Empiric Treatment of Protracted Idiopathic Purpura Fulminans in an Infant

A Case Report and Review of the Literature

Fima Macheret; Kavitha N Pundi; Eileen M Broomall; Dawn M Davis; Vilmarie Rodriguez; Chad K Brands

Disclosures

J Med Case Reports. 2011;5 

In This Article

Discussion

After the extensive negative work-up and given the lack of a definitive diagnosis, a peripheral inserted central catheter line was placed for the initiation of high-dose IV prednisone (Four mg/kg/day). He was started empirically on IV ampicillin/sulbactam (200 mg/kg/day, seven-day course). Corticosteroids were tapered over the next seven days.

One week later he showed no clinical improvement. Following interdisciplinary conference and consultation with pediatric coagulation experts, we decided to treat him empirically for idiopathic purpura fulminans with dalteparin (two SQ doses at 250 U/kg/day). This regimen was adjusted to 350 U/kg/day divided into two SQ doses to achieve a therapeutic heparin level. Acetylsalicylic acid was also added. Physical therapists were consulted because of motor skill regression with skin contractures.

At his follow-up examination one week later, his parents reported that no new lesions had developed. The eschars had begun to regress centrifugally from their borders, revealing healing pink scars, especially in his upper extremities. After several weeks, peripheral areas of crusting had shed, revealing healed, scarred skin (Figures 2a and 2b).

Figure 2.

Healing skin lesions one week after initiation of anti-coagulation. Both arms are shown in the top panel. Right leg and right foot are displayed in the bottom panel. No new lesions had formed, and pink, healing scars had begun to form under the eschars.

Follow-up at two months demonstrated dramatic healing (Figures 3a and 3b). While on heparin therapy, he had transient recurrence of petechiae one day after receiving an H1N1 virus vaccination. Any attempt to reduce the low-molecular-weight heparin from twice to once daily led to symmetric recurrence of lesions on his buttocks and thighs. He was transitioned to chronic anti-coagulation with warfarin 1 mg/day, and the lesions have been well controlled when his international normalized ration is in the therapeutic range of two to three. Subsequent urine amino acid analysis and genomic microarray analyses were unremarkable.

Figure 3.

Healing skin lesions two months after initiation of therapy. Both arms are shown in the top panel. Left leg and left foot are shown in the bottom panel. Eschars have completely given way to pink, healing scars with no new lesions formed.

About one year after initial presentation, our patient was experiencing developmental delays that were especially noted in gross motor function. Neurology consultation was sought, and their work-up revealed proximal muscle weakness and areflexia. Further investigation revealed that he is heterozygous for a duplication of a thymine nucleoside in his SMN1 gene at position 91 in codon 31, which causes a frame shift mutation and is consistent with spinal muscular atrophy.

The differential diagnosis for an infant with necrotic skin lesions is listed in Table 2. After interdisciplinary consultation, we arrived at a diagnosis of idiopathic PF, a rare prothrombotic syndrome characterized by thrombosis of dermal vasculature and progressive, widespread purpura with necrosis. Our patient's extensive characteristic lesions and stereotypical features on skin biopsy were consistent with those described in prior reported cases. Indeed, our patient's impressive response to anti-coagulation was strikingly similar to that described in prior cases and argues in favor of this diagnosis.

The most novel divergence of our patient's idiopathic PF from prior cases was the disparity in laboratory evidence. Fascinatingly, our patient had no absolute or relative deficiencies in protein C and S levels or activities, features present in the prior reported cases. Protein C activity was measured using venom activator and chromogenic peptide substrate; therefore, it is possible that a congenital protein C variant may not have been identified that would require a clot-based assay. Protein S antigen was measured using free protein S assay, and protein S activity was measured using a clot-based end point. This protein S assay can be affected by the presence of lupus anti-coagulant or a specific factor V inhibitor, but we did not identify either of these humoral factors.

Also, the peripheral smear abnormalities, especially the Döhle bodies, can be associated with DIC-linked purpura fulminans, yet we saw no evidence of consumptive coagulopathy characteristic of DIC. The specific role of N. animaloris in the progression of his lesions remains undefined. He may have a novel form of idiopathic PF, possibly preceded by an unidentified infection or caused by a defect in protein S that we were unable to detect using conventional laboratory assays. We are also unable to assess the potential contribution of his series of vaccines to his disease presentation, and although it would be unlikely for a child to develop autoantibodies before 6 months of age, we do not rule out the possibility that he may have developed autoantibodies after immunization.

Another important aberration in the patient's presentation was his age, because he was older than the expected age for neonatal PF and younger than all of the other reported cases of idiopathic PF that we reviewed. While our patient's initial response to anti-coagulation therapy was the aspect of his presentation and outcome, which fit most closely with that of idiopathic PF, his long-term need for anti-coagulation is not consistent with the previously described etiology of this disease.

The photographs associated with this case offer a dramatic example of clinical management for the pediatrician or dermatologist who may see similar lesions in a non-septic infant with an unrevealing laboratory evaluation. The decision to empirically anti-coagulate represented our best scientific response to the overlapping and non-specific findings for idiopathic PF.

In light of his impressive response to treatment as depicted in the final set of images (Figure 3), we wish to highlight an evidence-based approach to empiric treatment of idiopathic PF. Table 3 summarizes the patient age, gender, protein S levels, varicella status, treatments and outcomes of several recent cases reported after the Francis case series.[12] On the basis of the hypothesized etiology of the disease, that is, the development of protein S autoantibodies with thrombogenesis, treatment should include plasmapheresis with intravenous immunoglobulin to eliminate protein S autoantibodies and heparin to improve hemostasis.[13] Fresh frozen plasma should be added to assist the recovery of clotting factors. The dosage of dalteparin was titrated up to 350 U/kg twice daily to reach a target anti-Xa level of 0.5 to 1.0. We also prescribed supplemental 81 mg aspirin once daily. Other emerging modalities have been used to treat acute infectious and neonatal PF and may be applicable in some cases of idiopathic PF, including protein C replacement, anti-thrombin III replacement, prostacyclin and even leech therapy.[3,14] Long-term management must include physical therapy to assist with weight-bearing if there is any evidence of contracture.

Responses to treatment in the referenced cases were similar to those of our patient. Lesions regressed as early as one day after therapy was initiated. Protein C and protein S levels often took weeks to months to return to normal reference levels. As noted in Table 3 some patients lost extremities to gangrene, emphasizing the need for immediate initiation of anti-coagulation as well as surgical excision of gangrene to prevent subsequent sepsis.

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