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. [4] 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. [4] 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. [2] Vitamin K deficiency bleeding disorder is an uncommon serious bleeding disorder due to the deficient activity of vitamin K-dependant coagulation factors. [2]
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. [2] Neonates are more prone to get vitamin K deficiency as the stores are limited at birth and intake is insufficient. [4]
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. [5] Factor II, VI, IX, X are the coagulation factors dependent on vitamin K for the activation. [2] 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. [4] 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. [2] 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 [2] 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. [6]
Hematuria Urogenital bleeding may present as haematuria. [6] Suburothelial bleeding may result in obstructive uropathy. [6]
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. [3]
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. [1]
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. [2]
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. [2]
History of hepatobiliary diseases Biliary atresia, α1-anti-trypsin deficiency, hepatitis like hepatobiliary diseases causes decrease synthesis of vitamin K leading to deficiency. [2]
History of drug use eg:- carbamazepine, phenytoin, barbiturates, cephalosporin, rifampicin, isoniazid coumarin, warfarin These drugs may also result in antagonism of vitamin K. [2,4] Particularly drugs like warfarin which is an oral anticoagulant inhibits vitamin K dependent γ-carboxylation of clotting factors II, VII, IX and X. [6]
References
  1. DANIELSSON N, HOA D, THANG N, VOS T, LOUGHNAN P. Intracranial haemorrhage due to late onset vitamin K deficiency bleeding in Hanoi province, Vietnam Arch Dis Child Fetal Neonatal Ed [online] 2004 Nov, 89(6):F546-F550 [viewed 15 October 2014] Available from: doi:10.1136/adc.2003.047837
  2. GAHALAUT P, CHAUHAN S. Vitamin K Deficiency Bleeding Presenting as Nodular Purpura in Infancy: A Rare and Life-Threatening Entity Indian J Dermatol [online] 2013, 58(5):407 [viewed 15 October 2014] Available from: doi:10.4103/0019-5154.117334
  3. PLANK RM, STEINMETZ T, SOKAL DC, SHEARER MJ, DATA S. Vitamin K Deficiency Bleeding and Early Infant Male Circumcision in Africa Obstet Gynecol [online] 2013 Aug, 122(2 0 2):503-505 [viewed 15 October 2014] Available from: doi:10.1097/AOG.0b013e31828b2f5c
  4. LIPPI G, FRANCHINI M. Vitamin K in neonates: facts and myths Blood Transfus [online] 2011 Jan, 9(1):4-9 [viewed 15 October 2014] Available from: doi:10.2450/2010.0034-10
  5. STERNDALE H. Haemarthrosis and haemophilia. Proc R Soc Med [online] 1967 Jan, 60(1):37-38 [viewed 01 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1901393
  6. LIM ANDY KH. Haematuria and Acute Kidney Injury Associated with Warfarin Anticoagulation. General Med [online] 2013 December [viewed 15 October 2014] Available from: doi:10.4172/2327-5146.1000105

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. [2] Skin bleeding may occur in 10-30% of patients. [2]
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. [2] These are appear as bluish-violet raised infiltrated purplish centerswith a 1.5 cm to 7.5 cm diameter. [2]
Ooozing of blood at surgical or puncture Same as above due to the defect in coagulation cascade. [2,4]
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. [1] Neurological signs would be one of the most common presenting feature in 50-80% of patients. [2]
Pallor Sometimes patient may be presenting with anaemia due to the overt bleeding.[3]
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. [3]
References
  1. DANIELSSON N, HOA D, THANG N, VOS T, LOUGHNAN P. Intracranial haemorrhage due to late onset vitamin K deficiency bleeding in Hanoi province, Vietnam Arch Dis Child Fetal Neonatal Ed [online] 2004 Nov, 89(6):F546-F550 [viewed 15 October 2014] Available from: doi:10.1136/adc.2003.047837
  2. GAHALAUT P, CHAUHAN S. Vitamin K Deficiency Bleeding Presenting as Nodular Purpura in Infancy: A Rare and Life-Threatening Entity Indian J Dermatol [online] 2013, 58(5):407 [viewed 15 October 2014] Available from: doi:10.4103/0019-5154.117334
  3. MCMILLAN D, WU J. Approach to the bleeding newborn Paediatr Child Health [online] 1998, 3(6):399-401 [viewed 15 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851303
  4. ] G, FRANCHINI M. Vitamin K in neonates: facts and myths Blood Transfus [online] 2011 Jan, 9(1):4-9 [viewed 15 October 2014] Available from: doi:10.2450/2010.0034-10

Differential Diagnoses

Fact Explanation
Haemophilia A Hemophilia A is due to the deficiency of functional plasma clotting factor VIII (FVIII), and is inherited as a X-linked, recessive manner and may be associated with spontaneous mutations. [10] Clinical manifestations are same as the haemophilia B. Factor VIII level will be reduced, Activated partial thromboplastin time (aPTT) [9] measures the activity of the intrinsic pathway of the clotting mechanism, and is prolonged in factor 8 deficiency. [11] Normal aPTT may be found in mild to moderate hemophilia. Bleeding time and prothrombin time International Normalized Ratio (INR) are normal as they assess the extrinsic coagulation pathway. [9]
Haemophilia B Haemophilia B is due to the deficiency of factor IX , that hydrolyses one arginine-isoleucine bond in factor X to form the activated factor X (Xa). [7] Activated factor VIII (FVIIIa) is important to improve the efficiency of this factor. Clinical features are same as in haemophilia A and coagulation studies will be the same with normal level of factor VIII and reduced level of factor IX.
Haemophilia C Hemophilia C is the deficiency of factor XI. [5] Though the bleeding manifestations are not severe, occasionally there can be lethal internal bleeding manifestations. [8] aPTT is grossly prolonged with normal othyer coagulation studies. Fator level may be reduced.
Von Willebrand disease This is an autosomal dominant condition and may be either inherited or acquired. [3] It is due to the defect in the Von Willebrand factor which is important to maintain normal clotting cunctions. Von Willebrand factor (vWF) is secreted by the endothelial cells and are circulate in the blood. When there is a endothelial injury, vWF is attached to the endothelium, then bind with platelets with the help of the glycoprotein complexes. [1] Absence of this factor causes increased tendency to bleeding giving the same clinical features as in haemophilia. Mucocutaneous bleeding is mild in type 1 disease. Severe joint bleeds are rare. [3] Diagnosis is by the decreased VWF activity assay. Platelet count is normal with the exception of decreased count in type 2 VWD patients. [3] Hemophilia A is different from von Willebrand disease as there is normal or elevated levels of vWF antigen and ristocetin cofactor activity in haemophilia.
Deficiency of other coagulation factors (factor V, VII, X, fibrinogen) These are rare inherited disorders due to the absence or reduced levels of clotting factors. Clinical manifestations may be depend on the type and magnitude of the deficient factor. These include deficiencies of factors II, V, VII, XIII and fibrinogen. Differentiation would be possible with coagulation factors assays. Factor XI assays are aPTT based and factors V, VII and X assays are PT based. Therefore deficiency of factor factors XII, XI, IX, and VIII is associated with isolated prolongation of aPTT and deficiency of factor VII with isolated prolongation of PT. [4,5] Prolongation of both aPTT and PT occurs in deficiency of the common pathway coagulation factors, factor X, V, and II, or a qualitative or quantitative fibrinogen defect.[6]
Platelet disorders Platelets are an integral part in the haemostatic mechanism, once there is a vascular distruption the platelets get the contact with the vascular endothelium forming a platelet plug. [1] Platelet dysfunction may be due to a disorder of connective tissue, platelet adhesion, aggregation or platelet-release reaction. [1] Disorders of platelets may be either due to due inadequate count or disordered function. Platelet adhesion disorders, such as von Willebrand disease, Bernard-Soulier syndrome, disorders of aggregation such as Glanzmann thrombasthenia, and acquired disorders of platelet function due to the drugs such as aspirin, NSAIDs, alcohol are some of the functional disorders. [2] Cliinical manifestations may be either with skin or mucosal bleeding. Number of platelets may be normal with prolongation of bleeding . Factor VIII and von Willebrand factor complex and other tests of platelet function may required. [1]
References
  1. HUEBSCH LB, HARKER LA. Disorders of Platelet Function: Mechanisms, Diagnosis and Management West J Med [online] 1981 Feb, 134(2):109-127 [viewed 01 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1272531
  2. SAHUD MA. Platelet disorders: a review of disturbances in adhesion, aggregation, and release reaction. Calif Med [online] 1972 Jan, 116(1):21-31 [viewed 01 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1518141
  3. BHARATI KP, PRASHANTH UR. Von Willebrand Disease: An Overview Indian J Pharm Sci [online] 2011, 73(1):7-16 [viewed 01 October 2014] Available from: doi:10.4103/0250-474X.89751
  4. SHARMA SK, KUMAR S, SETH T, MISHRA P, AGRAWAL N, SINGH G, SINGH AK, MAHAPATRA M, TYAGI S, PATI H, SAXENA R. Clinical Profile of Patients with Rare Inherited Coagulation Disorders: A Retrospective Analysis of 67 Patients from Northern India Mediterr J Hematol Infect Dis [online] , 4(1):e2012057 [viewed 01 October 2014] Available from: doi:10.4084/MJHID.2012.057
  5. CASTAMAN G. Prophylaxis of bleeding episodes and surgical interventions in patients with rare inherited coagulation disorders Blood Transfus [online] 2008 Sep, 6(Suppl 2):s39-s44 [viewed 01 October 2014] Available from: doi:10.2450/2008.0036-08
  6. HOOD J. L., EBY C. S.. Evaluation of a Prolonged Prothrombin Time. Clinical Chemistry [online] 2008 April, 54(4):765-768 [viewed 01 October 2014] Available from: doi:10.1373/clinchem.2007.100818
  7. ORLOVA NA, KOVNIR SV, VOROBIEV II, GABIBOV AG. Coagulation Factor IX for Hemophilia B Therapy? Acta Naturae [online] 2012, 4(2):62-73 [viewed 01 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408704
  8. GENTRY PA, BRUSH PJ. Factor XI Deficiency in Canadian Holsteins Can Vet J [online] 1987 Mar, 28(3):110 [viewed 01 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1680365
  9. SHARMA SK, KUMAR S, SETH T, MISHRA P, AGRAWAL N, SINGH G, SINGH AK, MAHAPATRA M, TYAGI S, PATI H, SAXENA R. Clinical Profile of Patients with Rare Inherited Coagulation Disorders: A Retrospective Analysis of 67 Patients from Northern India Mediterr J Hematol Infect Dis [online] , 4(1):e2012057 [viewed 01 October 2014] Available from: doi:10.4084/MJHID.2012.057
  10. JUNEJA S, GANJOO P, TANDON MS, SHARMA A. Perioperative management of a hemophilia B infant with intracranial hemorrhage J Pediatr Neurosci [online] 2012, 7(3):239-240 [viewed 06 October 2014] Available from: doi:10.4103/1817-1745.106494
  11. SAHU S, LATA I, SINGH S, KUMAR M. Revisiting hemophilia management in acute medicine J Emerg Trauma Shock [online] 2011, 4(2):292-298 [viewed 01 October 2014] Available from: doi:10.4103/0974-

Investigations - for 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. [4] 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. [1]
Full blood count Platelet counts is normal and it is important to assess in a case of bleeding manifestations. [1,2]
Fibrinogen level Fibrinogen level is normal [1,2]
Circulating acarboxy proteins Circulating acarboxy proteins are present. [2]
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. [3]
References
  1. GAHALAUT P, CHAUHAN S. Vitamin K Deficiency Bleeding Presenting as Nodular Purpura in Infancy: A Rare and Life-Threatening Entity Indian J Dermatol [online] 2013, 58(5):407 [viewed 15 October 2014] Available from: doi:10.4103/0019-5154.117334
  2. PLANK RM, STEINMETZ T, SOKAL DC, SHEARER MJ, DATA S. Vitamin K Deficiency Bleeding and Early Infant Male Circumcision in Africa Obstet Gynecol [online] 2013 Aug, 122(2 0 2):503-505 [viewed 15 October 2014] Available from: doi:10.1097/AOG.0b013e31828b2f5c
  3. LIPPI G, FRANCHINI M. Vitamin K in neonates: facts and myths Blood Transfus [online] 2011 Jan, 9(1):4-9 [viewed 15 October 2014] Available from: doi:10.2450/2010.0034-10
  4. RIZOLI SB, SCARPELINI S, CALLUM J, NASCIMENTO B, MANN KG, PINTO R, JANSEN J, TIEN H. Clotting Factor Deficiency in Early Trauma-Associated Coagulopathy J Trauma [online] 2011 Nov, 71(5 Suppl 1):S427-S434 [viewed 01 October 2014] Available from: doi:10.1097/TA.0b013e318232e5ab

Investigations - Fitness for Management

Fact Explanation
Haemoglobin level, haematocrict Anemia and leukocytosis have been reported in patients with vitamin K deficiency. [1] Bleeding manifestations, occurring as a result of clotting factor abnormalities may occasionally cause reduction in the , HCT and haemolobin level. [2]
References
  1. GAHALAUT P, CHAUHAN S. Vitamin K Deficiency Bleeding Presenting as Nodular Purpura in Infancy: A Rare and Life-Threatening Entity Indian J Dermatol [online] 2013, 58(5):407 [viewed 15 October 2014] Available from: doi:10.4103/0019-5154.117334
  2. MCMILLAN D, WU J. Approach to the bleeding newborn Paediatr Child Health [online] 1998, 3(6):399-401 [viewed 15 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851303

Investigations - Followup

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. [2] Prolonged APTT and PT normalized within 10 hours of first dose. [1]
References
  1. GAHALAUT P, CHAUHAN S. Vitamin K Deficiency Bleeding Presenting as Nodular Purpura in Infancy: A Rare and Life-Threatening Entity Indian J Dermatol [online] 2013, 58(5):407 [viewed 15 October 2014] Available from: doi:10.4103/0019-5154.117334
  2. LIM ANDY KH. Haematuria and Acute Kidney Injury Associated with Warfarin Anticoagulation. General Med [online] 2013 December [viewed 15 October 2014] Available from: doi:10.4172/2327-5146.1000105

Investigations - Screening/Staging

Fact Explanation
Fine needle aspiration cytology Patient may occasionally present with purpuric nodules and FNAC reveal frank blood. [1]
Factor V, VII or X level Extremely rare hereditary deficiencies of factors V, VII or X need to be excluded to make a diagnosis. [1]
References
  1. GAHALAUT P, CHAUHAN S. Vitamin K Deficiency Bleeding Presenting as Nodular Purpura in Infancy: A Rare and Life-Threatening Entity Indian J Dermatol [online] 2013, 58(5):407 [viewed 15 October 2014] Available from: doi:10.4103/0019-5154.117334

Management - General Measures

Fact Explanation
Immediate management Assessment of airway and breathing, is particularly important as they can present with respiratory and cardiovascular problems following bleeding. [2] Circulatory collapse may occur in a massive haemorrhage. [2]
Management of other complications Upper GI bleeding, haematuria, intracranial haemorrhage may need specific supportive management after correcting the vitamin K level. [3] 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 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). [4] 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. [3]
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. [1] 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). [2] 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. [2]
References
  1. CLARKE P, SHEARER MJ. Vitamin K deficiency bleeding: the readiness is all Arch Dis Child [online] 2007 Sep, 92(9):741-743 [viewed 15 October 2014] Available from: doi:10.1136/adc.2007.116962
  2. MCMILLAN D, WU J. Approach to the bleeding newborn Paediatr Child Health [online] 1998, 3(6):399-401 [viewed 15 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851303
  3. DANIELSSON N, HOA D, THANG N, VOS T, LOUGHNAN P. Intracranial haemorrhage due to late onset vitamin K deficiency bleeding in Hanoi province, Vietnam Arch Dis Child Fetal Neonatal Ed [online] 2004 Nov, 89(6):F546-F550 [viewed 15 October 2014] Available from: doi:10.1136/adc.2003.047837
  4. GAHALAUT P, CHAUHAN S. Vitamin K Deficiency Bleeding Presenting as Nodular Purpura in Infancy: A Rare and Life-Threatening Entity Indian J Dermatol [online] 2013, 58(5):407 [viewed 15 October 2014] Available from: doi:10.4103/0019-5154.117334

Management - Specific Treatments

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). [1] 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. [3]
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. [2] Vitamin K found in humans is the vitamin K1 available in the diet. [2] 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. [2]
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. [3,4] Malabsorption related problems are managed by a gastroenterologist.
References
  1. GAHALAUT P, CHAUHAN S. Vitamin K Deficiency Bleeding Presenting as Nodular Purpura in Infancy: A Rare and Life-Threatening Entity Indian J Dermatol [online] 2013, 58(5):407 [viewed 15 October 2014] Available from: doi:10.4103/0019-5154.117334
  2. LIPPI G, FRANCHINI M. Vitamin K in neonates: facts and myths Blood Transfus [online] 2011 Jan, 9(1):4-9 [viewed 15 October 2014] Available from: doi:10.2450/2010.0034-10
  3. MOOREHEAD PC, RAY J, BARROWMAN NJ, LEMYRE B, KLAASSEN R. A survey of the management of newborns with severe hemophilia in Canada Paediatr Child Health [online] 2013 Apr, 18(4):189-193 [viewed 20 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805619
  4. ARRIETA-BLANCO JJ, OñATE-SáNCHEZ R, MARTíNEZ-LóPEZ F, OñATE-CABRERIZO D, CABRERIZO-MERINO MC. Inherited, congenital and acquired disorders by hemostasis (vascular, platelet & plasmatic phases) with repercussions in the therapeutic oral sphere Med Oral Patol Oral Cir Bucal [online] 2014 May, 19(3):e280-e288 [viewed 20 October 2014] Available from: doi:10.4317/medoral.19560