Coagulopathy in Zellweger spectrum disorders: a role for vitamin K

Zellweger spectrum disorders (ZSD) are a group of autosomal recessively inherited disorders with a deficiency of functional peroxisomes caused by mutations in one of the peroxisome assembly protein (PEX) genes. (Wanders and Waterham 2006). One of the biochemical consequences of peroxisomal dysfunction is accumulation of very long-chain fatty acids and bile acid intermediates [e.g., dihydroxycholestanoic acid (DHCA) and trihydroxycholestanoic acid (THCA)], contributing to a variety of symptoms with a spectrum of severity, including liver disease, developmental delay, and hearing and vision deficits (Klouwer et al. 2015).

In general, severe liver disease is associated with impairment of coagulation, since the liver synthesizes multiple coagulation factors. Deficiencies of fat-soluble vitamins are common among ZSD patients (Klouwer et al. 2015), and vitamin K deficiency may coexist and partially attribute to the coagulopathy in these patients. Most ZSD patients therefore receive supplementation orally of vitamin K and other fat-soluble vitamins (Berendse et al. 2016). Although ZSD patients most likely have an increased bleeding diathesis, recent studies state coagulation rebalance occurs in patients with liver disease, with higher risks of both bleeding and thrombosis (Lisman and Porte 2011; Magnusson et al. 2016). The presence of hemorrhages, thrombosis, or effect of vitamin K supplementation orally have not been systematically studied in ZSD patients. Intravenous (IV) administration of vitamin K might be more effective than orally, as shown by Pereira et al. in adults with liver cirrhosis (Pereira et al. 2003). In this study, subclinical vitamin K deficiency was corrected in 15 of 16 patients receiving 10 mg vitamin K IV compared with three of 15 receiving oral supplementation. In another study, infants with hyperbilirubinemia had lower vitamin K concentrations after oral versus IV administration of vitamin K, reflecting the low efficiency of intestinal absorption (Pereira et al. 2005).

We retrospectively evaluated the incidence and severity of bleeding and thrombotic complications, the pathogenesis of coagulopathy, and the effect of vitamin K supplementation orally in ZSD patients. Furthermore, the effect of vitamin K IV was prospectively studied in five ZSD patients.

This is the first study to investigate the incidence and severity of bleeding and thrombotic complications in ZSD patients. Major intracranial bleedings developed in 13.3%, including one patient born prematurely as a confounding risk factor, and minor bleedings in almost 50% of patients with a ZSD. These are most likely underreported due to the study’s retrospective design. None of the 30 ZSD patients developed thrombotic events. However, most patients were young, and their risk of late-onset thrombosis is unknown. The coagulopathy is partly caused by liver disease, probably due to accumulation of toxic bile-acid intermediates (Ferdinandusse et al. 2009). PT was prolonged in most patients and more prolonged in patients with higher bile-acid intermediates. Although PT can be used to investigate a loss of function in the procoagulant system, it does not predict the risk of bleeding in patients with liver disease (Lisman and Porte 2011). It is known that children with liver disease can develop severe bleeding as well as thrombotic complications (Magnusson et al. 2016). Reduced synthetic capability of liver cells results in decreased levels of both procoagulant and anticoagulant factors. In addition, hyperfibrinolysis may occur in children with chronic liver disease, especially if the disease is cirrhotic (El-Sayed et al. 2013). Whether a pediatric patient with liver disease and loss of reserve capacity develops bleeding or thrombosis depends on the vascular bed and additional risk factors in the individual patient (Magnusson et al. 2016). In children, various diseases are associated with liver failure, including infections, cholestatic disorders, metabolic disorders, and ischemia due to cardiac diseases. These diseases are different than those seen in adults and vary with age. In some diseases, bleedings occur more often, for example, in biliary atresia or α1-antitrypsin deficiency (Fischler and Lamireau 2014; Magnusson et al. 2016). Other diseases, such as cystic fibrosis, are more frequently linked to thrombotic events (Takemoto 2012). Many metabolic disorders are associated with bleeding complications (Croffie et al. 1999; Preston et al. 2013), and our study extended those findings by showing that in ZSD patients, bleeding complications are more prevalent than thromboses.

Impaired hepatic synthesis is not the only cause of coagulopathy in ZSD patients. The many risk factors for developing vitamin K deficiency, including steatorrhea, poor oral intake of the vitamin and frequent antibiotic treatment. PIVKA-II is a functional indicator of vitamin K status. In our retrospective study, all patients had increased levels in the absence of vitamin K therapy, consistent with vitamin K deficiency. Vitamin K supplementation orally decreased PIVKA-II levels by 38% but did not normalize them in most patients. The three patients with a rise in PIVKA-II levels after supplementation orally also had a decrease in FV and an increase in PT. This could be explained by further progression of the disease, since the time interval between both measurements varied from 6 to 10 years.

In the prospective study, we aimed to improve one of the causes of coagulopathy in ZSD patients, i.e., vitamin K status, by giving vitamin K IV. This had no effect on global coagulation parameters but did lower PIVKA-II levels by another 23%. This decrease was most apparent in patients with the highest levels before IV therapy. In one patient, PIVKA-II increased from 27 to 36 mAU/ml but remained within the normal range of 21–56 mAU/ml. Furthermore, thrombin generation was significantly improved, although it remains to be determined whether regular vitamin K supplementation IV will diminish bleeding complications in ZSD patients. Nevertheless, in clinical situations, including during bleeding episodes or before dental or surgical procedures, it seems to have an additional positive effect on coagulation. As ZSD patients have a high risk of bleeding, consultation with a hematologist before a surgical procedure or after trauma is important to discuss patient coagulation status and management. There is insufficient evidence, however, to give vitamin K IV on a regular basis, since it is a real burden for those children. However, it may be useful to measure PIVKA-II more often, as supportive care with vitamin K therapy orally could be improved or in some cases boosted with IV administration. More comprehensive research is indicated in larger populations to examine the clinical relevance of our laboratory findings.

In conclusion, both liver disease and vitamin K deficiency contribute to coagulopathy in ZSD patients, which particularly manifests as bleeding complications. Vitamin K deficiency is partly corrected by administering vitamin K therapy orally, and added IV administration improves vitamin K status, as shown by further decrease of PIVKA-II and improved thrombin generation.