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Coagulation

Acquired bleeding disorders

Vitamin K deficiency / warfarin use


Reviewers: Kendall Crookston, M.D., Ph.D., University of New Mexico; Lizabeth Rosenbaum, MD, University of New Mexico; Julie Gober-Wilcox, M.D., Resident, University of New Mexico (see Reviewers page)
Revised: 10 March 2011, last major update March 2011
Copyright: (c) 2002-2011, PathologyOutlines.com, Inc.

Definition
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● Hemorrhage is a complication of both warfarin therapy and vitamin K deficiency (see etiology below)

Warfarin (Coumadin):
● The most widely prescribed therapeutic anticoagulant for the prevention or treatment of venous thrombosis, pulmonary embolism, and thromboembolic complications
● Its mechanism of action relates to its ability to impair the regeneration of the active form of vitamin K, which is required in the carboxylation of glutamic acid residues of coagulation factors II, VII, IX and X (as well as anticoagulant proteins C and S)

Vitamin K:
● 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 and S

Terminology
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● The International Normalized Ratio (INR) is defined as the ratio of a patientís PT to the control sample (normal) PT raised to the ISI value of the control sample:




Each manufacturer assigns an ISI value (International Sensitivity Index) for any tissue factor they manufacture. The ISI value indicates how the particular batch of tissue factor compares to an internationally standardized sample

The INR was developed to standardize results due to differences in tissue factor between manufacturers that can lead to differences in PT values

Epidemiology
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● The incidence of major bleeding events in patients prescribed warfarin is approximately 2-13%
● The incidence of vitamin K deficiency bleeding in newborns (hemorrhagic disease of the newborn) is reported between 1.6-8.6 per 100,000 live births

Sites
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● Skin and mucosa, soft tissue, genitourinary tract, gastrointestinal tract, CNS, respiratory tract, abdomen (see clinical features below)

Etiology
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Warfarin-related bleeding
● There is significant inter-individual variability in the dosing of warfarin that is a result of many variables including genetic factors [due to polymorphisms in the genes that encode hepatic cytochrome P450 enzyme (CYP2C9) and vitamin K epoxide reductase (VKORC1)], drug-drug interactions, specific disease states (e.g. hypo/hyperthyroidism) and dietary vitamin K intake that can lead to increased risk of bleeding complications

Vitamin K deficiency:
● Due to fat malabsorption syndromes (vitamin K is a fat soluble vitamin), malnutrition, antibiotics (destroy bacteria producing vitamin K or interfere with vitamin K carboxylation), newborns

Clinical features
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● Easy bruising, soft tissue hematoma, gastrointestinal bleeding, epistaxis, intracranial bleeding, hematuria, hemoptysis, intraperitoneal and retroperitoneal bleeding
● Bleeding in vitamin K deficiency can include the above as well as bleeding after circumcision and umbilical cord stump bleeding

Laboratory
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● Both warfarin administration and vitamin K deficiency cause prolonged PT (severe cases of vitamin K deficiency can also result in prolonged PTT)
● Anticoagulant effect of warfarin is monitored by PT/INR

Prognostic factors
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● Risk factors associated with hemorrhagic complications of warfarin include age (>65 yrs), concomitant comorbidities (e.g. atrial fibrillation, gastrointestinal bleeding, renal insufficiency, cerebrovascular disease), concomitant medications (e.g. aspirin, amiodarone)

Case reports
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● Spontaneous supraglottic hemorrhage in a patient on warfarin therapy (Emerg Med J 2001;18:406)
● Vitamin K deficiency presenting as impending brain herniation in a 2 month-old male infant (J Pediatr Neurosci 2010;5:55)

Treatment
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Warfarin overdose - INR > 5.0:
● Fresh frozen plasma or vitamin K
● PT should normalize within 12-24 hours
Clinical note: if a large dose of vitamin K is given, then it may be difficult to reach a therapeutic level of warfarin very quickly if the patient continues on warfarin therapy

Treatment (vitamin K deficiency):
● Vitamin K once, then 12-24 hours later, then measure PT (should normalize)

Differential diagnosis
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● Liver disease
● DIC

Additional references
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Am J Clin Pathol 2008;129:876, Discov Med 2009;8:196. Thromb Res 2008;122 Suppl 2:S13, J Thromb Thrombolysis 2008;25:151

End of Coagulation > Acquired bleeding disorders > Vitamin K deficiency / warfarin use


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