Manifestation of Antiphospholipid Syndrome among Saudi patients :examining the applicability of sapporo

Criteria

Farjah H AlGahtani Associate professor ,MD,MPH

Leukemia ,Lymphoma in adolescent ,Thromboembolic Disease

Oncology Center , King Saud University

OUTLINE :

• Historical Back ground of APS

• APS Morbidity

• Pathogenesis

• Sign and symptoms of APS

• Clinical criteria of APS

• APS in Saudia Arabia

1952-1963 Circulating anticoagulants in SLE are named lupus

anticoagulants ( LA) because they prolong the clotting

times in phospholipid dependent assays.LA believed to

cause clinical hemorrhagic disease

1963 LA are reported by Bowie et al to be associated with

thrombosis in SLE patients.

1983 LA are identified by Harris et al to be antibodies that

react with cardiolipin Lupus anticoagulants react with

purified cardiolipin and they are identified as anticardiolipin

antibodies by RIA

1963 Edward John Walter Bowie, MD Mayo Medical School identified APS as an acquired thrombophilia

1984 Graham Robert Vivian Hughes MD FRCP. St Thomas Hospital UK identified APS as a generalized autoimmune disorder

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Antiphospholipid antibodies the most significant target antigen is the Beta 2 glycoprotein-1

In 1990 Monica Galli and her group in Bergamo, Italy reported that the true antigenic targets of antiphospholipid antibodies are not the phospholipids but a plasma protein beta 2 glycoprotein-1 bound to an anionic surface. Galli M,Comfurius P, Massen C et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein co-factor. Lancet 1990;334: 1544-1547

APS morbidity

• APS is the most common cause of acquired thrombophilia.

• Prevalence in general population: 2-4%

• 15-20% of all DVT with or without PE.

• 1/3 of new strokes in patients < 50 years age.

• 10-15% women with recurrent pregnancy losses.

• APS: significant proportion of thromboembolic disease and pregnancy loss in SLE.

• APL Abs present in 30-40% SLE. One third of those patients have clinical manifestations of APS.

• aCL positivity may precede a more severe form of SLE.

PATHOGENESIS

Two mechanisms are identified in the induction of autoimmune Antiphospholipid antibodies (a PL).

• Apoptotic phospholipid beta 2 glycoprotein-1 complexes.

• Phospholipids released from injured cells bound to beta 2 glycoprotein 1

• Infection related

antiphospholipid antibodies.

• From experiments in mice, antiphospholipid antibodies are produced by binding of beta2-glycoprotein 1 to phospholipid viral or bacterial proteins by molecular mimicry

“Listen to your patients , he is telling you the diagnosis”

Multiple Strokes

in a Young Woman

(Brain MRI)

Occlusion of Right Middle Cerebral Artery

In a 3 Years Old Child with

Severe Headache and Hemiparesis

With aCL Antibodies +

Other recognized features of APS

Thrombocytopenia Haemolytic anaemia Livedo reticularis Cerebral involvement

Epilepsy, cerebral infarction, chorea and migraine, transverse myelopathy/myelitis mitral valve

Heart valve disease Hypertension Pulmonary hypertension Leg ulcers

1000 patients with APS

• Deep vein thrombosis / PE 48%

• Pregnancy loss 35%

• Thrombocytopenia 30%

• Livedo reticularis 24%

• Stroke / TIA 20%

• Superficial thrombophlebitis 9%

• Hemolytic anemia 7%

Cervera et al. Arthritis Rheum 2002

Thrombotic events n = 1000 over 10 years

Baseline 10 years DVT 39% 4% Stroke/TIAs 31% 9% Pulmonary emboli 14% 4% Myocardial infarction 6% 2%

Cervera R et al Ann Rheum Dis 2015;74:1011

Antiphospholipid syndrome

Cervera R et al Ann Rheum Dis 2015;74:1011

Antiphospholipid syndrome

Obstetric manifestations n = 1000 over 10 years Baseline 10 years Pre-eclampsia 5% 6% Early pregnancy loss < 10 wks 35% 17% Late pregnancy loss ≥ 10 wks 17% 5% Live birth with prematurity 11% 48% Live birth with IUGR 2% 26%

Clinical criteria for the diagnosis of APS

Thrombosis Venous

Arterial

Small vessel (e.g. thrombotic microangiopathy in

kidney)

Pregnancy

morbidity ≥3 consecutive miscarriages (

Diagnosis Of APS

• Anticardiolipin antibodies are measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits. Medium or high titres of IgG or IgM are required.

• Firm diagnosis of APS requires two or more positive readings for LA and/or aCL at least 6 -12weeks apart, plus at least one of the clinical criteria listed before.

Background

Objectives

Method

Results Conclusion

• Antiphospholipid syndrome (APS) is a systematic autoimmune disease featured with vascular thrombosis and pregnancy morbidity.

• The revised Sapporo criteria are widely used classification criteria for APS.

• This study aims to examine clinical and serological manifestations of a cohort of Saudi APS patients.

• To examine the applicability of revised Sapporo criteria in this cohort.

• This was a single center, retrospective study. • Data were collected from the records of APS patients in King

Saud University Medical City. • The Sapporo criteria were applied and divided patients into

definitive APS cases (fulfilled the criteria) and possible APS cases (failed the criteria).

• Independent sample T-test was used to examine the difference in clinical and laboratory manifestations and comorbidities between the two group.

• Logistic regression was used to examine the association between Sapporo criterial fulfillment and major clinical manifestations.

• A total of 72 (90%) females were included. The mean (±SD) age at diagnosis was 28.1 (± 8.7) years.

• 22 patients (27.5%) fulfilled the revised Sapporo criteria (definitive APS).

• There was no significant difference in the clinical manifestations or treatment between the two group (p>0.2).

• Most patients did not fulfill the revised Sapporo criteria. • Our study identified a gap in applying these criteria in Saudi

patients. • Future studies of examining the diagnostic validity of APS

laboratory manifestations are needed

Farjah Al-Qahtani1, Abdulrahman S. Arfaj2, Sayedah Asfar2 and Mohammed A. Omair2 1 Division of Hematology, Department of Medicine, King Saud University, Riyadh, Saudi Arabia 2 Division of Rheumatology, Department of Medicine, King Saud University, Riyadh, Saudi Arabia

Clinical and Laboratory Manifestations of Antiphospholipid Syndrome Among Saudi Patients: Examining the Applicability of Sapporo Criteria

Total (%, N=80)

Definitive APS (%, N=22)

Possible APS (%, N=58)

P value

Age at diagnosis, yr 28.5 (8.8) 29.7 (9.3) 28.1 (8.7) 0.46

Year at diagnosis 2002 (4) 2001 (4) 2002 (4) 0.6

Female 72 (90) 18 (81.8) 54 (93.1) 0.13

Nationality (Saudi) 71 (88.8) 18 (81.8) 53 (91.4) 0.23

Complications (Y/N) 10 (12.5) 6 (27.3) 4 (6.9) 0.014

Follow-up response

Remission without recurrent event 30 (37.5) 8 (36.4) 22 (37.9)

0.94 Recurrent event 14 (17.5) 4 (18.2) 10 (17.2)

Single visit 35 (43.8) 10 (45.5) 25 (43.1)

Died 1 (1.25) 0 (0) 1 (1.72)

Model 1 Model 2 Model 3

OR (95% CI) P value OR (95% CI) P value OR (95% CI) P value

Vascular thrombosis 1.87 (0.66, 5.25) 0.24 1.59 (0.55, 4.65) 0.39 1.61 (0.55, 4.71) 0.39

DVT or PE1 1.83 (0.68, 4.92) 0.23 1.54 (0.55, 4.32) 0.41 1.53 (0.55, 4.31) 0.42

Recurrent2 DVT or PE 0.65 (0.15, 2.79) 0.56 0.77 (0.14, 4.21) 0.77 0.67 (0.12, 3.81) 0.65

Pregnancy morbidity 0.53 (0.19, 1.46) 0.22 0.61 (0.21, 1.84) 0.39 0.63 (0.21, 1.92) 0.42

Serology Thrombosis2 Pregnancy morbidity3 Thrombocytopenia4 Asymptomatic Total

+ve5 aCL 7 (22.6) 12 (40) 3 (42.9) 6 (75) 28 (48.3)

+ve LA1 3 (9.7) 2 (6.7) 1 (14.3) 2 (25) 8 (13.8)

-ve 21 (67.7) 16 (53.3) 3 (42.9) - 40 (69.0)

Total 31 30 7 8

Table 1. Study population characteristics

Table 3. The association of Sapporo criteria fulfillment with major clinical manifestations

Model 1: crude associations Model 2: adjusted for age at diagnosis, gender, nationality Model 3: adjusted for covariates in model 2 and follow-up response 1 DVT: deep vein thrombosis; PE: pulmonary embolism 2 Analysis for recurrent DVT or PE was restricted to 35 patients with previous DVT or PE event

Table 2. The serology results of the possible APS patients in relation to their clinical manifestations (N=58)

Figure 1. The age distribution of definitive and possible APS cases

Lessons learned

• Diagnosis is absolutely necessary for the proper clinical management

• Lupus Anticoagulant is the “ identifier” or “ biomarker” unique to the

Antiphospholipid syndrome and consider the

• Auto-antibodies that prolong clotting times in phospholipid dependent

clotting assays are termed “lupus anticoagulant”

Special Coagulation Laboratory Recipe for APS diagnosis

• APTT clotting times must be prolonged at least twice control plasma clotting times (correlates with high antibody titer)

• APTT prolonged clotting times does not correct in mixing patient plasma with pooled normal plasma

• ELISA identifies beta2-glycoprotein 1 antigen and auto-antibodies.

• Testing is repeated as indicated. • APS induced by viral or bacterial proteins disappears after

infection is cured

SAUDI-APS RESEARCH GRUOP

AIMS of THE Saudi APS-Research Group :

• Describe outcomes of arterial venous and pregnancy complications .

• Describe CAPS presentation in Saudi Population and the outcome .

•Assess drug respond in APS . • assess quality of life / depression in APS patients

• Role of genetics Factors of APS including familial and sporadic cases

• Develop an APS registry and maybe guidelines under the hematology society

• We need to manage getting different national /international collaboration Centers onboard .

THANK YOU