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C T Esmon

Publications and source records attributed to C T Esmon.

At least 145 records · Page 8Linked to original sources
PubMed1990

Complement proteins C5b-9 induce vesiculation of the endothelial plasma membrane and expose catalytic surface for assembly of the prothrombinase enzyme complex.

Assembly of the terminal complement proteins C5b-9 on human endothelial cells results in increased cytosolic calcium and nonlytic secretion of high molecular weight multimers of von Willebrand factor from intracellular storage granules. We now demonstrate that this C5b-9-induced secretory response is accompanied by vesiculation of membrane particles from the endothelial surface which express binding sites for factor Va and support prothrombinase activity. Exposure of factor Va binding sites after C5b-9 assembly was accompanied by greater than 2-fold increase in prothrombinase activity, which was not observed for cells exposed to C5b-8 (in the absence of C9). By contrast, only a 3-16% increase in prothrombinase activity was observed when these cells were maximally stimulated to secrete by either histamine, thrombin, or the Ca2+ ionophore A23187. Increased prothrombinase activity after C5b-9 was not accompanied by a change in thrombomodulin activity, and was unrelated to cell lysis, the complement-treated cells remaining greater than 99% viable. Endothelial prothrombinase activity was predominately associated with small membrane vesicles (less than 1 microns diameter) released from the cell monolayer. Analysis by fluorescence-gated flow cytometry revealed that these vesicles incorporate the C5b-9 proteins and express binding sites for factor Va. The capacity of the C5b-9 proteins to induce vesiculation of the endothelial plasma membrane and thereby expose catalytic surface for the prothrombinase enzyme complex may contribute to fibrin deposition associated with immune endothelial injury.

Calcimycin↗
PubMed1990

Recombinant human protein C derivatives: altered response to calcium resulting in enhanced activation by thrombin.

Calcium plays a dual role in the activation of protein C: it inhibits protein C activation by alpha-thrombin, whereas it is required for protein C activation by the thrombomodulin-thrombin complex. Available information suggests that these calcium effects are mediated through calcium induced structural changes in protein C. In this paper, we demonstrate that substitution of Asp167 (located in the activation peptide of human protein C, occupying position P3 relative to the peptide bond Arg169-Leu170 which is susceptible to hydrolysis by thrombin) by either Gly or Phe results in protein C derivatives which are characterized by an altered response to calcium. At 3 mM calcium, alpha-thrombin activated the derivatives 5- to 8-fold faster compared with the wild-type, an effect which was shown to be caused by a decreased inhibitory effect of calcium on the reaction. These same single amino acid substitutions enhanced the affinity of the thrombomodulin-thrombin complex for the substrate at 3 mM calcium 3-(Gly-substitution) to 6-(Phe-substitution) fold, either without influencing kcat (Gly-substitution) or with a 2.5-fold decrease of kcat. For both derivatives, the calcium concentrations resulting in half maximal inhibition of activation by alpha-thrombin and in half maximal stimulation of activation by the thrombomodulin-thrombin complex increased from 0.3 mM to 0.6 mM. It is concluded that Asp167 is involved in the calcium induced inhibition of protein C activation by thrombin. Moreover, our studies demonstrate that it is feasible to enhance the efficiency of enzymatic reactions by introducing point mutations in the substrate.

Amino Acid Sequence↗
PubMed1990

Infection of vascular endothelial cells with herpes simplex virus enhances tissue factor activity and reduces thrombomodulin expression.

Latent infection of vascular cells with herpes-viruses may play a pathogenic role in the development of human atherosclerosis. In a previous study, we found that cultured human umbilical vein endothelial cells (HUVECs) infected with herpes simplex virus 1 (HSV-1) became procoagulant, exemplified both by their enhanced assembly of the prothrombinase complex and by their inability to reduce adhesion of platelets. We now report two further procoagulant consequences of endothelial HSV infection: loss of surface thrombomodulin (TM) activity and induction of synthesis of tissue factor. Within 4 hr of infection of HUVECs, TM activity measured by thrombin-dependent protein C activation declined 21 +/- 3% (P less than 0.05) and by 18 hr, 48 +/- 5% (P less than 0.001). Similar significant TM decrements accompanied infection of bovine aortic endothelial cells. Identical TM loss was induced with HSV-2 infection but not with adenovirus infection. Decreased surface expression of TM antigen (measured by the specific binding of a polyclonal antibody to bovine TM) closely paralleled the loss of TM activity. As examined by Northern blotting, these losses apparently reflected rapid onset (within 4 hr of HSV infection) loss of mRNA for TM. In contrast, HSV infection induced a viral-dose-dependent increase in synthesis of tissue factor protein, adding to the procoagulant state. The results indicate that loss of endothelial protein-synthetic capacity is not a universal effect of HSV infection. We suggest that the procoagulant state induced by reduction in TM activity and amplified tissue factor activity accompanying HSV infection of endothelium could contribute to deposition of thrombi on atherosclerotic plaques and to the "coagulant-necrosis" state that characterizes HSV-infected mucocutaneous lesions.

Cell Transformation, Viral↗
PubMed1989

Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane. Studies in Scott syndrome: an isolated defect in platelet procoagulant activity.

Activation of human platelets by complement proteins C5b-9 is accompanied by the release of small plasma membrane vesicles (microparticles) that are highly enriched in binding sites for coagulation factor Va and exhibit prothrombinase activity. We have now examined whether assembly of the prothrombinase enzyme complex (factors VaXa) is directly linked to the process of microparticle formation. Gel-filtered platelets were incubated without stirring with various agonists at 37 degrees C, and the functional expression of cell surface receptors on platelets and on shed microparticles was analyzed using specific monoclonal antibodies and fluorescence-gated flow cytometry. In addition to the C5b-9 proteins, thrombin, collagen, and the calcium ionophore A23187 were each found to induce formation of platelet microparticles that incorporated plasma membrane glycoproteins GP Ib, IIb, and IIIa. These microparticles were enriched in binding sites for factor Va, and their formation paralleled the expression of catalytic surface for the prothrombinase enzyme complex. Little or no microparticle release or prothrombinase activity were observed when platelets were stimulated with epinephrine and ADP, despite exposure of platelet fibrinogen receptors by these agonists. When platelets were exposed to thrombin plus collagen, the shed microparticles contained activated GP IIb-IIIa complexes that bound fibrinogen. By contrast, GP IIb-IIIa incorporated into C5b-9 induced microparticles did not express fibrinogen receptor function. Platelets from a patient with an isolated defect in inducible procoagulant activity (Scott syndrome) were found to be markedly impaired in their capacity to generate microparticles in response to all platelet activators, and this was accompanied by a comparable decrease in the number and function of inducible factor Va receptors. Taken together, these data indicate that the exposure of the platelet factor Va receptor is directly coupled to plasma membrane vesiculation and that this event can be dissociated from other activation-dependent platelet responses. Since a catalytic membrane surface is required for optimal thrombin generation, platelet microparticle formation may play a role in the normal hemostatic response to vascular injury.

Antibodies, Monoclonal↗
PubMed1989

The active site of the thrombin-thrombomodulin complex. A fluorescence energy transfer measurement of its distance above the membrane surface.

The location of the active site of the membrane-bound anticoagulant complex of thrombin and thrombomodulin has been determined relative to the membrane surface using fluorescence energy transfer. Thrombin was reacted with 5-(dimethylamino)-1-naphthalenesulfonylglutamylglycylarginyl chloromethyl ketone (DEGR-CK) to yield DEGR-thrombin, an analogue of thrombin with a fluorescent dye covalently attached to its active site. When DEGR-thrombin was titrated with thrombomodulin that had been reconstituted into phospholipid vesicles containing octadecylrhodamine, singlet-singlet energy transfer was observed between the donor dyes, each in an active site of a DEGR-thrombin bound to thrombomodulin, and the acceptor dyes at the outer surface of the phospholipid bilayer. The extent of energy transfer reached a maximum when DEGR-thrombin and thrombomodulin were equimolar in the sample, as expected for the formation of a 1:1 complex between thrombin and thrombomodulin. This energy transfer was dependent upon the binding of DEGR-thrombin to thrombomodulin because no energy transfer was observed with vesicles that lacked thrombomodulin, and the extent of energy transfer was reduced greatly by the addition of excess unmodified nonfluorescent thrombin to compete with DEGR-thrombin for binding to the thrombomodulin. From the dependence of the energy transfer upon the acceptor density and assuming kappa 2 = 2/3, the distance of closest approach between a dye in the active site of the thrombin-thrombomodulin complex and a dye at the membrane surface was determined to average 66 A (65 +/- 3 A for phosphatidylcholine vesicles without and 67 +/- 5 A for those with 20% phosphatidylserine). This distance was also insensitive to the presence or absence of Ca2+. These direct measurements indicate that the active site of the membrane-bound thrombin-thrombomodulin complex is located far above the phospholipid surface, that the peptide bond cleaved during the activation of protein C is situated about 66 A above the membrane, that the thrombin binding site on thrombomodulin is positioned more than 45 A above the membrane, ant that thrombin, with a diameter near 40 A, is not positioned alongside thrombomodulin near the membrane to form the thrombin-thrombomodulin complex but is instead bound "on top" of thrombomodulin.

Amino Acid Chloromethyl Ketones↗
PubMed1989

Ca2+-dependent structural changes in bovine blood coagulation factor Va and its subunits.

The calcium dependence of the structures of bovine blood coagulation factor Va and its subunits (Vh and Vl) has been examined spectroscopically in order to characterize the conformational changes which accompany the binding of Ca2+ to Vh and Vl to form factor Va. The far-UV CD spectra of the isolated subunits indicate that the secondary structures of both Vh and Vl are predominantly beta-sheet (greater than 45%), with little alpha-helix content (less than 15%). No change in the far-UV CD spectrum was observed when factor Va was formed by the addition of Ca2+ to an equimolar mixture of Vl and Vh. Hence, no detectable change in secondary structure occurs during the formation of factor Va. In contrast, the addition of Ca2+ to an equimolar mixture of Vh and Vl caused a small (2%) increase in the total intrinsic fluorescence intensity and a blue shift in the emission spectrum that resulted from a tertiary structural change and/or the association of nonpolar surfaces at the subunit interface. This fluorescence change correlated closely with the appearance of functional factor Va, since the rate of the spectral change was the same as the rate of recovery of cofactor activity, and since both were half-maximal near 50 microM Ca2+. This fluorescence change required both subunits, was reversed by the addition of EDTA, and was observed only with metal ions that can substitute for Ca2+ in reconstituting factor Va activity from Vh and Vl (Mn2+ and Tb3+; not Mg2+). When a sample containing ANS (8-anilino-1-naphthalenesulfonate) and an equimolar mixture of calcium-free Vh and Vl was titrated with Ca2+, the ANS emission intensity decreased by about 30%, most likely because the association of Vl and Vh caused nonpolar regions at the subunit-subunit interface to become inaccessible for ANS binding. The calcium dependence of this spectral change yielded a Kd of 51 +/- 2 microM, and the rate of the decrease in ANS fluorescence occurred at nearly the same rate as the recovery of factor Va activity. Thus, both intrinsic and extrinsic fluorescence data, as well as other data, indicate that the calcium binding site in factor Va has an apparent Kd of 50 microM under our conditions and that the calcium-mediated binding between Vl and Vh involves hydrophobic interactions between the subunits.(ABSTRACT TRUNCATED AT 400 WORDS)

Anilino Naphthalenesulfonates↗
PubMed1989

Interaction of clotting factor V heavy chain with prothrombin and prethrombin 1 and role of activated protein C in regulating this interaction: analysis by analytical ultracentrifugation.

Changes in the affinity of the heavy subunit of blood coagulation factor Va (Vh) for prothrombin are thought to be important in regulating the rate of thrombin production. Using analytical ultracentrifugation, we have measured the affinity of bovine Vh for prothrombin and for the prethrombin 1 fragment of prothrombin at 23.3 degrees C, pH 7.65, in 50 mM tris(hydroxymethyl)aminomethane, 0.1 M NaCl, 0.1 mM benzamidine, and either 2 mM Ca2+ or 2 mM ethylenediaminetetraacetate (EDTA). Under these conditions a 1:1 complex of Vh with prothrombin is formed that is governed by a dissociation constant (Kd) of 10 microM, regardless of whether the buffer contains Ca2+ or EDTA. An identical Kd is observed when prethrombin 1 is substituted for prothrombin. This indicates that the fragment 1 portion of prothrombin, containing the gamma-carboxyglutamic acid residues, does not influence the association. Substitution of human prethrombin 1 for the bovine molecule also results in a 1:1 Vh-prethrombin 1 complex governed by a slightly weaker Kd (27 microM). Discrete proteolysis of bovine Vh by the anticoagulant activated protein C converts the Vh to a form with little or no affinity for prethrombin 1 (Kd greater than 1 mM), without detectable change in the mass of the Vh.

Animals↗
PubMed1989

Microthrombomodulin. Residues 310-486 from the epidermal growth factor precursor homology domain of thrombomodulin will accelerate protein C activation.

Thrombomodulin is the endothelial cell cofactor for thrombin-catalyzed activation of protein C. Recently, we isolated a 10-kDa thrombin binding fragment, CB3, from the epidermal growth factor precursor homology domain (epidermal growth factor (EGF)-like regions) of thrombomodulin (Kurasawa, S., Stearns, D. J., Jackson, K.W., and Esmon, C.T. (1988) J. Biol. Chem. 263, 5993-5996). The CB3 fragment did not, however, support protein C activation. A 29-kDa fragment, called CB23, has now been isolated and corresponds to residues 310-486 in the EGF-like region of thrombomodulin. The CB23 fragment bound thrombin and accelerated thrombin-catalyzed protein C activation. With two separate preparations of CB23, the Km for protein C was 1.6 and 1.9 microM and the Kd for thrombin was 8.9 and 13.2 nM. The carboxyl terminus of CB23 and CB3 was identified by isolation and sequence analysis of a tryptic peptide from CB3. The sequence of this peptide corresponded to Asn457-Ser486, indicating that the carboxyl terminus of these fragments is 6 residues beyond the sixth EGF-like region of thrombomodulin. In addition, although CB3 cannot accelerate protein C activation, CB3 did inhibit the rate of thrombin-catalyzed fibrinopeptide release from fibrinogen. Thus, like native thrombomodulin, CB3 will alter thrombin's substrate specificity, but protein C activation requires additional information all of which can be provided by other regions of the EGF-like domain.

Amino Acid Sequence↗
PubMed1989

The molecular weight and oligomerization of rabbit thrombomodulin as assessed by sedimentation equilibrium.

Lubrol-solubilized rabbit thrombomodulin has been examined by equilibrium sedimentation in buffers that include sufficient D2O to make the detergent neutrally buoyant. Data were acquired at rotor speeds from 12,000 to 28,000 rpm from two thrombomodulin preparations, at protein concentrations from 0.01 to 0.07%, and in buffer containing 0.01 to 0.23% Lubrol. Examination of the data from different rotor speeds shows that the thrombomodulin exists as a heterogeneous mixture containing monomer (Mr 65,000), trimer, and higher oligomers. The oligomers do not equilibrate over the time scale of the experiment. The weight fraction as monomer varies from preparation to preparation, and appears to be independent of detergent concentration. Thus, experimenters should be cautious when interpreting binding or kinetic results obtained under similar buffer conditions.

Animals↗
PubMed1989

Unfractionated heparin inhibits thrombin-catalysed amplification reactions of coagulation more efficiently than those catalysed by factor Xa.

We have proposed previously that the steps in coagulation most sensitive to inhibition by heparin are the thrombin-dependent amplification reactions, and that prothrombinase is formed in heparinized plasma only after Factor Xa activates Factor VIII and Factor V. These propositions were based on the demonstration that both heparin and Phe-Pro-Arg-CH2Cl completely inhibited 125I-prothrombin activation for up to 60 s when contact-activated plasma (CAP) was replenished with Ca2+. Furthermore, the addition of thrombin to CAP before heparin or Phe-Pro-Arg-CH2Cl completely reversed their inhibitory effects. Additional support for the above hypotheses is provided in this study by demonstrating that, when the activity of thrombin is suppressed by heparin (indirectly) or by Phe-Pro-Arg-CH2Cl (directly), exogenous Factor Xa reverses the ability of these two agents to inhibit prothrombin activation. Prothrombin activation was initiated by adding Factor Xa (1 nM) or thrombin (1 or 10 nM) simultaneously with CaCl2 to CAP. In the absence of heparin or Phe-Pro-Arg-CH2Cl, prothrombin activation was seen 15 s later in either case. Heparin failed to delay, and Phe-Pro-Arg-CH2Cl delayed for 15 s, prothrombin activation in CAP supplemented with Factor Xa. In contrast, heparin and Phe-Pro-Arg-CH2Cl completely inhibited prothrombin activation for at least 45 s in CAP supplemented with 1 nM-thrombin. Heparin failed to delay prothrombin activation in CAP supplemented with 10 nM-thrombin, whereas Phe-Pro-Arg-CH2Cl completely inhibited prothrombin activation in this plasma for 45 s. These results suggest that in CAP: (1) Factor Xa can effectively activate Factor VIII and Factor V when the proteolytic activity of thrombin is suppressed; (2) heparin-antithrombin III is less able to inhibit Factor Xa than thrombin; (3) suppression of the thrombin-dependent amplification reactions is the primary anticoagulant effect of heparin.

Antithrombin III↗
PubMed1989

Tumor necrosis factor leads to the internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture.

Tumor necrosis factor (TNF), a mediator of the inflammatory response, induces tissue factor and decreases the expression of thrombomodulin (TM) on endothelial cells, thus shifting the hemostatic properties of the endothelium. To determine the mechanism of TM downregulation, bovine aortic endothelial cells in culture were treated with TNF (2 nmol/L) and the fate of TM followed. Both surface expressed TM (antigen and activity), and the total TM pool (measured by radioimmunoassay and activity in detergent extracts) dropped to less than or equal to 20% of control values within 12 hours of TNF treatment. TM was not found in an immunologically recognizable form in the supernatants of treated cultures. Chloroquine (greater than or equal to 100 mumol/L) was able to abrogate the TNF effect on the total TM pool but not the effect on surface-expressed TM activity. We conclude that TNF induces the internalization and subsequent degradation of the TM molecule. None of the components of the protein C anticoagulant pathway, either alone or in combination, prevented the TNF-dependent downregulation of TM antigen.

Animals↗
PubMed1988

A 10-kDa cyanogen bromide fragment from the epidermal growth factor homology domain of rabbit thrombomodulin contains the primary thrombin binding site.

We have isolated a fragment (approximately equal to 10 kDa) of thrombomodulin containing the fifth and sixth epidermal growth factor (EGF)-like regions which retains thrombin binding capacity. The amino-terminal sequence of a 50-kDa active fragment of thrombomodulin derived from elastase proteolysis begins 11 residues before the first EGF-like structure of native thrombomodulin. Subsequent digestion with cyanogen bromide yields a 10-kDa thrombin binding fragment. The amino-terminal sequence of this fragment starts at the fifth EGF-like structure (Phe407). The amino acid composition suggests that this fragment contains the fifth and sixth EGF-like structures with a total of approximately 77 residues. This fragment lacks cofactor activity, but acts as a competitive inhibitor for protein C activation (Ki = 8.6 +/- 1.4 nM). We propose that the fifth and sixth EGF-like structures contain the thrombin binding site of thrombomodulin.

Amino Acid Sequence↗
PubMed1988

Evidence for multiple conformational changes in the active center of thrombin induced by complex formation with thrombomodulin: an analysis employing nitroxide spin-labels.

Thrombomodulin (TM) is an endothelial cell surface protein that binds thrombin to form a reversible complex with altered enzyme specificity. The complex rapidly converts protein C to the anticoagulant enzyme activated protein C and has decreased fibrinogen clotting activity. To investigate whether formation of this complex elicits conformational changes in the active center of thrombin, we employed the following fluorosulfonyl spin-label inhibitors: N-(2,2,5,5-tetramethyl-1-oxy-3-pyrrolidinyl)-m-(fluorosulfonyl)benzamide (m-V); O-(2,2,6,6-tetramethyl-1-oxy-4-piperidinyl) N-[m-(fluorosulfonyl)phenyl]carbamate (m-VI); N-[4-(fluorosulfonyl)phenyl]-2,2,5,5-tetramethyl-1-oxy-3-pyrroline -3-carboxamide (p-I); N-(2,2,5,5-tetramethyl-1-oxy-3-pyrrolidinyl)-p-(fluorosulfonyl)benzamide (p-V). To compare the spectra of the free thrombin with those of the complex, the viscosity of the solution was adjusted with sucrose to give similar tumbling rates (isokylindric spectra) or the macromolecular rotational contribution to the spectra was essentially eliminated with saturated sucrose. Both a buffer-soluble proteolytic derivative of TM and the intact molecule elicited changes in the electron spin resonance signals of many of the labeled thrombins employed. Two of the labels, p-I and p-V, had previously been shown to exhibit decreased mobility when indole derivatives were bound to thrombin. When TM complexes with thrombin, the mobility of the p-I label increases while the mobility of the p-V label decreases.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

The interaction of a Ca2+-dependent monoclonal antibody with the protein C activation peptide region. Evidence for obligatory Ca2+ binding to both antigen and antibody.

Protein C undergoes Ca2+-induced conformational changes required for activation by the thrombin-thrombomodulin complex. A Ca2+-dependent monoclonal antibody (HPC4) that blocks protein C activation was used to study conformational changes near the activation site in protein C. The half-maximal Ca2+ dependence was similar for protein C and gamma-carboxy-glutamic acid-domainless protein C for binding to HPC4 (205 +/- 23 and 110 +/- 29 microM Ca2+, respectively), activation rates (214 +/- 22 and 210 +/- 37 microM), and intrinsic fluorescence of gamma-carboxyglutamic acid-domainless protein C (176 +/- 34 microM). Protein C heavy chain binding to HPC4 was half-maximal at 36 microM Ca2+, although neither the heavy chain nor HPC4 separately bound Ca2+ with high affinity. The epitope was lost when the activation peptide was released. A synthetic peptide, P (6-17), which spans the activation site, exhibited Ca2+-dependent binding to HPC4 (half-maximal binding = 6 microM Ca2+). Thus, each decrease in antigen structure resulted in a reduced Ca2+ requirement for binding to HPC4. Tb3+ and Ca2+ binding studies demonstrated a Ca2+-binding site in HPC4 required for high affinity antigen binding. These studies provide the first direct evidence for a Ca2+-induced conformational change in the activation region of a vitamin K-dependent zymogen. Furthermore, Ca2+ binding to HPC4 is required for antigen binding. The multiple roles of Ca2+ described may be useful in interpretation of other metal-dependent antibody/antigen interactions.

Amino Acid Sequence↗
PubMed1988

Protein C and the endothelium.

With the continued accumulation of clinical and animal studies, it is becoming abundantly clear that the protein C anticoagulant pathway plays a critical role in the regulation of coagulation. Investigations also indicate that this pathway is intimately involved in the interaction of the coagulation and inflammatory systems. Although no direct information is presently available, the function of this pathway is likely depressed in the regions of atherosclerotic plaque. It is clear that monocytes accumulate in this region and release many growth factors and monokines that are capable of endothelial function perturbation. Perturbation of the protein C anticoagulant pathway is one viable mechanism for the hypercoagulable state in this disease. As indicated here, the endothelial cells of the vessel wall play a critical role in the initiation, and possibly expression, of this pathway. Any injury to these cells that affects the proper expression of thrombomodulin, synthesis of protein S, or Factor Va inactivation complex formation could potentially lead to a hypercoagulable state and thrombotic complications. As has been discussed, several inflammatory mediators are already known that fulfill the criteria of endothelial cell perturbants that may lead to such a state. What other entities might have similar effects, either directly or indirectly through induction of cytokines, is not known at this time. A more complete understanding of this critical pathway and the effects of vascular disease on it should lead to a better understanding of many diverse disease processes and potential therapeutic strategies in the future.

Animals↗
PubMed1988

Acquired deficiencies of protein S. Protein S activity during oral anticoagulation, in liver disease, and in disseminated intravascular coagulation.

Protein S is a vitamin K-dependent plasma protein which serves as the cofactor for activated protein C. Protein S circulates in both an active, free form and in an inactive complex with C4b-binding protein. To elucidate the role of protein S in disease states and during oral anticoagulation, we developed a functional assay for protein S that permits evaluation of the distribution of protein S between free and bound forms and permits determination of the specific activity of the free protein S. In liver disease, free protein S antigen is moderately reduced and the free protein S has significantly reduced specific activity. In disseminated intravascular coagulation, reduced protein S activity occurs due to a redistribution of protein S to the inactive bound form. During warfarin anticoagulation, reduction of free protein S antigen and the appearance of forms with abnormal electrophoretic mobility significantly decrease protein S activity. After the initiation of warfarin, the apparent half-life of protein S is 42.5 h. In patients with thromboembolic disease, transient protein S deficiency occurs due to redistribution to the complexed form. Caution should be exercised in diagnosing protein S deficiency in such patients by use of functional assays.

Adult↗