Prof hanan anti phospholipid syndrome with highlights on criteria and seronegative antiphospholipid Head of internal medicine, faculty of medicine, Beni-Suef University First lupus day October 2018

1. Anti-phospholipid Syndrome
Prof. Hanan Aly Taha
Head of Internal Medicine Dept.
Head of Clinical Immunology Unit.
Director of Skill Lab.
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2. A 32-year-old woman presents to the ED with a 4-h
history of acute onset shortness of breath and left-side
chest pain. She was diagnosed with SLE 3 years ago.
Her ANA and dsDNA were positive and kidney biopsy
revealed mesangioproliferative glomerulonephritis
(WHO grade II). She was started on prednisolone along
with azathioprine.
She has been married for 10 years and has one boy aged
9 years; that pregnancy was followed by two
spontaneous 1st trimester abortions at the age of 25
and 27 years.
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3. OE
The patient is apyrexial and looks dyspnoeic; her
pulse is 116/min, blood pressure is 100/76
mmHg and respiratory rate is 28/min.
There are no skin lesions, oral ulcers or alopecia.
Cardiovascular examination reveals normal
peripheral pulses and no obvious abnormality
of the heart except tachycardia.
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4. Haemoglobin (13.5 g/dL); white cell count 7.8 × 109/L; platelet
count 98 × 109/L; ESR 24 mm/h.
Renal and liver function tests are normal.
Dipstick examination of urine reveals 3+ protein.
Arterial blood gas analysis reveals: PaO2 (65 mmHg) and
PaCO2 (18 mmHg) on 40% oxygen.
A 12-lead electrocardiogram (ECG) shows sinus tachycardia
and a chest X-ray reveals blunting of left costophrenic
angle.
An echocardiogram of the heart and Doppler studies of the
carotid arteries are normal.
A D-dimer test is strongly positive
A computed tomography pulmonary angiography scan (CTPA)
reveals thrombus in the left main pulmonary artery (Fig.). A
subsequent Doppler ultrasound of the legs is normal.
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5. CT pulmonary angiogram showing extensive thrombus in the left main
pulmonary artery (arrows), in coronal (A) and sagittal (B) views
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6. Autoantibodies:
ANA – positive (1 : 320 homogenous pattern)
ANCA – negative;
anticardiolipin antibody (aCL) IgG – 52 GPL U/mL
(normal<12 GPL U/mL),
aCL IgM – 26 MPL U/mL (normal <12 MPL U/mL)
anti- β2-glycoprotein I antibody (IgG) – 22 U/mL
(normal <8 U/mL).
lupus anticoagulant LAC is positive,
protein C, protein S and antithrombin III
concentrations are normal.
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7. • APS can occur as an isolated diagnosis
(primary APS), or it can be associated with
systemic lupus erythematosus (SLE) or
another rheumatic disease.
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8. When considering the patient having APS ?
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10. mechanism of anti-phospholipid antibody (aPL)-
related thrombosis and placental injury
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11. Seronegative APS:
Is it really SNAPS or Underdiagnosed APS????
•EXPENSIVE
1) Do we routinely ask for Anti–β-2-glycoprotein1 antibody of IgG or
IgM isotype??
• ISIH-SCC (2009)
• BCSH (2012)
• CLSI H 60-A (2014)
• false-positive and false-negative lupus anticoagulant test results may occur
2) LA testing guidelines
Screen, Confirm, Mix, Exclusion
• Antibodies to Domain I of 𝛽2-GPI
• IgA Anti-𝛽2-GPI
• Antibodies to Prothrombin and Prothrombin/Phosphatidylserine Complex.
• Antibodies to Protein S/Protein C.
• Antibodies to Vimentin/Cardiolipin Complex
• Antibodies to Annexin A5 and Annexin A2.
• Antibodies to Phospholipid Antigens (PS, PE, PI, CL)
New specificities of APS
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13. Non-criteria clinical and laboratory
manifestations of obstetric antiphospholipid
syndrome.
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Testing for non-criteria aPLs can increase the diagnostic yield in SNAPS patients.
Standardized tools and longitudinal studies are needed to confirm the clinical relevance of non-criteria antibodies
in SNAPS.
Diagnosis and management of non-criteria obstetric antiphospholipid syndrome
Deepa R. Jayakody Arachchillage1,2; Samuel J. Machin1; Ian J. Mackie1; Hannah Cohen1,2

14. Thrombosis risk factors other than APS ?
• Independent coagulopathies :
 Protein C, protein S, and antithrombin III
 Factor V Leiden (A506G), prothrombin (G20210A), and methylene
tetrahydrofolate reductase (MTHFR, C677T) mutations
• Acquired
 Hypertension,
 Diabetes,
 Nephrotic syndrome,
 Venous insufficiency,
 Immobility
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15. Practice Points
 When should we test for APL?
• Samples can be negative when presenting with an acute VTE and
serial samples may show a positive APL
• NOACs (rivaroxaban and apixaban) will give false positive LAC
results –if essential, retest after NOAC ceased or transition to
LMWH for several weeks
• Must repeat after 12 weeks to meet criteria
 Consider APL testing in: atypical sites of VTE (e.g.cerebral sinus)
• recurrent VTE without a family history
• younger patients with arterial events
• combined arterial and venous thrombi
• unexplained multiorgan failure and likely microvascular ischaemia
 clinical history guides therapy rather than assay results
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16. Treatment Recommendations
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17. Asymptomatic Anti-phospholipid
Antibody–Positive Persons
• Anticoagulation is not indicated.
• discussion of warning signs
• Elimination of reversible thrombosis risk factors
and prophylaxis during high-risk periods, such as
surgical procedures
• low-dose aspirin ?
• drugs that induce lupus (e.g., hydralazine and
phenytoin) may also induce aPLs, they may be
prescribed for patients with aPLs if no
alternatives are available
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18. Pregnancy Morbidity
[Eminence based not evidence based]
• In the study of Mekinian et al (2016) patients with non-conventional APL
have a significant decrement of pregnancy losses if they receive
treatment for APS during their pregnancy.
• Recurrent embryonic losses: controversial
• Prior fetal losses at later than 10th week: prophylactic heparin
(enoxaparin, 30 to 40 mg subcutaneously once daily) +LDA
• Prior thromboses : full anticoagulation (enoxaparin, 1 mg/kg
subcutaneously twice daily or 1.5 mg/kg subcutaneously once daily)
• continues until 48 hours before anticipated delivery
• Warfarin after the first trimester ???
• Early and severe preeclampsia or growth restriction: LDA±LMWH
• HCQ
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Effect of heparin

19. What about treatment failure?
• (IVIG) (0.4 g/kg per day for five days each month during the
next attempted pregnancy
• Plasmapheresis ( case reports).
• Interleukin -3 (Experimental).
• Glucocorticoids — conflicting results. Risk/benefit ratio
prednisolone 10 mg/day in the first trimester can be
considered for selected patients
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Is any role for steroid intake ? ……. When

20. • LMWH resumes for 8 to 12 weeks postpartum.
• Breastfeeding is allowed with both heparin and
warfarin
 Assessment of aPL was not indicated among couples undergoing IVF.
 Some recommend evaluation and treatment of women with aPL undergoing fertility
therapy. LDA±LMWH according to risk profile.
 LDA should be stopped three days before egg retrieval and resumed the following day.
 Patients taking LMWH should stop it at least 12 hours prior to the procedure and
resume it the very same day as long as there is no bleeding.
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What about postpartum period & breast feeding?
Are there precuations during assisted reproduction techniques?

21. Catastrophic Anti-phospholipid
Syndrome
• Immunosuppression
• IVIG
• Plasmapheresis
• Rituximab
• Eculizumab
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22. Potential new therapies in APL
 N-acetyl cysteine –scavenge oxygen radicals
 Statins –upregulate endothelial NO synthase
 Hydroxychloroquine-antiplatelet and prevents disruption
of AnnexinA5 matrix on endothelium by APL
 Inhibitors of PDI –higher ratio of oxidisedb2GPI in APS, TF
 Eculizimab–inhibits complement C5
 Inhibitors of B-cell activating factor (BAFF) –belimumab
approved in SLE, prevented thrombosis in mouse model
 Inhibitors of FXIa–dysregulated in APS
Giannakopoulos and KrilisNEJM 2013
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23. Use of direct oral anticoagulants in antiphospholipid
syndrome.
• The Trial Rivaroxaban in Antiphospholipid
Syndrome (TRAPS) suggests that rivaroxaban has
the potential to be an effective and convenient
alternative to warfarin in thrombotic APS patients
with a single venous thromboembolism event.
• However, further studies, in particular to provide
better long-term efficacy and safety data, are
needed before it can be widely recommended.
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24. References
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25. ‫شكرا‬
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