Thrombophylaxia in Antiphospholipid Antibody Syndrome

1. Thrombophylaxia in Antiphospholipid Antibody Syndrome

2. The antiphospholipid syndrome (APS) is an acquired autoimmune condition. The clinical features are thrombosis (venous, arterial and microvascular) and/or pregnancy complications and failure

3. Diagnosis of Antiphospholipid Antibody Syndrome (APS)

4. Classification Criteria for the Antiphospholipid Antibody Syndrome Criteria ------------------------------------------------------------------ Clinical -------------------------------------------------------------------   Thrombosis(Unexplained venous, arterial, or small vessel thrombosis in any organ or tissue) ----------------------------------------------------------------------  Pregnancy (One or more unexplained fetal losses after 10 weeks; three or more consecutive miscarriages before 10 weeks; or preterm delivery for severe preeclampsia or placental insufficiency before 34 completed weeks)

5. Classification Criteria for the Antiphospholipid Antibody Syndrome Laboratory -------------------------------------------------------------   Anticardiolipin antibodies (IgG or IgM isotypes in medium to high titers at least 6 weeks apart) --------------------------------------------------------------  Lupus anticoagulant (Identified twice, at least 6 weeks apart)

6. Diagnosis of Antiphospholipid Antibody Syndrome (APS) • one of two clinical criteria, which include vascular thrombosis or certain pregnancy morbidity, must be present. In addition, at least two laboratory criteria that include LAC activity or medium- to high-positive specific IgG- or IgM-ACAs must be confirmed on two occasions 6 weeks apart.

7. Phospholipids are the main lipid constituents of cell and organelle membranes. Several antibodies directed against these various phospholipids and to proteins bound to phospholipids . These antibodies include lupus anticoagulant (LAC) and anticardiolipin antibodies (ACAs). They may be of IgG, IgM, and IgA classes, alone or in combination. Cardiolipin is but one of many phospholipids and is found in mitochondrial membranes and platelets

8. Pathophysiology Many patients with lupus have circulating antibodies specifically directed either against phospholipids or against phospholipid-binding proteins such as ß2-glycoprotein I (apolipoprotein H). Anticardiolipin antibodies apparently bind directly to ß2-glycoprotein I, and this protein acts as a co-factor in this antigen-antibody reaction

9. ß2-Glycoprotein I • The major activity of this protein appears to be its phospholipid-dependent anticoagulant inhibition of prothrombinase activity of platelets and ADP-induced platelet aggregation .ß2-Glycoprotein I competitively inhibits the binding of coagulation factors, especially factor XII, and the prothrombinase complex to phospholipid surfaces. This prevents activation of the coagulation cascade.

10. ß2-Glycoprotein I • ß2-Glycoprotein I is found in high concentrations on the surface of the syncytiotrophoblast. This seems intuitive because the decidua is a critical area in which to prevent coagulation.

11. ß2-Glycoprotein I • In addition, ß2-glycoprotein I may be involved in implantation because it is known that this protein binds heparin. Moreover, trophoblastic cells have heparin-like binding sites.

12. ß2-Glycoprotein I • Thus, a local loss ofß2-glycoprotein I by an antibody directed against it might prevent implantation or result in intervillous space thrombosis, or both.

13. Lupus Anticoagulant • LAC appears to require a cofactor for its in vitro anticoagulant function. Specifically, it does not bind directly to negatively charged phospholipids, but instead, LAC binds to phospholipid-bound prothrombin • Other phospholipid-binding proteins may be involved in the pathophysiology of the antiphospholipid antibody syndrome.

14. These include protein C and protein S, which are both endogenous anticoagulants, and annexin V . The last is also known as placental anticoagulant protein I or lipocortin V, and annexin V coats the syncytiotrophoblast in high concentration

15. Tests for the LAC are nonspecific coagulation tests. The partial thromboplastin time is generally prolonged because the anticoagulant interferes with conversion of prothrombin to thrombin in vitro. Tests considered most specific are the dilute Russell viper venom test (dRVVT) and the platelet neutralization procedure. There is currently disagreement as to which of these is best for screening. If either is positive after addition of normal plasma, the diagnosis is confirmed

16. In general, among aPL, the specificity for thrombosis is higher for LA than aCL or anti-b2GPI and greater for higher than lower titre aCL

17. When reporting the results, the method, cut-off value, and an interpretation as LA-positive or LA-negative should be given

18. Which tests should be done? • LA is the most predictive test for thrombosis and the presence of IgG aCL or IgG anti-b2GPI in those who are La positive increases the specificity

19. • In patients with thrombosis, measuring IgM antibodies does not add useful information (2B). • In patients with pregnancy morbidity, the role of IgM antibodies is unclear (2C). • Testing for IgA antibodies is not recommended (1B).

20. Pathophysiology of Antiphospholipid Antibodies in Pregnancy • The combination of lupus anticoagulant and high levels of ACAs is strongly associated with decidual vasculopathy, placental infarction, fetal-growth restriction, early-onset preeclampsia, and recurrent fetal death.

21. Recommendation We recommend that primary thromboprophylaxis should not be used in those incidentally found to have aPL (2B)

22. Adverse Pregnancy Outcomes • the incidence of antiphospholipid antibodies in the general obstetrical population is about 5 percent • Increased rates of fetal wastage • Approximately a third of women with APS will develop preeclampsia during pregnancy • In women with a history of recurrent pregnancy loss, those with antiphospholipid antibodies had a higher rate of preterm delivery

23. Which patients with obstetric complications should be tested for aPL and how should the result affect management?

24. Recommendations • Women with recurrent pregnancy loss (3 pregnancy losses) before 10 weeks gestation should be screened for aPL (1B). • For women with APS with recurrent (3) pregnancy loss, antenatal administration of heparin combined with low dose aspirin is recommended throughout pregnancy (1B). In general, treatment should begin as soon as pregnancy is confirmed. • For women with APS and a history of pre-eclampsia or FGR, low dose aspirin is recommended. • Women with aPL should be considered for post-partum thromboprophylaxis (1B).

25. Treatment Guidelines • Aspirin • Heparin - Heparin binds toß2-glycoprotein I, which coats the syncytiotrophoblast. This prevents binding of anticardiolipin and antiß-2-glycoprotein I antibodies to their surfaces, which likely prevents cellular damage - Heparin also binds to antiphospholipid antibodies in vitro and likely in vivo

26. Treatment Guidelines • Immunotherapy -Glucocorticoids likely should not be used with primary APS—that is, without an associated connective-tissue disorder. - In instances of secondary APS seen with lupus the dose of prednisone should be maintained at the lowest effective level to prevent flares

27. Treatment Guidelines • Immunoglobulin therapy has usually been reserved for women with overt disease, heparin-induced thrombocytopenia, or both. It is used when other first-line therapies have failed, especially in the setting of preeclampsia and fetal-growth restriction • Immunosuppressive therapy has also not been well evaluated, but azathioprine and cyclosporine do not appear to improve standard therapies

28. Low-Dose Aspirin Plus Heparin • Current data suggest the most efficacious therapy to be low-dose heparin—7500 to 10,000 units administered subcutaneously, twice daily—given concurrently with low-dose aspirin, 60 to 80 mg once daily (American College of Obstetricians and Gynecologists, 2007b). If active lupus coexists, then prednisone is usually also given

29. Thrombophylaxia in Antiphospholipid Antibody Syndrome • Only positive Antiphospholipid Antibodies : 6 weeks Postnatal

30. Thrombophylaxia in Antiphospholipid Antibody Syndrome Antiphospholipid syndrome (previous VTE) : very high risk, • Antenatal : High Dose Prophylactic • Postnatal: 6 weeks Antiphospholipid syndrome (Recurrent Miscarriage, IUGR/Pre-eclampsia) : • Antenatal :Prophylactic + Aspirin , • Postnatal: 6 weeks