ARTICLE
Purpura fulminans (PF) is an uncommon disorder
characterized by the acute onset of skin necrosis and hemorrhagic changes
due to dermal vascular thrombosis and disseminated intravascular coagulation
(DIC). PF usually develops a few days after a relatively benign viral
or bacterial infection or in conjunction with a severe infectious illness,
particularly bacterial sepsis [1]. Most PF cases have been reported in
children, although it can occur at all ages, and sometimes it represents
a fatal disorder [2, 3]. In rare instances, PF appears to be secondary
to drug intake [4].
We report a case of PF in an adult female with previous staphylococcal
infection and pancytopenia of unknown origin, who developed skin and coagulation
abnormalities after the administration of colony stimulating factors (CSF).
Case report
A 24-year-old female native of the province of Chubut (1400 km
away from our Hospital) with no significant personal medical history presented
fever and pharyngitis treated with acetyl salicylic acid 500 mg three
times daily, loratadine 10 mg/day and cephalexine 4 g/day. Due
to the persistence of fever and general condition worsening, laboratory
studies and blood cultures were performed which showed pancytopenia (hematocrit
27 %, hemoglobin 9 g/dL; leukocyte 2,000 cells/mm3
with absolute neutrophil count of 100 cells/mm3; and platelets
86.500/mm3) and positive blood cultures for coagulase-negative
Staphylococcus aureus. The patient was treated with sodic ampicillin
1 g/day and gentamicin 240 mg/day. The hematologist interpreted
pancytopenia as drug-induced (no bone marrow aspiration was performed)
and indicated G-CSF 300 mug/day i.m. Eleven days later, clinical
improvement was noted but hematological abnormalities persisted, and G-CSF
was switched to GM-CSF 300mug/day i.m. Forty eight hours later and after
administration of two doses of GM-CSF, the patient presented fever (39.5 &sup0;C),
bilateral and symmetric red-violet plaques in the upper and lower limbs,
and breast. The lesions were painful. Blood examinations showed the presence
of leukocytosis (12,500/mm3), anemia (hematocrit 26 %),
thrombocytopenia (120,000/mm3) and coagulation abnormalities,
with reduced fibrinogen (100 mg/ml) and prothrombin time (58 %),
and increased INR (1.45) and kaolin partial thromboplastin time (KPTT,
49 sec). Skin lesions were interpreted as the result of vasculitis,
and the patient was treated with prednisone 120 mg/day, amikacin
1 g/day and nadroparin 7500 IU every 12 hours, whereas
GM-CSF was discontinued. Renal and liver function tests were normal. No
skin biopsy was performed. As the clinical features were so dramatic,
the patient was sent to our hospital for further investigation and treatment.
On admission, she presented widespread red-violet plaques with geographical
erythematous borders and purpura lesions, symmetrically distributed on
the breast and four limbs. The back, buttocks, face, fingers and abdomen
were not affected. The lesions rapidly evolved into necrotic-hemorragic
blisters and necrotic eschars (Figs.
1, 2). Laboratory tests showed anemia, leukocytosis, thrombocytopenia
and alteration in the coagulation parameters suggestive of DIC (Table I).
Liver and renal function tests,
as well as rheumatology tests (ANA, lupus anticoagulant, anticardiolipin
antibodies, complement fraction levels, cryoglobulins) were within normal
limits, except reactive P-ANCA 1/320. Blood and skin cultures gave negative
results. Skin biopsy specimens from the border of three different plaques
showed diffuse dermal edema and vessel occlusion by fibrin thrombi (Fig.
3). Small vessels also showed some hemorrhagic areas with focal necrosis
of their walls and erythrocyte extravasation. No inflammatory infiltrates
were observed. The patient received metilprednisolone 100 mg/day.
As the lesions remained clinically stable, surgical debridement of necrotic
tissue followed by application of skin autografts taken from the patient's
thighs was performed. Three months later the patient had completely recovered
showing only residual scarring (Fig.
4).
Discussion
PF occurs predominantly in three clinical settings: (i) in neonates
with congenital homozygous deficiency of protein C or protein S (neonatal
PF); (ii) during a severe, acute infectious disease, usually due to Neisseria
meningitidis sepsis, but occasionally caused by Staphylococcus
aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus
influenzae or other gram-negative bacteria, where a temporary
C protein deficit can also occur (acute infectious PF); (iii) during the
convalescent phase of an infection, more commonly streptococcal or a viral
exanthema (postinfectious idiopathic PF), often associated with a temporary
protein S deficit of autoimmune origin [1-4]. Regardless of the precipitating
condition, PF presents initially with erythematous macules and petechiae,
which rapidly evolve into painful, indurated and well-demarcated purpuric
plaques. Late findings include hemorrhagic bullae, skin necrosis and eschars.
Necrosis may extend to subcutaneous tissue, muscles and bones. Characteristic
histopathologic feature is dermal vessel thrombosis. PF typically occurs
in the setting of DIC. Vascular changes may be widespread and involve
multiple organ systems, rendering PF a life-threatening disorder [1-4].
Diagnosis of PF in our patient was based on
the presence of purpuric necrotic skin lesions, coagulation abnormalities
consistent with DIC (elevated D-dimers, elevated fibrinogen degradation
products, consumption of fibrinogen and platelets) and the presence of
thrombi in dermal vessels with a previous record of staphylococcal infection.
We cannot accurately determine whether this was an infectious PF or an
idiopathic PF since neither protein C or protein S, nor anti-protein S
antibodies dosage was performed. According to Frutos Martinez et al.
[4], even though both protein S and protein C levels can be diminished
in the context of DIC by consumption, antithrombin III, factors II and
VII normal values suggest that protein S deficit is the crucial factor
of the pathogenesis of idiopathic PF. This argument, together with the
fact that our patient had been suffering from staphylococcal infection
for 11 days with a favorable evolution, would support the diagnosis
of idiopathic PF. In addition, the idiopathic variety is often confined
to the skin, as in our case. We also want to stress the fact that the
development of the lesions was very closely associated with the administration
of CSFs. Indeed, drug intake has been indicated as a possible PF trigger
[4]. In 1995, Mueller et al. reported the case of a child with
HIV infection and DIC apparently caused by exposure to G-CSF [5]. They
hypothesized that if granulopoiesis is stimulated on a long-term basis
by G-CSF, it is possible that the disturbed maturation of these cells
might lead to their disintegration in the marrow, thereby releasing thromboplastins,
in a manner similar to the mechanism of DIC that commonly occurs during
acute promyelocytic leukemia. In conclusion, although staphylococcal infection
is probably involved in the aetiology of PF in our case, may be possible
that CSF also played a role in the development of DIC associated with
PF.
Article accepted on 10/12/2002REFERENCES
1
Nolan J, Sinclair R. Review of management of purpura fulminans and
two case reports. Br J Anaesth 2001; 86: 581-6.
2
Darmstadt GL. Acute infectious purpura fulminans: pathogenesis and
medical management. Pediatr Dermatol 1998; 15: 169-83.
3
Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg M, Austen KF. Dermatology
in General Medicine. Mc Graw Hill. 3rd Ed., 1986, p. 2112.
4
Frutos Martinez C, Iturrioz Mata A, Gonzalez Perez-Yarza E, et
al. Púrpura fulminante idiopática con déficit
transitorio de proteína S An Esp Pediatr 2001; 55: 360-73.
5
Mueller BU, Burt R, Gulick L, et al. Disseminated intravascular
coagulation associated with granulocyte- colony- stimulating factor therapy
in a child with human immunodeficiency virus infection. J Pediatr
1995; 126: 749-52.
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