Observational prospective study to evaluate the efficacy of Vitamin K Intravenously on the coagulopathy in patients with peroxisomal biogenesis disorders (PBD)

Patients with peroxisomal biogenesis disorders (PBD) have mutations in one of
the PEX genes causing absent or dysfunctional peroxisomes. The biochemical
characteristics of peroxisomal dysfunction are primarily accumulation of very
long chain fatty acids and bile acid intermediates. The clinical spectrum of
PBD ranges from the severe Zellweger syndrome to patients that survive into
adulthood. Most patients have liver disease ranging from prolonged neonatal
jaundice to liver failure. Patients with PBD often show abnormalities of the
hemostatic system, and even have haemorrhagic complications, such as severe
intracranial bleeding. The exact pathophysiology of liver disease and the
coagulation disorder in PBD has not been elucidated. Most patients with PBD
receive oral vitamin K (and other fat soluble vitamins), but the efficacy has
not been systematically studied in a cohort of patients.
Since no literature is available on this subject, a retrospective cohort-study
in 38 patients (0 to 34 years old) with PBD was performed in the Emma
Children*s Hospital Academic Medical Centre in Amsterdam (EKZ AMC) very
recently (S. Zeynelabidin et al, unpublished data, attached document). This
study showed that coagulopathy in PBD patients is multifactorial and probably
at least partially caused by liver disease due to toxic bile acid intermediates
resulting in reduced coagulation factors and by vitamin K deficiency due to
malabsorption. Nowadays, the supplementation of oral vitamin K in PBD patients
is non-uniform and orally given. The study S. Zeynelabidin et al. clearly shows
that oral vitamin K therapy does not correct the coagulopathy caused by vitamin
K deficiency sufficiently in most patients. The protein Induced by Vitamin K
absence (PIVKA) levels are still increased after high oral dosages of vitamin K
in 90% of the patients of our cohort. Furthermore, in the study group of 38
patients, four (10%) patients developed an intracranial haemorrhage. Two of
them had increased PIVKA levels despite high oral dosages of vitamin K
supplementation and normal platelet counts, pointing out a vitamin K deficient
bleeding. PIVKAs of the third patient with intracranial haemorrhages was normal
and the PIVKAs of the last patient were not measured.
Pereira et al. showed that intestinal absorption of oral vitamin K therapy was
unreliable in patients with severe acute liver disease. They conducted a double
blind randomized controlled trial in adults : only 20% developed a rise in
vitamin K levels compared to 94% of the patients given intravenous vitamin K. A
study in infants with hyperbilirubinemia revealed that oral vitamin K
supplementation gave inconsistent changes in PIVKA levels, which did not occur
in patients given intravenous vitamin K supplementation. In summary, oral
supplementation of vitamin K does not seem to be effective in all our PBD
patients and few studies suggest that intravenous vitamin K supplementation
might be more effective in patients with liver disease. As a consequence, we
want to evaluate the effect of intravenous vitamin K supplementation in
patients with PBD disorders in order to reduce vitamin K deficient bleeding
complications, including intracranial haemorrhages

Primary objective: To evaluate the effect of intravenous vitamin K therapy on
the vitamin K dependent coagulopathy in patients with peroxisomal biogenesis
disorders measured with APTT, PT, FV, FVII, fibrinogen, d-dimer, thrombocytes
and PIVKA.
Secondary objective: To evaluate the effect of intravenous vitamin K therapy on
the Calibrated Automated Thrombogram (CAT) (= thrombin generation assay).

An observational prospective pilot study with five patients will be conducted.
We include the five patients in three months and it will take place in the EKZ
AMC.

Patients with known vitamin K deficiency will be treated with vitamin K
intravenously.

Before administration of vitamin K, blood will be collected for determination
of baseline level of APTT, PT, FV, FVII, fibrinogen, d-dimer, thrombocytes,
PIVKA and Calibrated Automated Thrombogram (CAT) (= thrombin generation assay).
(2x 2.7 ml citrate whole blood). The needle or line that has already been
inserted to take blood will be utilised for the insertion of vitamin K, so that
the number of *jabs* is kept to the minimum.

To evaluate the effect of vitamin K, a second sample of blood will be taken for
determination of APTT, PT, FV, FVII, fibrinogen, d-dimer, thrombocytes, PIVKA
and CAT after 3 to 7 days. (The half-life of prothrombin is 60 hours) (2x 2.7
ml citrate whole blood)

These patients normally receive oral vitamin K and have routinely check ups to
evaluate the effect of vitamin K, and other medication, through blood samples.
Therefore these patients will only be punctured one time extra, the first time
we take blood and insert vitamin K, since the check up is routine.

Before administration of vitamin K, blood will be collected for determination
of baseline level of APTT, PT, FV, FVII, PIVKA, thrombocytes, d-dimer
fibrinogen and Calibrated Automated Thrombogram (CAT) (= thrombin generation
assay). (2x 2.7 ml citrate whole blood). The needle or line that has already
been inserted to take blood will be utilised for the insertion of vitamin K, so
that the number of *jabs* is kept to the minimum.

To evaluate the effect of vitamin K, a second sample of blood will be taken for
determination of APTT, PT, FV, FVII, PIVKA, thrombocytes, d-dimer, fibrinogen
and CAT after 3 to 7 days. (The half-life of prothrombin is 60 hours) (2x 2.7
ml citrate whole blood)

The study S. Zeynelabidin et al. clearly shows that oral vitamin K therapy does
not correct the coagulopathy caused by vitamin K deficiency sufficiently in
most patients with PBD. The Protein Induced by Vitamin K Absence (PIVKA) levels
are still increased after high oral dosages of vitamin K in 90% of the patients
of our cohort. Furthermore, in the study group of 38 patients, four (10%)
patients developed an intracranial haemorrhage. Two of them had increased PIVKA
levels despite high oral dosages of vitamin K supplementation and normal
platelet counts, pointing out a vitamin K deficient bleeding. Studies suggest
that intravenous vitamin K supplementation might be more effective in patients
with liver disease, which these patients also have.
The patients will have one extra visit. They normally have a routine check up
of their medication, so only their first visit where they receive vitamin K
will be different. Since children usually don*t prefer punctures, emla crème
will be used. Intravenous vitamin K rarely causes an allergic reaction but this
risk is minimal when injected slowly.
This study can only be done using this patient group since these specific
children show no response to oral vitamin K therapy for their coagulopathy. The
risk they have of a brain haemorrhage is 10%. We therefore think that the risks
of this intervention are negligible and the burden minimal. As a consequence,
we want to evaluate the effect of intravenous vitamin K supplementation in
patients with PBD disorders in order to reduce vitamin K deficient bleeding
complications, including intracranial haemorrhages.