ARTICLE
Leg ulcer is a common disease occurring in many kinds of abnormalities.
Coagulation disorders, such as protein C deficiency [1], antithrombin
III deficiency [2] and plasminogen activator inhibitor deficiency in Klinefelter
syndrome [3], have been known to cause leg ulcers. Congenital afibrinogenaemia,
a rare hemorrhagic disorder characterized by the complete absence of fibrinogen
in the plasma first described 1920 [4], is also one of the coagulation
disorders. Approximately 250 cases exhibiting autosomal recessive inheritance
have been reported [5]. Plasma fibrinogen is a 340 kDa precursor protein
of fibrin extracted as an insoluble protein, and is composed of 3 kinds
of polypeptides. It is synthesized in hepatocytes and secreted into the
plasma. Recently, congenital afibrinogenaemia have been reported to show
trace amounts of fibrinogen in the plasma [6]. We report the second case
of congenital afibrinogenaemia presented with leg ulcer, in which the
ulcer was successfully treated with fresh frozen plasma (FFP).
Case report
A 30-year-old man presented with a lifelong history of prolonged bleeding.
His parents were cousins. His family including his parents, brother, sister
showed no bleeding abnormalities clinically and in laboratory examinations.
At birth, he showed bleeding from his umbilical cord even after the umbilical
cord stump. He was successfully treated with a blood transfusion. He repeatedly
showed bleeding from nasal mucosa and various parts of the skin when he
was injured. Subdural haematoma was also found. He repeatedly showed haematomas
on the medial malleolus of his left leg following trauma. He was diagnosed
as having congenital afibrinogenaemia because of plasma fibrinogen deficiency
when he was 6 years old. Since the age of 26, his leg ulcer gradually
increased in size. He was admitted to the Dermatology Department on May
2nd in 1998 for treatment. Physical examination revealed a leg ulcer of
5 cm in diameter over the medial malleolus on the left leg covered with
coagulated blood (Fig. 1).
Pitting edema and brown-colored pigmentation were found on the surrounding
skin. Laboratory examinations revealed prolonged bleeding time (> 10
min, normal 1-3 min), prolonged coagulation time (> 30 min, normal
5-13 min), prolonged prothrombin time (> 200 sec, normal 10-14 sec),
prolonged activated partial thromboplastin time (> 200 sec, normal
30-50 sec) and the plasma fibrinogen was not measurable (< 5 g/l, normal
12-34 g/l). Other laboratory findings including anticardiolipin antibody,
serum protein C, serum protein S were unremarkable. Histological examination
of the biopsy specimen from the surrounding skin showed hyperkeratosis,
acanthosis and severe fibrotic change in the whole dermis (Fig.
2). The blood vessel walls in the dermis showed intimal proliferation
and several blood vessels contained thrombosis. Severe hemosiderin deposit
in the middle dermis was also found (Fig.
3). A venous angiography showed poor visualization of the left deep
veins. Several parts of the left deep veins, popliteal and femoral veins
in his leg were visualized, but not others. Collateral veins at the proximal
part of left greater and the lesser saphenous veins were dilated.
Treatment with Actosin® (bucladesine sodium) ointment
and bed rest showed no improvement. He complained of pain in his abdomen
and in the left leg 10 days after admission. A CT-scan of the pelvis revealed
a haematoma around the iliac muscle. Three weeks later on May 26th, the
treatment with FFP (10 uint/day) administration was begun. He showed hypotension,
bronchospasm and a cutaneous rash. His reaction was successfully treated
with anti-allergic drugs (chlorpheniramine and azelastine) and methylprednisolone
on the estimation of hypersensitive reactions to fibrinogen. After the
beginning of FFP administration, pain improved markedly, bleeding time,
coagulation time, prothrombin time, activated partial thromboplastin time
improved, and the plasma fibrinogen became normal. His leg ulcer cured
2 months after the beginning of FFP administration, and he was discharged.
One month after the discharge, he was admitted again because of the recurrence
of the leg ulcer. He was successfully treated with skin transplantation
after the excision of leg ulcer, and discharged.
Discussion
Congenital afibrinogenaemia subjects show repeated bleeding from birth.
All the reported cases including ours show a long bleeding time from the
umbilical cord. Central nervous system hemorrhage, renal hemorrhage and
splenic rupture often happen [7, 8]. Menorrhagia, haematoma following
minor trauma, gastrointestinal bleeding, gingival bleeding and mucous
membrane bleeding are also often observed. Congenital afibrinogenaemia
with leg ulcer was first described by Rupec et al. in 1996 [9].
The present case is the second case of congenital afibrinogenaemia presented
with leg ulcer, and the first case successfully treated with FFP administration
and skin transplantation. The leg ulcer healed after treatment with FFP,
but recurred one month later. The heeling of leg ulcer was considered
to be due to FFP treatment rather than bed rest. At first, the leg ulcer
in the present case was treated with bed rest and topical application
of ointment without success. The leg ulcer improved after the treatment
of FFP for the intra-abdominal hemorrhage. The result of venous angiography
suggested the presence of venous insufficiency in the left lower extremity.
Recurrent ulcerations at the medial malleolus in the same leg were induced
by the venous insufficiency. It is very hard to cure ulceration in patients
with congenital afibrinogenemia, because they have difficulty in obtaining
blood clotting. As a result, recurrent ulcerations in patients with congenital
afibrinogenemia are difficult to heal.
The plasma fibrinogen in the present case was
not measurable because of its trace amount. Congenital afibrinogenaemia
had been thought to have no plasma fibrinogen. Recently, however, al-Mondhiry
and Ehmann reported that congenital afibrinogenaemia show a trace amount
of fibrinogen [6]. Fibrinogen is a fibrillar glycoprotein of the keratin-myosin
family, and takes part in blood coagulation in wound healing. The conversion
of fibrinogen into fibrin with the help of factor XIII, calcium ion and
thrombin, takes place during blood coagulation. Fibrin consolidates the
unstable platelet plug, and fibroblasts accumulate in the stabilized fibrin
clot and synthesize connective tissue. Fibronectin on the surface of fibroblasts
combines with fibrinogen, fibrin and collagen fiber, accelerating the
wound healing process. In congenital afibrinogenaemia, the process takes
a long time because of the trace amount of fibrinogen. Consequently, the
leg ulcer due to afibrinogenaemia takes long time for improvement. The
administration of FFP speeds up the improvement because of fibrinogen
replacement. Hypersensitive reactions to FFP, however, took place in the
present case. Antifibrinogen antibodies have been reported to appear after
replacement therapy in afibronogenaemia [10, 11]. Treatment with anti-allergic
drugs and/or methylprednisolone is recommended.
Article accepted on 5/6/01
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