1. The document discusses antiphospholipid syndrome (APS), providing definitions, diagnostic criteria, pathogenesis, clinical manifestations, management recommendations, and considerations for special populations. 2. Key points include that APS is an acquired autoimmune disorder associated with recurrent thrombosis and/or pregnancy morbidity, the importance of identifying a high-risk antibody profile to guide treatment, and recommendations for anticoagulation and immunosuppression to prevent recurrent events. 3. Special sections address catastrophic APS, obstetric APS, nephropathy, and neurological manifestations of APS. Management involves controlling risk factors, anticoagulation, immunomodulation for refractory cases, and individualized strategies for special patient groups

1. APS IN DAILY
PRACTICE
ABDELAZEIM ELHEFNY
Prof of internal medicine, rheumatology & immunology
Ain Shams University

2. AGENDA
■ APS
– Definition
– Pathogenesis
– Diagnosis & classification criteria
– Seronegative / non criteria
■ Thrombotic APS
■ Obst APS
■ *** CAPS***
■ DOAC in APS
■ Peripartum Anticoagulants
■ CONCLUSION
Risk stratification
Management

3. Antiphospholipid antibody syndrome
■ APS is an acquired autoimmune disorder that manifests clinically
as recurrent venous &/or arterial thrombosis and/or fetal losses,
■ + Persistently elevated levels of antibodies directed against
membrane anionic phospholipids
■ It affects mainly females in their childbearing age with F:M ratio of
5-9:1.
■ It may be primary or secondary to other rheumatic or autoimmune
disorder eg. SLE.

5. Pathophysiology of
AP-associated
thrombosis.
The thrombotic response is much
stronger after a second hit (for
example, a minor vascular
injury) owing to the priming of
immune cells, platelets and
endothelial cells by anti-β2-GP
1 AB (the first hit).
Complement is activated, which
strongly accelerates the
formation of a thrombus.
LRP8, low-density lipoprotein
receptor-related protein 8;
MAPK, mitogen-activated protein
kinase;
NF-κB, nuclear factor-κB;
TLR, Toll-like receptor.
Thrombosis
Thrombotic APS

6. APA recognizing β2-glycoprotein 1 expressed by trophoblasts
promote an anti-angiogenic profile and reduce cell
proliferation and migration through LDL receptor-related
protein 8 (LRP8) (part a)
APA trigger secretion of inflammatory
cytokines and chemokines by activating
Toll-like receptor (TLR) and
inflammasome pathways (part b)
APA activate complement on the cell
surface, leading to neutrophil and
monocyte activation with release of
reactive oxygen species (ROS), TNF, anti-
angiogenic factors and tissue factor (TF)
causing placental injury, IUGR & fetal
loss.
Trophoblast
Obstetric APS

7. DIAGNOSIS

8. Indications For Antiphospholipid Antibodies Testing
When to suspect APS?

9. REVISED SAPPORO CLASSIFICATION CRITERIA FOR APS
Miyakis et al. J Thromb 2006; 4: 295-306
Time interval
between serology and
clinical manifestations
should not exceed 5 ys

10. (Libman–Sacks endocarditis)

11. * aPL triple positivity is associated with a 4-fold increased risk of recurrent thrombosis
* IgG aCL/ B2GP1 is more pathologic > IgM
* Venous thromboses are more frequent than arterial thromboses.
Extremities
Venous: deep vein thrombosis
Arterial: ischemia and gangrene
Liver Venous: Budd-Chiari syndrome
Arterial: liver infarction
Central nervous system Venous: sagittal sinus thrombosis
Arterial: cerebrovascular accident
Lung Venous: thromboembolism
Arterial: pulmonary hypertension
Kidney Venous: renal vein thrombosis
Arterial: renal artery thrombosis and thrombotic microangiopathy
Skin Venous: ulcers
Arterial: livedo, gangrene, ulcers
Eyes Venous: retinal vein thrombosis
Arterial: retinal artery thrombosis
Thrombotic manifestations of APS

12. Obst. APAs
• APS-PAH >>> maternal mortality is 43%. (preg is not advised)
Pregnancy morbidity rate in women with obstetrical APS is around 30%.

13. Clinical manifestation of antiphospholipid syndrome.

15. REVISTA MEDICALÅ ROMÂNÅ – VOLUMUL LXII, NR. 1, An 2015

16. Current Neurology and Neuroscience Reports (2021)
(aPS/PT)

18. MANAGEMENT

19. Tektonidou MG, et al. Ann Rheum Dis 2019

20. Risk factors for VTE include:
• Age. Being older than 60 increases the risk of DVT
• Lack of movement. ...
• Injury or surgery. ...
• Pregnancy. ...
• Birth control pills (oral contraceptives) or hormone
replacement therapy. ...
• Being overweight or obese. ...
• Smoking. ...
• Cancer.
■ Heart failure. ** Thrombophilia
■ Inflammatory bowel disease. Genetics & family history
Major risk factors for developing CVD
■ age, sex,
■ high blood pressure,
■ smoking,
■ dyslipidemia, and
■ diabetes

21. adjusted Global Anti Phospholipid Syndrome Score
Radin M, et al. Semin Arthritis Rheum. 2019;49:464-468
>10/17 = the best risk accuracy in terms of sensitivity
& specificity.

22. 1.
• Determination of the presence of a high-risk aPL profile (multiple aPL positivity, LA
or persistently high aPL titres), history of thrombotic and/or obstetric APS,
coexistence of other systemic autoimmune diseases such as SLE, & the presence
of traditional CVR factors.
2.
•Screening for and strict control of CVR factors (smoking cessation; management of HTN,
dyslipidaemia and DM; and regular physical activity) in all individuals and particularly those
with a high-risk aPL profile, screening for and management of VTE risk factors, and use of
LMWH in high-risk situations such as surgery, hospitalisation, prolonged immobilisation and
the puerperium.
3.
• Treatment adherence, INR monitoring in patients treated with VKA, use of
perioperative bridging therapy with LMWH for patients on oral anticoagulants, oral
CCP use, pregnancy and postpartum period, postmenopausal hormone therapy,
and lifestyle recommendations (diet, exercise)
EULAR Recommendations For The Prevention
& Management Of APS In Adults
Overarching principles

23. 1.
•In asymptomatic aPL carriers (no vascular or obstetric APS criteria) with
a high-risk aPL profile with or without traditional risk factors:-
prophylactic treatment with LDA (75–100 mg daily) is recommended
2.
•In patients with SLE and no history of thrombosis or pregnancy losses:-
•A. With high-risk aPL profile, prophylactic treatment with LDA
•B. With low-risk aPL profile, prophylactic treatment with LDA may be
considered
3.
•In non-pregnant women with a history of obstetric APS only (with or
without SLE), prophylactic treatment with LDA after adequate
risk/benefit evaluation is recommended
EULAR Recommendations For The Prevention
& Management Of APS In Adults
Recommendations Primary thromboprophylaxis in aPL-positive subjects

24. 4.
•In patients with definite APS and first venous thrombosis:
•A. Treatment with VKA with a target INR 2–3 is recommended
4.
•B. Rivaroxaban should not be used in triple aPL positivity due to the high
risk of recurrent events.
•DOACs could be considered in patients not able to achieve a target INR
despite good adherence to VKA or those with contraindications to VKA
4.
•C. In patients with unprovoked first VT, anticoagulation should be
continued long term
•D. In patients with provoked first VT, anticoagulation continued for a 3m.,
Longer anticoagulation could be considered in patients with high-risk aPL
profile in repeated measurements or other risk factors for recurrence
EULAR Recommendations For The Prevention
& Management Of APS In Adults
Recommendations Secondary thromboprophylaxis in APS subjects

25. 5.
•In patients with definite APS and recurrent venous thrombosis despite
treatment with VKA with target INR of 2–3:
A.
•Investigation of, and education on, adherence to VKA
treatment, along with frequent INR testing, should be
considered
B.
•If the target INR of 2–3 had been achieved, addition of LDA,
increase of INR target to 3–4 or change to LMWH may be
considered
EULAR Recommendations For The Prevention
& Management Of APS In Adults
Recommendations Secondary thromboprophylaxis in APS subjects

26. 6.
•In patients with definite APS and first arterial thrombosis:
A.
•Treatmentt wih VKA is recommended over treatment with LDA
only
B.
•Treatment with VKA with INR 2–3 or INR 3–4 is
recommended, considering the individual’s risk of bleeding
and recurrent thrombosis. Treatment with VKA with INR 2–3
plus LDA may also be considered
C.
•Rivaroxaban (DOACs) should not be used in patients with triple aPL
positivity and arterial events due to the high risk of recurrent thrombosis
EULAR Recommendations For The Prevention
& Management Of APS In Adults
Recommendations Secondary thromboprophylaxis in APS subjects

27. 7. In patients with recurrent arterial thrombosis despite
adequate treatment with VKA,
after evaluating for other potential causes,
an increase of INR target to 3–4, addition of LDA or switch to
LMWH can be considered
EULAR Recommendations For The Prevention
& Management Of APS In Adults

28. ■ Individuals with obstetrical APS can be separated
into three different clinical phenotypes:-
1. those with recurrent pregnancy loss,
2. those with previous complications of
placental insuffeciency.
1. those with previous maternal thromboses
each of these
phenotypes is
associated with
different pregnancy
outcomes.

29. Management of obs APS

31. Catastrophic APS
■ CAPS is a sever fatal disease, it represents less than 1% of cases of PAPS, with a
significant mortality rate that might reach 30%.
■ The following four criteria are required for the diagnosis of definite CAPS:
– (1) involvement of 3 or more organs, systems, and/or tissues;
– (2) development of manifestations in less than 1 week;
– (3) histological confirmation of small-vessel occlusion in at least one organ or
tissue;
– (4) aPL positivity.
■ The pathophysiology of CAPS is not fully understood; however, it may be due to
infections, surgery, trauma, and malignancy, which may induce endothelial
injury, resulting in cytokines overproduction and thrombotic storm in the
microcirculation.
■ CAPS may occur as 1st manifestation or complicate an already known APS.

32. EULAR Recommendations For The Prevention
& Management Of APS In Adults

33. MANAGEMENT OF
OBST APS

34. Heparins, VKAs and aspirin are all safe concerning breastfeeding.

36. Thromb Haemost 2015; 113(01): 13-19

37. ■ Women with non criteria obstetric APS appear to be at a higher
risk than other women for pre-eclampsia, placenta- mediated
complications and neonatal mortality, and also at increased long-
term risk of thrombotic events.
■ women with recurrent pregnancy loss, and non-criteria APS may
benefit from standard treatment for obstetric APS ie. LMWH plus
LDA, with good pregnancy outcomes.
Thromb Haemost 2015; 113(01): 13-19
Treatment of non-criteria
(seronegative) Obs-APS

38. Enoxaparin

39. IMMUNOMODULATORY
THERAPY IN
REFRACTORY OBST APS

41. ■ Statin (pravastatin=Lipitor 20) treatment was associated with positive outcomes
(the pathogenesis of APS involves inflammatory and thrombogenic pathways).
■ In a murine model of obstetrical APS, hydroxychloroquine was able to prevent
placental and fetal abnormalities in parallel to lowering serum C5a levels.
■ low dose prednisolone 5mg/d
■ Future management trials may include B cell directed therapy (rituximab) and
complement 5 inhibition with eculizumab.
■ IVIG can also be used in refractory cases./ plasma exchange.
■ In a systematic review of haematopoietic stem cell transplantation in refractory
APS, 32 of 44 (73%) individuals were able to discontinue anticoagulation after
transplantation. (carries a considerable mortality).
Management of Refractory
Obstetric APS (~30%).

42. DOAC IN APS

43. • They are contra indicated during pregnancy because of insufficient data.
• Ongoing and emerging DOAC RCTs should provide further information to guide
their use in APS patients
• DOACs appear to be a safe and effective treatment option for APS.
• However larger prospective studies are needed for DOACs to be routinely
considered.
©
2018 International Society on Thrombosis and Haemostasis

44. ANTICOAGULANT
DURING LABOR

45. ■ Anesthesia and obstetrical guidelines agree that 24 h should pass
between the last dose of therapeutic LMWH and insertion of a
neuroaxial catheter. & restart is safe 12-24 h of catheter removal
■ For prophylactic LMWH, catheter insertion should occur no sooner
than 10–12 h after the last LMWH dose & resumption of
prophylactic LMWH 4 - 12 h following delivery; after epidural catheter
removal.
■ At some centers, women are converted from therapeutic adjusted-
dose LMWH to SC twice daily therapeutic UFH in the last month of
pregnancy
Anticoagulants DURING Labor

46. Antiphospholipid Syndrome
Nephropathy
■ acute thrombotic microangiopathy lesions
■ chronic intrarenal vascular lesions such as:-
– interlobular fibrous intimal hyperplasia,
– arterial and arteriolar recanalizing thrombosis,
– fibrous arterial occlusion, and
– focal cortical atrophy.
■ The most frequent clinical features are hypertension, microscopic
hematuria, proteinuria (ranging from mild to nephritic levels), and
renal insufficiency.

47. ■ It is uncertain whether antiphospholipid nephropathy is driven mainly by
thrombotic or by inflammatory processes.
■ The most common lesion In APS –nephritis; is thrombotic microangiopathy that
leads to activation of the complement cascade, tissue factor, and characterized by
fibrin thrombi without inflammatory cells or immune complexes & in LN it was
associated with worse renal prognosis & increased risk of early graft loss due to post-
transplant thrombosis of graft vessels or thrombotic microangiopathy
■ Treatment approaches in patients with APS nephropathy lesions may include the
use of heparin based on its role on complement activation pathway inhibition or
the use of IVIG and/or plasma exchange.
■ Targeted therapies may also be considered (experimental) based on potential APS
nephropathy pathogenetic mechanisms such as B-cell directed therapies,
complement inhibition, tissue factor inhibition, or anti-interferon antibodies.
Antiphospholipid Syndrome Nephropathy

48. Neurologic Manifestations of
Antiphospholipid Syndrome
■ There is a growing interest in better
assessing the role of inflammatory and
direct neuronal effects in the pathogenesis
of noncriteria manifestations in P-APS.
■ There are a few recent reports suggesting a
possible benefit of anticoagulation for
selected non-criteria manifestations that
are not classically considered to be
thrombotic
■ CNS disease in SLE is significantly
associated with the presence of aPL
antibodies & MORE with 2ry APS.
Current Neurology and Neuroscience Reports (2021) 21: 41

49. CONCLUSION

50. Treatment Algorithm For APS
HCQ, LOW DOSE CS,&/OR IVIG
FOR RECURRENT OR REFRACTORY CASES

51. Other considerations
■ Every patient should be instructed to avoid factors that
increase thrombotic risk.
■ Advising the patient to stop smoking, control obesity, properly
treat comorbidities such as diabetes, dyslipidemia and
hypertension is essential to reduce the risk of thromboses.
■ The use of oral contraceptives containing estrogen or hormone
replacement therapy is contraindicated in aPL-positive women.

52. ■ The most recommended methods of contraception for efficacy
and safety are the progestin-releasing IUD, injectable
medroxyprogesterone & barrier methods or oral progesterone
only contraceptives (may be used but are less effective).
■ Patients taking VKA therapy should receive vitamin D/ calcium
supplementation in addition to PPI, considering, respectively,
the risk of osteoporosis and the risk of GI bleeding, associated
with prolonged use of oral anticoagulants.
Other considerations

53. REFERENCES
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MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, editors. Rheumatology. 5. ed. Philadelphia: Elsevier Mosby; 2011. p. 1445-53.
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