses

l thrombotic

thrombocytopenic purpura, l haemolytic uraemic syndrome l disseminated intravascular coagulation

l Mortality

in this syndrome approaches

50%

Treatment of CAPS
l Prophylactic

therapy l Specific therapies l Nonspecific therapies : ICU

Treatment of CAPS

Prophylactic therapy
l to

prevent the catapulting of the APS into multiorgan failure l any infection should be treated with appropriate antibiotics l APS patients undergoing surgical procedures patients with SLE flares, and puerperal period should all receive parenteral anticoagulation.

Specific therapies
l Intravenous

heparin: Intravenous heparin (1500 U/h) or low molecular weight heparin for 710 days followed by oral anticoagulants to an INR of 23 l Plasma exchange (PE): clearly improves patient survival. l Intravenous immunoglobulins (IVIG) l Cyclophosphamide

Specific therapies
l anticoagulation

(AC) + corticosteroids (CS) is the most commonly used regimen (19.8%), followed by AC + CS + plasma exchange (PE) and/or intravenous immunoglobulin (IVIG) (17.4%). l The best results are achieved with combination of AC + CS + PE (77.8%), followed by AC + CS + PE and/or IVIG (69%)

Nonspecific therapies
l ICU

care

Sneddon's syndrome
l

infrequent disorder combining skin and ischaemic cerebral lesions in patients without recognizable connective tissue or inflammatory or chronic infectious disease. The skin lesions consist of a purplish motting of the skin and central nervous system manifestations ranging from transient ischaemic attacks tomultiple strokes. Anti-phospholipid antibodies (aPL) are frequently observed and there is an overlap of SS with the primary antiphospholipid antibody syndrome

Sneddon's syndrome
l Seizures,

headache and cardiac valve diseases are frequent in patients with SS l 77% of these young patients showsigns of mild vascular impairment with loss of concentration ability, memory disturbances or frontal type of behavioral changes

Sneddon's syndrome
Skin biopsies including deep dermis should be taken in the central normal areas within the bordering of the livedo to confirm the diagnosis l cardiovascular work-up l extensive neuro-imaging, including MRI and MR angiography l warfarin isprobably more effective than aspirin for stroke recurrence in SS.
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Reference
Diagnosis and management of the antiphospholipid syndrome, Danielle Cohen, et al. BMJ 22 may 2010 | Volume 340 l Antiphospholipid syndrome, Guillermo RuizIrastorza, et al. Lancet September 6, 2010 DOI:S0140-6736(10)60709-X l Catastrophic antiphospholipid syndrome K Shanmuganandan, et al. Indian Journal of Rheumatology 2010 June Review Article Volume 5, Number 2; pp. 7684
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Thank You.