Management of Primary Antiphospholipid Syndrome (APS) with Pregnancy

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Management of Primary Antiphospholipid Syndrome (APS) with Pregnancy:

Management of Primary Antiphospholipid Syndrome (APS) with Pregnancy Mohammed Abdel Gawad Nephrology Specialist Kidney & Urology Center (KUC) Alexandria What is the Evidence? What is t he Debate?

Antiphospholipid Syndrome (APS) (Hughes Syndrome):

Antiphospholipid Syndrome (APS) (Hughes Syndrome) First recognized by Graham Hughes in 1983

APS and the Kidney:

APS and the Kidney Renal involvement in primary APS is primarily characterized pathologically by noninflammatory thrombotic occlusion of renal blood vessels, (ranging from glomerular capillaries to the main renal artery and vein) (1) Nochy D, Daugas E, Droz D, et al. J Am Soc Nephrol 1999; 10:507. Renal vessels thrombosis TMA

Management Cycle:

Management Cycle Known APS First presentation TMA APS + Miscarriage ± Thrombosis (including renal vessels) Counseling & General Care

Counseling & General Care of Pregnancy with Antiphospholipid Syndrome:

Counseling & General Care of Pregnancy with Antiphospholipid Syndrome Guilherme Ribeiro etal . Curr Rheumatol Rep. 2012 Feb;14(1):79-86 Ruiz- Irastorza G etal . Rheum Dis Clin North Am. 2007;33(2):287–97 Ruiz- Irastorza G etal . Lancet. 2010;376(9751):1498–509

Management Cycle:

Management Cycle ` Counseling & General Care Known APS First presentation TMA APS + Miscarriage ± Thrombosis (including renal vessels) APS + Miscarriage ± Thrombosis (including renal vessels)

Available Therapies:

Available Therapies Aspirin Heparin (LMWH, Unfractionated ) Warfarin Steroids ?? IV Ig ?? Plasma Exchange ?? What is the Evidence? APS ± Thrombosis (including renal vessels) Is Aspirin beneficial? Dose heparin add benefit? Which is better LMW or Unfractionated heparin? APS + Miscarriage ± Thrombosis (including renal vessels)

APS + Recurrent Early Miscarriage (No history of thrombosis):

APS + Recurrent Early Miscarriage (No history of thrombosis) Aspirin Meta-analysis shown a significant reduction of pregnancy complications in women at high risk for pre- eclampsia who were given antiplatelet agents (mostly aspirin ). Askie LM etal . Lancet. 2007; 369: 1791–98.

PowerPoint Presentation:

Carmona F etal . Am J Reprod Immunol 2001; 46: 274–79. Silver RK etal . Am J Obstet Gynecol 1993; 169: 1411–17. Pattison NS etal . Am J Obstet Gynecol 2000; 183: 1008–12. Lima F etal . Clin Exp Rheumatol 1996; 14: 131–36. Granger KA etal . Lupus 1997; 6: 509–13. Huong DLT etal . J Rheumatol 2001; 28: 2025–30. Munoz-Rodriguez FJ etal . Semin Arthritis Rheum 1999; 29: 182–90. Several observational studies have reported pregnancy success rates of 79–100% with low-dose aspirin alone. (1-7) APS + Recurrent Early Miscarriage (No history of thrombosis) Aspirin

Available Therapies:

Available Therapies Aspirin Heparin (LMWH, Unfractionated ) Warfarin Steroids ?? IV Ig ?? Plasma Exchange ?? What is the Evidence? APS ± Thrombosis (including renal vessels) Is Aspirin beneficial? Dose heparin add benefit? Which is better LMW or Unfractionated heparin? APS + Miscarriage ± Thrombosis (including renal vessels)

PowerPoint Presentation:

Rai R etal . BMJ 1997; 314: 253–57. Kutteh WH. Am J Obstet Gynecol 1996; 174: 1584–89. The proportion of successful pregnancies substantially improved with the addition of unfractionated heparin to low-dose aspirin. APS + Recurrent Early Miscarriage (No history of thrombosis) Aspirin alone vs Aspirin + Heparin

PowerPoint Presentation:

Low-molecular-weight heparin, proved to be of no benefit. Laskin CA etal . J Rheumatol 2009; 36: 279–87. APS + Recurrent Early Miscarriage (No history of thrombosis) Aspirin alone vs Aspirin + Heparin

PowerPoint Presentation:

2 RCT proved heparin adds benefit (1,2) RCT heparin adds no benefit (3) Rai R etal . BMJ 1997; 314: 253–57. Kutteh WH. Am J Obstet Gynecol 1996; 174: 1584–89. Laskin CA etal . J Rheumatol 2009; 36: 279–87. The difference in the results may depend on the differences in the selected cohorts as the risk of pregnancy loss is low in LA-negative patients. APS + Recurrent Early Miscarriage (No history of thrombosis) Aspirin alone vs Aspirin + Heparin

PowerPoint Presentation:

Low-molecular-weight heparin, proved to be of no benefit. Laskin CA etal . J Rheumatol 2009; 36: 279–87. APS + Recurrent Early Miscarriage (No history of thrombosis) Aspirin alone vs Aspirin + Heparin

PowerPoint Presentation:

Despite the obvious controversies raised by these trials, a Cochrane systematic review concluded that women with recurrent miscarriage and APS should be given a combination of heparin 5000 IU subcutaneously twice daily and low-dose aspirin. Empson M, Lassere M, Craig J, Scott J. Cochrane Database Syst Rev 2005; 18: CD002859. APS + Recurrent Early Miscarriage (No history of thrombosis)

Available Therapies:

Available Therapies Aspirin Heparin (LMWH, Unfractionated ) Warfarin Steroids ?? IV Ig ?? Plasma Exchange ?? What is the Evidence? APS ± Thrombosis (including renal vessels) Is Aspirin beneficial? Dose heparin add benefit? Which is better LMW or Unfractionated heparin? APS + Miscarriage ± Thrombosis (including renal vessels)

LMW vs Unfractionated Heparin:

LMW vs Unfractionated Heparin No differences in pregnancy outcomes when comparing unfractionated heparin with low-molecular-weight heparin, both combined with aspirin. Noble LS etal . Fertil Steril 2005; 83: 684–90. Stephenson MD etal . J Obstet Gynaecol Can 2004; 26: 729–34. APS + Recurrent Early Miscarriage (No history of thrombosis)

PowerPoint Presentation:

Table Source: Ruiz- Irastorza G etal . Lancet. 2010;376(9751):1498–509 APS + Recurrent Early Miscarriage (No history of thrombosis)

Available Therapies:

Available Therapies Aspirin Heparin (LMWH, Unfractionated ) Warfarin Steroids ?? IV Ig ?? Plasma Exchange ?? APS ± Thrombosis (including renal vessels) What is the Evidence? APS + Miscarriage ± Thrombosis (including renal vessels)

APS + No history of thrombosis with fetal death (>10 weeks’ gestation) or previous early delivery (<34 weeks’ gestation) due to severe pre-eclampsia or placental insufficiency :

APS + No history of thrombosis with fetal death (>10 weeks’ gestation) or previous early delivery (<34 weeks’ gestation) due to severe pre- eclampsia or placental insufficiency Results from RCT do not define optimum treatment Most experts recommend low-dose aspirin and either prophylactic or intermediate-dose heparin (1,2,3) Branch DW, Khamashta MA. Obstet Gynecol 2003; 101: 1333–44. Empson M, Lassere M, Craig J, Scott J. Cochrane Database Syst Rev 2005; 18: CD002859. Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J. Chest 2008; 133: 844S–86S.

APS + No history of thrombosis with fetal death (>10 weeks’ gestation) or previous early delivery (<34 weeks’ gestation) due to severe pre-eclampsia or placental insufficiency :

Table Source: Ruiz- Irastorza G etal . Lancet. 2010;376(9751):1498–509 APS + No history of thrombosis with fetal death (>10 weeks’ gestation) or previous early delivery (<34 weeks’ gestation) due to severe pre- eclampsia or placental insufficiency

Available Therapies:

Available Therapies Aspirin Heparin (LMWH, Unfractionated ) Warfarin Steroids ?? IV Ig ?? Plasma Exchange ?? APS ± Thrombosis (including renal vessels) What is the Evidence? APS + Miscarriage ± Thrombosis (including renal vessels)

APS + Previous Thrombotic Episodes:

APS + Previous Thrombotic Episodes Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J. Chest 2008; 133: 844S–86S. Low-dose aspirin + therapeutic dose heparin or LMW heparin anticoagulation are recommended. Depending on experts opinion

PowerPoint Presentation:

Table Source: Ruiz- Irastorza G etal . Lancet. 2010;376(9751):1498–509 APS + Previous Thrombotic Episodes

Available Therapies:

Available Therapies Aspirin Heparin (LMWH, Unfractionated ) Warfarin Steroids ?? IV Ig ?? Plasma Exchange ?? What is the Evidence? Is Warfarin safe? Which is better Warfarin or Heparin? What is the recommended INR target? APS ± Thrombosis (including renal vessels) APS + Miscarriage ± Thrombosis (including renal vessels)

Warfarin:

Warfarin can be used during pregnancy as an alternative to heparin after organogenesis is complete, so it must be avoided from 6 to 12 weeks Warfarin Is Warfarin Safe? Ruiz- Irastorza G etal . Rheum Dis Clin North Am. 2007;33(2):287–97. APS ± Thrombosis (including renal vessels) APS + Miscarriage ± Thrombosis (including renal vessels)

Warfarin:

An observational study of 54 pregnancies. Warfarin Warfarin vs Heparin? Pauzner R, Dulitzki M, Langevitz P, et al. Thromb Haemost . 2001;86 (6):1379–84. Compared enoxaparin with warfarin and found no difference in pregnancy outcome, with successful pregnancy rates of 87% and 86%, respectively. APS ± Thrombosis (including renal vessels) APS + Miscarriage ± Thrombosis (including renal vessels)

Warfarin:

Patients with APS and venous event: Receive oral anticoagulant to a target INR of 2 to 3 (1) Warfarin Recommended INR Ruiz- Irastorza G, Cuadrado MJ, Ruiz- Arruza I, et al. Lupus. 2011;20(2):206–18. Rosove MH, Brewer PM. Ann Intern Med. 1992;117(4):303–8. Khamashta MA, Cuadrado MJ, Mujic F, et al. N Engl J Med. 1995;332(15):993–7. Ruiz- Irastorza G, Hunt BJ, Khamashta MA. Arthritis Rheum. 2007;57(8):1487–95. APS ± Thrombosis (including renal vessels) P atients with arterial or recurrent events , experts recommend INR target of 3 to 4 (2-4) APS + Miscarriage ± Thrombosis (including renal vessels)

Warfarin:

Warfarin Recommended INR APS ± Thrombosis (including renal vessels) Crowther MA etal . N Engl J Med 2003; 349:1133–1138. APS + Miscarriage ± Thrombosis (including renal vessels)

Warfarin:

Warfarin Recommended INR APS ± Thrombosis (including renal vessels) Finazzi G etal. J Thromb Haemost 2005; 3:848–853. APS + Miscarriage ± Thrombosis (including renal vessels)

Available Therapies:

Available Therapies Aspirin Heparin (LMWH, Unfractionated ) Warfarin Steroids ?? IV Ig ?? Plasma Exchange ?? What is the Evidence? APS ± Thrombosis (including renal vessels) APS + Miscarriage ± Thrombosis (including renal vessels)

Steroids:

Steroids Steroids do not influence: the titers of aPLs , or the hypercoagulable state of APS, or the adverse pregnancy outcomes. Carmona F, Font J, Azulay M, et al. Am J Reprod Immunol 2001; 46: 274–79. Silver RK etal . Am J Obstet Gynecol 1993; 169: 1411–17. Two randomized trials showed no benefit in using these steroids in obstetric APS. They may induce serious side effects . APS ± Thrombosis (including renal vessels) APS + Miscarriage ± Thrombosis (including renal vessels)

Available Therapies:

Available Therapies Aspirin Heparin (LMWH, Unfractionated ) Warfarin Steroids ?? IV Ig ?? Plasma Exchange ?? What is the Evidence? APS ± Thrombosis (including renal vessels) APS + Miscarriage ± Thrombosis (including renal vessels)

IV immunoglobulin:

RCTs showed no benefit from use of IV Ig either when added to heparin or used alone.(1-3) Cochrane analysis concluded that IV Ig s were associated with an increased risk of pregnancy loss or premature birth, compared with heparin and low-dose aspirin.(4) IV immunoglobulin Triolo G, Ferrante A, Ciccia F, et al. Arthritis Rheum 2003; 48: 728–31 Branch DW, Peaceman AM, Druzin M, et al. Am J Obstet Gynecol 2000; 182: 122–27. Vaquero E, Lazzarin N, Valensise H, et al.. Am J Reprod Immunol 2001; 45: 174–79. Empson M, Lassere M, Craig J, Scott J. Cochrane Database Syst Rev 2005; 18: CD002859. APS ± Thrombosis (including renal vessels) APS + Miscarriage ± Thrombosis (including renal vessels)

Available Therapies:

Available Therapies Aspirin Heparin (LMWH, Unfractionated ) Warfarin Steroids ?? IV Ig ?? Plasma Exchange ?? What is the Evidence? APS ± Thrombosis (including renal vessels) APS + Miscarriage ± Thrombosis (including renal vessels)

Plasma Exchange:

Indications: In triple-positive patients with impending pregnancy loss In whom the standard (LMWH plus low-dose aspirin) protocol fails (about 30% of cases) (1-3) Catastorophic APS (4) Plasma Exchange Owing to the small number of treated patients, the efficacy ⁄ safety of these protocols is not yet established. Ruffatti A, TonelloM,Cavazzana A,Bagatella P,Pengo V. ThrombRes2009;123:482–7. Ruffatti A, TonelloM, Del Ross T et al. ThrombHaemost2006;96:337–41. Ruffatti A, Calligaro A, Hoxha A et al. Arthritis Care Res (Hoboken) 2010; 62:302–7. Asherson RA, Espinosa G, Cervera R, Font J, Reverter JC. 2002; 8:157–65. APS ± Thrombosis (including renal vessels) Depending on experts opinion Plasma exchange with or without i.v . IV Igs (4) APS + Miscarriage ± Thrombosis (including renal vessels)

Management Cycle:

Management Cycle ` Counseling & General Care Known APS First presentation TMA APS ± Thrombosis (including renal vessels) TMA

Available Therapies:

Available Therapies TMA Plasma Exchange Corticosteroids ± Immunosuppressive + Anticoagulant The available evidence is very SOFT depending on case reports of non pregnants . What is the Evidence?

PowerPoint Presentation:

TMA R. K. Sharma etal . Indian J Nephrol. 2011 Oct-Dec; 21(4): 280–282.

PowerPoint Presentation:

TMA There is a good response (improving renal condition) to Cyclophoshamide + Prednisolone and Azathioprine

Management Cycle:

Management Cycle

Postpartum Prophylaxis Thromboprophylaxis:

Aspirin Postpartum Prophylaxis Thromboprophylaxis Bates SM etal . Chest 2008; 133: 844S–86S. Obstetric Clinical Algorithm: Management & Evidence. By E.R. Norwitz . 2010 Heparin Warfarin

Postpartum Prophylaxis Thromboprophylaxis:

Postpartum Prophylaxis Thromboprophylaxis Levy RA etal . Lupus. 2010;19(4):457–9. In patients with prior fetal death or recurrent pregnancy loss, the use of low dose aspirin after pregnancy is still controversial. Aspirin Heparin Warfarin

Postpartum Prophylaxis Thromboprophylaxis:

Postpartum Prophylaxis Thromboprophylaxis Warfarin (1), Heparin & Low Dose Aspirin (2) are safe to use during breastfeeding. Duhl AJ, Paidas MJ, Ural SH, et al. Am J Obstet Gynecol. 2007;197(5):457 e1–21. Khamashta MA. Best Pract Res Clin Rheumatol . 2006;20(4):685–94.

PowerPoint Presentation:

It is important to avoid estrogens at all costs. Levy RA etal . Lupus. 2010;19(4):457–9. Postpartum Prophylaxis Take Care

Management Cycle:

Management Cycle ` `

Pre – Conception Counseling & General Care:

Pre – Conception Counseling & General Care Patients must be informed that: T here is an increased risk of serious complications can take place during pregnancy and puerperium (1) Gestational results with live births are improved to about 80% when antithrombotic therapy is used, but failure in 20% to 30% of the cases (2) Even if the proper treatment is chosen (1,2) Ruiz- Irastorza G etal . Rheum Dis Clin North Am. 2007;33(2):287–97. Bramham K et al. Lupus 2010; 19: 58–64.

Take Care :

Take Care ` Ruiz- Irastorza G etal . Lupus 2008; 17: 416–20 Ruiz- Irastorza G etal . Lancet. 2010;376(9751):1498–509 `

Pre conception Low Dose Aspirin:

Pre conception Low Dose Aspirin Some authors consider that preconception use of aspirin may have more benefits, but there is no strong evidence to support this opinion. Carmona F etal . Am J Reprod Immunol 2001; 46: 274–79.

Bone density:

Bone density Bone density studies may be performed after pregnancy completion in patients who used heparin, especially after two or more pregnancies. When evidence of osteoporosis exists: advice against lactation may be prudent. Supplemental calcium (1000 mg elemental calcium per day), vitamin D (800 international units), weight bearing activity (eg, walking, lifting weights) Ruiz- Irastorza G etal . Lupus. 2001;10(9):597–600.

Potential future therapies for APS:

Potential future therapies for APS Ruiz- Irastorza G etal . Lancet. 2010;376(9751):1498–509

Potential future therapies for APS:

Potential future therapies for APS Ruiz- Irastorza G etal . Lancet. 2010;376(9751):1498–509 Bill Giannakopoulos etal . N Engl J Med 2013;368:1033-44.

PowerPoint Presentation:

Take Home Messages

Take Home Messages During Pregnancy:

Take Home Messages During Pregnancy APS + Recurrent Early Miscarriage + no history of thrombosis APS + Miscarriage after 10 week + no history of thrombosis APS + history of thrombosis Aspirin Protective (by RCT) Expert opinion Expert opinion Heparin Protective (RCT) Expert opinion Expert opinion `

Take Home Messages During Pregnancy:

Take Home Messages During Pregnancy No difference between LMW and unfractionated heparin

Take Home Messages During Pregnancy:

Take Home Messages During Pregnancy Warfarin Warfarin is safe after the 12 week and can substitute heparin Warfarin has the same outcome on pregnancy as heparin Recommended INR 2-3 (higher intervals have no benefit with higher risk of bleeding)

Take Home Messages During Pregnancy:

Take Home Messages During Pregnancy Steroids, IV Ig show no benefit Plasma exchange effect needs RCT

Take Home Messages TMA:

Take Home Messages TMA The evidence of plasma exchange & immunosuppressive based on case reports

Take Home Messages Post partum prophylaxis:

Take Home Messages Post partum prophylaxis Long life anticoagulation prophylaxis depends on the history of thrombosis Aspirin is controversial

Take Home Messages:

Take Home Messages Failure in 20% to 30% of the cases even if the proper treatment is chosen

Research Recommendations:

Research Recommendations All the available evidence is very soft , even the available RCT are of small number of patients. All the available therapies available for APS must be restudied by large well designed trials.

PowerPoint Presentation:

ذهبت أناجي طبيب الورى وقلبي يناجي طبيب السماء ذاك ليـــــــــصـــــف لــــي الـــدوا وذاك ليـــــــجعل فيه الشــــفاء جزاكم الله خيراً Gawad drgawad@gmail.com

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