Acknowledgements
Résumé
Abreviations
Summary
1. The antiphospholipid syndrome
1.1. Introduction
1.2. Antigens and antibodies in the antiphospholipid syndrome
1.2.1. Antigens
A) Phospholipids (PL)
B) Proteins
Beta
2
glycoprotein I (
b
2
GPI)
Vitamin K-dependent proteins
Annexins
Other proteins
1.2.2. Antibodies
A) Immunoglobulin classes
1.3. Laboratory detection of apla
1.3.1. History
1.3.2. Laboratory criteria for APS
1.3.3. Immunologic assays for ACA
1.3.4. Coagulation assays for LA
A) Screening assays for LA (Table 2)
B) Mixing studies for LA
C) Confirmatory assays for LA
1.3.5. Indications for laboratory testing
1.4. Clinical manifestations of antiphospholipid syndrome
1.4.1. Clinical relevance of APLA
A) APLA in healthy population
B) APLA in patients with no thrombosis or pregnancy morbidity, but with infections, drugs, auto-immune disorders
C) APLA in patients with thrombosis and/or pregnancy morbidity / primary APS /
1.4.2. Clinical criteria for APS
A) Vascular thrombosis
Venous thrombosis
Arterial thrombosis
Thrombotic complications associated with APLA
B) Pregnancy morbidity
1.4.3. Other manifestation of APS
A) Thrombocytopenia
B) Atherosclerosis
C) Catastrophic APS
1.5. Pathogenesis of the antiphospolipid syndrome
1.5.1. Effects of APLA on the cells involved in hemostasis
A) Endothelial cells
Resting EC
Resting EC are mainly antithrombotic and thus thanks to different mechanisms. The main molecules are indicated in Table 7 (next page).
Activated EC
Endothelial activation leads to loss of anticoagulant properties (Table 7) and is characterised by several modifications.
B) Platelets
C) Monocytes
D) Polymorphonuclear cells
1.5.2. Effects of APLA on coagulation
A) Interference of APLA with the components of the protein C/S pathway
B) Impairment of fibrinolysis by APLA
C) Additional effects of APLA
1.5.3. Potential mechanisms involved in APLA-associated foetal loss
1.6. Management of the antiphospholipid syndrome
1.6.1. Treatment and prevention of venous thromboembolism
1.6.2. Treatment and prevention of arterial thrombosis
1.6.3. Prevention of pregnancy failure
A) Primary thromboprophylaxis in case of APLA
B) Thromboprophylaxis with statins in case of APLA
2. Statins and antiphospholipid syndrome
2.1. Introduction
2.2. Pharmacological properties of statins
2.2.1. Origin and chemistry
2.2.2. Solubility and protein binding
2.3. Stucture and chemical interactions of statins with HMG-CoA reductase
2.4. Mechanism of actions and effects of statins
2.4.1. Inhibition of cholesterol synthesis
2.4.2. Statins and isoprenylated proteins
A) Pleiotropic effects of statins on vascular cells
B) Pleiotropic effects of statins on extravascular system
2.4.3. Other effects of statins
A) Inhibition of dolichol synthesis
B) Activation of protein kinase Akt
C) Regulation of caveolin
D) Statins and HMG-CoA independent effects
3. Experimental work
3.1. Patients and methods
3.1.1. Patients
3.1.2. Reagents
3.1.3. Cell cultures
A) Human umbilical vascular endothelial cells (HUVEC)
B) Human saphenous vein cells (HSVEC)
3.1.4. Methods
A) Purification of patient IgG
B) Analysis of adhesion molecule expression on EC by flow cytometry (FACS)
C) Cell Enzyme Linked Immunosorbent Assay (ELISA)
D) Statistical analysis
3.2. Results
3.2.1. Induction of E-selectin and VCAM-1 expression by IgG from patients with APS
3.2.2. Effect of statins on the expression of E-selectin and VCAM-1 on EC
A) Effect of statins on TNF-
a
activated EC
a1) Simvastatin effect on HUVEC
a2) Simvastatin effect on saphenous vein EC
b) Fluvastatin effect on EC
c) Pravastatin effect on EC
B) Effect of statins on bacterial lipopolysaccharide activated EC
C) Effect of statins on APLA activated EC
3.2.3. The effect of statins on adhesion molecule expression is reversed by isoprenoid intermediates
3.2.4. Inhibition of protein geranylgeranylation, but not protein farnesylation mimicks the effect of statins
4. Discussion and conclusion