Presentation Vitamin K.pdf

Vitamin K Absorption, Functions and Deficiency  HISTORY Vitamin K was discovered 1929, when the Danish Nutritional scientist Dr. Henrik Dam was investigating the role of cholesterol. After several weeks of feeding chicks a totally fat-free diet the an...

Vitamin K Absorption, Functions and Deficiency  HISTORY Vitamin K was discovered 1929, when the Danish Nutritional scientist Dr. Henrik Dam was investigating the role of cholesterol. After several weeks of feeding chicks a totally fat-free diet the animals started to suffer from uncontrolled bleeding under their skin. The bleeding could not be stopped with purified cholesterol. Dr. Dam isolated a previously unknown fat-soluble nutrient, which he appropriately named the vitamin “K” after the first letter of the Germanic spelling for coagulation („Koagulations vitamin“). PANCHALI MOITRA 2  HISTORY Building upon Dam's discovery, American biochemict Edward A. Doisy uncovered the structure and chemical nature of vitamin K. Their combined efforts were rewarded in 1943 when Dam and Doisy received the Nobel Prize in Medicine for their work on vitamin K. For several decades, the vitamin K-deficient chick model was the only method of quantifying vitamin K in various foods: the chicks were made vitamin K-deficient and subsequently fed with known amounts of vitamin K-containing food. The extent to which blood coagulation was restored by the diet was taken as a measure for its vitamin K content. PANCHALI MOITRA 3  Types Vitamin K is a family of similar, fat-soluble, 2-methyl-1,4- naphthoquinones, that occur naturally as two chemically distinct forms called vitamin K1 and vitamin K2. Vitamin K1 (Phylloquinone, phytonadione) occurring naturally in plants, algae, and photosynthetic bacteria, green leafy vegetables, and vegetable oils. Vitamin K2 or Menaquinone can be found predominately in meat, as well as in fermented products, certain types of cheese, butter, chicken, egg yolk and natto. PANCHALI MOITRA 4  Although K2 vitamins comprise only 10% of our total dietary vitamin K intake, they may form half of the total vitamin K absorbed due to the much better, nearly complete absorption and also significantly longer biological half-life of the long-chain menaquinones. There also exist three synthetic types of vitamin K: vitamins K3, K4, and K5. Vitamin K3 or menadione is considered to be a provitamin which can transform into the fat soluble Vitamin K forms in organism PANCHALI MOITRA 5  Absorption and Transport Phylloquinone is absorbed from the jejunum by an energy dependent process. Menaquinones and menadiones are absorbed from the small intestine and colon by passive diffusion. Absorption of vitamin K is enhanced in presence of bile salts and pancreatic juice. Within the cell, Vit k is incorporated into chylomicron that enters the lymphatic and then the circulatory system for transport into tissues. Chylomicron remnants deliver vitamin K to liver. Extra hepatic tissues that store vit K include adrenal glands, lungs, bone marrow, kidney and lymph nodes PANCHALI MOITRA 6 Vitamin K Cycle or K Epoxide Cycle Vitamin K is an essential cofactor for the posttranslational conversion of glutamate (Glu) residues into gamma- carboxyglutamate (Gla). Vitamin K in the body is present in its oxidized quinone form because of the presence of oxygen in blood Carboxylation of vitamin K-dependent proteins conveys ability to bind calcium ions, which is essential for their biological activity. Compared to other vitamin K analogues, vitamin K2 has the most potent gamma-carboxylation activity. PANCHALI MOITRA 7 PANCHALI MOITRA 8  Excretion Vitamin K is extensively metabolised in the liver and excreted in the urine and bile. In tracer experiments it was found that about 20 percent of an injected dose of phylloquinone was recovered in the urine whereas about 40-50 percent was excreted in the faeces via the bile PANCHALI MOITRA 9  Role of Vit K in blood clotting mechanism For blood to clot, fibrinogen, a soluble protein must be converted into fibrin, an insoluble fiber network. Thrombin catalyses the proteolysis of fibrinogen into fibrin. Fibrin molecules aggregate to form a polymer which then undergoes cross linking by fibrin stabilizing factor to form an insoluble clot and stop bleeding (hemorrahage) PANCHALI MOITRA 10  Intrinsic & Extrinsic Pathway The main difference between intrinsic and extrinsic pathways in blood clotting is that intrinsic pathway is activated by a trauma inside the vascular system whereas extrinsic pathway is activated by external trauma. The common pathway consists of factors I, II, V, VIII, X. The factors circulate through the bloodstream as zymogens and are activated into serine proteases. These serine proteases act as a catalyst to cleave the next zymogen into more serine proteases and ultimately activate fibrinogen PANCHALI MOITRA 11  Intrinsic Pathway In the intrinsic pathway, the coagulation process is initiated by the adsorption of factor XII onto a substance such as collagen. Once factor XII is activated, it initiates a cascade that proceeds to complete the conversion of fibrinogen to fibrin for clot formation. The four factors, II( prothrombin), VII, IX and X are vit k dependent. Carboxylation of glutamic acid residues facilitate their binding to calcium. Calcium then mediates the binding of Gla proteins to phospholipid membrane surfaces. This adsorption of specific protein on phospholipid surfaces is essential for initiation, progression and regulation of blood clotting In extrinsic pathway, (during tissue injury), compounds such as tissue thromboplastin activate VII. Through a similar cascade of reactions, thrombin is synthesized from prothrombin. PANCHALI MOITRA 12 PANCHALI MOITRA 13  Intrinsic Pathway This pathway is the longer pathway of secondary hemostasis. It begins with the activation of Factor XII (a zymogen, inactivated serine protease) which becomes Factor XIIA (activated serine protease) after exposure to endothelial collagen. Endothelial collagen is only exposed when endothelial damage occurs. Factor XIIA acts as a catalyst to activate factor XI to Factor XIA. Factor XIA then goes on to activate factor IX to factor IXA. Factor IXA goes on to serve as a catalyst for turning factor X into factor Xa. This is known as a cascade. When each factor is activated, it goes on to activate many more factors in the next steps. The intrinsic pathway is clinically measured as the partial thromboplastin time (PTT). PANCHALI MOITRA 14  Extrinsic pathway The extrinsic pathway is the shorter pathway of secondary hemostasis. Once the damage to the vessel is done, the endothelial cells release tissue factor which goes on to activate factor VII to factor VIIa. Factor VIIa goes on to activate factor X into factor Xa. This is the point where both extrinsic and intrinsic pathways become one. The extrinsic pathway is clinically measured as the prothrombin time (PT). PANCHALI MOITRA 15 PANCHALI MOITRA 16  The other vit k dependent proteins involved in blood clotting are Protein C ( a protease that inhibits coagulation), protein S (promotes fibrinolysis and lysis of clot). Protein M promotes thrombin synthesis from prothrombin PANCHALI MOITRA 17  Negative Feedback To prevent over-coagulation, which causes widespread thrombosis, there are certain processes to keep the coagulation cascade in check. As thrombin acts as a procoagulant, it also acts as a negative feedback by activating plasminogen to plasmin and stimulating the production of antithrombin (AT). 1. Plasmin acts directly on the fibrin mesh and breaks it down. 2. AT decreases the production of thrombin from prothrombin and decreases the amount of activated factor X. PANCHALI MOITRA 18  Role of Liver One of the organs intimately involved in the coagulation process is the liver. The liver is responsible for the formation of factors I, II, V, VII, VIII, IX, X, XI, XIII, and protein C and S. Factor VII is created by the vascular endothelium. A decrease in coagulation factors typically means severe liver damage PANCHALI MOITRA 19  Deficiency of Factors Hemophilia A and B are inherited in an x-linked recessive pattern. In hemophilia A there is a deficiency in factor VIII. In hemophilia B there is a deficiency in factor IX Hemophilia C is an autosomal recessive mutation, where there is a deficiency in factor XI. PANCHALI MOITRA 20  Role of Vit K in bone health Vitamin K-dependent γ-carboxylation is essential to several bone- related proteins, including osteocalcin, anticoagulation factor protein S, matrix γ-carboxylated glutamate (Gla) protein (MGP), Gla- rich protein (GRP), and periostin (originally called osteoblast-specific factor-2). Vitamin K is a coenzyme for glutamate carboxylase, which mediates the conversion of glutamate to gamma-carboxyglutamate (Gla). Gla residues attract Ca2+ and incorporate these ions into the hydroxyapatite crystals Osteocalcin is the major non-collagenous protein incorporated in bone matrix during bone formation While Vit D stimulates osteocalcin synthesis, vit k regulates its calcium binding capacity through vitamin K-dependent γ- carboxylation of three glutamic acid residues PANCHALI MOITRA 21 Role of other K dependent proteins Protein S appears to play a role in the breakdown of bone, mediated by osteoclasts. Individuals with inherited protein S deficiency suffer complications related to increased blood clotting and impaired bone turnover. MGP has been found in cartilage, bone, and soft tissue, including blood vessel walls MGP has been involved in the prevention of calcification at various sites, including cartilage, vessel wall, skin elastic fibers, or human eye. PANCHALI MOITRA 22  Vit K and Vasculature Another vit K dependent protein which plays a role in vasculature is growth arrest specific 6 (GAS-6) protein GAS- 6 is structurally similar to anti- coagulant protein S and can be produced either by platelets or vascular smooth muscle cells. Gas6 is a vitamin K dependent (VKD) protein, a member of a family that includes coagulation factors II, VII, IX, and X, protein C, protein S, and protein Z. Its structural relationship to these critical components of the clotting system and genetic data suggest that Gas6 participates in vascular disease by promoting platelet aggregation. Gas 6 of platelet origin promotes thrombin formation and hence aids in the blood clotting process. Any interference in the production of Gas6 may result in decreased platelet aggregation, clot retraction, and tissue factor expression PANCHALI MOITRA 23 PANCHALI MOITRA 24  Deficiency Overt vitamin K deficiency results in impaired blood clotting Symptoms include easy bruising and bleeding that may be manifested as nosebleeds, bleeding gums, blood in the urine, blood in the stool, tarry black stools, or extremely heavy menstrual bleeding. In infants, vitamin K deficiency may result in life-threatening bleeding within the skull (intracranial hemorrhage) Because bleeding can occur spontaneously and because no screening test is available, it is now common paediatric practice to protect all infants by giving vitamin K supplements in the immediate perinatal period. PANCHALI MOITRA 25  Vitamin K deficiency is uncommon in healthy adults for a number of reasons: (1) vitamin K is widespread in foods; (2) the vitamin K cycle conserves vitamin K (through Vitamin K oxidation-reduction cycle); and (3) bacteria that normally inhabit the large intestine synthesize menaquinones (vitamin K2) aids in are absorption of Vit K At risk Individuals: those taking vitamin K antagonists and individuals with significant liver damage or disease. Additionally, individuals with fat malabsorption disorders, including inflammatory bowel disease and cystic fibrosis area t greater risk. PANCHALI MOITRA 26  Infants- Newborn babies who are exclusively breast-fed are at increased risk for vitamin K deficiency, due to reasons: (1) vitamin K transport across the placental barrier is limited; (2) liver storage of vitamin K is very low; (3) the vitamin K cycle may not be fully functional in newborns, especially premature infants; and (4) the vitamin K content of breast milk is low. Keeping this in mind, a supplementation is advised for all neonates- 0.5-1.0mg phylloquinine is injected intramuscularly, shortly after birth PANCHALI MOITRA 27  Assessment of Vitamin K Status Conventional coagulation assays are useful for detecting overt vitamin K-deficient states which are associated with a risk of bleeding. A more sensitive measure of vitamin K sufficiency can be obtained from tests that detect under-carboxylated species of vitamin K-dependent proteins. In states of vitamin K deficiency, under-carboxylated species of the vitamin K-dependent coagulation proteins are released from the liver into the blood; their levels increase with the degree of severity of vitamin K deficiency PANCHALI MOITRA 28  Any deficit of vitamin K in bone will cause the osteoblasts to secrete under-carboxylated species of osteocalcin (ucOC) into the bloodstream. It has been proposed that the concentration of circulating ucOC reflects the sufficiency of vitamin K Other criteria of vitamin K sufficiency that have been used are plasma measurements of phylloquinone and the measurement of urinary Gla. It is expected and found that the excretion of urinary Gla is decreased in vitamin K deficiency. PANCHALI MOITRA 29  Reference for Further reading http://www.fao.org/3/y2809e/y2809e0g.htm http://departments.weber.edu/chpweb/hemo philia/mechanisms_of_blood_coagulation.ht m https://lpi.oregonstate.edu/mic/vitamins/vita min-K PANCHALI MOITRA 30