In this review we will discuss the possible interference of antiphospholipid antibodies with the protein C system. Antiphospholipid antibodies can interfere with the protein C system in different ways: (i) via inhibiting the formation of thrombin; (ii) via interference with the activation of protein C by the thrombomodulin-thrombin complex; (iii) via inhibition of the assembly of the protein C complex; (iv) via inhibition of the activity of protein C, directly or via its cofactor protein S, and (v) via antibodies directed against the substrates of APC, factors Va and VIIIa, thereby protecting them for inactivation. The experimental and theoretical indications that one of these mechanisms will explain the pathogenesis of the antiphospholipid syndrome is critically examined.
LovePESantoroSA. Antiphospholipid antibodies: Anticardiolipin and the Lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Ann. Intern. Med1990; 112: 682–698
2.
De GrootPhGOostingJDDerksenRHWM. Antiphospholipid antibodies: specificity and pathophysiology. Baillière's Clin Haematol1993; 6: 691–709
3.
RoubeyRAS. Autoantibodies to phospholipid-binding plasma proteins: A new view of lupus anticoagulants and other ‘antiphospholipid’ autoantibodies. Blood1994; 84: 2854–2867
4.
McNeilHPSimpsonRJChestermanCNKrelisSA. Antiphospholipid antibodies are directed against a complex antigen that includes a lipid binding inhibitor of coagulation: β2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA1990; 87: 4120–4124
5.
GalliMAnticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet1990; 335: 1544–1547
6.
OostingJDLupus anticoagulant activity is frequently dependent on the presence of β2-glycoprotein I. Thromb Haemostas1992; 67: 499–502
7.
BeversEM (1991) Lupus anticoagulant IgG's (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemostas 1991; 66: 629–632
8.
OostingJDAntiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C or protein S—An explanation for their pathogenic mechanism?. Blood1993; 81: 2618–2625
9.
AmiralJLarrivazICluzeauDAdamM. Standardization of immunoassays for antiphospholipid antibodies with β2GPI and the role of other phospholipid cofactors. Haemostasis1994; 24: 191–203
10.
de GrootPhGDerksenRHWM. Protein C pathway, antiphospholipid antibodies and thrombosis. Lupus1994; 3: 229–233
11.
EsmonCTOwenWG. Identification of an endothelial cell cofactor for thrombin-catalysed activation of protein C. Proc Natl Acad Sci USA1981; 78: 2249–2252
12.
DahlbäckB. The protein C anticoagulant system: Inherited defects as basis for venous thrombosis. Thromb Res1995; 77: 1–43
13.
IshiiHMajerusPW. Thrombomodulin is present in human plasma and urine. J Clin Invest1985; 76: 2178
14.
FreyssinetJMGauchyJCazenaveJP. The effect of phospholipids on the activation of protein C by human thrombin-thrombimodulin complex. Biochem J1986; 238: 151–157
15.
MitchellCAKelemanSMSalemHH. The anticoagulant properties of a modified form of protein S. Thromb Haemostas1988; 60: 298–304
16.
HeebMJBinding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C. J Biol Chem1993; 268: 2872–2877
17.
HansonSRAntithrombotic effects of thrombin-induced activation of endogenous protein C in primates. J Clin Invest1993; 92: 2003–2012
18.
CompPCdeBaultLEEsmonNLEsmonCT. Human thrombomodulin is inhibited by IgG from two patients with non specific anticoagulants. Blood1983; 62: 299 (abstract)
19.
FreyssinetJMAn IgM lupus anticoagulant that neutralizes the enhancing effect of phospholipids on purified endothelial thrombomodulin activity. A mechanism for thrombosis. Thromb Haemostas1986; 55: 309–313
20.
CariouREffect of lupus anticoagulant on antithrombotic properties of endothelial cells. Inhibition of thrombomodulin-dependent protein C activation. Thromb Haemostas1988; 60: 54–58
21.
OostingJDIn vitro studies of antiphospholipid antibodies and its cofactor, β2-glycoprotein I, show negligible effects on endothelial cell mediated protein C activation. Thromb Haemostas1991; 66: 666–671
22.
WatsonKVSchorerAE. Lupus anticoagulant inhibition of in vitro prostacyclin release is associated with a thrombosis-prone subset of patients. Am J Med1991; 90: 47–53
23.
KeelingDMRole of β2-glycoprotein I and anti-phospholipid antibodies in activation of protein Cin vitro. J Clin Pathol1993; 46: 908–911
24.
PötzschBAcquired protein C dysfunction but not decreased activity of thrombomodulin is a possible marker of thrombophilia in patients with lupus anticoagulant. J Lab Clin Med1995; 125: 56–65
25.
TsakirisDASettasLMakrisPEMarbetGA. Lupus anticoagulant-antiphospholipid antibodies and thrombophilia. Relation to protein C-protein S-thrombomodulin. J Rheumatol1990; 17: 785–789
26.
OostingJDPreissnerKTDerksenRHWMde GrootPHG. Autoantibodies directed against the epidermal growth factor-like domains of thrombomodulin inhibit protein C activationin vitro. Br J Haematol1993; 85: 761–768
27.
GibsonJAutoantibodies to thrombomodulin: development of an enzyme immunoassay and a survey of their frequency in patients with the lupus anticoagulant. Thromb Haemostas1992; 67: 507–509
28.
Ruiz-ArgüellesVázquez-PradoJTenorio-MendozaC. Demonstration de anticuerpos naturales antifosfolipido con reactividadanti-idiotipo de anticuerpos xenogenicos dirigidos contra la proteina C humana de la coagulation. Revista Mexicana de Rheumatologia1989; 4: 4
29.
KawakamiMPlasma thrombomodulin and α2-plasmin inhibitor-plasmin complex are elevated in active systemic lupus erythematosus. J Rheumatol1992; 19: 1704–1709
30.
TakayaMSerum thrombomodulin and anticardiolipin antibodies in patients with systemic lupus erythematosus. Clin Exp Rheumatol1991; 9: 495–499
31.
SmimovMDEsmonCT. Phosphatidylethanolamine incorporated into vesicles selectively enhances factor Va inactivation by activated protein C. J Biol Chem1994; 269: 816–819
32.
SmimovMDOn the role of phosphatidylethanolamine in the inhibition of activated protein C activity by antiphospholipid antibodies. J Clin Invest1995; 95: 309–316
33.
MoriTβ2-Glycoprotein I modulates the anticoagulant activity of activated protein C on the phospholipid surface. Thromb Haemostas1996; 75: 49–55
34.
KitchenSMaliaRGPrestonFE. Inhibition of protein S cofactor activity by antiphospholipid antibodies. Br J Haematol1989; 71: 3
35.
MarciniakERomondEH. Impaired catalytic function of activated protein C: a new in vitro manifestation of lupus anticoagulant. Blood1989; 74: 2426–2432
36.
LoSCStudies on the natural anticoagulant proteins and anticardiolipin antibodies in patients with the lupus anticoagulant. Br J Haemotol1990; 76: 380–86
37.
MaliaRGKitchenSGreavesMPrestonFE. Inhibition of activated protein C and its cofactor S by antiphospholipid antibodies. Br J Haematol1990; 76: 101–107
38.
BorrellMImmunoglobulin fractions isolated from patients with antiphospholipid antibodies prevent the inactivation of factor Va by activated protein C on human endothelial cells. Thromb Haemostas1992; 68: 268–272
39.
AmerLKisielWSearlesRPWilliams RCJr. Impairment of the protein C anticoagulant pathway in a patient with systemic lupus erythematosus, anticardiolipin antibodies and thrombosis. Thromb Res1990; 57: 247–258
40.
Manco-JohnsonMJHypercoaglability associated with lupus anticoagulant in childeren. Thromb Haemostas1995; 73: 1264
41.
MatsudaJResistance to activated protein C activity of an anti-β2-glycoprotein I antibody in the presence of β2-gIycoprotein I. Brit J Haematol1995; 90: 204–206
42.
SthoegerZMTransient anticardiolipin antibodies, functional protein S deficiency and deep vein thrombosis. Am J Hematol1991; 36: 206–207
43.
HarrisonRLAlperinJB. Concurrent protein C deficiency and lupus anticoagulant. Am J Haematol1992; 40: 33–37
44.
SimioniPLazzaroAZanardiSGirolamiA. Letter to the editor Spurious protein C deficiency due to antiphospholipid antibodies. Am J Hematol1991; 36: 299–300
45.
StankiewiczAISteinerMLallyEVKaplanSRAbnormally high levels of C4b binding protein and deficiency of free fraction of protein S in a patient with systemic lupus erythematosus and recurrent thrombosis. J Rheumatol1991; 18: 82–87
46.
Ruiz-ArguellesGJNatural anticoagulants in systemic lupus erythematosus. Deficiencies of protein S bound to C4bp associated with recent history of venous thrombosis, antiphospholipid antibodies and the antiphospholipid syndrome. J Rheumatol1991; 18: 552–558
47.
ParkeALThe thrombotic diathesis associated with the presence of phospholipid antibodies may be due to low levels of free protein S. Am J Med1992; 93: 49–56
48.
Ruiz-ArguellesAPresence of serum antibodies to coagulation protein C in patients with systemic lupus erythematosis is not associated with antigenic or functional protein C deficiencies. Am J Haematol1993; 85: 761–768
49.
HasselaarPRisk factors for thrombosis in lupus patients. Ann Rheum Dis1989; 48: 933–940
50.
HorbachDALupus anticoagulant is the strongest independent risk factor for thrombosis in patients with systemic lupus erythematosis. 1996; Thromb Haemostas 1996; dec issue
51.
RandJHReduction of annexin V (placental anticoagulant protein-I) on placental villi of woman with antiphospholipid antibodies and recurrent spontaneous abortion. Am J Obstet Gynecol1994; 171: 1566–1572
52.
van HeerdeWLAnnexin V is highly abundant in cells which possess a barrier function between blood and tissue and circulates in plasmas of patients with systemic lupus erythematosus. Thromb Haemostas1995; 73: 1265
