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Wednesday, June 9, 2021




Vitamin K is an essential nutrient that is required as a cofactor for the production of a handful of coagulation cascade proteins. It is a fat-soluble vitamin that is efficiently stored in the human body. Vitamin K deficiency is rare and is typically seen only transiently in neonates and infants during the first 6 months of life. Affected neonates may show abnormally prolonged bleeding after minor trauma. Patients may have an elevated pro- thrombin time (PT) and decreased serum levels of vitamin K and coagulation factors. Therapy consists of replacement of vitamin K to normal levels and a search for any possible underlying cause, such as liver or gastrointestinal disease. Neonatal and infantile vitamin K deficiency is most likely caused by maternal breast milk insufficiency of vitamin K.

Vitamin K deficiency is rarely seen in adults, because most diets contain enough vitamin K for normal physiological functioning. Adult patients with liver disease and malabsorption states are at highest risk for the development of vitamin K deficiency. Vitamin K may be found in two natural forms: vitamin K1 (phylloquinone) and vitamin K2 (menaquinone). K1 is found in plants, and K2 is produced by various bacteria that make up the normal flora of the gastrointestinal tract. Anti- biotics may cause a decrease in the bacterial production of vitamin K2, resulting in a lack of vitamin K available for absorption. This is typically not a clinical issue unless the patient is taking a vitamin K antagonist such as warfarin. Vitamin K is absorbed in the distal jejunum and ileum via passive diffusion across the cell membrane. The majority of vitamin K is stored normally in the liver. There, the vitamin is converted to its active state, hydroxyquinone. An efficient vitamin K salvage pathway normally prevents an individual from becoming deficient in the vitamin. The enzyme vitamin K epoxide reductase is responsible for converting the inactive epoxiquinone to the active hydroxyquinone form of vitamin K.

Warfarin is a synthetic analogue of vitamin K and is the main vitamin K antagonist. It is indicated for use as an anticoagulant in the treatment of a number of conditions, including atrial fibrillation and deep venous thrombosis, and after heart valve replacement surgery. Warfarin acts by inhibiting the enzymes that are responsible for carboxylation of glutamate residues and epoxide reductase. This both decreases the available clotting factors and induces vitamin K deficiency, leading to added reduction of available clotting factors. Clinical Findings: Vitamin K antagonists have been shown to cause a specific type of cutaneous eruption known as warfarin necrosis, which occurs in approximately 0.05% of patients taking the medication. Warfarin necrosis affects the areas of the body that have increased body fat, such as the breasts, the abdominal pannus, and the thighs. The feet are also particularly prone to development of warfarin necrosis. The skin initially develops small, red to violaceous petechiae and macules preceded by paresthesias. These regions become erythematous and purple (ecchymoses) with intense edematous skin. The lesions eventually ulcerate or form hemorrhagic bullae. The hemorrhagic bullae desquamate, leaving deep ulcers. Painful cutaneous ulcers may occur, with some extending into the subcutaneous tissue, including muscle. Most ulcers appear within 5 to 7 days after the initiation of warfarin therapy. Secondary infection may be a cause of significant morbidity. The affected areas continue to undergo necrosis unless the warfarin is withheld and the patient is treated with a different class of anticoagulant. The feet and lower extremities may have a reticulated, purplish dis- coloration called “purple toe syndrome.” This cutaneous drug reaction can be eliminated or at least drastically decreased if the patient is pretreated with heparin or another equivalent anticoagulant before warfarin is initiated.

Histology: Skin biopsies from areas of warfarin necrosis show an ulcer with a mixed inflammatory infiltrate. Thrombosis is seen within the small vessels (venules and capillaries) of the cutaneous vasculature. Arterial involvement is absent. Minimal to no inflammatory infiltrate is present. Red blood cell extravasation is prominent. The main histopathological finding is microthrombi. Findings of inflammation, a neutrophilic infiltrate, arterial involvement, a strong lymphocytic infiltrate, or the presence of bacteria in or around vessels mitigate against the diagnosis of warfarin necrosis. Bacteria will be present on the surface of the ulcer and are believed to be a secondary phenomenon.

Pathogenesis: Vitamin K is needed for the modification of many coagulation cascade proteins, including protein C, protein S, factor II (prothrombin), factor VII, factor IX, and factor X. Factors II, VII, IX, and X are critical in forming a clot and are produced in the liver as inactive precursors. Preactivation of these clotting factors requires the action of vitamin K carboxylation on glutamate amino acid residues. Once preactivated, the clotting factors are available for full activation and clot formation when exposed to calcium and phospholipids on the surface of platelets.


Inhibition of  these clotting  factors by vitamin  K antagonists leads to anticoagulation. Warfarin works by inhibiting the carboxylation of glutamate. On the other hand, protein C and protein S are responsible for turning off the clotting cascade and play a natural regulatory role in normal coagulation. When these proteins are inhibited, the clotting cascade may proceed unimpeded, allowing for excessive clotting. Protein C and protein S have shorter half-lives than factors II, VII, IX, and X. Therefore, when individuals are treated initially with warfarin, the levels of protein C and protein S are depleted before the other factors, leading to a prothrombic state.  This initial prothrombic state is responsible for the clinical signs and symptoms of microvasculature blood clotting and skin necrosis. The clotting takes place in areas of increased adipose tissue because of the sluggish flow of blood through the fine vasculature in these regions. For this reason, most patients are given heparin or a similar anticoagulant until the full effect of warfarin on all clotting factors has occurred.

Therapy: Treatment of warfarin necrosis requires discontinuation of warfarin and initiation of heparin anticoagulation and supportive care with fresh-frozen plasma and vitamin K replace the lost protein C and protein S. Surgical debridement may be required, and one should be vigilant for any signs or symptoms of secondary infection. Therapy consists of proper replacement of vitamin K and supportive care. Menadione is a synthetic form vitamin K that can be given therapeutically.

Vitamin K deficiency in neonates and infants is diagnosed by an isolated elevation in the prothrombin time. The levels of the vitamin K–dependent clotting cofactors can each be measured, and vitamin K replacement should be administered to those who are deficient. Breast milk is not a strong source of vitamin K, and if the mother had previous children with vitamin K deficiency, the newborn should be given supplemental vitamin K. The best method for supplementation has yet to be determined, but it can be achieved with a one-time intramuscular injection or with oral replacement.

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