scholarly journals Human plasma protein Z antigen: range in normal subjects and effect of warfarin therapy

Blood ◽  
1987 ◽  
Vol 69 (6) ◽  
pp. 1580-1586
Author(s):  
JP Miletich ◽  
GJ Jr Broze
Keyword(s):  
Vitamin K ◽  
Plasma Protein ◽  
Total Protein ◽  
Protein C ◽  
Warfarin Therapy ◽  
Normal Subjects ◽  
Plasma Vitamin ◽  
Protein Z ◽  
The Mean ◽  
Log Normal

In contrast to the other well-studied vitamin K-dependent proteins that circulate in plasma, protein Z antigen is much more variable. The concentration in plasmas collected in EDTA from 455 normal, healthy donors is normally distributed with a mean of 2.9 micrograms/mL (46 nmol/L) and a SD of 1.0 microgram/mL (95% interval of 32% to 168% of the mean). No significant correlation to age or sex could be detected. In comparison, the concentration of protein C antigen measured with the same type of assay on the same 455 samples has a log normal distribution with a mean of 4.0 micrograms/mL (65 nmol/L) and a 95% interval of 70% to 138% of the mean. Also in marked contrast to other plasma vitamin K-dependent proteins, the total protein Z antigen level is extremely low in patients on stable warfarin therapy (range 1% to 16% of normal). Moreover, even though greater than 95% of the antigen in normal plasmas adsorbs to barium citrate (a crude reflection of the presence of gamma-carboxyglutamic acid (Gla) residues), in the patients taking warfarin almost all of the small amount of the antigen failed to adsorb, suggesting that virtually no protein Z had its full complement of Gla residues. Total protein C antigen in the same 25 patients averaged 53% of normal (34% to 72%) and 54% (average) of the total remaining antigen still adsorbed to barium citrate. The concentration of protein Z antigen in the plasma of a normal individual given a loading dose of warfarin fell at an initial rate of approximately 20% a day, indicating a plasma half-life (t1/2) of 2 to 3 days.

scholarly journals Human plasma protein Z antigen: range in normal subjects and effect of warfarin therapy

Blood ◽  
1987 ◽  
Vol 69 (6) ◽  
pp. 1580-1586 ◽  
Author(s):  
JP Miletich ◽  
GJ Jr Broze
Keyword(s):  
Vitamin K ◽  
Plasma Protein ◽  
Total Protein ◽  
Protein C ◽  
Warfarin Therapy ◽  
Normal Subjects ◽  
Plasma Vitamin ◽  
Protein Z ◽  
The Mean ◽  
Log Normal

Abstract In contrast to the other well-studied vitamin K-dependent proteins that circulate in plasma, protein Z antigen is much more variable. The concentration in plasmas collected in EDTA from 455 normal, healthy donors is normally distributed with a mean of 2.9 micrograms/mL (46 nmol/L) and a SD of 1.0 microgram/mL (95% interval of 32% to 168% of the mean). No significant correlation to age or sex could be detected. In comparison, the concentration of protein C antigen measured with the same type of assay on the same 455 samples has a log normal distribution with a mean of 4.0 micrograms/mL (65 nmol/L) and a 95% interval of 70% to 138% of the mean. Also in marked contrast to other plasma vitamin K-dependent proteins, the total protein Z antigen level is extremely low in patients on stable warfarin therapy (range 1% to 16% of normal). Moreover, even though greater than 95% of the antigen in normal plasmas adsorbs to barium citrate (a crude reflection of the presence of gamma-carboxyglutamic acid (Gla) residues), in the patients taking warfarin almost all of the small amount of the antigen failed to adsorb, suggesting that virtually no protein Z had its full complement of Gla residues. Total protein C antigen in the same 25 patients averaged 53% of normal (34% to 72%) and 54% (average) of the total remaining antigen still adsorbed to barium citrate. The concentration of protein Z antigen in the plasma of a normal individual given a loading dose of warfarin fell at an initial rate of approximately 20% a day, indicating a plasma half-life (t1/2) of 2 to 3 days.

scholarly journals Vitamin K-Dependent Coagulation Factors That May be Responsible for Both Bleeding and Thrombosis (FII, FVII, and FIX)

2018 ◽  
Vol 24 (9_suppl) ◽  
pp. 42S-47S ◽  
Author(s):  
Antonio Girolami ◽  
Silvia Ferrari ◽  
Elisabetta Cosi ◽  
Claudia Santarossa ◽  
Maria Luigia Randi
Keyword(s):  
Venous Thrombosis ◽  
Vitamin K ◽  
Protein C ◽  
Protein S ◽  
Coagulation Factors ◽  
Bleeding Tendency ◽  
Clotting Factors ◽  
Protein Z ◽  
Clinical Observations

Vitamin K-dependent clotting factors are commonly divided into prohemorrhagic (FII, FVII, FIX, and FX) and antithrombotic (protein C and protein S). Furthermore, another protein (protein Z) does not seem strictly correlated with blood clotting. As a consequence of this assumption, vitamin K-dependent defects were considered as hemorrhagic or thrombotic disorders. Recent clinical observations, and especially, recent advances in molecular biology investigations, have demonstrated that this was incorrect. In 2009, it was demonstrated that the mutation Arg338Leu in exon 8 of FIX was associated with the appearance of a thrombophilic state and venous thrombosis. The defect was characterized by a 10-fold increased activity in FIX activity, while FIX antigen was only slightly increased (FIX Padua). On the other hand, it was noted on clinical grounds that the thrombosis, mainly venous, was present in about 2% to 3% of patients with FVII deficiency. It was subsequently demonstrated that 2 mutations in FVII, namely, Arg304Gln and Ala294Val, were particularly affected. Both these mutations are type 2 defects, namely, they show low activity but normal or near-normal FVII antigen. More recently, in 2011-2012, it was noted that prothrombin defects due to mutations of Arg596 to Leu, Gln, or Trp in exon 15 cause the appearance of a dysprothrombinemia that shows no bleeding tendency but instead a prothrombotic state with venous thrombosis. On the contrary, no abnormality of protein C or protein S has been shown to be associated with bleeding rather than with thrombosis. These studies have considerably widened the spectrum and significance of blood coagulation studies.

scholarly journals Protein C, an antithrombotic protein, is reduced in hospitalized patients with intravascular coagulation

Blood ◽  
1982 ◽  
Vol 60 (1) ◽  
pp. 261-264 ◽  
Author(s):  
JH Griffin ◽  
DF Mosher ◽  
TS Zimmerman ◽  
AJ Kleiss
Keyword(s):  
Liver Disease ◽  
Serine Protease ◽  
Vitamin K ◽  
Protein C ◽  
Activated Protein C ◽  
Coagulation System ◽  
Antigen Concentration ◽  
Intravascular Coagulation ◽  
The Mean

Abstract Activated protein C is a potent anticoagulant and profibrinolytic enzyme that can be derived from the vitamin-K-dependent serine protease zymogen, protein C, by the action of thrombin. Protein C antigen concentration was determined in plasmas from normals (n = 40) and from 38 patients with intravascular coagulation as evidenced by positive FDP (greater than micrograms/ml). Plasma protein C was 4 micrograms/ml in normals and was significantly depressed (less than 2 SD below the mean of normals) in 19 of the 38 patients. Of 15 patients with suspected intravascular coagulation but normal FDP, protein C was decreased in 5 individuals; 3 of these 5 patients had liver disease. Based on these results, we suggest that extensive activation of the coagulation system in vivo causes a significant consumption of protein C, presumably due to its activation by thrombin and subsequent clearance.

Thrombin Generation Is Normal in Most Patients with Cirrhosis despite a Prolonged INR.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1826-1826
Author(s):  
Alexander Gatt ◽  
Anne Riddell ◽  
Vincenza Calvaruso ◽  
Michael Makris ◽  
Edward Tuddenham ◽  
...  
Keyword(s):  
Liver Disease ◽  
Tissue Factor ◽  
Patient Group ◽  
Protein C ◽  
Thrombin Generation ◽  
Control Sample ◽  
Normal Subjects ◽  
Sensitivity Index ◽  
Clotting Factors ◽  
The Mean

Abstract Introduction: Advanced liver disease is associated with prolongation of the prothrombin time (PT). In order to decrease the inter-laboratory variability of PT measurement, the international normalised ratio (INR) calculated as the ratio of patient’s PT to a normal (control) sample, raised to the power of the international sensitivity index (ISI) of the particular thromboplastin used was developed. However, the ISI is derived from PT results of patients on warfarin and results cannot be extrapolated to liver patients. Despite this, the INR is still commonly performed to assess bleeding risk in patients with liver disease worldwide. Furthermore the INR is only affected by factors I, II, V, VII, and X and is not influenced by other factors such as factor VIII which is usually raised in hepatic cirrhosis. Recently it has been reportd that thrombomodulin addition (to take into account the protein C pathway) normalises thrombin generation (TG)1 despite these patients having a low TG if thrombomodulin is not used. Aim: We speculated that TG, which is a global assay of coagulation and sensitive to all coagulation factors, when triggered by a low tissue factor (TF) concentration might not correlate with the INR in patients with liver disease and that contact inhibition with corn trypsin inhibitor (CTI) might better reflect the coagulation potential in this patient group. Results: 73 unselected patients with liver cirrhosis due to various diseases and 25 normal subjects were studied. INR and TG using the calibrated automated thrombogram (CAT) at 1pM tissue factor (TF) with CTI, 5pM without CTI and with and without Protac (a Protein C activator) were performed using platelet poor plasma (PPP). The INR range was 0.8–4.0 (mean 1.6). At 5pM TF without Protac, the patient group had a significantly lower endogenous thrombin potential (ETP) than the controls (mean ETP difference 752nM/min; P <0.0001). With Protac, no significant differences could be detected between the 2 groups. However, if the ETP without Protac was divided by the ETP with Protac x 100, the liver group showed more resistance to PC activation (mean % difference 25.4; P 0.0002). At 1pM TF, the mean ETP in the cirrhosis cohort was slightly lower than the normal group (difference between means 216nM/min; P 0.03). However, only 7 (9.6%) patients had ETP values less than the normal range (mean±2SD). No correlation was found between the ETP at 1pM and the INR. The mean FVIII:C was raised at 185.6 (78–420U/dl). Conclusion: TG measured at low TF with CTI is normal in the majority of patients with cirrhosis. These patients are also more resistant to PC activation and have supranormal FVIII:C. Thus most patients have a normal or high thrombin potential despite an abnormal INR. These findings have important implications as in the absence of bleeding, “prophylactic” plasma and clotting factors are unnecessary.

Plasma Protein Z and Protein C Inhibitors and Their Role in Hypercoagulability of Thalassemia

2007 ◽  
Vol 118 (3) ◽  
pp. 136-140 ◽  
Author(s):  
Giovanni Carlo Del Vecchio ◽  
Antonia Nigro ◽  
Paola Giordano ◽  
Federico Schettini ◽  
Maria Altomare ◽  
...  
Keyword(s):  
Plasma Protein ◽  
Protein C ◽  
Protein Z

Plasma vitamin K concentrations depend on CYP4F2 polymorphism and influence on anticoagulation in Japanese patients with warfarin therapy

2015 ◽  
Vol 135 (5) ◽  
pp. 861-866 ◽  
Author(s):  
Keita Hirai ◽  
Yuto Yamada ◽  
Hideki Hayashi ◽  
Masaki Tanaka ◽  
Kohei Izumiya ◽  
...  
Keyword(s):  
Vitamin K ◽  
Warfarin Therapy ◽  
Japanese Patients ◽  
Plasma Vitamin

scholarly journals Low total protein S antigen but high protein S activity due to decreased C4b-binding protein in neonates

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 562-565
Author(s):  
HP Schwarz ◽  
W Muntean ◽  
H Watzke ◽  
B Richter ◽  
JH Griffin
Keyword(s):  
Vitamin K ◽  
Total Protein ◽  
Protein C ◽  
Binding Protein ◽  
Anticoagulant Activity ◽  
Active Form ◽  
Activated Protein C ◽  
Newborn Infants ◽  
Protein S ◽  
High Level

Protein S, a vitamin K-dependent cofactor for activated protein C, exists in normal adult plasma in a free anticoagulantly active form and in an inactive form complexed to C4b-binding protein. Immunologic and functional levels of protein S and C4b-binding protein in plasma were determined for 20 newborn infants and compared with adult normal pooled plasma. Total protein S antigen levels averaged 23%, similar to other vitamin K-dependent plasma proteins. However, the protein S anticoagulant activity was 74% of that of adult normal plasma. This apparent discrepancy of activity to antigen was shown to be due to low or undetectable levels of C4b-binding protein, which results in the presence of most if not all of protein S in its free and active form. The relatively high level of anticoagulantly active protein S in infants may enhance the potential of the protein C pathway, thereby minimizing risks of venous thrombosis in this group.

scholarly journals A functional assay of protein C in human plasma

Blood ◽  
1984 ◽  
Vol 63 (3) ◽  
pp. 671-675 ◽  
Author(s):  
N Sala ◽  
WG Owen ◽  
D Collen
Keyword(s):  
Enzymatic Activity ◽  
Human Plasma ◽  
Vitamin K ◽  
Protein C ◽  
Normal Subjects ◽  
Accurate Estimation ◽  
Functional Assay ◽  
Functional Protein ◽  
Standard Curve ◽  
Normal Plasma

Abstract A three-step spectrophotometric assay was developed for measuring functional protein C (PC) in human plasma. The assay is based on: (1) adsorption of citrated platelet-poor plasma on barium citrate and elution of the vitamin K-dependent factors with EDTA; (2) activation of PC by incubation of the mixture of vitamin K-dependent factors with a complex of thrombin and its endothelial cell cofactor, thrombomodulin; (3) addition of antithrombin III and heparin to the system to inhibit thrombin and other coagulation enzymes generated during incubation and measurement of the activated PC with a synthetic (chromogenic) substrate. The assay appears to be specific for PC because: (a) PC- depleted plasma (by immunoadsorption) is inactive; (b) addition of purified PC to PC-depleted plasma reconstitutes its activity; and (c) no enzymatic activity is generated in the absence of the thrombin- thrombomodulin complex. Mixtures of a normal plasma pool with PC- depleted plasma yielded an amount of enzymatic activity proportional to the fraction of normal plasma. Using this as a standard curve, the amount of PC in the plasma of 23 normal subjects was 97% +/- 15%. The within-assay coefficient of variation was 3.5% and the between-assay coefficient 6.5%. A linear correlation (r = 0.86) was found between PC as measured with the functional assay and with a radioimmunoassay. In 3 patients with congenital PC deficiency, the functional PC level was 37% +/- 9% and the antigen level 64% +/- 11%. It is concluded that the present assay may be used for reliable and accurate estimation of activatable PC in human plasma.

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