prof. francesco violi università degli studi di roma “la sapienza” aps
TRANSCRIPT
Prof. Francesco Violi
Università degli Studi di Roma “La Sapienza”
APS
APS (Antiphospholipid syndrome)
• Definition• Clinical manifestations:
a) venous and arterial thrombosis and foetal loss
b) bleeding disorders
• Mechanism of disease
• Management
The Antiphospholipid Syndrome
It’s a clinical syndrome with widespread arterial and venous thrombosis associated with antibodies directed against phospholipids.
The disorder was classified as “primary” (PAPS), in absence of a concurrent autoimmune condition, such as systemic lupus erythematosus, and secondary (APS) in presence of another autoimmune disease.
Features include stroke and transient ischaemic attack, coronary artery disease, livedo reticularis, pulmonary hypertension, and recurrent aborption. Minor features include labile hypertension, migraine, epilepsy, minor myelopathy,thrombocytaemia, hearth valve disease and ocular ischaemia.
Preliminary Classification Criteria for Antiphospholipid Antibody Syndrome, as Proposed at an International Consensus Workshop, October, 1998
One or more episodes of• Arterial, or• Venous, or• Small vessel thrombosis, in any tissue or organ, confirmed by imaging or Doppler
studies or histopathology. For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall
• Three or more unexplained consecutive miscarriages with anatomic, genetic or hormonal causes excluded or
• One or more unexplained deaths of a morphologically normal fetus at or after the terth week of gestation with fetal morphology documented by ultrasound or by direct examination of the fetus or
• One of more premature birtrhs of a morphologically normal neonate at or before the 34th week of gestation associated with severe preclampsia or severe placental insufficiency.
Clinical CriteriaVascular Thrombosis:
Pregnancy morbidity:
Lockshin Thromb Haemostas 82:641-648, 1999
• IgG and/or IgM isotype present in• Medium or higher titer,• On two or more occasion, 6 weeks or more apart, and• Measured by standardized ELISA for 2Glycoprotein I-dependent anticardiolipin antibody
Abnormality present in plasma on• Two or more occasions 6 weeks or more apart and• Detected according to the guidelines of the SSC subcommittee on lupus
anticoagulant/phospholipid dependent antibodies in the following steps: Demonstration of a prolonged phospholipid-dependent coagulation screening test (e.g., activated
partial thromboplastin time) kaolin clotting time, dilute Russell viper venom time, dilute prothrombin time, and Textarian time
Failure to correct the prolonged screening test by mixing with normal platelet-poor plasma
Shortening or correction of the prolonged screening test by the addition of excess phospholipid.
Exclusion of other coagulopathies as clinically indicated (e.g., factor VIII inhibitor) and heparin
Preliminary Classification Criteria for Antiphospholipid Antibody Syndrome, as Proposed at an International Consensus Workshop, October, 1998
Laboratory CriteriaAnticardiolipin antibody
Lupus anticoagulant
Lockshin Thromb Haemostas 82:641-648, 1999
Prevalence of antiphospholipid antibody in various pregnancy series
Author Study Group APL ELISA (% +)
LAC (% +)
Harris and Spinnato 1,499 normal pregnancies 1.8
Lockwood et al. 737 normal pregnancies 0.2
Rix et al. 2,856 normal pregnancies 7
Lynch et al. 389 normal pregnancies 4.6 13.7
Infante-Rivard et al. 331 post first pregnancy loss
993 post normal delivery 1.5 1.5
1.8 3.8
Haddoe et al. 309 woman with late
pregnancy loss 618 normal women
0.3 high +
0 high +
Lockshin Thrombosis and Haemostasis 82:641-648, 1999
NORMAL PREGNANCY
Prevalence of antiphospholipid antibody in various pregnancy series
Author Study Group APL ELISA (% +)
LAC (% +)
Parke et al. 81 women with 3+ pregnancy losses
88 normal pregnancies 64 not pregnant
16 7 3
Out et al. 102 women with 3+ early or 1 late
pregnancy losses 102 normal women
21
10
5
0
Petri et al. 44 women with 3+ pregnancy losses 40 women with 0-1 pregnancy loss
11 2.5
9 0
RECURRENT ABORTION
Lockshin Thromb Haemostas 82:641-648, 1999
Bleeding Disorder in APA Patients
• Rare
• Hypoprothrombinemia (20%) and piastrinopenia
• Corticosteroid Treatment
APS (Antiphospholipid syndrome)
• Definition
• Clinical manifestations:
a) venous and arterial thrombosis and foetal loss
b) bleeding disorders
• Mechanism of disease• Management
Mainantigenic Targets Of Antiphospholipid Antibodies (Apl)(React With Antigenic Epitopes In Phospholipid-protein Complexes)
ANIONIC PHOSPHOLIPIDS
(Cardiolipin Phosphatidylserine) Annexin V has potent anticoagulant properties in
vitro, based on its high affinity for anionic phospholipids and its capacity to displace coagulation factors from phospholipids surface. aPL IgG fractions reduce the
quantity of Annexin V in cultured throphoblast and endothelial cells and accelerate the coagulation of plasma
incubated with the cells. The hypothesis is that Annexin V plays a thrombomodulatory apical role on the surface of cells lining the
placental and systemic vasculatures.
PLASMA PHOSPHOLIPID-BINDING PROTEINS
2-Glycoprotein I (2GPI) is the most common and well-characterized antigenic target; aPL preferentially
bind 2GPI that has immobilized on anionic phospholipid membrane.
PROTHROMBIN
(to allow proper immune recognition, must be adsorbed on suitable anionic
surface). The majority of anti-prothrombin antibodies display lupus
anticoagulant activity.
OXIDIZED LOW DENSITY LIPOPROTEIN (LDL)
The major antigenic epitopes are induced in apolipoprotein B during oxidative modification of LDL.
APS: Mechanism of disease
• Experimental studies in animals• In vitro and ex vivo studies:
a) endothelial cell
b) monocytes
c) platelets
Immunogen Area m2 Formation Disappearance Total
-2GP1 2233.7 293.3* 1.9 0.5 5.3 1.7* 7.2 1.8*
IgG-APS 1930.4 212.0* 2.2 1.1 5.4 1.6* 7.6 2.0*
HSA 1266.8 358.6 1.7 0.6 3.1 0.6 4.8 1.1
Time min
Dynamics of thrombus formation in immunized mice
Values are mean SD
* Statistically significant difference from control. Differences between the means of the 2GP1 and IgG-APS groups were not statistically significant
Pierangeli et al. Circulation 94:1746-1751; 1996.
APS: Mechanism of disease
• Experimental studies in animals
• In vitro and ex vivo studies:
a) endothelial cell b) monocytes
c) platelets
Rand et al. N Engl J Med 337:154-60, 1997
O2· OH ·
Native Cardiolipin
Monocyte
Rearrangement
Oxidised Cardiolipin
Antibodies against oxidised cardiolipin
Praticò et al. Blood 93:3401-3407, 1999
APS (Antiphospholipid syndrome)
• Definition
• Clinical manifestations:
a) venous and arterial thrombosis and foetal loss
b) bleeding disorders
• Mechanism of disease
• Management
Randomized Controlled Trials of Treatment for Recurrent Fetal Loss in Women with Antiphospholipid Antibody
Author No.A/B
Regimen A Regimen B Fetalsurvival
A
Fetalsurvival
B
Cowchock et al.12/8 Heparin 12,000 U
bid + ASA 81 mgPrednisone
40mg + ASA 81 mg
80 75*
Kutteh et al.25/25 Heparin 13,300 U
bid + ASA 81 mgASA 81 mg 80 44
Rai et al.45/45 Heparin 5,000 U
bid + ASA 81 mgASA 81 mg 70 40
Kutteh et al.25/25 Heparin 8,100 U
bid + ASA 81 mgHeparin 13,300
U bid +ASA 81 mg
76 80
Lockshin Thrombos Haemostas 82:641-648, 1999
*Marked increase in fetal and maternal morbidity compared to regimen A. ASA=acetyl salicylic acid
Khamashta MA et al. N Engl J Med 332:993-7, 1995
Pat
ien
t s F
r ee
o f T
hr o
mb
o si s
(%
)
Years
Crowther MA et al. N Engl J Med 2003
Andrè et al – Circulation. 2002
Andrè et al – Circulation. 2002
aPL-negative aPL-positive patients (n=16) patients (n=14) p
value
Age (years), Mean ± SD 35±9 39±12
n.s.
Range 18-54 20-56 n.s.
Male sex (n) (%) 2 (13) 1 (7) n.s.
Diabetes Mellitus (n) (%) 5 (31) 5 (35)
n.s.
Hypertension (n) (%) 6 (37) 5 (35)
n.s.
Smoking (n) (%) 6 (37) 4 (29)
n.s.
Platelet count / mm3 191000±52000 212000±49000
n.s.
Disease Activity: SLEDAI score
Low disease activity (n) (%) 11 (69) 10 (71)
n.s.(score 2-9)
High disease activity (n) (%) 5 (31) 4 (29)
n.s.(score _10)
Arth. Rheum. (in press)
Arth. Rheum. (in press)
Arth. Rheum. (in press)