Purpura Fulminans Due to Acquired Protein C Deficiency.

Purpura fulminans (PF) may be the presenting symptom in a patient with protein C (PC) deficiency. It is a hematological emergency and presents with extensive areas of hemorrhagic necrosis of the skin. PC deficiency is usually genetically inherited. However, we report a 1 year and 4 months boy, who presented with acquired PC deficiency possibly of postinfectious etiology and developed PF.

What was known?

Purpura fulminans may follow protein C deficiency.

Introduction

Purpura fulminans (PF) is a medical emergency and is characterized by areas of skin necrosis. It may also present with disseminated intravascular coagulation. It usually manifests following severe sepsis with Neisseria, Staphylococcus, Pneumococcus, and Hemophilus has also been reported. One of the causes of PF is a genetic deficiency of the anticoagulant protein C (PC) and protein S, which is commonly seen in neonates. Here, we present a 1 year and 4 months child who developed PF and was detected to have PC deficiency due to unknown etiology, possibly postinfectious as he had a history of infection 2 weeks back. Late manifestation of PC deficiency as PF has been rarely reported.

Case Report

A 1 year and 4 months male child was admitted with a history of reddish black macular lesions on the right thigh since last 5 days. According to the mother, it initially started as a tiny 2 mm lesion, which she noticed 5 days back. There was a preceding history of upper respiratory tract infection 2 weeks back for which he had been treated with oral antibiotics. No vaccinations had been administered to him over the last 2 months. This lesion then gradually progressed to involve the entire right thigh and the buttock. The child was also in severe pain and was having fever since the last 2 days in the range of 100–102 F.

On examination, the right thigh appeared inflamed and swollen. There were multiple erythematous maculopapular lesions, with few areas of central hemorrhagic necrosis, with irregular margins over the right thigh and gluteal region [Figure 1a and b]. The lesions were progressing rapidly to involve the back and left buttock as well. Our patient preferred to lie down prone. His peripheries were warm to touch and peripheral pulses were well palpable. There were no sites of external bleed. He had a previous history of chickenpox 6 months back.

Figure 1

(a and b) Reddish black erythematous maculopapular lesions. (c) Arrest of the spread of lesions after initiating treatment with plasma and heparin. (d) Necrosed areas with healing at the time of discharge

Routine blood counts demonstrated hemoglobin of 10.3 mg/dl. Total leukocyte count was 8900/mm3 with neutrophils 54% and lymphocyte 42%. Platelet count was 218,000/mm3. C-reactive protein was 11.2 (N <5). The peripheral blood smear did not show any abnormal cells. His prothrombin time was 15 s (control 12–16 s), international normalized ratio of 1.3 (control 0.8–1.3), and activated partial thromboplastin time of 26 s (control 22–34 s).

On further testing, he had a PC activity of 11% (normal 70–140%) and a protein S activity of 88%, which was normal. His fibrinogen levels and factor V Leiden levels were also normal. Father had a PC activity of 98% and mother had 132% which thereby made us to believe that our patient was having a PF due to acquired PC deficiency (What if it were a heterozygous disorder?).

Ultrasonography (USG) Doppler of lower limbs was done and vascularity was intact. He was administered fresh frozen plasma (FFP) and low molecular weight heparin (rationale?) daily for the next 5 days. From the 2nd day of treatment, the spread of the lesions were arrested [Figure 1c]. However, on the 6th day, he suddenly developed a left sided scrotal swelling and was in pain. USG showed fluid (possibly hemorrhagic) in the left scrotal sac with edema of testis and left scrotal wall. We stopped heparin and continued with transfusions of plasma 1 ml/kg/day for 3 more days.

The child showed dramatic improvement. The scrotal pain and swelling subsided. The skin lesions had stopped spreading. He was finally discharged with the advice of applying topical antibiotics as the areas were raw and undergoing healing [Figure 1d].

At 1-month follow-up PC activity was found to be 180.2%. We thereby were able to confirm inferred that this was a case of PF in acquired PC deficiency possibly due to postinfectious etiology. At 1 year follow-up, the lesions have healed with a few areas of scarring.

Discussion

Protein C is a Vitamin K-dependent coagulation protein, which plays an essential role in the regulation of thrombin. It is synthesized within the hepatocytes and circulates in plasma in a very low concentration. Activated protein C, supported by protein cofactors (protein S and factor V) and lipid cofactors, cleave specific sites in the activated procoagulant factors V and VIII, thereby inactivating these enzymes. Patients having deficiency of PC have a reduced capacity to down-regulate the propagation of thrombin generation by factor Va and VIIIa when they have been activated by the small amounts of thrombin produced in the initiation phase of coagulation activation.[12]

Purpura fulminans is a rapidly progressive thrombotic disorder. It affects neonates[3] and children and is characterized by hemorrhagic necrosis of the skin and disseminated intravascular coagulation. When it occurs in a previously well child, postinfectious etiology should always be considered. However, we may not have any documentary evidence of recent infection. Varicella may be a precipitating cause for PF. Our patient had the infection 6 months back. However, as he had been fully cured of it with no active skin lesions at present, PF here was not due to varicella.PF caused by autoantibodies against PC has been reported rarely.[4] Our patient had a low PC level on admission.

Purpura fulminans also occurs when there is a severe loss of PC anticoagulant function caused by homozygous or compound heterozygous PROC mutations. Most cases have been diagnosed in neonates with severe manifestation of the disease.[3] These children have recurrent episodes of thromboembolic episodes. They have almost undetectable levels of PC on diagnosis unlike our patient.[4]

On suspecting homozygous or compound heterozygous PC deficiency, testing of parents is essential. Most parents of infants with severe PC deficiency are asymptomatic and have PC levels compatible with heterozygous status. The late presentation and the normal PC levels of parents led us to believe that he was suffering from an acquired PC deficiency.[5]

Fresh frozen plasma or a human plasma-derived, viral inactivated PC concentrate are used for neonatal PF due to PC deficiency.[3] A total of 1 IU/kg of PC concentrate or 1 ml/kg of FFP increases the plasma concentration by 1 U/dl. Long-term management of these patients is with PC concentrate or with warfarin or low molecular weight heparin.[678] Literature states the role of low molecular weight heparin in PF.[9] As we were not sure about the etiology initially, we decided to manage the child aggressively so as to prevent the complications. However, as we became sure that this was a case of acquired PC deficiency, low molecular weight heparin was withdrawn after 5 days. As our patient was an acquired PC deficiency, we did not discharge him on any anticoagulants. He was reviewed every fortnightly, and there has been no recurrence of the disease at 1-year follow-up.

PF due to acquired PC deficiency possibly due to unknown etiology (possibly postinfectious) in the pediatric age group has been rarely reported (Please substantiate this statement).

What this case report adds: Acquired PC deficiency following a previous infection is extremely rare. These patients may simply be treated with FFP in resource-poor setting and need not be discharged with heparin or warfarin.

What is new?

Acquired PC deficiency following a previous infection is extremely rare. These patients may simply be treated with FFP in resource-poor setting and need not be discharged with heparin or warfarin.