Relationship between vitamin K dependent coagulation factors and anticoagulants (protein C and protein S) in neonatal vitamin K deficiency.

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.

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Two Types of Prothrombin in Vitamin K Deficiency

Thrombosis and Haemostasis ◽

10.1055/s-0038-1654194 ◽

1970 ◽

Vol 23 (03) ◽

pp. 633-637 ◽

Cited By ~ 21

Author(s):

H. C Hemker ◽

Annemarie D. Muller ◽

E. A Loeliger

Keyword(s):

Vitamin K ◽

Oral Anticoagulants ◽

Coagulation Factors ◽

The Other ◽

Vitamin K Deficiency ◽

Two Stage ◽

K Deficiency

SummaryIn vitamin K deficiency (either absolute or induced by oral anticoagulants) two types of prothrombin occur. One is not distinguishable from normal prothrombin. It generates thrombin quickly in a medium in which the factors V, VII and X, thromboplastin and Ca++ are present in sufficient amounts. The other is converted into thrombin much more slowly under the same conditions. In the onestage prothrombin assay only the first form is measured, in a two-stage prothrombin assay both forms are estimated. This accounts for the well-known discrepancy between these two tests in vitamin K deficiency. The abnormal prothrombin can be considered one of the Proteins Induced by Vitamin K Absence. The occurrence of this kind of proteins fits in the concept of the action of vitamin K as a co-factor in a system that converts polypeptide-precursors into coagulation factors.

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Vitamin K Deficiency Bleeding in Infancy

Nutrients ◽

10.3390/nu12030780 ◽

2020 ◽

Vol 12 (3) ◽

pp. 780

Author(s):

Shunsuke Araki ◽

Akira Shirahata

Keyword(s):

Oral Administration ◽

Vitamin K ◽

Placental Transfer ◽

Late Onset ◽

Newborn Infants ◽

Coagulation Factors ◽

Epidemiological Studies ◽

Vitamin K Deficiency ◽

Vitamin K Deficiency Bleeding ◽

K Deficiency

Vitamin K is essential for the synthesis of few coagulation factors. Infants can easily develop vitamin K deficiency owing to poor placental transfer, low vitamin K content in breast milk, and poor intestinal absorption due to immature gut flora and malabsorption. Vitamin K deficiency bleeding (VKDB) in infancy is classified according to the time of presentation: early (within 24 h), classic (within 1 week after birth), and late (between 2 week and 6 months of age). VKDB in infancy, particularly late-onset VKDB, can be life-threatening. Therefore, all infants, including newborn infants, should receive vitamin K prophylaxis. Exclusive breastfeeding and cholestasis are closely associated with this deficiency and result in late-onset VKDB. Intramuscular prophylactic injections reduce the incidence of early-onset, classic, and late-onset VKDB. However, the prophylaxis strategy has recently been inclined toward oral administration because it is easier, safer, and cheaper to administer than intramuscular injection. Several epidemiological studies have shown that vitamin K oral administration is effective in the prevention of VKDB in infancy; however, the success of oral prophylaxis depends on the protocol regimen and parent compliance. Further national surveillance and studies are warranted to reveal the optimal prophylaxis regimen in term and preterm infants.

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A Method for Systematic Purification from Bovine Plasma of Six Vitamin K-Dependent Coagulation Factors: Prothrombin, Factor X, Factor IX, Protein S, Protein C, and Protein Z1

The Journal of Biochemistry ◽

10.1093/oxfordjournals.jbchem.a135187 ◽

1985 ◽

Vol 97 (5) ◽

pp. 1347-1355 ◽

Cited By ~ 50

Author(s):

Nobukazu HASHIMOTO ◽

Takashi MORITA ◽

Sadaaki IWANAGA

Keyword(s):

Vitamin K ◽

Protein C ◽

Protein S ◽

Coagulation Factors ◽

Factor Ix ◽

Factor X ◽

S Protein ◽

Bovine Plasma

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Congenital Deficiency of Vitamin K-Dependent Coagulation Factors and Protein C

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661097 ◽

1984 ◽

Vol 51 (03) ◽

pp. 343-346 ◽

Cited By ~ 24

Author(s):

V Vicente ◽

R Maia ◽

I Alberca ◽

G P T Tamagnim ◽

A Lopez Borrasca

Keyword(s):

Vitamin K ◽

Protein C ◽

Coagulation Factors ◽

Vitamin K3 ◽

Congenital Deficiency ◽

History Of ◽

K Deficiency ◽

Dependent Protein ◽

Fresh Plasma ◽

Intravenous Vitamin

SummaryA 15-month-old girl from Coimbra (Portugal) had a history of numerous hemorrhagic episodes with multiple bruises, hematomas but not hemarthroses. On serial testing she showed deficiency of factors II, VII, IX, X and protein C. Malabsorption- induced vitamin K deficiency, liver disease or ingestion of a coumarin compound were excluded. An absence of detectable abnormalities was found among her relatives. Consanguinity was not present. The immunologic assay, immunoelectrophoresis or antibody neutralization, revealed much higher levels of these factors than the clotting assay. The non-physiological activator (Echis carinatus venom) produced higher levels of prothrombin activation than those detected by physiological activation. Twodimensional immunoelectrophoresis of the patient’s plasma in calcium showed that prothrombin had the same mobility as acarboxyprothrombin. No significant response to large doses of intravenous vitamin K3 (6 mg) was observed. Transfusion of 120 ml of frozen fresh plasma led to an immediate increase in the procoagulant activities of vitamin K dependent protein, similar to that found after perfusion of plasma plus vitamin K3. The results obtained from this patient suggest a defect in the gammacarboxylation mechanism inside the hepatocyte.

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PREVELANCE OF PRIMARY COAGULATION DEFICIENCIES IN PATIENTS WITH DEEP VENOUS THROMBOSIS

10.1055/s-0038-1643046 ◽

1987 ◽

Author(s):

B Grossman ◽

A Duncan

Keyword(s):

Venous Thrombosis ◽

Vitamin K ◽

Protein C ◽

Antithrombin Iii ◽

Comprehensive Evaluation ◽

Young Patients ◽

Protein S ◽

Coagulation Factors ◽

Protein C Deficiency ◽

Normal Ranges

Hereditary causes of thrombosis are becoming more evident as assays (and antibodies) for antithrombin III, protein C, and protein S become more widely available. From March 1986 to January 1987, ninety-nine patients with venous thrombosis were referred to our laboratory for evaluation.This included 55 males and 42 females (age ranges:(1- 79 years). In 79 patients protein C antigens and activities were performed and 24 abnormally low values were obtained. Fourteen of these patients had multiple low values of other vitamin K dependent coagulation factors, reflecting warfarin therapy. Ten patients (12.7%) had isolated protein C deficiency with the other vitamin K dependent factors being within our normal ranges. Of 75 free protein S antigens performed there were 32 abnormally low values. Thirteen (17.3%) were isolated deficiencies. Of 62 antithrombin III antigens and activities measured, there were 8 (12.9%) abnormally low values. The prevelance of these hereditary deficiencies are higher in our referral population than previously reported. This may represent a true increase prevelance in our referral population or reflect a selection bias because of our careful screening of the patient́s history prior to performing the test, or an increased availability of the test to the clinicians. These test should be performed routinely in young patients with venous thrombosis and without predisposing risk factors. These results confirm that all patients with thrombosis should have a comprehensive evaluation done. Not only will the etiology be determined but given the cost of these evaluations, it is more efficient to profile rather than to order isolated request for one factor, as has often been the habit in the past

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Hepatic and Vascular Vitamin K Status in Patients with High Cardiovascular Risk

Nutrients ◽

10.3390/nu13103490 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3490

Author(s):

Nikolas Rapp ◽

Vincent M. Brandenburg ◽

Nadine Kaesler ◽

Stephan J. L. Bakker ◽

Robert Stöhr ◽

...

Keyword(s):

Vitamin K ◽

Research Question ◽

Coagulation Factors ◽

Matrix Gla Protein ◽

Weak Correlation ◽

Vitamin K Deficiency ◽

Disease Etiology ◽

Cardiovascular Morbidity And Mortality ◽

K Deficiency ◽

Calcific Uremic Arteriolopathy

Vitamin K dependent proteins (VKDP), such as hepatic coagulation factors and vascular matrix Gla protein (MGP), play key roles in maintaining physiological functions. Vitamin K deficiency results in inactive VKDP and is strongly linked to vascular calcification (VC), one of the major risk factors for cardiovascular morbidity and mortality. In this study we investigated how two vitamin K surrogate markers, dephosphorylated-undercarboxylated MGP (dp-ucMGP) and protein induced by vitamin K absence II (PIVKA-II), reflect vitamin K status in patients on hemodialysis or with calcific uremic arteriolopathy (CUA) and patients with atrial fibrillation or aortic valve stenosis. Through inter- and intra-cohort comparisons, we assessed the influence of vitamin K antagonist (VKA) use, vitamin K supplementation and disease etiology on vitamin K status, as well as the correlation between both markers. Overall, VKA therapy was associated with 8.5-fold higher PIVKA-II (0.25 to 2.03 AU/mL) and 3-fold higher dp-ucMGP (843 to 2642 pM) levels. In the absence of VKA use, non-renal patients with established VC have dp-ucMGP levels similar to controls (460 vs. 380 pM), while in HD and CUA patients, levels were strongly elevated (977 pM). Vitamin K supplementation significantly reduced dp-ucMGP levels within 12 months (440 to 221 pM). Overall, PIVKA-II and dp-ucMGP showed only weak correlation (r2 ≤ 0.26) and distinct distribution pattern in renal and non-renal patients. In conclusion, VKA use exacerbated vitamin K deficiency across all etiologies, while vitamin K supplementation resulted in a vascular VKDP status better than that of the general population. Weak correlation of vitamin K biomarkers calls for thoughtful selection lead by the research question. Vitamin K status in non-renal deficient patients was not anomalous and may question the role of vitamin K deficiency in the pathogenesis of VC in these patients.

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THROMBO-HEMORRHAGIC SKIN NECROSIS DUE TO RAPID DEVELOPMENT OF SEVERE VITAMIN K DEFICIENCY ASSOCIATED WITH CHOLESTASIS

10.1055/s-0038-1644311 ◽

1987 ◽

Cited By ~ 1

Author(s):

J J Michiels ◽

R M Bertina

Keyword(s):

Vitamin K ◽

Skin Necrosis ◽

Protein C ◽

Degradation Products ◽

Rapid Development ◽

Factor Vii ◽

Vitamin K Deficiency ◽

Antigen Concentration ◽

Severe Vitamin ◽

K Deficiency

A female patient is presented, who developed thrombotic and hemorrhagic skin necrosis of the feet and toes during an acute episode of severe vitamin K deficiency due to cholestasis in the absence of coumarin treatment. Painful blue toes and feet progressed to erythematous swelling and bluish discoloration with blister formations and immanent gangrene. The histo-pathology of skin excisions from the erythematous skin lesions showed extravasation of erythrocytes and extensive fibrin thrombus formations in capillaries and venules as has been described in patients with coumarin skin necrosis. At the time of painful acrocyanosis the results of coagulation investigations (platelets 109 × 109/1, APTT 56/35 sec., PT 61/15 sec., ThrombotestR (TT) less than 3%, NormotestR (NT) less than 10%, fibrinogen 1,6 g/l, absence of fibrin monomers and degradation products, factor V 1.00 u/ml, antithrombin lil 1.03 u/ml and alfa2 antiplasmin 0.97 u/ml were consistent with severe vitamin K deficiency. Measurements of vitamin K dependent factors revealed very low levels for procoagulant factor VII (16%) and protein C (22%) antigen concentration and normal levels for procoagulant factor II (97%) and procoagulant factor X (87%) antigen concentration. After substitution of 5 mg vitamin K1 both the TT and NT normalized.These data confirm the hypothesis that an imbalance within procoagulant and anticoagulant vitamin K dependent factors (severe protein C and factor VII deficiency as compared to the procoagulant factors IX, X and II due to rapid development of vitamin K deficiency) contributes to the pathogenesis of thrombo-hemorrhagic skin necrosis and that the so-called coumarin necrosis is not due to drug toxicity.

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Protein S and C4b-Binding Protein: Components Involved in the Regulation of the Protein C Anticoagulant System

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646373 ◽

1991 ◽

Vol 66 (01) ◽

pp. 049-061 ◽

Cited By ~ 233

Author(s):

Björn Dahlbäck

Keyword(s):

Vitamin K ◽

Complement System ◽

Protein C ◽

Protein S ◽

High Affinity ◽

Anticoagulant System ◽

Dependent Protein ◽

The Complement System ◽

Β Chain ◽

Dependent Domain

SummaryThe protein C anticoagulant system provides important control of the blood coagulation cascade. The key protein is protein C, a vitamin K-dependent zymogen which is activated to a serine protease by the thrombin-thrombomodulin complex on endothelial cells. Activated protein C functions by degrading the phospholipid-bound coagulation factors Va and VIIIa. Protein S is a cofactor in these reactions. It is a vitamin K-dependent protein with multiple domains. From the N-terminal it contains a vitamin K-dependent domain, a thrombin-sensitive region, four EGF)epidermal growth factor (EGF)-like domains and a C-terminal region homologous to the androgen binding proteins. Three different types of post-translationally modified amino acid residues are found in protein S, 11 γ-carboxy glutamic acid residues in the vitamin K-dependent domain, a β-hydroxylated aspartic acid in the first EGF-like domain and a β-hydroxylated asparagine in each of the other three EGF-like domains. The EGF-like domains contain very high affinity calcium binding sites, and calcium plays a structural and stabilising role. The importance of the anticoagulant properties of protein S is illustrated by the high incidence of thrombo-embolic events in individuals with heterozygous deficiency. Anticoagulation may not be the sole function of protein S, since both in vivo and in vitro, it forms a high affinity non-covalent complex with one of the regulatory proteins in the complement system, the C4b-binding protein (C4BP). The complexed form of protein S has no APC cofactor function. C4BP is a high molecular weight multimeric protein with a unique octopus-like structure. It is composed of seven identical α-chains and one β-chain. The α-and β-chains are linked by disulphide bridges. The cDNA cloning of the β-chain showed the α- and β-chains to be homologous and of common evolutionary origin. Both subunits are composed of multiple 60 amino acid long repeats (short complement or consensus repeats, SCR) and their genes are located in close proximity on chromosome 1, band 1q32. Available experimental data suggest the β-chain to contain the single protein S binding site on C4BP, whereas each of the α-chains contains a binding site for the complement protein, C4b. As C4BP lacking the β-chain is unable to bind protein S, the β-chain is required for protein S binding, but not for the assembly of the α-chains during biosynthesis. Protein S has a high affinity for negatively charged phospholipid membranes, and is instrumental in binding C4BP to negatively charged phospholipid. This constitutes a novel mechanism for control of the complement system on phospholipid surfaces. Recent findings have shown circulating C4BP to be involved in yet another calcium-dependent protein-protein interaction with a protein known as the serum amyloid P-component (SAP). The binding sites on C4BP for protein S and SAP are independent. SAP, which is a normal constituent in plasma and in tissue, is a so-called pentraxin being composed of 5 non-covalently bound 25 kDa subunits. It is homologous to C reactive protein (CRP) but its function is not yet known. The specific high affinity interactions between protein S, C4BP and SAP suggest the regulation of blood coagulation and that of the complement system to be closely linked.

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Placental Transfer of Vitamin K1 and Its Implications in Fetal Hemostasis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647631 ◽

1988 ◽

Vol 60 (01) ◽

pp. 039-043 ◽

Cited By ~ 52

Author(s):

L Mandelbrot ◽

M Guillaumont ◽

M Leclercq ◽

J J Lefrère ◽

D Gozin ◽

...

Keyword(s):

Vitamin K ◽

High Performance ◽

Ultrasound Guidance ◽

Placental Transfer ◽

Vitamin K1 ◽

Vitamin K Deficiency ◽

Prothrombin Activity ◽

Oral Supplementation ◽

K Deficiency ◽

The Mean

SummaryVitamin K status was evaluated using coagulation studies and/ or vitamin IQ assays in a total of 53 normal fetuses and 47 neonates. Second trimester fetal blood samples were obtained for prenatal diagnosis under ultrasound guidance. Endogenous vitamin K1 concentrations (determined by high performance liquid chromatography) were substantially lower than maternal levels. The mean maternal-fetal gradient was 14-fold at mid trimester and 18-fold at birth. Despite low vitamin K levels, descarboxy prothrombin, detected by a staphylocoagulase assay, was elevated in only a single fetus and a single neonate.After maternal oral supplementation with vitamin K1, cord vitamin K1 levels were boosted 30-fold at mid trimester and 60 fold at term, demonstrating placental transfer. However, these levels were substantially lower than corresponding supplemented maternal levels. Despite elevated vitamin K1 concentrations, supplemented fetuses and neonates showed no increase in total or coagulant prothrombin activity. These results suggest that the low prothrombin levels found during intrauterine life are not due to vitamin K deficiency.

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