An IgM Lupus Anticoagulant that Neutralizes the Enhancing Effect of Phospholipid on Purified Endothelial Thrombomodulin Activity-A Mechanism for Thrombosis

Freyssinet, J M; Wiesel, Marie-Louise; Gauchy, J; Boneu, B; Cazenave, J. P.

doi:10.1055/s-0038-1661553

Cited by 135 publications

(55 citation statements)

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“…In these latter studies it was emphasized that the 4-carboxyglutamic acid domain was essential for activation by the thrombin-thrombomodulin complex, suggesting that interaction of the substrate with membrane is an essential prerequisite of the activation process. This was corroborated by the observation that an IgM lupus anticoagulant, with specificity directed towards anionic phospholipids, was able to neutralize the enhancing effect of phospholipids on purified thrombomodulin activity (Freyssinet et al, 1986b).…”

Section: Introductionmentioning

confidence: 64%

“…But in this case one would expect a competitive inhibition between protein C and fragment 1 for binding to phospholipids. In another study it was noticed that treatment of purified thrombomodulin with phospholipase C had no influence on its cofactor activity (Freyssinet et al, 1986b). Self-association of prothrombin fragment 1 and the formation of heterodimers between the vitamin K-dependent proteins (Harlos et al, 1987) have been recently demonstrated.…”

Section: Discussionmentioning

confidence: 99%

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Interference of blood-coagulation vitamin K-dependent proteins in the activation of human protein C. Involvement of the 4-carboxyglutamic acid domain in two distinct interactions with the thrombin-thrombomodulin complex and with phospholipids

Freyssinet

Beretz

Klein-Soyer

et al. 1988

Biochemical Journal

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Human protein C is the precursor of a serine proteinase in plasma which contains nine 4-carboxyglutamic acid residues and functions as a potent anticoagulant. It is activated by thrombin in the presence of an essential endothelial-cell-membrane glycoprotein cofactor, thrombomodulin. In a purified human system, vitamin K-dependent proteins such as factor X, prothrombin and prothrombin fragment 1 were able to inhibit protein C activation by the thrombin-thrombomodulin complex, using either detergent-solubilized thrombomodulin or thrombomodulin reconstituted into vesicles consisting of phosphatidylcholine and phosphatidylserine (1:1, w/w). Factors VII and IX and protein S were much less efficient. Prothrombin fragment 1 behaved as a non-competitive inhibitor with apparent K1 values of 4 /tM in the absence, and of 2-2.5 ,LM in the presence, of phospholipids. Heat decarboxylation of fragment 1 abolished its ability to interfere in protein C activation, and high phospholipid concentrations could attenuate its inhibitory effect and were responsible for a gradual loss of the non-competitive character. Fragment 1 also inhibited the activation of 4-carboxyglutamic acid-domainless protein C, a proteolytic derivative of protein C lacking the 4-carboxyglutamic acid residues, without any influence from phospholipids. At high thrombin concentrations, with respect to thrombomodulin, the inhibitory effect of fragment 1 was diminished. Fragment 1, at 3.8 /LM, inhibited by 50 % the activation of protein C (0.1 or 0.3 4aM) by thrombin. These results suggest that the 4-carboxyglutamic acid domain of vitamin K-dependent proteins can act as a modulator of the protein C anticoagulant pathway through two distinct types of interaction. The functional 4-carboxyglutamic acid domain would be necessary to allow the enhancement of protein C activation in the presence of anionic phospholipids and it could recognize a phospholipid-independent binding site on the thrombin-thrombomodulin complex.

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Section: Introductionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Interference of blood-coagulation vitamin K-dependent proteins in the activation of human protein C. Involvement of the 4-carboxyglutamic acid domain in two distinct interactions with the thrombin-thrombomodulin complex and with phospholipids

Freyssinet

Beretz

Klein-Soyer

et al. 1988

Biochemical Journal

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“…The first stage of the reaction, which contained 20 MI TBSG (TBS containing 1 mg/ml gelatin, pH 7.4), 10 TBS by centrifugation (8000 g, 1 min); resuspended in 50 1l TBS containing 5 mM CaCl2; mixed with 100 MI liposomes (1 mg/ml of total phospholipid in TBS); incubated 2 h on an orbital shaker at 370C; pelleted by centrifugation; washed two times with 1 ml of TBS; resuspended in 1 ml TBS containing 1 mg/ml gelatin, 1 mg/ml ovalbumin, and 10 mg/ml BSA; incubated 2 h at room temperature on a shaker; washed two times with 1 ml TBS; and resuspended in 500 IL TBS.`4C-PC incorporated into the liposomes was used to calculate the concentration of adsorbed liposomes. The phospholipid concentration in the final suspension was 50 pg/ml for both PS/PC and PE/PS/PC adsorbed liposomes.…”

Section: Thrombin Formation In Plasmamentioning

confidence: 99%

“…Indeed, both protein C activation (8)(9)(10) and activated protein C (APC)' anticoagulant activity (7,(11)(12)(13) have been shown to be partially inhibited by the lupus anticoagulants. Although antibodies to protein components of the pathway contribute in a small number of patients (see for instance reference 14), most patients appear to exhibit these protein C pathway inhibitory activities only in the presence of a membrane surface.…”

Section: Introductionmentioning

confidence: 99%

On the role of phosphatidylethanolamine in the inhibition of activated protein C activity by antiphospholipid antibodies.

et al. 1995

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Phosphatidylethanolamine (PE) is an important membrane component for supporting activated protein C anticoagulant activity but has little influence on prothrombin activation. This difference constitutes a potential mechanism for selective inhibition of the protein C anticoagulant pathway by lupus anticoagulants and/or antiphospholipid antibodies. In this study, we demonstrate that the presence of PE augments lupus anticoagulant activity. In the plasma of some patients with lupus anticoagulants, activated protein C anticoagulant activity is more potently inhibited than prothrombin activation. As a result, in the presence of activated protein C and PE, these patient plasmas clot faster than normal plasma. Patients with minimal lupus anticoagulant activity are identified whose plasma potently inhibits activated protein C anticoagulant activity. This process is also PE dependent. In three patient plasmas, these phenomena are shown to be due to immunoglobulins. The PE requirement in the expression of activated protein C anticoagulant activity and the PE dependence of some antiphospholipid antibodies provide a mechanistic basis for the selective inhibition of the protein C pathway. Inhibition of activated protein C function may be a common mechanism contributing to increased thrombotic risk in certain patients with antiphospholipid antibodies. (J. Clin. Invest. 1995. 95:309-316.)

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“…Proposed mechanisms include: direct endothelial damage [30]; inhibition of prostacyclin, and enhanced thromboxane A 2 production [31,32] and inhibition of endogenous anticoagulants such as thrombomodulin [33], protein C [34] and antithrombin III [35].…”

Section: Discussionmentioning

confidence: 99%

Anticardiolipin Antibodies in South African Patients with Lupus Nephritis: A Clinical and Renal Pathological Study

Naiker¹,

Rughubar²,

Duursma³

et al. 2000

Am J Nephrol

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Aims: This study was conducted prospectively to ascertain the prevalence of anticardiolipin antibodies (ACAs) in patients with lupus nephritis and to determine whether this subgroup of patients differed clinically and histologically from patients without the antibody. Patients and Methods: 40 SLE patients (26 Blacks, 14 Indians, 37 females, 3 males) with evidence of renal involvement underwent clinical assessment and percutaneous renal biopsy. Special investigations included: urinary protein quantitation; radioisotope glomerular filtration rate (GFR); complement levels, and antinuclear antibodies and ACAs. Histology was reviewed by a single senior pathologist blinded to the ACA results. In addition to the standard WHO classification, specimens were examined for intrarenal thrombosis. Results: The prevalence of ACA was 45% (18 of 40 patients). Thrombocytopenia was more frequent in patients with ACA (33 vs. 13.6%, p = 0.015). Patients with ACA did not differ from controls with regard to the incidence of thrombosis, neurological disorders, recurrent fetal loss, active disease and hypertension. Mean GFR and 24-hour urine protein (ACA vs. controls) were 51.3 versus 67 ml/min (NS) and 2.4 versus 3.7 g (NS), respectively. Intrarenal microvascular thrombosis (glomerular and arteriolar) occurred in 27.7% of ACA patients versus 9% of controls (p = 0.025). Apart from a higher incidence of class-III nephritis in the controls, standard histology (WHO classification) did not differ between the 2 groups. Conclusion: The prevalence of ACA in our patients with lupus nephritis was 45%. This subgroup did not differ from patients without the antibody apart from a higher incidence of thrombocytopenia and intrarenal microvascular thrombosis.

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An IgM Lupus Anticoagulant that Neutralizes the Enhancing Effect of Phospholipid on Purified Endothelial Thrombomodulin Activity-A Mechanism for Thrombosis

Cited by 135 publications

References 10 publications

Interference of blood-coagulation vitamin K-dependent proteins in the activation of human protein C. Involvement of the 4-carboxyglutamic acid domain in two distinct interactions with the thrombin-thrombomodulin complex and with phospholipids

Interference of blood-coagulation vitamin K-dependent proteins in the activation of human protein C. Involvement of the 4-carboxyglutamic acid domain in two distinct interactions with the thrombin-thrombomodulin complex and with phospholipids

On the role of phosphatidylethanolamine in the inhibition of activated protein C activity by antiphospholipid antibodies.

Anticardiolipin Antibodies in South African Patients with Lupus Nephritis: A Clinical and Renal Pathological Study

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