The Role of Vitamins in Hemostasis

1975 ◽  
Vol 33 (02) ◽  
pp. 191-198
Author(s):  
Armand J Quick
Keyword(s):  
Vitamin K ◽  
Physiological Mechanism ◽  
Factor Vii ◽  
Clotting Factors ◽  
The Third ◽  
Abnormal Bleeding ◽  
Vitamin Q ◽  
Tissue Thromboplastin ◽  
And Control

SummaryThe physiological mechanism to prevent and control abnormal bleeding is dependent on three vitamins (C, K, and Q). Two of these are unequivocally established as essential for hemostasis while the existence of the third (Q) is supported by experimental evidence and by clinical and therapeutic observations (Quick 1972; Quick 1974). The interrelationship of these three vitamins has remained moot except for clue observations. Both vitamins C and K have a key structure in their molecules which supplies a redox mechanism, ascorbic acid and 2-methyl, 1,4-naphthoquinone, respectively. Both vitamins are concerned with growth. Lack of vitamin C, which clinically is the basic defect in scurvy, does not appear to cause a defect in blood coagulation while vitamin K affects the clotting mechanism by being essential for the production of four distinct clotting factors: prothrombin, factors VII, IX and X.In this presentation an attempt is made to correlate the action of the vitamin K-dependent clotting factors grouping them in a diagram to show how two systems of thrombin formation exist, one being essentially intrinsic, the second extrinsic requiring tissue thromboplastin and factor VII. The possible interlocking of vitamin Q in this mechanism is presented.

The Cradle of Exotica

2020 ◽  
pp. 4-25
Author(s):  
Karen Polinger Foster
Keyword(s):  
Cultural Identity ◽  
Natural World ◽  
The Third ◽  
Political Status ◽  
Third Millennium ◽  
Commercial Enterprise ◽  
Key Aspects ◽  
And Control ◽  
Clay Tablet

This chapter discusses the role of exotica in the Mesopotamian mind. By 1875, The Epic of Gilgamesh had begun to emerge from the thousands of clay tablet fragments freshly unearthed in the remains of the great royal library of Assurbanipal at Nineveh. Gilgamesh’s drive to possess the exotic is rooted in long-standing Mesopotamian tradition. From the third millennium on, when he supposedly reigned, scholar-scribes organized and classified nearly all aspects of the natural world. Thematic lists of flora and fauna, heavenly bodies, precious and semiprecious materials, and topographical features provided the educated elite with a means of conceptualizing patterns and interrelationships. For Gilgamesh, as for many Mesopotamian rulers, the acquisition and display of exotica were key aspects of kingship. Once secured within the walled, urban cores of Mesopotamian cultural identity, exotica offered tangible signs of wide-ranging military might, commercial enterprise, and political status and control.

VKORC1 deficiency in mice causes early postnatal lethality due to severe bleeding

2009 ◽  
Vol 101 (06) ◽  
pp. 1044-1050 ◽  
Author(s):  
Gabriele Spohn ◽  
Andre Kleinridders ◽  
F. Thomas Wunderlich ◽  
Matthias Watzka ◽  
Frank Zaucke ◽  
...  
Keyword(s):  
Vitamin K ◽  
Knockout Mice ◽  
Severe Bleeding ◽  
Clotting Factors ◽  
Vitamin K Cycle ◽  
Severe Deficiency ◽  
Epoxide Reductase ◽  
Bone Calcification

SummaryVitamin K hydroquinone is oxidised to the epoxide form (K>O) during vitamin K-dependent posttranslational γ-glutamyl carboxylation resulting in biological active so called vitamin K-dependent proteins. In turn, K>O is reduced by the enzyme VKORC1 (vitamin K epoxide reductase complex component 1) to complete the vitamin K cycle. To investigate the biological role of VKORC1 in vivo, we generated VKORC1 knockout mice. Homozygous VKORC1-deficient mice developed normally until birth. Within 2–20 days after birth, the knockout mice died due to extensive, predominantly intracerebral haemorrhage. Bleeding resulted from a severe deficiency of γ-carboxylated clotting factors. This lethal phenotype could be rescued by oral administration of vitamin K. Additionally, morphometric analysis of the limbs in VKORC1-deficient animals revealed reduced length of bone calcification relative to wild-type control mice. The observed phenotype of VKORC1 knockout mice excludes the existence of other enzymes with VKOR activity that can substitute to supply vitamin K hydroquinone required for maturation of blood clotting factors. Thus, our study underscores the essential role of VKORC1 in vitamin K-dependent γ-glutamyl carboxylation.

scholarly journals Reduction of salivary tissue factor (thromboplastin) activity by warfarin therapy

Blood ◽  
1979 ◽  
Vol 53 (3) ◽  
pp. 366-374 ◽  
Author(s):  
LR Zacharski ◽  
R Rosenstein
Keyword(s):  
Tissue Factor ◽  
Vitamin K ◽  
Coagulation Factors ◽  
Human Saliva ◽  
Factor Vii ◽  
Clotting Factor ◽  
Activate Factor ◽  
Total Protein Content ◽  
Factor X ◽  
Clotting Factors

Abstract The coagulant of normal human saliva has been identified as tissue factor (thromboplastin, TF) by virtue of its ability to cause rapid coagulation in plasmas deficient in first-stage coagulation factors and to activate factor x in the presence of factor VII and by virtue of the fact that its activity is expressed only in the presence of factor VII and is inhibited by an antibody to TF. The TF is related to cells and cell fragments in saliva. Salivary TF activity has been found to be significantly reduced in patients taking warfarin. The decline in TF activity during induction of warfarin anticoagulation occurs during the warfarin-induced decline in vitamin-K-dependent clotting factor activity, as judged by the prothrombin time. The decrease in TF activity is not related to a reduction in salivary cell count or total protein content or to a direct effect of warfarin on the assay. It is hypothesized that the mechanism by which warfarin inhibits TF activity may be related to the mechanism by which it inhibits expression of the activity of the vitamin-K-dependent clotting factors. Inhibition of the TF activity may be involved in the antithrombotic effect of warfarin.

Clinical Implications of Crosstalk Between Coagulation and Inflammation: The Role of Anticoagulation in Treating Sepsis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2874-2874
Author(s):  
Zhi Xu ◽  
Elizabeth Phillips ◽  
Prasanta Basak ◽  
Stephen Jesmajian
Keyword(s):  
Vitamin K ◽  
Inflammatory Responses ◽  
Conflicts Of Interest ◽  
Vitamin K Antagonist ◽  
Coagulation Cascade ◽  
Factor Vii ◽  
Clinical Implications ◽  
Factor X ◽  
All Cause Mortality

Abstract BACKGROUND: Despite decades of active investigation, sepsis remains one of the leading causes of mortality worldwide. Multiple lines of evidence have illustrated that up-regulation of the activated Factor VII (FVIIa)/Tissue Factor (TF) complex, and its downstream extrinsic coagulation cascade, are major contributors to coagulopathies and inflammatory response during sepsis. For example, decreased mortality and inflammatory responses during sepsis were observed in mice with significantly reduced FVII expression. Another recent study demonstrated the association of increased mortality with higher levels of FVIIa in septic patients. Similar results have been demonstrated for Factor X (FX) and thrombin. In addition, several studies have been conducted to investigate the role of heparin in treating sepsis and have yielded promising results, however, the exact mechanisms remain elusive, and the clinical implications of crosstalk between coagulation pathways and sepsis are yet to be determined. Furthermore, the role of vitamin-K antagonist in sepsis has not been investigated. OBJECTIVE: To assess the effects of pre-existing anticoagulation with warfarin on the clinical course of septic patient. METHODS: This was a retrospective observational study undertaken in a community-based teaching hospital. Patients who were admitted with a primary diagnosis of sepsis from January 01 to June 30, 2012 were included in the study. The clinical characteristics between patient groups without and with prior anticoagulation were compared and analyzed. The primary outcomes include the severity of sepsis, length of hospitalization, and mortality rate during hospitalization. RESULTS: A total of 134 septic patients were included in the study. Among them, 105 patients were not anticoagulated, while 29 patients were anticoagulated, prior to admission (mean age: 76.0 + 1.2 vs. 77.5 + 2.6, p = 0.603). All of the patients with anticoagulation had been taking warfarin due to either pre-existing atrial fibrillation (79.3%) or deep vein thrombosis/pulmonary embolism (20.7%). There were significant differences in International Normalized Ratio (INR) of prothrombin time between groups without and with anticoagulation at the time of admission (1.28 + 0.04 vs. 4.59 + 0.83, p < 0.001). Septic patients who did not take warfarin prior to admission presented with higher Sepsis Indices (0.93 + 0.03 vs. 0.82 + 0.05, p < 0.05), resulting in longer hospitalizations (11.60 + 1.02 vs. 8.40 + 0.70, p < 0.001). The overall all-cause mortality rates during the hospitalization between patients without anticoagulation and those with anticoagulation were 23% vs. 14%, respectively. CONCLUSION: To our knowledge, this is the first study to demonstrate that septic patients with prior anticoagulation by a vitamin-K antagonist presented with less severity of sepsis, reduced length of hospital stay, and decreased all-cause mortality during hospitalization as compared with those without anticoagulation. In our study, prior administration of anticoagulation with warfarin may have had significant clinical implications in septic patients. This warrants further prospective studies. Disclosures No relevant conflicts of interest to declare.

The Role of Factor IX in Tissue Thromboplastin Induced Coagulation

1982 ◽  
Vol 48 (01) ◽  
pp. 054-058 ◽  
Author(s):  
A M H P van den Besselaar ◽  
I E Ram ◽  
G H J Alderkamp ◽  
R M Bertina
Keyword(s):  
Human Factor ◽  
Factor Ix ◽  
Factor Vii ◽  
Factor Xii ◽  
Factor Xi ◽  
Proteolytic Activation ◽  
Human Factor Ix ◽  
Tissue Thromboplastin ◽  
The Difference

SummaryTissue thromboplastin apoprotein was partially purified from human brain. The apoprotein was recombined with mixed phospholipids to yield active thromboplastin. The recombined thromboplastin induced proteolytic activation of isolated human factor IX in the presence of factor VII and Ca2+. The clotting times of various deficient plasmas were determined as a function of apoprotein concentration, keeping the phospholipid concentration constant. The clotting times of a factor XII-deficient plasma were the same as those of a factor XII/factor IX-deficient plasma, except at very low apoprotein concentrations. However, under those conditions the difference in clotting times was independent of the presence of anti-factor VII serum. Similar observations were made for factor XI-deficient plasma in comparison with factor XI/factor IX-deficient plasma. These results indicate that activation of factor IX by factor VII/tissue thromboplastin does not significantly contribute to plasma coagulation.

Cystic Fibrosis Presenting with Severe Hemorrhage Due to Vitamin K Malabsorption: A Report of Three Cases

PEDIATRICS ◽  
1970 ◽  
Vol 45 (5) ◽  
pp. 857-861
Author(s):  
Ordean L. Torstenson ◽  
G. Bennett Humphrey ◽  
J. Roger Edson ◽  
Warren J. Warwick
Keyword(s):  
Cystic Fibrosis ◽  
Differential Diagnosis ◽  
Vitamin K ◽  
Bleeding Tendency ◽  
Clotting Factors ◽  
Vitamin K Deficiency ◽  
The Third ◽  
Severe Hemorrhage ◽  
K Deficiency ◽  
Low Levels

Three patients are discussed who presented with hemorrhagic diatheses who were subsequently diagnosed as having cystic fibrosis. Their prolonged prothrombin times and low levels of vitamin K-dependent clotting factors were due to vitamin K deficiency. In two patients we believe that the vitamin K deficiency was principally due to malabsorption caused by cystic fibrosis. In the third patient, malabsorption, diarrhea, antibiotic therapy, and low dietary intake all played a part in the development of vitamin K deficiency. Cystic fibrosis should be included in the differential diagnosis of patients under 1 year of age presenting with a bleeding tendency.

Properties of Recombinant Human Thromboplastin that Determine Sensitivity to Vitamin K-Dependent Coagulation Factors.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 533-533
Author(s):  
Stephanie A. Smith ◽  
James H. Morrissey
Keyword(s):  
Ionic Strength ◽  
Vitamin K ◽  
Phospholipid Composition ◽  
Coagulation Factors ◽  
Factor Vii ◽  
Clotting Factor ◽  
Sensitivity Index ◽  
Clotting Factors ◽  
Individual Factor ◽  
Factor Deficiency

Abstract Patients undergoing oral anticoagulant therapy (OAT) with coumarins have reduced plasma levels of vitamin K-dependent clotting factors. The primary laboratory test for monitoring OAT is the prothrombin time (PT), in which clotting is initiated by tissue factor (TF). Clotting factors that contribute to the PT, and whose levels respond to OAT, are factor VII (FVII), factor X (FX), and prothrombin, although they are not suppressed to the same extent. Thromboplastin reagents (the source of TF activity in PT tests) can vary dramatically in their sensitivities to the effects of OAT. A calibration system, the International Sensitivity Index (ISI), is widely used to correct the PT for variable thromboplastin sensitivity, but discrepant responses by reagents of similar ISI have been reported. We have undertaken studies aimed at understanding which factors control the sensitivity of thromboplastin reagents, with a goal of creating “designer thromboplastins” whose sensitivities to specific clotting factors can be individually tailored. Thromboplastin reagents were prepared by reconstituting recombinant human TF into phospholipid vesicles containing varying amounts of phosphatidylcholine, phosphatidylserine (PS), and phosphatidylethanolamine (PE). Thromboplastins containing low levels of PS and high ionic strength had the highest sensitivity to OAT (i.e., lowest ISI). PE shifted the dose-response such that lower levels of PS were required to obtain the same ISI value. These studies demonstrate that multiple combinations of phospholipid composition and ionic strength can be used to produce reagents of identical ISI. We hypothesized that reagents of identical ISI values but different composition could have very different responses to changes in the levels of individual coagulation factors. Accordingly, thromboplastin reagents of varying composition were evaluated for their responses to deficiencies of FVII, FX and prothrombin. PT tests were performed using pooled normal plasma mixed with individual factor-depleted plasmas to yield 10%, 3%, 1% or 0.3% of the normal level of the specific clotting factor. Responses of thromboplastin reagents to individual factors were compared by plotting the clotting times obtained with these plasmas on log-log scales versus the percent factor level and fitting lines to the data by linear regression. Interestingly, altering the composition of the thromboplastin reagents dramatically and independently altered their sensitivities to individual clotting factors. For example, increasing ionic strength had no impact on the response to FVII, but markedly enhanced the response to prothrombin deficiency. Furthermore, the effect of changes in ionic strength on specific factors levels differed depending upon the phospholipid composition. These studies demonstrate that thromboplastin reagents of dissimilar composition but nearly identical ISI values can have very different sensitivities to deficiencies in FVII, FX, or prothrombin, so reagents of identical ISI do not necessarily respond to the factor deficiencies induced by OAT in an identical fashion. These studies evaluated samples with isolated individual factor deficiency, whereas patients on OAT have combined factor deficiency and therefore have more potential for discrepancy in PT responses between reagents. Controlling the responsiveness of thromboplastin reagents to deficiencies in individual clotting factors may therefore be desirable for monitoring OAT and for the other clinical diagnostic uses to which PT tests are commonly applied.

Prolonged Coagulopathy Secondary to Superwarfarin Brodifacoum Rodenticide Ingestion

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4425-4425
Author(s):  
Abhinav B. Chandra ◽  
Nanda K. Methuku ◽  
Yiwu Huang
Keyword(s):  
Vitamin K ◽  
Half Life ◽  
Conflicts Of Interest ◽  
Active Form ◽  
Factor Vii ◽  
Factor Xii ◽  
Vitamin K1 ◽  
Clotting Factors ◽  
Duration Of Action ◽  
Intentional Ingestion

Abstract Abstract 4425 Case description– A 47 year old man presented to emergency room due to back pain, hematuria and persistent gum bleed for more than one week after dental procedure. He had also noted easy bruisability for the last two months. He was found to have elevated PT and PTT. On admission, his PT was >120 sec with INR > 9.9 and his PTT > 100 sec. The abnormal PT and PTT were completed corrected by the addition of normal plasma on mixing study. Factor assay showed factor II level 19%, factor VII 1.5%, factor IX 7.4%, factor × 15%, factor V 87%, factor VIII 140%, factor XI 96%, and factor XII 49%. Since he had no other medical conditions and no history of hepatic dysfunction that would cause his coagulopathy, superwarfarin toxicity was suspected. Blood toxicology screen was positive for superwarfarin compound brodifacoum. He received few units of FFP and was given a loading dose of 50 mg phytonadione (vitamin K) followed by 20 mg three times daily. His PT and INR normalized and gum bleeding and hematuria resolved. The patient was discharged from hospital. Patient denied any intentional ingestion of rat poison, any suicidal ideation or any conflicts within family. He was exposed to rodenticide at his workplace. During outpatient follow up, patient was again found to have elevated PT/INR and on questioning informed that he was taking Chinese herbal medications provided by his friends to facilitate excretion of the rat poison. Patient was advised to stop taking any alternative therapies. His phytonadione was increased to 240 mg/day for more than two months which have normalized his coagulopathy. Discussion– Human toxicity from ingestion of older rodenticides that contain warfarin is uncommon because these products contain less warfarin and the drug is rapidly metabolized. Newer derivates of warfarin (superwarfarins) brodifacoum, difethialone and difenicoum have been developed to overcome warfarin resistance. These compounds are more toxic to humans than warfarin because of their more avid binding to hepatic microsomes and longer duration of action. Brodifacoum and difenicoum are far more potent and have a much longer half-life than warfarin. The half-life of brodifacoum has been described as long as 30 days. Superwarfarins produce their anticoagulation effect by inhibiting the conversion of vitamin K1 2,3 epoxide to vitamin K1. This reaction is coupled to the carboxylation reaction required to produce the active form of prothrombin and the other vitamin K dependent clotting factors. There is increase in the vitamin K epoxide to vitamin K ratio and severely decreased activity of vitamin K dependent clotting factors. The duration of coagulation disturbance can be from few weeks to as long as few months. As illustrated by our patient, the treatment of superwarfarin posioning requires large doses of phytonadione, ranging from 50 – 800 mg/day administered for several months. Our patient has required daily 240 mg of phytonadione over two months to normalize his coagulopathy. Disclosures: No relevant conflicts of interest to declare.

Mathematical modelling of platelet rich plasma clotting. Pointwise unified model

2018 ◽  
Vol 33 (5) ◽  
pp. 265-276 ◽  
Author(s):  
Anna A. Andreeva ◽  
Mohan Anand ◽  
Alexey I. Lobanov ◽  
Andrey V. Nikolaev ◽  
Mikhail A. Panteleev ◽  
...  
Keyword(s):  
Platelet Rich Plasma ◽  
Sol Gel ◽  
Unified Model ◽  
Polymerization Process ◽  
Factor Vii ◽  
Clotting Factors ◽  
Rosenbrock Method ◽  
Sensitivity Analysis Method ◽  
Sol Gel Transition

AbstractThe mechanistic modelling of blood clotting and fibrin-polymer mesh formation is of significant value for medical and biophysics applications. This paper presents a combination of two pointwise kinetic models represented by system of ODEs. One of them represents the reaction dynamics of clotting factors including the role of the platelet membranes. The second one describes the fibrin-polymer formation as a multistage polymerization process with a sol-gel transition at the final stage. Complex-value second order Rosenbrock method (CROS) is employed for the computational experiments. A sensitivity analysis method built into the computational scheme helps clarify non-evident dependencies in the exhaustive system of ODEs. The unified model was primarily verified using conditions of factor VII deficiency. The model, however requires a significant effort to be tested against experimental data available.

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