Deficiency of vitamin K

Endocrinology, Metabolism and Nutrition

Clinicals - History

Fact Explanation
Introduction Vitamin K is a group of lipophilic, hydrophobic vitamins that belong to the class of 2-methyl-1,4-naphthoquinone derivatives. Vitamin K1/ phylloquinone is the naturally occurring compound which is the primary source of vitamin K in humans and is acquired through the diet. There are several functions in the body that are dependent on the vitamin. Blood coagulation, bone metabolism (osteocalcin, periostin and matrix Gla protein), vascular biology, cell growth are some of these areas that need vitamin K for its normal function. Vitamin K deficiency may be either idiopathic or secondary. Idiopathic vitamin K deficiency is an acquired prothrombin complex deficiency and secondary is due to the causes such as mal absorption, hepatobiliary disorders and drugs. Vitamin K deficiency bleeding disorder is an uncommon serious bleeding disorder due to the deficient activity of vitamin K-dependant coagulation factors. Introduction
Vitamin K is a group of lipophilic, hydrophobic vitamins that belong to the class of 2-methyl-1,4-naphthoquinone derivatives. Vitamin K1/ phylloquinone is the naturally occurring compound which is the primary source of vitamin K in humans and is acquired through the diet. There are several functions in the body that are dependent on the vitamin. Blood coagulation, bone metabolism (osteocalcin, periostin and matrix Gla protein), vascular biology, cell growth are some of these areas that need vitamin K for its normal function. Vitamin K deficiency may be either idiopathic or secondary. Idiopathic vitamin K deficiency is an acquired prothrombin complex deficiency and secondary is due to the causes such as mal absorption, hepatobiliary disorders and drugs. Vitamin K deficiency bleeding disorder is an uncommon serious bleeding disorder due to the deficient activity of vitamin K-dependant coagulation factors.
Age of onset Depending on the age of onset, vitsmin K deficiency can be subdivided into early that is occurring within 24 hours of birth, classical that is occurring at day 1-7 of birth and late bitamin K deficiency bleeding after 1 week to 12 months of birth. Neonates are more prone to get vitamin K deficiency as the stores are limited at birth and intake is insufficient. Age of onset
Depending on the age of onset, vitsmin K deficiency can be subdivided into early that is occurring within 24 hours of birth, classical that is occurring at day 1-7 of birth and late bitamin K deficiency bleeding after 1 week to 12 months of birth. Neonates are more prone to get vitamin K deficiency as the stores are limited at birth and intake is insufficient.
Bleeding after minor trauma and oozing from venipuncture sites and easy bruising Body’s normal mechanisms to stop the bleeding consists of main three responses: vascular, platelet and coagulatory response. Defect in any part of these responses can lead to abnormal bleeding manifestations. Coagulation cascade has main three pathways. Factors VII in extrinsic pathway, factors VIII, IX, XI and XII intrinsic pathway and V, X, fibrinogen and prothrombin in common pathway.
Factor II, VI, IX, X are the coagulation factors dependent on vitamin K for the activation. Vitamin K-dependent coagulation factors undergo γ-carboxylation of glutamic acid residues at their Gla which is catalysed by a vitamin K-dependent enzyme, γ-glutamyl carboxylase. Absence of these factor activation leads to impaired coagulation cascade leading to bleeding manifestations
Bleeding after minor trauma and oozing from venipuncture sites and easy bruising
Body’s normal mechanisms to stop the bleeding consists of main three responses: vascular, platelet and coagulatory response. Defect in any part of these responses can lead to abnormal bleeding manifestations. Coagulation cascade has main three pathways. Factors VII in extrinsic pathway, factors VIII, IX, XI and XII intrinsic pathway and V, X, fibrinogen and prothrombin in common pathway.
Factor II, VI, IX, X are the coagulation factors dependent on vitamin K for the activation. Vitamin K-dependent coagulation factors undergo γ-carboxylation of glutamic acid residues at their Gla which is catalysed by a vitamin K-dependent enzyme, γ-glutamyl carboxylase. Absence of these factor activation leads to impaired coagulation cascade leading to bleeding manifestations
Epistaxis and gum bleeding Late vitamin K deficiency bleeding usually presents as mucosal haemorrhages. Epistaxis is the bleeding from the nose and oral mucosal bleeding result in gum bleeding. Epistaxis and gum bleeding
Late vitamin K deficiency bleeding usually presents as mucosal haemorrhages. Epistaxis is the bleeding from the nose and oral mucosal bleeding result in gum bleeding.
Haematamesis and or malena Gastrointestinal bleeding Same as above due to the mucosal bleeding from the mucosal surface of the gastrointestinal tract may cause passage of blood with vomitus(haematemesis), and black tary stools (malena) associated with upper GI bleeding. Haematamesis and or malena
Gastrointestinal bleeding Same as above due to the mucosal bleeding from the mucosal surface of the gastrointestinal tract may cause passage of blood with vomitus(haematemesis), and black tary stools (malena) associated with upper GI bleeding.
Menorrhagia Excess menstrual bleeding may be found in females. Menorrhagia
Excess menstrual bleeding may be found in females.
Hematuria Urogenital bleeding may present as haematuria. Suburothelial bleeding may result in obstructive uropathy. Hematuria
Urogenital bleeding may present as haematuria. Suburothelial bleeding may result in obstructive uropathy.
Pathological fractures Vitamin K is essential for the bone metabolism particularly for the function of osteocalcin, periostin and matrix Gla protein. Terefore its deficiency will be associated with increased postmenopausal bone loss. Pathological fractures
Vitamin K is essential for the bone metabolism particularly for the function of osteocalcin, periostin and matrix Gla protein. Terefore its deficiency will be associated with increased postmenopausal bone loss.
Headache, weakness in limbs Risk of late onset vitamin K deficiency causing intracranial haemorrhage is higher in infants who have not received the prophylaxis with vitamin K. Headache, weakness in limbs
Risk of late onset vitamin K deficiency causing intracranial haemorrhage is higher in infants who have not received the prophylaxis with vitamin K.
Exclusive breastfeeding Idiopathic variety of the vitamin K deficiency is mainly due to the exclusive breast feeding. Low vitamin K level in the mother's breast milk Is also important factor for the development of vitamin K deficiency in infant. Exclusive breastfeeding
Idiopathic variety of the vitamin K deficiency is mainly due to the exclusive breast feeding. Low vitamin K level in the mother's breast milk Is also important factor for the development of vitamin K deficiency in infant.
History of celiac disease, cystic fibrosis These are some secondary causes for the vitamin K deficiency. Celiac disease and cystic fibrosis cause mal-absorption of vitamin K. History of celiac disease, cystic fibrosis
These are some secondary causes for the vitamin K deficiency. Celiac disease and cystic fibrosis cause mal-absorption of vitamin K.
History of hepatobiliary diseases Biliary atresia, α1-anti-trypsin deficiency, hepatitis like hepatobiliary diseases causes decrease synthesis of vitamin K leading to deficiency. History of hepatobiliary diseases
Biliary atresia, α1-anti-trypsin deficiency, hepatitis like hepatobiliary diseases causes decrease synthesis of vitamin K leading to deficiency.
History of drug use eg:- carbamazepine, phenytoin, barbiturates, cephalosporin, rifampicin, isoniazid coumarin, warfarin These drugs may also result in antagonism of vitamin K. Particularly drugs like warfarin which is an oral anticoagulant inhibits vitamin K dependent γ-carboxylation of clotting factors II, VII, IX and X. History of drug use eg:- carbamazepine, phenytoin, barbiturates, cephalosporin, rifampicin, isoniazid coumarin, warfarin
These drugs may also result in antagonism of vitamin K. Particularly drugs like warfarin which is an oral anticoagulant inhibits vitamin K dependent γ-carboxylation of clotting factors II, VII, IX and X.

Clinicals - Examination

Fact Explanation
Ecchymosis, petechiae, hematomas Child may present with multiple areas of bluish skin discolourations and raised swellings on trunk and extremities which may be haematomas due to the bleeding manifestations associated with coagulation factor II, VI, IX, X deficiency. Skin bleeding may occur in 10-30% of patients. Ecchymosis, petechiae, hematomas
Child may present with multiple areas of bluish skin discolourations and raised swellings on trunk and extremities which may be haematomas due to the bleeding manifestations associated with coagulation factor II, VI, IX, X deficiency. Skin bleeding may occur in 10-30% of patients.
Nodular purpura Subcutaneous tissue bleeding associated with deep ecchymoses will be seen as characteristic ‘nodular purpura’that involves the lower extremities, back, chest abdomen, buttocks, upper extremities face, and neck. These are appear as bluish-violet raised infiltrated purplish centerswith a 1.5 cm to 7.5 cm diameter. Nodular purpura
Subcutaneous tissue bleeding associated with deep ecchymoses will be seen as characteristic ‘nodular purpura’that involves the lower extremities, back, chest abdomen, buttocks, upper extremities face, and neck. These are appear as bluish-violet raised infiltrated purplish centerswith a 1.5 cm to 7.5 cm diameter.
Ooozing of blood at surgical or puncture Same as above due to the defect in coagulation cascade. Ooozing of blood at surgical or puncture
Same as above due to the defect in coagulation cascade.
Birth defects in babies Underdevelopment of the face, nose, fingers, and bones are linked to a Vitamin K-deficient state. Birth defects in babies
Underdevelopment of the face, nose, fingers, and bones are linked to a Vitamin K-deficient state.
Focal neurological signs Late onset vitamin K deficiency can cause intracranial haemorrhage particularly in infants who have not received the prophylaxis with vitamin K.
Neurological signs would be one of the most common presenting feature in 50-80% of patients.
Focal neurological signs
Late onset vitamin K deficiency can cause intracranial haemorrhage particularly in infants who have not received the prophylaxis with vitamin K.
Neurological signs would be one of the most common presenting feature in 50-80% of patients.
Pallor Sometimes patient may be presenting with anaemia due to the overt bleeding. Pallor
Sometimes patient may be presenting with anaemia due to the overt bleeding.
Difficulty in breathing and abnormal heart rate in newborns Bleeding in the new born may occur before or during the birth presenting as cardiovascular or respiratory instability at birth. Difficulty in breathing and abnormal heart rate in newborns
Bleeding in the new born may occur before or during the birth presenting as cardiovascular or respiratory instability at birth.

Investigations - Diagnosis

Fact Explanation
Prothrombin time (PT ) & activated partial thromboplastin (aPTT) Factors VII is involved in the extrinsic pathway, factors VIII, IX, XI and XII are in the intrinsic pathway and V, X, fibrinogen and prothrombin in common pathway. Factor II, VI, IX, X are the coagulation factors dependent on vitamin K for the activation. Therefore PT & APTT Investigations reveal raised activated partial thromboplastin time and prothrombintime in severe disease. Prothrombin time (PT ) & activated partial thromboplastin (aPTT)
Factors VII is involved in the extrinsic pathway, factors VIII, IX, XI and XII are in the intrinsic pathway and V, X, fibrinogen and prothrombin in common pathway. Factor II, VI, IX, X are the coagulation factors dependent on vitamin K for the activation. Therefore PT & APTT Investigations reveal raised activated partial thromboplastin time and prothrombintime in severe disease.
Full blood count Platelet counts is normal and it is important to assess in a case of bleeding manifestations. Full blood count
Platelet counts is normal and it is important to assess in a case of bleeding manifestations.
Fibrinogen level Fibrinogen level is normal Fibrinogen level
Fibrinogen level is normal
Circulating acarboxy proteins Circulating acarboxy proteins are present. Circulating acarboxy proteins
Circulating acarboxy proteins are present.
Specific vitamin K-dependent factors (II, VII, IX, X) specific vitamin K-dependent factors (II, VII, IX, X) are low in these patients and those levels are rapidly corrected by the parenteral administration of 1 mg vitamin K. Specific vitamin K-dependent factors (II, VII, IX, X)
specific vitamin K-dependent factors (II, VII, IX, X) are low in these patients and those levels are rapidly corrected by the parenteral administration of 1 mg vitamin K.

Investigations - Management

Fact Explanation
Prothrombin time (PT ) & activated partial thromboplastin (aPTT) 7.5 mg vitamin K1 intra-muscularly once-daily for 3 days will give a dramatic improvement in the patient. Prolonged APTT and PT normalized within 10 hours of first dose. Prothrombin time (PT ) & activated partial thromboplastin (aPTT)
7.5 mg vitamin K1 intra-muscularly once-daily for 3 days will give a dramatic improvement in the patient. Prolonged APTT and PT normalized within 10 hours of first dose.
Haemoglobin level, haematocrict Anemia and leukocytosis have been reported in patients with vitamin K deficiency. Bleeding manifestations, occurring as a result of clotting factor abnormalities may occasionally cause reduction in the , HCT and haemolobin level. Haemoglobin level, haematocrict
Anemia and leukocytosis have been reported in patients with vitamin K deficiency. Bleeding manifestations, occurring as a result of clotting factor abnormalities may occasionally cause reduction in the , HCT and haemolobin level.
Fine needle aspiration cytology Patient may occasionally present with purpuric nodules and FNAC reveal frank blood. Fine needle aspiration cytology
Patient may occasionally present with purpuric nodules and FNAC reveal frank blood.
Factor V, VII or X level Extremely rare hereditary deficiencies of factors V, VII or X need to be excluded to make a diagnosis. Factor V, VII or X level
Extremely rare hereditary deficiencies of factors V, VII or X need to be excluded to make a diagnosis.

Management - Supportive

Fact Explanation
Immediate management Assessment of airway and breathing, is particularly important as they can present with respiratory and cardiovascular problems following bleeding. Circulatory collapse may occur in a massive haemorrhage. Immediate management
Assessment of airway and breathing, is particularly important as they can present with respiratory and cardiovascular problems following bleeding. Circulatory collapse may occur in a massive haemorrhage.
Management of other complications Upper GI bleeding, haematuria, intracranial haemorrhage may need specific supportive management after correcting the vitamin K level. Associated psychological disturbances , learning problems due to recurrent school abstinence may need special attention Management of other complications
Upper GI bleeding, haematuria, intracranial haemorrhage may need specific supportive management after correcting the vitamin K level. Associated psychological disturbances , learning problems due to recurrent school abstinence may need special attention
Management of underlying problem There can be underlying factors leading to vitamin K deficiency such as hepatobiliary diseases, celiac disease, cystic fibrosis and drug use (carbamazepine, phenytoin, barbiturates, cephalosporin, rifampicin, isoniazid coumarin, warfarin). These conditions need specific management and stopping the Management of underlying problem
There can be underlying factors leading to vitamin K deficiency such as hepatobiliary diseases, celiac disease, cystic fibrosis and drug use (carbamazepine, phenytoin, barbiturates, cephalosporin, rifampicin, isoniazid coumarin, warfarin). These conditions need specific management and stopping the
Management of underlying causative factor There can be underlying causes for the the vitamin K deficiency such as hepatobiliary diseases, celiac disease, cystic fibrosis, and use of drugs (carbamazepine, phenytoin, barbiturates, cephalosporin, rifampicin, isoniazid coumarin, warfarin etc). These conditions need specific management and supportive care as and when needed. Stopping/limiting the causative drugs are required when possible. Management of underlying causative factor
There can be underlying causes for the the vitamin K deficiency such as hepatobiliary diseases, celiac disease, cystic fibrosis, and use of drugs (carbamazepine, phenytoin, barbiturates, cephalosporin, rifampicin, isoniazid coumarin, warfarin etc). These conditions need specific management and supportive care as and when needed. Stopping/limiting the causative drugs are required when possible.
Patient education Parents of the affected child need a full explanation of the nature of the disease, its complications and importance of complying with the treatment. Patient education
Parents of the affected child need a full explanation of the nature of the disease, its complications and importance of complying with the treatment.
Prophylaxis Single dose of IM vitamin K prophylaxis is given to new born babies within the first 6 hours after birth following initial stabilisation of the baby which provides universal long‐term protection against the vitamin K deficiency. Dose will be 0.5 mg (for babies weighing 1,500 g or less at birth) or 1.0 mg (for babies weighing more than 1,500 g at birth). There is no issue regarding the compliance as it is a single dose regime. Oral vitamin K is also available though it is not good in term of compliance. Prophylaxis
Single dose of IM vitamin K prophylaxis is given to new born babies within the first 6 hours after birth following initial stabilisation of the baby which provides universal long‐term protection against the vitamin K deficiency. Dose will be 0.5 mg (for babies weighing 1,500 g or less at birth) or 1.0 mg (for babies weighing more than 1,500 g at birth). There is no issue regarding the compliance as it is a single dose regime. Oral vitamin K is also available though it is not good in term of compliance.

Management - Specific

Fact Explanation
Vitamin K administration Infants with vitamin K deficiency bleeding are given 5-10 mg of parenteral vitamin K1. Mal-absorption disorders are treated with chronic administration of high doses of oral vitamin K (2.5 mg twice/week to 5 mg/day). Newborns with a diagnosis of hemophilia are having a tendency to bleed following intramuscular injections, and therefore oral vitamin K is preferred in newborns with hemophilia. Vitamin K administration
Infants with vitamin K deficiency bleeding are given 5-10 mg of parenteral vitamin K1. Mal-absorption disorders are treated with chronic administration of high doses of oral vitamin K (2.5 mg twice/week to 5 mg/day). Newborns with a diagnosis of hemophilia are having a tendency to bleed following intramuscular injections, and therefore oral vitamin K is preferred in newborns with hemophilia.
Improve the dietary supply Usual daily requirement of vitamin K is 2 μg for infants in the first 6 months of life, 2.5 μg for infants aged 7–12 months, 30 μg in 1–3 years, 75 μg for adolescents, and for others a daily average of 1 μg per kg of body weight is recommended. Vitamin K found in humans is the vitamin K1 available in the diet. Leafy green vegetables such as spinach, Swiss chard, Brassica (e.g. cabbage, kale, cauliflower, turnip, and Brussels sprout), fruits such as avocado, banana, vegetable oils, especially soybean oil are the good sources of vitamin K. Cooking does not affect the amounts of vitamin K in the diet. Improve the dietary supply
Usual daily requirement of vitamin K is 2 μg for infants in the first 6 months of life, 2.5 μg for infants aged 7–12 months, 30 μg in 1–3 years, 75 μg for adolescents, and for others a daily average of 1 μg per kg of body weight is recommended. Vitamin K found in humans is the vitamin K1 available in the diet. Leafy green vegetables such as spinach, Swiss chard, Brassica (e.g. cabbage, kale, cauliflower, turnip, and Brussels sprout), fruits such as avocado, banana, vegetable oils, especially soybean oil are the good sources of vitamin K. Cooking does not affect the amounts of vitamin K in the diet.
Consultation with specialists Vitamin K deficiency is a condition that require involvement of various specialties for the management. Hematologist should be involved in the management of bleeding manifestations. Malabsorption related problems are managed by a gastroenterologist. Consultation with specialists
Vitamin K deficiency is a condition that require involvement of various specialties for the management. Hematologist should be involved in the management of bleeding manifestations. Malabsorption related problems are managed by a gastroenterologist.

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