Association of Broad-Spectrum Antibiotic Therapy and Vitamin E Supplementation with Vitamin K Deficiency-Induced Coagulopathy: A Case Report and Narrative Review of the Literature

Abstract

Vitamin K is a lipid-soluble vitamin that is normally maintained within appropriate levels by means of dietary intake and bacterial production in the intestinal microflora. It holds a central role in coagulation homeostasis, and thus its depletion leads to hypocoagulation and haemorrhagic diathesis. The association of antibiotic therapy and vitamin E supplementation with vitamin K deficiency was previously described in animal experiments, clinical studies, and case reports. Broad-spectrum antibiotic therapy potentially leads to intestinal microflora dysbiosis and restriction of vitamin K-producing bacterial populations, resulting in decreased vitamin K levels, whereas antibiotics of the cephalosporin class with 1-N-methyl-5-thiotetrazole (NMTT) or 2-methyl-1,3,4-thiadiazole (MTD) side groups inhibit vitamin K function. Vitamin E supplementation interferes with both the bioavailability and function of vitamin K, yet its mechanisms are not fully understood. We present the case of a 45-year-old male patient, with a history of epilepsy and schizophrenia, catatonically incapacitated and immobilised, who was hospitalised in our centre for the investigation and management of aspiration pneumonia. He demonstrated a progressively worsening prolongation of international normalised ratio (INR), which was attributed to both broad-spectrum antibiotic therapy and vitamin E supplementation and was reversed upon administration of vitamin K. We highlight the need for close monitoring of coagulation parameters in patients receiving broad-spectrum antibiotic therapy, especially those with underlying malnutritive or malabsorptive conditions, and we further recommend the avoidance of NMTT- or MTD-containing antibiotics or vitamin E supplementation, unless absolutely necessary, in those patients.

Keywords: antibiotics; coagulopathy; international normalised ratio; prothrombin time; vitamin E; vitamin K.

Figure 1

Chest imaging of the patient. Chest X-ray showed opacities in the right lower lung field, a finding compatible with aspiration pneumonia.

Figure 2

Vitamin K sources and metabolism. Vitamin K₁ (phylloquinone) is intaken by consumption of plants, especially green leafy vegetables, as it is found on the photosynthetic membranes of chloroplasts in plant cells (1a). Vitamin K₂ (menaquinone) is produced by specific bacterial species in the intestinal microflora (1b). Vitamin K₁ is bound to proteins, which are lysed by the action of pancreatic enzymes in the small intestine. Both dietary and bacteria-derived vitamin K is absorbed by enterocytes after it is solubilised into micelles by bile salts (2). Vitamin K is then incorporated into chylomicrons, transferred to the systemic circulation through lymphatic vessels, bypassing the portal circulation, and eventually transported to the liver (3). In the liver, vitamin K is Incorporated into very low-density lipoproteins (VLDL) and in this form it re-enters the systemic circulation and it is distributed to the body (4). Created with: BioRender.com (accessed on 30 August 2023).

Figure 3

The role of vitamin K in the coagulation pathway. Vitamin K-dependent coagulation factors II, VII, IX, and X as well as proteins C, S, and Z are transformed into their active forms by the carboxylation of the glutamic acid residues in their molecules. In this reaction, which is catalysed by vitamin K-dependent gamma-glutamyl carboxylase, molecular oxygen (O₂) and carbon dioxide (CO₂) also take part, while vitamin K is oxidised from vitamin K hydroquinone into vitamin K-2,3-epoxide. The levels of the active form of vitamin K are replenished by the action of vitamin K epoxide reductase, which reduces vitamin K-2,3-epoxide into vitamin K hydroquinone. Created with: BioRender.com (accessed on 30 August 2023).

Figure 4

Factors leading to low vitamin K bioavailability and interfering with its function. Malnutritive or malabsorptive states result in decreased dietary intake of vitamin K (mostly vitamin K₁) or intestinal absorption of vitamin K (both vitamins K₁ and K₂), respectively. The use of broad-spectrum antibiotic therapy potentially leads to dysbiosis and restriction of the vitamin K₂ producers in intestinal microflora. Antibiotics containing the NMTT or MTD side groups in their molecule additionally inhibit the γ-carboxylation and activation of vitamin K-dependent clotting factors. Furthermore, vitamin E supplementation in high doses unfavourably interacts with vitamin K, yet with undetermined mechanisms, while vitamin K antagonists, such as warfarin among other anticoagulants, inhibit the conversion of vitamin K in its active reduced form (not shown in this figure). Low vitamin K bioavailability and impairment of its function eventually lead to disturbance of coagulation homeostasis and heightening of haemorrhagic risk. Abbreviations: NMTT: 1-N-methyl-5-thiotetrazole; MTD: 2-methyl-1,3,4-thiadiazole. Created with: BioRender.com (accessed on 30 August 2023).