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\begin{document}

\title{Rare Late Presentation of Severe Congenital Hemophilia A in an Adult
Ugandan Soldier Following Elective Circumcision}



\author[1]{Barnabas Atwiine}%
\author[2]{Gladstone Airewele}%
\affil[1]{Mbarara University of Science and Technology}%
\affil[2]{Texas Children's Cancer Center and Hematology Centers}%


\vspace{-1em}



  
  \date{May 30, 2024}


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\selectlanguage{english}
\begin{abstract}
Severe hemophilia symptoms usually start in infancy. Affected
individuals require coagulation factor routinely to live a normal life.
A 25-year old active-duty soldier was diagnosed with severe congenital
hemophilia A after presenting with initial episode of prolonged
bleeding. His case demonstrates a rare late presentation of hemophilia.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Hemophilia A is an X-linked congenital deficiency of coagulation factor
VIII and is characterized by spontaneous or prolonged bleeding after
trauma. Individuals with the most severe form, hemophilia A, typically
develop symptoms during infancy and get diagnosed by a demonstration of
serum coagulation factor VIII levels that are \textless{}1\% of the
normal. These individuals require lifelong plasma-derived or recombinant
coagulation factor concentrate routinely or prior to surgical procedures
to prevent bleeding and are usually excluded from contact sports or
other activities or professions with a high risk of trauma and resultant
bleeding. It is very unusual for the severe form of hemophilia A to
present in an adult, who reports no prior abnormal bleeding symptoms.

\textbf{Case}

A 25-year-old soldier serving in the Uganda People's Defense Force
(UPDF) was referred for consultation to the hematology clinic due to
abnormal bleeding. One month earlier, he bled excessively after an
elective circumcision uneventfully performed by freehand. Bleeding
started 12 hours after surgery and lasted for two weeks. To manage the
bleeding, he was admitted to hospital, his wound explored, and an
incisional hematoma evacuated. During hospitalization, he received
intravenous tranexamic acid and vitamin K, plus intravenous antibiotics.
His vital signs remained normal throughout.

In the hematology clinic, the patient reported no history of painful
joint swelling, abnormal bruising, or bleeding and he had completed
rigorous military training without any problems. Additionally, none of
his family members including his mother, seven full siblings with 4
brothers, several maternal cousins, and three maternal uncles had
experienced abnormal bleeding, bruising, or joint deformity.

He was of normal stature, weighed 69.8kg; a height of 183.6 cm and a
normal body mass index (BMI) of 20.7m\textsuperscript{2}. He had no
joint swellings, tenderness or deformity and no skin or mucous membrane
bruising. His circumcision wound was dry and clean.

Laboratory evaluation included haemoglobin of 14.8 g/dL; platelet count
257,000/\selectlanguage{greek}µ\selectlanguage{english}L; activated partial thromboplastin time (aPTT) 58 seconds
(reference range 27--43 seconds); prothrombin time (PT) 13.9 seconds
(reference range 11.5--15.5 seconds); and INR 1.25. Given his elevated
aPTT, a mixing study with normal plasma was done which demonstrated
correction of aPTT into the normal range (30 seconds). Subsequent factor
VIII activity assay was \textless{} 1\% and factor IX assay 104\%.
Similar results were obtained on repeat testing after one week in
another laboratory. He was enrolled in the hemophilia clinic, from where
he will receive on-demand treatment with factor VIII if he bleeds. He is
back in the military barracks and his superiors have been apprised of
his diagnosis and its implications.

\textbf{Discussion}

Although hemophilia is thought to occur in about 1 in 3500--5000 male
births without major geographic or ethnic
differences,\textsuperscript{1,2} the actual number of affected patients
reported from low-income countries (LIC) is significantly lower than
expected. For example, Uganda with a current population of 45 million
and 1.7 million births yearly reported a total of only 221 individuals
living with hemophilia in 2018.\textsuperscript{3} This wide disparity
between the expected number and the actual number of individuals living
with haemophilia in Uganda is most likely due to a high number of
undiagnosed patients combined with premature death due to bleeding. Data
from the World Federation of Hemophilia (WFH) show a consistent
relationship between the economic status of individual countries and the
prevalence of hemophilia.\textsuperscript{4} As a group, countries with
a gross national product lower than \$2000 report only about one third
of the expected total number of individuals with
hemophilia.\textsuperscript{4}

While almost all patients with severe hemophilia (defined as
\textless{}1 percent factor VIII or IX activity) in high-income
countries (HIC), are diagnosed during the first few months of
life,\textsuperscript{5,6} diagnosis is often delayed in LIC due to a
dearth of hematologists, basic knowledge about bleeding disorders, and
hematology laboratory infrastructure. Our patient bled for two weeks
after circumcision, was hospitalized to evacuate a hematoma, and was not
diagnosed with hemophilia until he presented to the hematology clinic.

We diagnosed our patient with congenital severe hemophilia A with milder
than expected clinical phenotype. Milder-than-expected severity of
hemophilia as we found likely results from differences in the specific
causal hemophilia mutation, as well as innate differences in the genetic
factors that control each individual's anticoagulant and fibrinolytic
systems.\textsuperscript{7,8} Similar to our patient, Shapiro et al.
diagnosed severe congenital hemophilia in a 33-year-old enlisted US
Marine with 10 years of active service when he presented with bleeding
after routine shoulder surgery.\textsuperscript{9}

Though the absence of a family history of bleeding in our patient
suggests sporadic haemophilia due to a spontaneous mutation, we were
unable to perform genetic testing of the patient and his mother, or to
obtain a reliable history of the patient's grandparents, plus their
siblings and the descendants of those siblings. Considering these
factors plus the possibility that familial severe hemophilia A may be
similarly mild in our patient's asymptomatic brothers, we advised them
to be screened with an aPTT test.

An alternative explanation for bleeding with isolated prolonged aPTT and
low factor VIII activity such as acquired hemophilia A from the
development of autoantibodies against endogenous factor VIII was
considered. However, this was ruled out based on the patient's excellent
general health, relatively young age, and full correction of his aPTT
when mixed 1:1 with normal plasma.

This case highlights the need to improve general knowledge about
bleeding disorders among health workers and the community, and upgrade
the quality of hematology laboratory infrastructure in LIC. This patient
bled for 2 weeks before he was diagnosed with severe hemophilia. One way
to accomplish these objectives is by building collaborative
relationships between medical organizations in LIC and their
counterparts in HIC. As an example, the hematology clinic where this
patient was diagnosed is the only one in Western Uganda -- a region with
a population of 10 million. It would not exist but for collaboration
between Makerere University in Uganda and Baylor College of Medicine in
Texas, United States to train haematologists in sub-Saharan Africa
(SSA). This Global Hematology-Oncology Pediatric Excellence (Global
HOPE) initiative from the Texas Children's Cancer and Hematology
Centers, in partnership with Makerere University College of Health
Sciences, the affiliated Mulago National Referral Hospital, and Uganda
Ministry of Health has graduated three sets of fellows from its 2-year
training program and currently enrolls 10 trainees from five SSA
countries.\textsuperscript{10} More opportunities for training like this
one will facilitate the comprehensive care of individuals with
hemophilia and secondarily stimulate the growth of organizations that
support individuals with hemophilia plus improve awareness in the
general population of LIC.

\textbf{Declaration of Conflicting Interests}

The Authors Declare No Competing Interests

\textbf{References}

1. Soucie JM, Evatt B, Jackson D. Occurrence of hemophilia in the United
States. \emph{Am J Hematol} . 1998;59(4):288-294.
doi:10.1002/(SICI)1096-8652(199812)59:4\textless{}288::AID-AJH4\textgreater{}3.0.CO;2-I

2. Iorio A, Stonebraker JS, Chambost H, et al. Establishing the
Prevalence and Prevalence at Birth of Hemophilia in Males: A
Meta-analytic Approach Using National Registries. \emph{Ann Intern Med}
. 2019;171(8):540. doi:10.7326/M19-1208

3. World Federation of Hemophilia. Report on the Annual Global Survey
2018. Accessed September 17, 2020.
http://www1.wfh.org/publications/files/pdf-1731.pdf

4. Evatt BL. Demographics of hemophilia in developing
countries.\emph{Semin Thromb Hemost} . 2005;31(5):489-494.
doi:10.1055/s-2005-922218

5. Chambost H, Gaboulaud V, Coatm\selectlanguage{ngerman}élec B, et al. What factors influence
the age at diagnosis of hemophilia? Results of the French hemophilia
cohort. \emph{J Pediatr} . 2002;141(4):548-552.
doi:10.1067/mpd.2002.128115

6. Ljung R, Petrini P, Nilsson IM. Diagnostic symptoms of severe and
moderate haemophilia A and B. A survey of 140 cases. \emph{Acta Paediatr
Scand} . 1990;79(2):196-200. doi:10.1111/j.1651-2227.1990.tb11438.x

7. Shetty S, Vora S, Kulkarni B, et al. Contribution of natural
anticoagulant and fibrinolytic factors in modulating the clinical
severity of haemophilia patients. \emph{Br J Haematol} .
2007;138(4):541-544. doi:10.1111/j.1365-2141.2007.06693.x

8. Santagostino E, Mancuso ME, Tripodi A, et al. Severe hemophilia with
mild bleeding phenotype: molecular characterization and global
coagulation profile. \emph{J Thromb Haemost JTH} . 2010;8(4):737-743.
doi:10.1111/j.1538-7836.2010.03767.x

9. Shapiro BH, Minter AR, McDonald LS. Unusual Late Presentation of
Hemophilia A in an Active Duty U.S. Marine Following Open Shoulder
Surgery. \emph{Mil Med} . 2015;180(12):e1277-e1280.
doi:10.7205/MILMED-D-15-00043

10. Lubega J, Airewele G, Frugé E, et al. Capacity building: a novel
pediatric hematology-oncology fellowship program in sub-Saharan
Africa.\emph{Blood Adv} . 2018;2(Suppl 1):11-13.
doi:10.1182/bloodadvances.2018GS112742

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