Purpura fulminans in a patient with malaria

ARTICLE

Malaria is a mosquito-born disease caused by the protozoan genus Plasmodium. This disease is characterized by a febrile systemic illness with cyclic fevers as the hallmark. Other clinical signs and symptoms include tachycardia, hypotension, headache, backache, vomiting, nausea, abdominal pain and altered consciousness. Cutaneous manifestations although noted, are rarely reported and have included jaundice [1], petechiae [1], vasculitis [2], purpura [3, 4], and gangrene [5]. Purpura fulminans is a term used to describe a severe skin condition of rapidly progressive hemorrhagic necrosis of the skin associated with hematological features of disseminated intravascular coagulation (DIC). A case of purpura fulminans in a patient is presented here.

Case report

We report a case of a 44 year old French woman living in Haiti who initially presented with jaundice and diarrhea of four days duration to her primary care physician. She was diagnosed with malaria by peripheral blood smear and started on chloroquine. After two doses of chloroquine the patient's condition continued to worsen. At this point, she was noted to have altered mental status in addition to renal insufficiency and purpura over her extremities. The chloroquine was discontinued, doxycycline and pentoxifylline were initiated, and within 48 hours the patient's fever and mental status changes resolved. At this point she was transferred to our university medical center for further management. Upon arrival she had purpuric plaques over the distal aspect of all toes. These purpuric areas were now studded with hemorrhagic bullae near the proximal nail beds, and black gangrenous plaques at the distal tips of the toes (Fig. 1A, B). She had a similar larger bullae on her left arm (Fig. 2), and hemorrhagic crusts over both lips. Laboratory results at the time of admission revealed thrombocytopenia (28,0000 cells/mm³), anemia (Hgb = 7.5 g/dl and Hct = 22%) and leukocytosis (16,600 cells/mm³) with no left shift. She had an elevated prothrombin time of 14.4 seconds and a normal activated partial thromboplastin time of 25 seconds. She also had a positive D-dimer result, but her fibrinogen level was within normal limits (149 mg/dl). Unfortunately, no other hematological parameters were obtained at this time. Skin biopsies of both arm and foot lesions revealed extensive red blood cell extravasations, and early adnexal and epidermal necrosis consistent with thrombo-occlusive disease. Deeper sections revealed multiple fibrin platelet thrombi and focal acute inflammation (Fig. 3). She was treated with intravenous heparin (750 U/hr), enteric coated aspirin 325 mg po QD and pentoxifylline 400 mg po TID for the thrombo-occlusive disease. The malaria was considered treated with the doxycycline she had received. Over the next three weeks the patient improved clinically with the plaque on her arm resolving completely. The distal aspect of her toes, although still with atrophic black plaques, were smaller and failed to ulcerate. Upon discharge from the hospital in good condition, the patient returned to Haiti, and therefore was not seen in follow-up.

Discussion

Malaria is a serious, potentially life-threatening illness infectious disease caused by the species Plasmodium. Most severe life-threatening cases of malaria with multiorgan system involvement are caused by Plasmodium falciparum. Skin findings seen in persons with malaria are rarely reported. We present a case of purpura fulminans in a patient with malaria. Purpura fulminans was initially described as a rapidly progressive skin necrosis occurring during a latent period after a benign infection. Although in the past many entities were labeled as purpura fulminans, there has been an attempt to use this term only to describe rapidly progressive skin necrosis associated with the signs of disseminated intravascular coagulation (DIC) [6]. Purpura fulminans can be classified into three categories: 1) acute infectious purpura fulminans; 2) hemostasis initiated purpura fulminans which occurs from hereditary or acquired dysfunction of the Protein C or other hemostasis regulatory mechanisms; and 3) idiopathic purpura fulminans which can be postinfectious or of unknown etiology [7, 8]. In our patient, the evidence of D-dimers allows us to make a diagnosis of DIC, and thus purpura fulminans. Calverley [9] states that the diagnosis of DIC should not be made without at least one positive test for excessive thrombin generation. Two such tests are the D-dimer assay and the more difficult to perform fibrin monomer assay. The D-dimers represent by-products of plasmin degraded fibrin monomers and are a new, more specific way of analyzing fibrin/fibrinogen degradation products. [9]. In addition to the specific positive D-dimer result, our patient had other indicators of DIC including thrombocytopenia and an elevated prothrombin time. However, the fibrinogen level was within normal limits. This result would appear to go against a diagnosis of DIC and thus purpura fulminans. However, there are multiple laboratory abnormalities associated with DIC, and low fibrinogen was the sixth most common in over 900 patients from combined studies [Reviewed in 9].

Although the laboratory findings consistent with DIC have been associated with malaria [10], rarely are pathological manifestations of DIC found at autopsy [11]. Our review of the literature suggests skin findings of DIC in patients with malaria have not been reported. Purpura as the presenting symptom in malaria was reported by Ghosh and Nicolson [3], but in their report there was no evidence of DIC. Cutaneous gangrene has been reported as a presenting complaint of malaria in the past [4]. However, although this patient had some similarities with our patient including edema with a bluish black discoloration of the distal fingers and toes, and a minimally prolonged prothrombin time, there was no evidence of hemorrhagic bullae, thrombocytopenia, anemia or fibrin degradation products.

Finally, we could find no mention of purpura fulminans associated with chloroquine. A single case report of chloroquine overdose is noted where the patient lacked skin findings, but did have evidence of DIC in the central nervous system at autopsy [12]. There were no reported cases of DIC associated with standard dosages of chloroquine.

Thus we present a case of purpura fulminans, a severe skin disorder associated with DIC, in a patient with malaria who was initially treated with chloroquine. Our patient had development of the associated skin findings after initiation of chloroquine, thus we are unable to say implicitly if malaria or chloroquine was responsible for the DIC and associated skin findings. Given that malaria has been associated with DIC more commonly in the past, it is probable this infection was responsible for the purpura fulminans.

Article accepted on 27/7/00

REFERENCES

1. Rook, Wilkinson, Ebbing Textbook of Dermatology Edited by R.H. Champion, J.L. Burton, D.A. Burns, and S.M. Breathnach. Sixth ed. Vol. 2, p. 1404.

2. Gopinathan VP, Bhalla IP. Peripheral vasculitis associated with falciparum malaria. Journal of the Association of Physicians of India 1987; 35: 742-3.

3. Ghosh SL. Malaria- the great mimic. British Medical Journal 1977; 1: 1136-7.

4. Sharma SN. Cutaneous gangrene in falciparum malaria: an unreported manifestation. Journal of the Association of Physicians of India 1987; 35: 150-2.

5. Adcock DM, Brozna J, Marlar RA. Proposed classification and pathologic mechanisms of purpura fulminans and skin necrosis. Semin Thromb Hemost 1990; 16: 333-40.

6. Woodruff AW. The treatment of severe and complicated malaria. Tropical Doctor: 1971; 156-9.

7. Darmstadt GL. Acute infectious purpura fulminans: pathogenesis and medical management. Pediatric Dermatology 1998; 15: 169-83.

8. Calverley DC, Liebman HA. In: Hematology: Basic Principles and Practice, 3rd edition. Ed. Hoffman R, Benz EJ, et al. Philadelphia: Churchill Livingstone, Inc., 2000: 1983-95.

9. Adcock DM, Hicks JH. Dermatopathology of skin necrosis associated with purpura fulminans. Seminars in Thrombosis and Hemostasis 1990; 16: 283-91.

10. Dennis LH, Eichelberger JW, Inman MM, Conrad ME. Depletion of coagulation factors in drug-resistant plasmodium falciparum malaria. Blood 1967; 29: 713-20.

11. Krogstad DJ. Plasmodium species. In: Mandell, Douglas and Bennett's principles and practice of infectious diseases. Mandell GL, ed. New York: Churchill Livingstone, Inc., 1995: 2415-21.

12. Muhm M, Stimpfl T, Malzer R, Mortinger H, Binder R, Vycudilik W, Berzlanovich A, Bauer G, Laggner A. Suicidal chloroquine poisoning: clinical course, autopsy findings, and chemical analysis. Journal of Forensic Sciences 1996: 1077-9.