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APLA SYNDROME

AYESHA FAREEDPHARM D

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Antiphospholipid Antibody Syndrome•Antiphospholipid Antibody Syndrome or APS is an autoimmune disorder in which the body recognizes certain normal components of blood and/or cell membranes as foreign substances and produces antibodies against them. •Patients with these antibodies may experience blood clots, including heart attacks and strokes, and miscarriages.

• APS may occur in people with systemic lupus erythematosus, other autoimmune diseases, or in otherwise healthy individuals.

•APS is also known as APLS, APLA, Hughes Syndrome or "Sticky Blood."

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APS is classified as primary or secondary, depending on its association with other autoimmune disorders.

•Primary APS is diagnosed in patients demonstrating the clinical and laboratory criteria for the disease without other recognized autoimmune disease.

• Secondary APS is diagnosed in patients with other autoimmune disorders, such as systemic lupus erythematosus (SLE).

Classification:

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Clinical Features of APS:

People with antiphospholipid antibodies have an increased risk of developing one or more of the following problems:

•Blood clots in veins, particularly deep vein thrombosis (DVT)•Blood clots that go to the lungs (pulmonary embolism)•Blood clots in arteries•Miscarriages – these can occur at any stage of pregnancy but are most common in the late first trimester or early second trimester•Pre-eclampsia, eclampsia, fetal growth retardation, premature delivery•Heart attacks, angina•Strokes•Brief stroke-like episodes called transient ischemic attacks (TIAs), for example, loss of vision•Decreased levels of platelets (small blood cells involved in blood clotting)•Heart valve problems, sometimes requiring valve surgery or valve replacement

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•Persistent or transient blotchy, lacy bluish rash (livedo reticularis)•Skin ulcers, most commonly on the legs or feet•“Catastrophic” APS – a very rare, life-threatening syndrome in which clots form in small blood vessels of multiple organs (such as heart, lungs, brain, kidneys)

Other features that might be associated with antiphospholipid antibodies include:

•Problems with thinking clearly (loss of concentration, difficulty with reading comprehension and performing calculations, memory loss)•Neurological problems similar to multiple sclerosis.•Migraine headaches, sometimes with visual disturbances•Other neurological symptoms including episodes of partial or total vision loss, dizziness, vertigo, loss of balance, seizures, and other abnormal movements

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Risk factors:The risk factors for antiphospholipid syndrome include:•Having lupus, Sjogren's syndrome, or some other autoimmune disorder. •Hepatitis C, syphilis, cytomegalovirus (CMV), the parvovirus B19 and some other infections. •Some medications, including hydralazine (used to treat hypertension) and some anti-epileptic drugs. •Genetics - people who have a family member with antiphospholipid syndrome have a higher risk of developing it themselves, compared to people who don't. •Gender - young and middle-aged women are more likely to develop antiphospholipid syndrome than males. However, both sexes can be affected, as well as people of any age.•Some people may have the antibodies that are linked to antiphospholipid syndrome, but never develop signs or symptoms.

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People with these antibodies are more likely to develop symptoms if they:•Are obese•Become pregnant•Have high cholesterol levels•Have hypertension (high blood pressure)•Receive HRT (hormone replacement therapy)•Smoke tobacco•Stay still for too long, as may be the case during a long-haul flight•Take oral contraceptives•Undergo a surgical procedure

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•Like other autoimmune disorders, APS does not have a known etiology, although it is known that the passive transfer of maternal antibodies mediates autoimmune disorders in the fetus and newborn.

•Certain genetic factors may be important, as indicated by a number of family and twin studies for SLE and the demonstration of an increased frequency of HLA-DR2, HLA-DR3, and HLA-DR4 null alleles in patients with SLE.

• As with other autoimmune disorders, women have a higher incidence than men and the diagnosis is more likely to be made in women of reproductive age.

ETIOLOGY:

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•The diagnosis of APS is based primarily on clinical history and laboratory data.• Patients with secondary APS are more likely to have findings on physical examination, although some physical findings may be associated with primary APS. •Thrombosis and stroke are possible residual neurologic findings in APS.Cutaneous manifestations of APS can include the following:Digital cyanosisLivedo reticularisDigital gangreneLeg ulcersDiscoid rash – that is, a raised, erythematous patch with keratotic scaling and follicular plugging; older lesions may be atrophicPhotosensitivity

PHYSICAL EXAMINATION:

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The common blood tests for antiphospholipid antibodies are as follows:•Anticardiolipin antibodies (IgG, IgM, and IgA)•Lupus anticoagulant – a panel of blood clotting tests that may include the dilute Russel Viper venom time (dRVVT), lupus aPTT, mixing studies, and hex phase phospholipid test, platelet neutralization procedure•Antibodies to b2-glycoprotein I (IgG, IgM, IgA)

Diagnosis:

Imaging studies:

Appropriate neurologic or imaging studies should be performed based on clinical findings; ie, a computed tomography (CT) or magnetic resonance imaging (MRI) scan can be carried out in the presence of central nervous system (CNS) symptoms.

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Management :

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Anticoagulation therapy:

•Anticoagulation with heparin is recommended in APS and pregnancy with a history of a thromboembolic event.

• Low-molecular-weight heparin (LMWH) may be used in these patients.

•Importantly, counsel the patient regarding potential adverse effects of heparin.

• Heparin-induced osteoporosis occurs in 1-2% of cases.

•Bone density studies should be considered in patients receiving anticoagulation therapy with heparin or LMWH due to the risks of osteopenia.

•Warfarin may be substituted for heparin during the postpartum period to limit further risk of heparin-induced osteoporosis and bone fracture.

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•In women without a history of a thromboembolic event, optimal therapy is not as clear.

• Anticoagulation may decrease recurrent pregnancy loss in this group of women.

• Low-dose aspirin combined with prophylactic doses of heparin or LMWH appears to be superior to aspirin therapy alone or maternal steroids.

•Subcutaneous LMWH (enoxaparin [Lovenox]) may also be used for obstetric or thrombosis prophylaxis.

• Lower doses (20-40 mg/d SC) are used to prevent fetal loss, while higher doses (1 mg/kg q12h or 1.5 mg/kg/d) are used for thrombosis prophylaxis in patients (pregnant or nonpregnant) who have had prior thrombotic events.

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•The antithrombotic properties of hydroxychloroquine have long been recognized and may be considered in the prophylactic treatment of a patient with SLE and a positive aPL antibody test result.

•Case reports suggest that clopidogrel may be effective because of its antiplatelet effect.

•Recently, statins have been suggested to have potential antithrombotic effects. Statins are recommended for APS patients with hyperlipidemia and, possibly, in aPL patients with recurrent thromboses despite adequate anticoagulation.

•In addition to full anticoagulation, plasma exchange and corticosteroids are generally used in the treatment of CAPS.

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•Intravenous immunoglobulin or cyclophosphamide may also be considered in selected patients with CAPS.

• For example, a recent retrospective study reported a decrease in late pregnancy complications in women with APS who received 0.2 g/kg of intravenous immunoglobulin.

•Rituximab has shown benefit in controlling severe thrombocytopenia, skin ulcers, and cognitive dysfunction that can be associated with APS

•Case reports have described the use of eculizumab, a humanized monoclonal antibody against C5 complement protein, in CAPS, and in aPL-positive patients undergoing renal transplantation.

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Intravenous immunoglobulin

•Infused immunoglobulins may modulate aCL antibodies levels by the following 3 mechanisms:

•Anti-idiotypic antibodies may be present in the intravenous immunoglobulin (IVIG) preparation; these anti-idiotypic antibodies may bind autoantibodies to form idiotype-antiidiotype dimers, resulting in neutralization of autoantibody effects.

•Anti-idiotype antibodies may bind and downregulate B-cell receptors, resulting in a decrease in autoantibody production.

•Anti-idiotype antibodies might bind receptors of regulatory T cells, resulting in suppression of lymphokine production and decreased activation of autoantibody-producing B cells

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•Immunosuppressive agents are recommended for patients with SLE with secondary APS.

•Thrombo prophylaxis is also recommended.

•In addition, patients should be evaluated for renal disease, (glomerulonephritis, end-stage renal disease), anemia, and thrombocytopenia.

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 Proposed Management for Women With aPL Antibodies 

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•As the main problem is sticky blood, doctors will usually prescribe medication that thins the blood - reduces the blood's propensity to clotting, such as low-dose aspirin.

•Aspirin plus Warfarin, and possibly Heparin - aspirin together with Warfarin are generally prescribed as a first option.

•If this combination does not work, the patient may either be prescribed a higher Warfarin dose, or an additional drug heparin will be given.  Patients will have to take anticoagulant medication for the rest of their lives 

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Pregnancy - women who have already been diagnosed with antiphospholipid syndrome will be advised by their doctors to plan for pregnancy. For treatment to be really effective it must start soon after any attempt to conceive. If the pregnancy is unplanned treatment may not begin until several weeks after conception. 

Pregnant patients with antiphospholipid syndrome are usually given aspirin, heparin or both. This will depend on whether they had previous pregnancy complications, and/or blood clots. Warfarin, which can cause birth defects, is not used during pregnancy. 

If the pregnant mother and baby reach the third trimester in good health, the heparin treatment may stop. The mother may have to continue taking aspirin right up the end of her pregnancy. 

The pregnant mother will be monitored closely with blood tests to make sure her blood can still coagulate (clot) enough to stop bleeding if she bruises or cuts herself.

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Cardiac Valvular Surgery and Splenectomy:

•Patients with APS, especially secondary APS, may require surgical interventions for long-standing complications of their autoimmune disorder.•Cardiac valvular surgery is recommended in patients with severe aortic regurgitation due to the noninfectious vegetations that are seen as a result of APS.•Splenectomy is recommended in patients with the chronic form of idiopathic thrombocytopenic purpura and is associated with remission in approximately 75% cases.•Thromboprophylaxis is recommended for any abdominal or orthopedic surgery. Manage thrombotic or hemorrhagic complications. •Be aware of associated thrombocytopenia, and use laboratory methods of perioperative anticoagulation monitoring in the setting of prolonged clotting times.

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Consultations and Follow-up•The patient should be informed about potential maternal and obstetric problems, including fetal loss, thrombosis or stroke, PIH, fetal growth restriction, and preterm delivery.

•Consultation with specialists in Maternal-Fetal Medicine and Rheumatology should be considered.

•In women with APS and 1 or more prior thrombotic events, lifelong anticoagulation with warfarin may be advisable to avoid recurrent thrombosis.

•An assessment by a rheumatologist or hematologist may also be helpful.

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Safety When Traveling:•Long trips, especially by air, have some clotting risk even for non-APS people.  •It is important for people with APS to get up and walk around at least every couple of hours. •On long car trip stop at least every two hours and walk. Drink plenty of water and wear compression stockings to help reduce your chance of DVT. • If you plan to be away during the time of a periodic blood test, arrange for the blood test before you leave for the trip.

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Prevention:A patient with antiphospholipid syndrome needs to take all possible measures to lower the risk of developing blood clots. To do this, it is important:•Not to smoke•To eat plenty of fruit and vegetables•To follow a diet which is well-balanced and low in fat and sugar•To maintain a healthy bodyweight. Obese and overweight patients should seriously consider losing weight.•To remain physically active

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Catastrophic antiphospholipid syndrome - •estimated to affect less than 1% of patients with antiphospholipid syndrome. •Blood clots abruptly develop all over the body, resulting in multiple organ failure. 20% of cases occur after trauma, surgery or an infection.• However, experts are not sure why catastrophic antiphospholipid syndrome occurs. Symptoms vary, depending on which organs are affected, and may include:•Abdominal pain•Coma•Confusion•Edema (swelling) in the extremities (ankles, feet or hands)•Fits (seizures)•Progressive breathlessness•Tiredness

Complications:

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•Symptoms typically appear suddenly and get worse rapidly.

•Catastrophic antiphospholipid syndrome is a medical emergency and the patient needs to get into an ICU (intensive care unit) as soon as possible so that the body's functions can be maintained while high-dose anticoagulants are administered.

•Unfortunately, even with the best medical care in the word, 50% of patients with catastrophic antiphospholipid syndrome do not survive

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•Suneel Movva, Antiphospholipid Syndrome MedicationMar 24, 2015http://emedicine.medscape.com/article/333221-medication#3

•Teresa G Berg et al.Antiphospholipid Syndrome and Pregnancy Treatment & ManagementUpdated: Apr 15, 2015

•Mary Katherine Farmer-Boatwright et al Venous Thromboembolism: Mechanisms, Treatment, and Public Awarenes,Venous Thrombosis in the Antiphospholipid Syndrome

•Robert A.S. Roubey et al Arteriosclerosis, Thrombosis, and Vascular Biology.2009; 29: 321-325doi: 10.1161/ATVBAHA.108.182204

•David Keeling et al. Guidelines on the investigation and management of•antiphospholipid syndrome; 2012 Blackwell Publishing Ltd 49•British Journal of Haematology, 2012, 157, 47–58

REFERENCES:

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