Bleeding Risks With Vitamin K Deficiency

Introduction

In 1894, the condition known as hemorrhagic disease of the newborn was first discovered to be related to a deficiency of vitamin K (VK), which is an essential cofactor for the synthesis of clotting factors, FII, FVII, FIX, FX, as well as the endogenous inhibitors of coagulation, proteins C and S in the liver. Deficiency of VK can lead to a quick decline in the levels of VK-dependent clotting factors because of their short half-life and can present with bleeding manifestations known as vitamin K deficiency bleeding (VKDB). VK deficiency occurs most commonly during the neonatal period and early infancy but can also be present in individuals with malabsorption syndromes, decreased production of bile salts, warfarin therapy, insufficient intake, or decreased intestinal flora related to antibiotic use.

Pathophysiology

VK is a lipid-soluble vitamin that is essential for the posttranslational modification of glutamic acid residues in the VK-dependent clotting factors, FII, FVII, FIX, FX, to γ-carboxyglutamic acid residues. This modification leads to the activation of these clotting proteins involved in the formation of the coagulation complexes (tenase and prothrombinase) to generate thrombin. Carboxylation of the factors is catalyzed by the enzyme γ-glutamyl carboxylase (GGCX) using the reduced form of VK (VK hydroquinone, KH ₂₎ as a cofactor, which in the process gets oxidized to VK epoxide (KO). This is then converted back to KH ₂ by the enzyme KO reductase complex subunit 1 (VKORC1), which completes the VK cycle as illustrated in Fig. 120.1 .

The major source of dietary VK is in the form of K ₁ (phylloquinone), which is primarily derived from yellow or green plants and oils and the daily requirement is 1 μg/kg. Optimal absorption of VK from food requires an intact intestine and is highly dependent on bile salts, which can be impaired with hepatic or intestinal disease. Another form of VK is K ₂ (menaquinones-n), which is endogenously synthesized from microbial gut flora and is found in animal and soy protein, which is less readily absorbed from the intestine. Decreased VK synthesis in the gut can occur either from the lack of adequate gut flora such as in immature gastrointestinal (GI) tract of newborns or with altered microbia from prolonged antibiotic use. Newborns are especially susceptible to VKDB, as they are born with limited VK stores because placental transfer of VK is low resulting in an almost 50% reduction in the VK-dependent clotting factors levels compared with adults. This gets further compounded in exclusively breastfed infants, as breast milk has very low levels of VK (5–15 μg/L) compared with infant formulas that are fortified (50–60 μg/L).