Acquired bleeding disorders

Vitamin K deficiency / warfarin use

Editorial Board Member: Mrigender Singh Virk, M.D.
Fatima Aldarweesh, M.D.

Last staff update: 28 September 2023 (update in progress)

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PubMed Search: Vitamin K deficiency / warfarin

Fatima Aldarweesh, M.D.
Page views in 2023 to date: 169
Cite this page: Aldarweesh F. Vitamin K deficiency / warfarin use. website. Accessed October 2nd, 2023.
Definition / general
  • Vitamin K plays an important role in coagulation pathways because it is a cofactor required for the activity of several key proteins (Adv Nutr 2012;3:182)
  • Warfarin and other vitamin K antagonists (VKA) are employed in a wide range of clinical settings
Essential features
  • Vitamin K deficiency and warfarin administration can result in prolonged prothrombin time (PT) / international normalized ratio (INR)
  • Mild vitamin K deficiency affects PT due to its predominant effect on factor VII; however, severe deficiency can cause prolonged PT and partial thromboplastin time (PTT) (StatPearls: Vitamin K Deficiency [Accessed 14 March 2023])
  • Warfarin anticoagulation is associated with increased risk of bleeding; therefore, appropriate dosing and monitoring are essential
  • Warfarin's effect varies depending on a number of genetic, dietary and medication factors (Br J Clin Pharmacol 2021;87:1717)
  • Vitamin K antagonist (VKA)
  • Vitamin K2 (menaquinone)
  • International normalized ratio (INR)
  • Deep vein thrombosis (DVT)
  • Pulmonary embolism (PE)
  • Prothrombin complex concentrate (PCC)
  • Disseminated intravascular coagulopathy (DIC)
  • Prothrombin time (PT)
  • Partial thromboplastin time (PTT)
  • Vitamin K is a fat soluble vitamin that participates as a cofactor in carboxylation of glutamic acid residues of factors II, VII, IX and X and proteins C, S and Z (Haematologia (Budap) 1985;18:71)
  • Vitamin K deficiency
    • Rare in general
    • Common in newborns who require routine vitamin K prophylaxis at birth (Blood Rev 2009;23:49)
    • Predisposing factors (J Perinatol 2016;36:S29)
      • Fat malabsorption syndromes (vitamin K is a fat soluble vitamin)
        • Cystic fibrosis
        • Primary biliary cholangitis
        • Primary sclerosing cholangitis
        • Biliary atresia
        • Intestinal diseases associated with malabsorption, such as inflammatory bowel disease, short bowel syndrome, active celiac disease
        • Malnutrition
        • Liver failure
      • Medications
        • Broad spectrum antibiotics
          • Diminish intestinal bacteria that are responsible for synthesizing absorbable vitamin K (K2)
          • Affect vitamin K activation in the liver by inhibiting the function of vitamin K epoxide reductase
        • Very high doses of vitamin E
    • Hereditary combined vitamin K dependent clotting factor deficiency (VKCFD) (Orphanet J Rare Dis 2010;5:21)
      • Very rare
      • Autosomal recessive
      • Implicated genes are gamma glutamyl carboxylase (GGCX) and vitamin K2,3 epoxide reductase complex (VKORC)
      • Activities for all vitamin K dependent factors are reduced and there could be some developmental and skeletal anomalies
      • PT and PTT are prolonged
      • Bleeding is often of mucocutaneous pattern
      • Management
        • Acute management (surgery, severe bleeding): vitamin K administration and plasma transfusion
        • Prophylaxis: vitamin K daily with INR monitoring
  • Warfarin (Coumadin) inhibits the function of the vitamin K epoxide reductase complex in the liver
    • Resulting in an impairment of the reduced form of vitamin K
    • Reduced form of vitamin K is required for the gamma carboxylation of vitamin K dependent coagulation factors (II, VII, IX and X) as well as anticoagulant proteins C and S
    • Indications (Chest 2008;133:160S)
      • Stroke
      • Atrial fibrillation
      • Heart failure
      • Prosthetic heart valve
      • Deep vein thrombosis
      • Pulmonary embolism
      • Antiphospholipid syndrome
    • Contraindications
      • Active clinically significant bleeding
      • Severe thrombocytopenia
      • Major trauma
      • Invasive procedure
      • Previous intracranial hemorrhage
      • Uncontrolled severe hypertension
    • There is significant interindividual variability in the dosing of warfarin that is a result of many variables (Br J Clin Pharmacol 2021;87:352)
      • Genetic factors due to polymorphisms in the genes that encode hepatic cytochrome P450 enzyme (CYP2C9) and vitamin K epoxide reductase (VKORC1) (JAMA Intern Med 2014;174:1330)
      • Drug - drug interactions
      • Concomitant comorbidities
      • Excessive dietary vitamin K intake
Clinical features
  • Vitamin K deficiency can result in
    • Easy bruising
    • Ecchymoses
    • Mucosal bleeding
    • Gastrointestinal bleeding
    • Epistaxis
    • Intracranial bleeding
    • Hematuria
    • Hemoptysis
  • Warfarin complications
    • Higher rates of thromboembolic and bleeding complications in some high risk patients (South Med J 2005;98:96)
      • Age > 65
      • Concomitant comorbidities (liver disease, atrial fibrillation, gastrointestinal bleeding, renal insufficiency, cerebrovascular disease)
      • Concomitant medications (aspirin, amiodarone)
    • Skin necrosis (Arch Dermatol 1986;122:1408)
      • Reported in some patients within the first few days of initiation of warfarin
      • Lesions occur in areas rich in subcutaneous fat (trunk, extremities, breast, penis)
      • Attributed to rapid reduction in protein C level, which induces a hypercoagulable state
      • Microscopically, fibrin thrombi with cutaneous vessels and associated interstitial hemorrhage
  • Prothrombin time (PT) and international normalized ratio (INR) (Hematology Am Soc Hematol Educ Program 2012;2012:460)
    • PT
      • PT measures the time it takes citrated patient's plasma to form a fibrin clot when exposed to tissue factor (TF) in the presence of phospholipids
      • PT measures the activity of the extrinsic (VII) and common pathways (I, II, V, X)
    • INR
      • INR is calculated as the ratio of a patient's PT to the control sample PT raised to the international sensitivity index (ISI) value of the control sample (INR = [patient PT รท control PT]ISI)
      • Each manufacturer assigns an ISI value for any tissue factor they manufacture
      • ISI value indicates how the particular batch of tissue factor compares to an internationally standardized sample
      • INR was developed to standardize results due to differences in tissue factor between manufacturers that can lead to differences in PT values
  • Point of care (POC) testing (Br J Haematol 2010;150:501)
    • POC testing can be performed using a device located at or near the location of the patient rather than in a central laboratory
    • Clotting times are among the tests that can be performed at POC
    • This can aid in home monitoring of warfarin therapy
  • Causes for prolonged PT / INR and a normal PTT
    • Mild vitamin K deficiency
    • Warfarin administration
    • Factor VII deficiency
    • Early disseminated intravascular coagulation
    • Mild liver disease
Case reports
  • Vitamin K deficiency and coagulopathy
    • Single dose of vitamin K followed by PT / INR after 12 - 24 hours
    • If coagulopathy persists, a second dose is administered in 48 - 72 hours
  • Warfarin associated bleeding or supratherapeutic INR (see Table 1)
    • Management is determined by whether or not the patient is bleeding and the degree of INR elevation
      • If not associated with bleeding, hold warfarin dose(s)
      • If associated with bleeding, discontinue warfarin and administer vitamin K
        • Prothrombin complex concentrate (PCC) can be given for serious bleeding to provide rapid and full reversal
        • If PCC is not available, donor plasma can be administered

Table 1: management of warfarin (Chest 2012;141:e152S, Blood Adv 2018;2:3257)
Clinical setting Management
  • Serious or life threatening bleeding
  • Any INR
  • 4 factor PCC
  • Vitamin K (intravenous)
  • Hold warfarin
  • No bleeding
  • INR > 10
  • Vitamin K (oral)
  • Hold warfarin
  • No bleeding
  • INR 4.5 to 10
  • Hold warfarin
  • Vitamin K (low dose, oral) is optional
Differential diagnosis
  • Disseminated intravascular coagulation (DIC):
    • In DIC, coagulation factors are depleted and consumed
    • If DIC is mild, only PT is prolonged
    • As DIC progresses in severity, PTT is prolonged along with PT
  • Liver disease:
    • Because all coagulation factors are synthesized in the liver, with the exception of factor VIII, liver disease will also affect vitamin K dependent factors
    • Measurement of factors V and VII can help distinguish between liver disease and vitamin K deficiency
  • Vitamin C deficiency:
    • Among the clinical presentation of vitamin C deficiency (scurvy) is mucocutaneous bleeding (perifollicular and gingival hemorrhage)
    • Vitamin C plays a role in collagen synthesis, especially type IV, which is the main component of blood vessel walls and skin
  • Malabsorption:
    • Maldigestion of nutrients in the intestinal lumen
    • There is usually a widespread mucosal involvement or a reduced absorptive surface
    • Classic presentation includes chronic diarrhea, unintentional weight loss and signs and symptoms related to nutrient deficiencies
Board review style question #1
A 7 day old boy presents with agitation, lethargy and poor feeding. He was born at term via spontaneous vaginal delivery. All postnatal supplements and vaccines were not administered due to parental refusal. The newborn was breastfed exclusively. His body is covered with ecchymoses. Complete blood count showed normocytic normochromic anemia, normal white blood cell count and mild thrombocytopenia. A transcranial ultrasound reveals hemorrhage in the left cerebral hemisphere. Which of the following abnormalities is likely to be seen in this patient?

  1. Congenital protein C deficiency
  2. Decreased factor VIII level
  3. Factor V Leiden mutation
  4. Prolonged partial thromboplastin time (PTT)
  5. Prolonged prothrombin time (PT)
Board review style answer #1
E. Prolonged prothrombin time (PT). The lack of postnatal vitamin K supplementation and exclusive breastfeeding increases risk of vitamin K deficiency, which usually results in prolonged PT. Answer A is incorrect because congenital protein C deficiency leads to an inability to inactivate clotting factors and control thrombin production and can be associated with thrombosis rather than bleeding. Answer B is incorrect because while decreased factor VIII level or hemophilia A can present with spontaneous intracranial hemorrhage in neonates, the lack of vitamin K supplementation and exclusive breast feeding are more likely to be associated with deficiency of vitamin K dependent coagulation factors. Answer C is incorrect because factor V Leiden mutation increases the likelihood of thrombosis, not bleeding. Answer D is incorrect because deficiency of vitamin K will impact its dependent factors II, VII, IX and X, with factor VII affected early due to short half life. In more advanced stages, PTT is expected to be prolonged as well.

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Reference: Vitamin K deficiency / warfarin use
Board review style question #2
A 68 year old woman with alcoholic hepatitis and advanced cirrhosis presents with ecchymoses. Partial thromboplastin time (PTT) is normal while prothrombin time (PT) is elevated. Complete blood count showed normocytic normochromic anemia, normal white blood cell count and mild thrombocytopenia. Which deficiency is the most probable cause of this clinical scenario?

  1. Fibrinogen
  2. Riboflavin
  3. Vitamin A
  4. Vitamin C
  5. Vitamin K
Board review style answer #2
E. Vitamin K. Vitamin K is essential for the synthesis of coagulation factors II, VII, IX and X, as well as the natural anticoagulants protein C and S. Patients with alcohol use disorders often have low dietary intake of vitamin K and may also have malabsorption. Vitamin K deficiency leads to prolonged PT, which measures the activity of the extrinsic and common pathways. Answers A - D are incorrect because hypofibrinogenemia, deficiency of riboflavin, vitamin A and vitamin C do not typically result in normal PTT and prolonged PT.

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Reference: Vitamin K deficiency / warfarin use
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