Differential response of factor VIII and protein C expression following multimodal therapy for esophageal carcinoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15106-15106
Author(s):  
M. Byrne ◽  
B. M ◽  
J. O’ Donnell ◽  
B. White ◽  
J. Kennedy ◽  
...  
Keyword(s):  
Risk Factor ◽  
Factor Viii ◽  
Oesophageal Cancer ◽  
Protein C ◽  
Protein S ◽  
Endothelial Damage ◽  
Time Points ◽  
Increased Risk ◽  
Significant Difference

15106 Background: Tumour growth is associated with development of a hypercoaguable state and increased risk of thrombosis. Factor VIII plasma concentration has been shown to be an independent and dose-dependant risk factor for venous thromboembolism. Von Willebrand factor, the carrier molecule of circulating FVIII is expressed by vascular endothelial cells and in vitro observations indicate that chemotherapy induces endothelial damage with subsequent dysfunction. This study assessed FVIII, Protein C and Protein S response following multi modal therapy for oesophageal carcinoma. Methods: Fifty oesophageal cancer patients were studied, (multimodal n= 25, surgery only, n=25), at time points 0 (pre-operatively, following the first and final cycles of chemoradiation, and on days 1, 3, 7, 14, 21 and 28 days, and at 3 and 6 months postoperatively. Blood samples were collected and centrifuged at 3000g for 20 minutes to botain platelet poor plasmad. Factor VIII levels were measured by one stage clotting assay with factor VIII-deficient plasma. Automated functional assays for Protein C and Protein S in plasma were performed. Results: Factor FVIII levels were significantly elevated in the multimodal cohort following the 1st (p<0.008) and 2nd (p<0.001) cycles of chemoradiotherapy and at all time points following surgery, compared to baseline readings (p<0.001). Similar elevation was noted in the surgery only patients. No significant difference in factor FVIII levels between the multimodal group and surgery only patients was seen, except on day 21 (p < 0.04). Preliminary findings indicate a significant difference between the multimodal and surgery only cohorts in Protein C (0.74–1.32 IU/ml) levels (p < 0.05) at two timepoints. Conclusion: Factor VIII serum levels are significantly elevated following preoperative chemoradiotherapy. The pattern of response post oesophagectomy did not differ between the two cohorts. Elevated levels are a risk factor for both primary and recurrent venous thrombolism. The precise pathogenetic mechanism and cause of this elevation remains to be elucidated. Further studies investigating Protein C activity and, relating Factor VIII to thrombosis and inflammation in the oesophageal cancer patient are required. No significant financial relationships to disclose.

Black-White Differences In Venous Thrombosis Risk: the Longitudinal Investigation of Thromboembolism Etiology (LITE)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 478-478 ◽  
Author(s):  
Neil Zakai ◽  
Pamela Lutsey ◽  
Aaron Folsom ◽  
Mary Cushman
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Venous Thrombosis ◽  
Factor Viii ◽  
Protein C ◽  
Cox Models ◽  
Longitudinal Investigation ◽  
Thrombosis Risk ◽  
Increased Risk ◽  
Age And Sex

Abstract Abstract 478 Black-White Differences in Venous Thrombosis Risk: The Longitudinal Investigation of Thromboembolism Etiology (LITE). Neil A. Zakai, Pamela L. Lutsey, Aaron R. Folsom, Mary Cushman. Introduction: Venous thrombosis (VT) is more common in blacks than whites. The reasons for this difference and whether it is explained by racial differences in VT risk factors is not known. Methods: VT was ascertained by physician review of medical records in the Longitudinal Investigation of Thromboembolism Etiology (LITE), a prospective observational study of 21,680 men and women age 45–100 years participating in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) cohorts. VT was classified as provoked if preceded within 90 days by major surgery, trauma, immobility, or associated with active cancer or chemotherapy. We used age- and sex-adjusted Cox models to evaluate whether certain VT risk factors explained the increased risk of VT in blacks vs whites. We also tested if the impact of VT risk factors differed by race using interaction terms. Most risk factors were assessed in both ARIC and CHS cohorts (body mass index (BMI), diabetes, hypertension, chronic kidney disease (CKD), factor VIII, and education) except the activated partial thromboplastin time (aPTT), von Willebrand factor (vWF), and protein C were measured in ARIC only and C-reactive protein was measured in CHS only. Results: With up to 15 years of follow up, among 20,964 participants (5,054 blacks) without VT at baseline, 648 developed new VT (200 blacks). The age- and sex-standardized incidence of VT per 1000 person-years was higher in blacks than whites for all VT (3.18 vs 1.96), whether the VT was provoked (2.11 vs. 1.24) or unprovoked (1.12 vs. 0.74), all p <0.01. Blacks and whites had a similar incidence of pulmonary embolism (PE) (0.83 vs. 0.76, p = 0.56). Blacks had more adverse levels of many VT risk factors except CKD and a lower aPTT: BMI (29.3 vs. 26.8 kg/m2), diabetes (21 vs 11%), hypertension (59 vs 38%), CKD (5 vs. 12%), high school graduation (58 vs 80%), factor VIII (146 vs 124%), vWF (134 vs 113%), CRP (2.4 vs 1.8 mg/L) protein C (3.13 vs. 3.18 mg/L), all p <0.01. In age- and sex-adjusted Cox models, the relative risk of total VT for blacks vs. whites was 1.67 (95% CI 1.41, 1.97). When risk factors were added to age-, sex- and race-adjusted Cox models, BMI explained 36% of the excess risk of VT in blacks, factor VIII 58%, and vWF 54%. The other risk factors had a minimal impact on the HR for race. When all risk factors measured in both cohorts were considered in the same model, the association of black race with VT was attenuated (HR 1.15; 95% CI 0.94, 1.42). Of the risk factors evaluated, there were significant interactions between race and hypertension, CKD, and aPTT below the median (29s). The table lists the HR for each of these risk factors stratified by race; hypertension and CKD were stronger risk factors for VT in blacks while an aPTT less than the median was a stronger risk factor for VT in whites. Conclusions: Blacks have a higher incidence of VT than whites, whether provoked or unprovoked. The increased risk in blacks was largely explained by a greater prevalence of VT risk factors among blacks, particularly obesity, higher factor VIII and higher vWF. Further, CKD and hypertension were stronger risk factors for VT in blacks, while a shorter aPTT was a weaker risk factor for VT in blacks. Larger studies of VT in blacks addressing environmental and genetic risk factors and health-care disparities are needed to fully understand reasons for these ethnic differences in VT incidence. Disclosure: No relevant conflicts of interest to declare.

Risk of Venous Thromboembolism Is Not Increased by Elevated TAFI Levels.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1484-1484
Author(s):  
Nienke Folkeringa ◽  
Jan Leendert P. Brouwer ◽  
Nic J.G.M Veeger ◽  
Jan van der Meer
Keyword(s):  
Risk Factor ◽  
Venous Thromboembolism ◽  
Protein C ◽  
Absolute Risk ◽  
Large Family ◽  
Protein S ◽  
High Plasma ◽  
Prothrombin G20210a ◽  
Chromogenic Assay ◽  
Increased Risk

Abstract TAFI (Thrombin-activatable fibrinolysis inhibitor) is a suppressor of fibrinolysis and high plasma levels of TAFI are assumed to induce venous thromboembolism (VTE). A few studies published on this subject identified TAFI as a mild risk factor for VTE. The risk may be increased if high TAFI levels are combined with other trombophilic defects. We performed a retrospective study to asses the absolute risk of VTE associated with elevated levels of TAFI and the contribution of concomitant thrombophilic defects. Subjects were recruited from a previous large family cohort study, which was designed to estimate the risk of VTE in first degree relatives of probands with documented VTE and a hereditary deficiency of antithrombin, protein C or protein S. Probands were excluded from analysis. Blood samples of relatives were tested on deficiencies of antithrombin, protein C and protein S, prothrombin G20210A, factor FV Leiden, hyperhomocysteinemia and increased levels of factor VIII:C, IX:C and XI:C. TAFI activity was additional measured by chromogenic assay on plasma samples stored at minus 80 degrees Celsius. We analysed 350 of 457 relatives, who were tested on TAFI. TAFI levels observed in women were lower than in men (median 97 versus 106 U/dL) and increased with age (median from 95 U/dL at age 15–30 yr to 107 U/dL at age>60 yr). Relatives with TAFI levels above the 90th percentile (>128 U/dL) had the same absolute risk of VTE as relatives with TAFI levels below the 90th percentile. Annual incidences (AI) were 0.74 versus 0.72 % per year: relative risk (RR) 1.0; 95% CI.0.51–2.10 (Table). Concomitant thrombophilic defects were demonstrated in 82% of the relatives. These defects were equally distributed among relatives with TAFI levels of >90th versus <90th percentile. Relatives with TAFI levels above the 90th percentile and concomitance of at least one other thrombophilic defect were not at increased risk of VTE compared to relatives with lower TAFI levels and concomitant thrombophilic defects (RR 0.83; 95% CI 0.41–1.68). Our data do not support that eleveated TAFI levels are a risk factor for VTE. The high absolute risk of VTE among relatives is mainly due to the presence of other thrombophilic defects rather than elevated TAFI levels, as interactions between TAFI and other thrombophilic defects were not demonstrated. VTE (n) Observation years AI (95% CI) RR (95% CI) TAFI > 90th percentile 9 1209 0.74 (0.3–1.4) 1.0 (0.51–2.10) Concomitance 9 1147 0.78 (0.4–14.9) 0.83 (0.41–1.68) No concomitance 0 62 0 TAFI < 90th percentile 53 7364 0.72 (0.5–0.9) Ref Concomitance 53 5724 0.93 (0.7–1.2) Ref No concomitance 0 1426 0

Protein S Regulates Factor IXa in the Absence and Presence of Factor VIIIa Independently of Activated Protein C

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1197-1197
Author(s):  
Rinku Majumder ◽  
Rima Chattopadhyay ◽  
Tanusree Sengupta
Keyword(s):  
Protein C ◽  
Thrombin Generation ◽  
Anticoagulant Activity ◽  
Activated Protein C ◽  
Protein S ◽  
Activity Measurement ◽  
Clotting Time ◽  
Thrombotic Risk ◽  
Increased Risk

Abstract Abstract 1197 Coagulation is a finely tuned process. During thrombin formation, several anticoagulant reactions are initiated to prevent systematic activation of coagulation, and impairment of anticoagulant activity causes an increased risk of venous thrombosis. One such anticoagulant factor is protein S, deficiencies of which have been linked to venous and arterial thrombosis. While protein S has been studied for over three decades, the precise role this protein plays in attenuating the hemostatic response is far from clear. Protein S is a vitamin K-dependent plasma protein that functions in feedback regulation of thrombin generation. Protein S was initially identified as a cofactor for activated protein C (APC) but later it was observed that there is only a 3–10 fold increase in APC activity in the presence of protein S. Plasma coagulation assays in the absence of APC suggest that protein S may have other anticoagulant role(s). We report here an anticoagulant activity of Protein S mediated by inhibition of fIXa in the absence and presence of fVIIIa independent of APC. Although an APC-independent anticoagulant activity has been reported for protein S interacting with fVIIIa, no study has shown that the inhibitory effect of protein S is mediated through its interaction with fIXa, thus making our observations novel and significant. Moreover, previous studies that reported an interaction between fVIIIa and protein S were performed with low amounts of phospholipid, a condition that produces activity measurement artifacts due to the presence of active protein S multimers. We used both ex vivo (plasma studies) and in vitro methods at high phospholipid (100–200 micro molar) concentration to determine whether and how the intrinsic pathway of blood coagulation is regulated by protein S. We obtained the following results: 1) activated partial thromboplastin time (aPTT) assays with protein S-supplemented plasma confirmed that protein S prolongs clotting time, and a normal clotting time was restored with addition of anti-protein S antibody, 2) a modified aPPT assay with fIX-deficient plasma confirmed that protein S affects fIX-initiated clotting time, 3) thrombin generation assay through fIXa/fVIIIa pathway, initiated with a limiting amount of tissue factor (TF), was regulated by protein S, 4) in vitro studies with fIXa/fVIIIa and protein S in the presence of phosphatidylserine (PS) vesicles showed ∼40% and ∼65% inhibition in the activity of fIXa in the absence and presence of fVIIIa, respectively, and 5) protein S altered only the KM for fX activation by fIXa but altered both kcat and KM for fX activation by fIXa and fVIIIa. Our findings underscore the central role of protein S in regulation of coagulation. We anticipate these results will unravel important implications for the evaluation of thrombotic risk associated with protein S-deficiency. Disclosures: No relevant conflicts of interest to declare.

Hypercoagulability in Cirrhotic Patients; Impact of Acquired Protein C Deficiency and Factor VIII Increase in Low Sensitivity to Thrombomodulin

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1420-1420
Author(s):  
Thomas Sinegre ◽  
Cedric Duron ◽  
Marc G. Berger ◽  
Armand Abergel ◽  
Aurelien Lebreton
Keyword(s):  
Monoclonal Antibody ◽  
Factor Viii ◽  
Protein C ◽  
Hypercoagulable State ◽  
Healthy Controls ◽  
Significant Difference ◽  
Before And After ◽  
Cirrhotic Patients ◽  
Low Sensitivity

Abstract Context: Cirrhosis impacts all the steps of haemostasis including coagulation. Levels of both inhibitors (including protein C (PC)) and prococagulants factors are decreased excepted factor VIII (FVIII) who is increased. Cirrhotic patients are exposed to thromboembolic diseases and cirrhosis induced hypercoagulability is a major determinant of this thrombotic process. A procoagulant state in cirrhotic patients has been demonstrated using modified thrombin generation assays (TGA) with thrombomodulin (TM), a cofactor for PC activation. With such assays, a low sensitivity to the action of TM has been highlighted in the cirrhotic population, increasing with the severity assessed by the Child-Pugh score. Studies showed that PC deficiency is one of the main determinants of this procoagulant state but the implication of the increased FVIII levels has not been yet accurately evaluated. The aim of this study was to investigate the impact of in vitro normalization of FVIII and PC levels on the procoagulant imbalance in cirrhotic patients using TGA in the presence of TM to precisely determine their role in the cirrhosis induced procoagulant state. Method: One hundred and six patients and 35 healthy controls were prospectively included in this study. Patients were confirmed cirrhotic patients, free of hepatocellular carcinoma and were not anticoagulated. TGA were performed using the calibrated automated thrombinography method in platelet poor plasma using 5 pM tissue factor, 4 nM TM. Plasma were tested before/after normalization of PC levels by in vitro addition of PC and before/after normalization of FVIII levels by the use of human anti-FVIII C2 domain monoclonal antibody (ESH8). All ethical requirements were obtained. Groups were compared using ANOVA, or the Kruskal-Wallis test when the ANOVA conditions were not met followed by the appropriate multiple comparisons post-hoc tests. Results are expressed as median (Q1 - Q3). Results:Among cirrhotic patients 68 were Child-Pugh A, 21 Child-Pugh B and 17 Child-Pugh C). TGA performed with TM show a gradually increased of endogenous thrombin potential (ETP) from healthy controls to Child-Pugh C patients with respectively 508 nM.min (410-725) and 1071 nM.min (701-1232) (p<0.0001) confirming the hypercoagulable state of cirrhosis in these conditions. After normalization, PC levels increase from 50% (41-76) to 100% (94-110) and become similar to controls (109% (100-122), p>0.05). Modified TGA with TM performed before and after PC normalization showed a decrease of the ETP values from 776 nM.min (626-991) to 566 nM.min (369-779), from 1120 nM.min (1062-1184) to 790 nM.min (617- 972) and from 995 nM.min (913-1443) to 790 nM.min (698 - 909) (p<0.0001) for Child-Pugh A, B and C patients respectively (p<0.0001). No significant difference was found between controls versus Child-Pugh A class patients (p=0.63) whereas higher significant ETP values persist in Child-Pugh B and C class when compared to healthy controls (p<0.01 and p<0.05 respectively) in these conditions. After normalization of FVIII increase by in vitro addition of anti-FVIII antibodies, FVIII levels decrease from 196% (165-222) to 94% (77-107) and became similar to controls (p>0.05). TGA performed before and after FVIII normalization showed a decrease of the ETP values from 929 nM.min (784-1086) to 621 nM.min (517-863), from 1122 nM.min (1035-1360) to 1081 nM.min (890-1171) and from 1221 (910-1407) to 1143 nM.min (892-1323) for Child-Pugh A, B and C patients respectively. There is no significant difference between healthy controls and Child-Pugh A patients but a difference persists with Child-Pugh B and C patients. When plasma levels of PC and FVIII are simultaneously corrected to normal ranges by in vitro addition of both PC and anti-FVIII monoclonal antibody, ETP decrease from 929 nM.min (784-1086) to 302 nM.min (167-583) in Child-Pugh A patients (p<0.0001), from 1122 nM.min (1035-1360) to 597 nM.min (285-686) for Child-Pugh B (p<0.0001) and from 1226 nM.min (1108-1488) to 586 (471-771) for Child-Pugh C. For all patients, ETP values were not significantly different when compared to healthy controls (p>0.05) after both PC and FVIII normalization. Fig 1 Conclusions: Low sensitivity to TM induced by cirrhosis is not only related to PC deficiency but also to FVIII increase. When PC deficiency and FVIII increase are in vitro redressed, no hypercoagulable state was found in cirrhotic patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Advances in Understanding Mechanisms of Thrombophilic Disorders

2020 ◽  
Vol 40 (01) ◽  
pp. 012-021
Author(s):  
Björn Dahlbäck
Keyword(s):  
Risk Factor ◽  
Genetic Risk ◽  
Protein C ◽  
Activated Protein C ◽  
Protein S ◽  
Medical Problem ◽  
Factor V ◽  
Apc Resistance ◽  
Thrombosis Risk ◽  
Increased Risk

AbstractVenous thromboembolism constitutes a major medical problem afflicting millions of individuals worldwide each year. Its pathogenesis is multifactorial, involving both environmental and genetic risk factors. The most common genetic risk factor known to date is a mutation in the factor V (FV) gene (R506Q or FV Leiden), which impairs the normal regulation of FV by activated protein C (APC). APC is an important regulator of blood coagulation, cleaving and inactivating not only FV/FVa but also activated factor VIII (FVIIIa). In FVa, APC cleaves several sites, Arg506 (R506) being one of them. The R506Q mutation results in the APC resistance phenotype and a lifelong hypercoagulable state. A prothrombin gene mutation is another relatively frequent thrombosis risk factor, whereas deficiencies of the anticoagulant proteins antithrombin, protein C, or protein S are less common. As a result of the high prevalence of FV and prothrombin mutations in the general population, combinations of genetic defects are relatively common. Such individuals have highly increased risk of thrombosis.

APC Resistance and other Haemostatic Variables during Pregnancy and Puerperium

1999 ◽  
Vol 81 (04) ◽  
pp. 527-531 ◽  
Author(s):  
U. Kjellberg ◽  
N.-E. Andersson ◽  
S. Rosén ◽  
L. Tengborn ◽  
M. Hellgren
Keyword(s):  
Factor Viii ◽  
Plasminogen Activator ◽  
Protein C ◽  
Activated Protein C ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Reference Level ◽  
Soluble Fibrin ◽  
Prothrombin Fragment ◽  
D Dimer

SummaryForty-eight healthy pregnant women were studied prospectively and longitudinally. Blood sampling was performed at 10-15, 23-25, 32-34 and 38-40 weeks of gestation, within one week and at eight weeks postpartum. Classic and modified activated protein C ratio decreased as pregnancy progressed. In the third trimester 92% of the ratios measured with the classic test were above the lower reference level whereas all modified test ratios were normal. Slight activation of blood coagulation was shown with increased levels of prothrombin fragment 1+2, soluble fibrin and D-dimer. Fibrinogen, factor VIII and plasminogen activator inhibitor type 1 and type 2 increased. Protein S and tissue plasminogen activator activity decreased. Protein C remained unchanged. No correlation was found between the decrease in classic APC ratio and changes in factor VIII, fibrinogen, protein S, prothrombin fragment 1+2 or soluble fibrin, nor between the increase in soluble fibrin and changes in prothrombin fragment 1+2, fibrinogen and D-dimer.

Activated Protein C Increases Fibrin Clot Lysis by Neutralization of Plasminogen Activator Inhibitor No Evidence for a Cofactor Role of Protein S

1988 ◽  
Vol 60 (02) ◽  
pp. 328-333 ◽  
Author(s):  
N J de Fouw ◽  
Y F de Jong ◽  
F Haverkate ◽  
R M Bertina
Keyword(s):  
Plasminogen Activator ◽  
Protein C ◽  
Blood Platelets ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Tissue Type ◽  
Clot Lysis ◽  
Activator Inhibitor ◽  
Pai 1

summaryThe effect of purified human activated protein G (APC) on fibrinolysis was studied using a clot iysis system consisting of purified glu-plasminogen, tissue-type plasminogen activator, plasminogen activator inhibitor (released from endothelial cells or blood platelets), fibrinogen, 125T-fibrinogen and thrombin. All proteins were of human origin.In this system APC could increase fibrinolysis in a dose dependent way, without affecting fibrin formation or fibrin crosslinking. However, this profibrinolytic effect of APC could only be observed when plasminogen activator inhibitor (PAI-l) was present. The effect of APC was completely quenched by pretreatment of APC with anti-protein C IgG or di-isopropylfluorophosphate. Addition of the cofactors of APC:protein S, Ca2+-ions and phospholipid-alone or in combination did not enhance the profibrinolytic effect of APC. These observations indicate that human APC can accelerate in vitro clot lysis by the inactivation of PAI-1 activity. However, the neutralization of PAI-1 by APC is independent of the presence or absence of protein S, phospholipid and Ca2+-ions.

Severe Arterial Cerebral Thrombosis in a Patient with Protein S Deficiency (Moderately Reduced Total and Markedly Reduced Free Protein S): A Family Study

1989 ◽  
Vol 61 (01) ◽  
pp. 144-147 ◽  
Author(s):  
A Girolami ◽  
P Simioni ◽  
A R Lazzaro ◽  
I Cordiano
Keyword(s):  
Arterial Thrombosis ◽  
Protein C ◽  
Protein S ◽  
Protein S Deficiency ◽  
Protein C Deficiency ◽  
Free Protein ◽  
Her Family ◽  
S Deficiency ◽  
Increased Risk ◽  
Patient Reported

SummaryDeficiency of protein S has been associated with an increased risk of thrombotic disease as already shown for protein C deficiency. Deficiencies of any of these two proteins predispose to venous thrombosis but have been only rarely associated with arterial thrombosis.In this study we describe a case of severe cerebral arterial thrombosis in a 44-year old woman with protein S deficiency. The defect was characterized by moderately reduced levels of total and markedly reduced levels of free protein S. C4b-bp level was normal. Protein C, AT III and routine coagulation tests were within the normal limits.In her family two other members showed the same defect. All the affected members had venous thrombotic manifestations, two of them at a relatively young age. No other risk factors for thrombotic episodes were present in the family members. The patient reported was treated with ASA and dipyridamole and so far there were no relapses.

Elevated Levels of Prothrombin Activation Fragment 1+2 in Plasma from Patients with Heterozygous Arg506 to Gin Mutation in the Factor V Gene (APC-Resistance) and/or Inherited Protein S Deficiency

1996 ◽  
Vol 75 (02) ◽  
pp. 270-274 ◽  
Author(s):  
Benget Zöller ◽  
Johan Holm ◽  
Peter Svensson ◽  
Björn Dahlbäck
Keyword(s):  
Plasma Concentration ◽  
Protein C ◽  
Protein S ◽  
Factor V ◽  
Protein S Deficiency ◽  
Apc Resistance ◽  
S Deficiency ◽  
Increased Risk ◽  
Factor V Gene ◽  
V Gene

SummaryInherited resistance to activated protein C (APC-resistance), caused by a point mutation in the factor V gene leading to replacement of Arg(R)506 with a Gin (Q), and inherited protein S deficiency are associated with functional impairment of the protein C anticoagulant system, yielding lifelong hypercoagulability and increased risk of thrombosis. APC-resistance is often an additional genetic risk factor in thrombosis-prone protein S deficient families. The plasma concentration of prothrombin fragment 1+2 (F1+2), which is a marker of hyper-coagulable states, was measured in 205 members of 34 thrombosis-prone families harbouring the Arg506 to Gin mutation (APC-resistance) and/or inherited protein S deficiency. The plasma concentration of F1+2 was significantly higher both in 38 individuals carrying the FV:Q506 mutation in heterozygous state (1.7 ± 0.7 nM; mean ± SD) and in 48 protein S deficient cases (1.9 ± 0.9 nM), than in 100 unaffected relatives (1.3 ±0.5 nM). Warfarin therapy decreased the F1+2 levels, even in those four patients who had combined defects (0.5 ± 0.3 nM). Our results agree with the hypothesis that individuals with APC-resistance or protein S deficiency have an imbalance between pro- and anti-coagulant forces leading to increased thrombin generation and a hypercoagulable state.

Platelet-mediated proteolytic down regulation of the anticoagulant activity of protein S in individuals with haematological malignancies

2012 ◽  
Vol 107 (03) ◽  
pp. 468-476 ◽  
Author(s):  
Ilze Dienava-Verdoold ◽  
Marina R. Marchetti ◽  
Liane C. J. te Boome ◽  
Laura Russo ◽  
Anna Falanga ◽  
...  
Keyword(s):  
Protein C ◽  
Normal Values ◽  
Anticoagulant Activity ◽  
Activated Protein C ◽  
Protein S ◽  
Intact Protein ◽  
The Impact ◽  
Independent Protein

SummaryThe natural anticoagulant protein S contains a so-called thrombin-sensitive region (TSR), which is susceptible to proteolytic cleavage. We have previously shown that a platelet-associated protease is able to cleave protein S under physiological plasma conditions in vitro. The aim of the present study was to investigate the relation between platelet-associated protein S cleaving activity and in vivo protein S cleavage, and to evaluate the impact of in vivo protein S cleavage on its anticoagulant activity. Protein S cleavage in healthy subjects and in thrombocytopenic and thrombocythaemic patients was evaluated by immunological techniques. Concentration of cleaved and intact protein S was correlated to levels of activated protein C (APC)-dependent and APC-independent protein S anticoagulant activity. In plasma from healthy volunteers 25% of protein S is cleaved in the TSR. While in plasma there was a clear positive correlation between levels of intact protein S and both APC-dependent and APC-independent protein S anticoagulant activities, these correlations were absent for cleaved protein S. Protein S cleavage was significantly increased in patients with essential thrombocythaemia (ET) and significantly reduced in patients with chemotherapy-induced thrombocytopenia. In ET patients on cytoreductive therapy, both platelet count and protein S cleavage returned to normal values. Accordingly, platelet transfusion restored cleavage of protein S to normal values in patients with chemotherapy-induced thrombocytopenia. In conclusion, proteases from platelets seem to contribute to the presence of cleaved protein S in the circulation and may enhance the coagulation response in vivo by down regulating the anticoagulant activity of protein S.

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