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\begin{document}

\title{Mixed Coagulopathy in Patient with Peroxisomal Disorder, Zellweger
Syndrome}



\author[1]{Nicholas Farris}%
\author[1]{Angela Sandell}%
\affil[1]{University of Rochester Medical Center}%


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  \date{June 14, 2024}


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Title: Mixed Coagulopathy in Patient with Peroxisomal Disorder,
Zellweger Syndrome

Authors: Nicholas Farris, MD\textsuperscript{1}; Angela Sandell,
MD\textsuperscript{2}

Affiliations

Assistant Professor, University of Rochester Medical Center, Division of
Pediatric Hematology and Oncology, Rochester, NY

Assistant Professor, University of Rochester Medical Center, Division of
Gastroenterology, Rochester, NY

Corresponding Author:

Nicholas Farris

Email: Nicholas\_farris@urmc.rochester.edu

Address: 601 Elmwood Ave, Box 777, Rochester NY, 14642

Phone: 585-273-4189

Fax: 575-273-1039

Word Count: 462

Tables, Figures, Supporting files: 0

Running Title: Mixed Coagulopathy in Patient with Zellwegers

Keywords: Coagulopathy, Peroxisome, Zellwegers, Intracranial Hemorrhage\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Protime & PT\tabularnewline
\midrule
\endhead
Activated Partial Thromboplatin Time & aPTT\tabularnewline
Alanine Transaminase & ALT\tabularnewline
Aspartate Transaminase & AST\tabularnewline
Dihydroxycholestanoic Acid & DHCA\tabularnewline
Trihydroxycholestanoic Acid & THCA\tabularnewline
\bottomrule
\end{longtable}

Dear Editor:

Peroxisome biogenesis disorders including Zellweger Syndrome can present
with severe bleeding due to hepatopathy and
coagulopathy.\textsuperscript{1} Pathogenesis can include both synthetic
and secondary ADEK vitamin deficiencies. While almost 50\% of patients
with Zellweger will have minor bleeding, 13\% of patients were reported
to have intracranial bleeding.\textsuperscript{1}

We care for an infant girl, born full term with initial newborn screen
findings of elevated very long-chain fatty acids. Genetic testing
demonstrated compound heterozygous mutations of the PEX12 gene:
pathogenic c987\_988del (p.Phe330Serfs*23) and variant of uncertain
significance c368\_370del (p.Leu123del). Initial newborn care included
vitamin K injection and standard care until the age of 5 months old. Due
to altered mental status and vomiting, she presented to the emergency
department; there was no reported inciting event. Head imaging
demonstrated subdural hematomas with mass effect and midline shift.
Hemostatic testing found prothrombin time (PT) \textgreater{}100s,
normal activated partial thromboplastin time and factor 7 activity of
2\%. She also had anemia to 3.5g/dL, reticulocytosis, leukemoid reaction
and normal platelet count. Liver function found aspartate
aminotransferase (AST) 111, alanine aminotransferase (ALT) 46, normal
fibrinogen by Clauss. PT mixing study normalized initially and stayed
corrected.

She was treated with activated factor 7, as well as appropriate
transfusion and supportive measures. She was started on IV vitamin K and
transitioned to oral vitamin K and exogenous cholic acids. Due to
persistently low levels including with parenteral administration, factor
7 gene was analyzed and found to have no pathogenic mutations. Over the
next 7 months, she remained on oral vitamin K (both as tablet and liquid
formulation); factor 7 remained persistently between 24 and 45\%.
Des-gamma-carboxy prothrombin levels were found to be 1.1 (normal 0-7.4
ng/mL). Most recent factor 7 activity level of 45\% was achieved with
liquid vitamin K 5mg daily. Bile acid intermediates
dihydroxycholestanoic acid (DHCA) and trihydroxycholestanoic acid (THCA)
were initially markedly elevated; DHCA has trended down.

While on oral vitamin K, Protein C was found to be low at 43\% while
having normal factors 5, 8, 9 and protein S. She had a persistent anemia
with reticulocytosis and low vitamin E level (1.8 alpha-tocopherol,
normal 3.5-8.0 mg/L). After starting ADEK vitamins her anemia resolved
due to presumed vitamin E deficient hemolytic anemia. Other than with a
recent illness, transaminase elevation and cholestasis improved;
synthetic function remained stable. She has been growing on elemental
formula. Her only bleeding since initial presentation was a brief
episode of self resolved hematochezia.

Our patient is an example of an otherwise spontaneous hemorrhage due to
secondary coagulopathy with a genetic predisposition and associated
malabsorption. Our patient benefited from a multidisciplinary approach
including hematology, gastroenterology, genetics and neurosurgery.
Considerations for future research in patients with peroxisome disorders
could include prophylactic ADEK vitamins though response to IV and oral
supplementation has been mixed.

Conflicts of Interest: The authors have no conflicts of interest.

Zeynelabidin S, Klouwer FCC, Meijers JCM, Suijker MH, Engelen M,
Poll-The BT, van Ommen CH. Coagulopathy in Zellweger spectrum disorders:
a role for vitamin K. J Inherit Metab Dis. 2018 Mar;41(2):249-255. doi:
10.1007/s10545-017-0113-8. Epub 2017 Nov 14. PMID: 29139025; PMCID:
PMC5830475.

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