Coagulopathy in Zellweger spectrum disorders: a role for vitamin K

Abstract

Introduction: Zellweger spectrum disorders (ZSDs) are caused by an impairment of peroxisome biogenesis, resulting in multiple metabolic abnormalities. This leads to a range of symptoms, including hepatic dysfunction and coagulopathy. This study evaluated the incidence and severity of coagulopathy and the effect of vitamin K supplementation orally and IV in ZSD.

Methods: Data were retrospectively retrieved from the medical records of 30 ZSD patients to study coagulopathy and the effect of vitamin K orally on proteins induced by vitamin K absence (PIVKA-II) levels. Five patients from the cohort with a prolonged prothrombin time, low factor VII, and elevated PIVKA-II levels received 10 mg of vitamin K IV. Laboratory results, including thrombin generation, at baseline and 72 h after vitamin K administration were examined.

Results: In the retrospective cohort, four patients (13.3%) experienced intracranial bleedings and 14 (46.7%) reported minor bleeding. No thrombotic events occurred. PIVKA-II levels decreased 38% after start of vitamin K therapy orally. In the five patients with a coagulopathy, despite treatment with oral administration of vitamin K, vitamin K IV caused an additional decrease (23%) of PIVKA-II levels and increased thrombin generation.

Conclusion: Bleeding complications frequently occur in ZSD patients due to liver disease and vitamin K deficiency. Vitamin K deficiency is partly corrected by vitamin K supplementation orally, and vitamin K administered IV additionally improves vitamin K status, as shown by further decrease of PIVKA-II and improved thrombin generation.

Keywords: Coagulopathy; Peroxisome biogenesis disorders; Vitamin K; Zellweger spectrum disorders.

Fig. 1

Relationship between last measured dihydroxycholestanoic acid (DHCA) (x axis, normal range 0.00–0.12 μmol/L) and prothrombin time (PT) (y axis, normal range 9.7–11.6 s). Trend line indicates a significant correlation of DHCA and PT (r = 0.76, p < 0.001)

Fig. 2

a Proteins induced by vitamin K absence (PIVKA-II) of 17 patients before (dots) and after (squares) vitamin K therapy administered orally. Cutoff range is <2.5 μg/L. Almost all patients showed a decreased PIVKA-II level (p ≤ 0.05). b PIVKA-II levels before (T = 0) and after (T = 72 h) vitamin K supplementation IV. Interrupted lines indicate reference range of 21–56 mAU/ml

Fig. 3

Thrombin generation analysis of Zellweger spectrum disorders (ZSD) patients. Thrombin generation was initiated with a1 pM or b 5 pM tissue factor. Thrombin generation was averaged for five patients before and after 72 h of vitamin K therapy IV