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Neonatal purpura fulminans: A Rare and fatal disorder – A case series from Western India
*Corresponding author: Sayan Kumar Das, Department of Paediatrics, Gujarat Medical Education and Research Society Medical College, Gandhinagar, Gujarat, India. dreamysayan@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Das SK, Prajapati N. Neonatal purpura fulminans: A rare and fatal disorder – A case series from Western India. Karnataka Paediatr J. doi: 10.25259/KPJ_88_2025
Abstract
A rare but potentially fatal thrombotic condition known as neonatal purpura fulminans (NPF) is brought on by a congenital or acquired lack of natural anticoagulant proteins, specifically protein C or protein S. Disseminated intravascular coagulation (DIC), dermal microvascular thrombosis, perivascular haemorrhage, and progressive haemorrhagic skin necrosis are the pathognomonic features of the syndrome. We present a case series of NPFs from our medical college that manifest as widespread purpura and necrotic skin lesions in the early neonatal era. Significantly low protein C levels and signs of DIC, along with other clinical features, were found during 2023– 2024. In view of fulminant sepsis, inotropic and ventilatory support was started in all the cases. Higher antibiotic therapy was given based on culture sensitivity. As blood investigations showed deranged coagulation parameters, platelet concentrates and fresh frozen plasma were administered. Protein C was given to one of the patients. The patients developed refractory septic shock with rapidly progressive purpura and gangrene involving multiple body areas. Although one of the patients showed remarkable improvement, it eventually led to septicaemia and multi-organ failure. The abrupt onset and rapid progression of gangrenous lesions, combined with documented low protein C (and S in one case) levels, were strongly indicative of NPFs. Early recognition of NPFs is critical, as prompt diagnosis and initiation of appropriate therapy, such as replacement of deficient anticoagulant proteins and management of DIC, can be lifesaving. Our case series demonstrates how crucial it is to take protein C shortage into account when newborns exhibit coagulopathy and extensive purpuric rashes.
Keywords
Disseminated intravascular coagulation
Neonatal purpura fulminans
Newborn
Protein C deficiency
Skin necrosis
Thrombosis
INTRODUCTION
Disseminated intravascular coagulation (DIC) and quickly progressing haemorrhagic skin necrosis are pathognomonic of purpura fulminans (PF), an uncommon and potentially fatal hematologic emergency. In 1962, when its aetiology was thought to be hereditary, it was first reported in a neonate. It was then conclusively linked to homozygous protein C deficiency, proving that coagulation system deficiencies play a key role in its pathophysiology. PF can be broadly categorised as either acquired or congenital. Congenital causes include homozygous or compound heterozygous deficiency of protein C or protein S. Acquired causes may arise from increased consumption of these anticoagulants in conditions such as acute venous thrombosis, DIC, presence of antiphospholipid antibodies, cardiopulmonary bypass, or severe infections (notably Group B Streptococcus). Conditions, such as congenital heart disease, severe hepatic dysfunction, galactosaemia, and the aftermath of warfarin medication, can all result in decreased production.[1] Acute infectious PF continues to be the most common kind among all of them. Neisseria meningitidis, Staphylococcus aureus, Group A and B Streptococci, and Streptococcus pneumoniae are common causal organisms.[2]
The disease has been reported in approximately 60–70% of children under 2 years of age, often with a fulminant course and high mortality. Here, we present a series of three neonatal cases of PF managed at our tertiary care hospital. Each case exhibited severe coagulopathy, markedly reduced protein C levels, and extensive purpuric and necrotic skin lesions, underscoring the need for early recognition and aggressive management of this devastating condition.
CASE SERIES
Case 1
Clinical description
A primigravida woman in a non-consanguineous marriage gave birth to a 2-day-old girl neonate weighing 2.6 kg through natural vaginal delivery. The prenatal and postpartum phases went smoothly. The infant had been exhibiting signs of poor feeding, skin rashes, irritability, and rapid breathing for 4–5 hours on the 2nd day of life. There was no noteworthy family or prenatal history. On admission, the neonate appeared lethargic and febrile (temperature 100.3°F), with tachycardia (200 bpm), tachypnoea (72 breaths/min), and prolonged capillary refill time (4 seconds). Cutaneous examination revealed dark red lesions over both lower limbs [Figure 1], which progressed to purple-black necrotic patches and gangrenous changes within 48 hours [Figure 2]. Laboratory tests revealed increased C-reactive protein (110 mg/L), leucocytosis (25,600/cumm), and thrombocytopenia (79,000/ cumm). Prolonged prothrombin time ([PT] 54.6 seconds), activated partial thromboplastin time ([aPTT] 49.6 seconds), and high International Normalised Ratio [INR] (6.8) were all indicative of a disturbed coagulation profile. According to electrolyte tests, there was hyperkalaemia (K+ 7.5 mEq/L) and hyponatraemia (Na+ 126 mEq/L). Protein C levels were markedly reduced (8.31%). Blood culture shows no growth, and arterial Doppler ultrasonography demonstrated bilateral femoral artery thrombosis.
- Haemorrhagic skin necrosis changes of bilateral lower limb.
- Extensive purpura fulminans on both upper and lower limbs. Gangrenous lesions of digits
Management
The neonate received intensive care, including mechanical ventilation, repeated fresh frozen plasma (FFP) transfusions every 12 hours, protein C concentrate for 2 days, daily low-molecular-weight heparin (LMWH), intravenous fluids, electrolyte correction, and broad-spectrum antibiotics.
Outcome
Although partial improvement was noted, the infant remained hemodynamically unstable. The family opted for discharge against medical advice. The baby, unfortunately, died at home 2 weeks later. Parental testing was also carried out, which again turned out to be a protein C deficiency, with a marginally low level in the mother later on (0.6U/mL).Both parents were, hence, counselled, and blood samples were collected for protein S activity testing also. However, due to logistical constraints, the results of parental assays of protein S were not received before the completion of this report.
Case 2
Clinical description
A 6-day-old female neonate (birth weight 2.95 kg) was born at 38 + 5 weeks of gestation to a third-gravida mother (G3P2) in a non-consanguineous marriage. The antenatal and peripartum periods were uneventful. On the 6th day of life, the neonate presented with high-grade fever and severe respiratory distress. A significant family history was present, as a previous sibling had died at 12 days of life with similar fulminant symptoms, which strongly raised suspicion for an inherited thrombophilic disorder. At admission, the infant was critically ill with a SpO2 of 70%, requiring immediate ventilatory support. Facial purpuric lesions had appeared 2 days before presentation [Figure 3]. Investigations showed severe coagulopathy (PT 86.6 s, aPTT 78.5 s, INR 9.1), thrombocytopenia (68,000/cumm), and elevated C-reactive protein (CRP) (96 mg/L). Importantly, protein C activity was profoundly low (9.77%), which is a level below physiological newborn norms, strongly suggestive of congenital protein C deficiency. Protein S levels were also on the lower side. Blood culture grew multidrug-resistant Klebsiella pneumoniae, likely serving as a precipitating factor for PF in a neonate already predisposed due to hereditary deficiency.
- Purpuric lesions over face.
The constellation of:
Early onset purpura
Severe coagulopathy
Critically reduced protein C and
Sibling death with a similar presentation
Strongly supported hereditary protein C deficiency with sepsis-triggered neonatal PF (NPF).
Management
The infant received mechanical ventilation, repeated FFP transfusions every 12 hours, daily LMWH, intravenous fluids, inotropic support, and broad-spectrum antibiotics adjusted per culture sensitivity.
Outcome
Despite aggressive management, the neonate developed refractory septic shock and worsening coagulopathy. She succumbed on the 10th day of life (4th day of hospitalisation). Due to a history of previous neonatal death, parental screening was strongly advised. Samples of both parents were collected. Given the clinical severity and markedly reduced protein C activity, samples from the affected neonates were preserved for PROC gene mutation analysis. Genetic testing was prioritised, and the sample was sent to a reference laboratory. Results were pending at the time of manuscript preparation.
Case 3
Clinical description
A 3-kg outborn female neonate, born at 39 + 2 weeks of gestation through lower-segment C-section to a human immunodeficiency virus-negative mother who conceived through assisted reproductive technology, was initially stable and feeding well. On day 7 of life, the baby developed erythematous rashes over the face and periumbilical region and was referred to our neonatal intensive care unit (NICU). At admission, the neonate appeared ill with leucocytosis (40,000/cumm; 77% neutrophils) and markedly elevated CRP (126 mg/L). A provisional diagnosis of staphylococcal scalded skin syndrome was considered. Skin swab and blood cultures subsequently grew S. aureus. By day 9, the infant showed rapidly progressive bluish discoloration of the extremities, evolving into dry gangrene involving thighs, back, and fingertips [Figure 4], highly suggestive of NPFs. Coagulation parameters became markedly abnormal, prompting thrombophilia testing, which revealed:
Low protein C levels
Low protein S levels
- Day 9- Skin lesions extended and involved lower limbs also.
The simultaneous depression of protein C and S, combined with early, extensive PF, strongly indicated an underlying hereditary deficiency, with sepsis serving as the precipitating insult. No family history of similar illness was initially known; however, the absence of testing in parents and siblings could not exclude autosomal-recessive or compound heterozygous inheritance. Abdominal distension developed, and radiographs showed early necrotising enterocolitis [Figure 5], signifying evolving multi-organ involvement.
- Necrotising enterocolitis changes on X-ray abdomen.
Management
The neonate received aggressive supportive care with inotropes, IV fluids, platelet transfusions, FFP, escalation of antibiotics to vancomycin, and wound care with paraffin gauze dressings. The clinical picture and laboratory findings guided management towards suspected hereditary protein C and S deficiency presenting as NPFs.
Outcome
Despite maximal supportive therapy, the infant developed refractory septic shock and extensive gangrene involving multiple body regions. She died on the 12th day of life due to septicaemia and multi-organ failure. The abrupt onset, severity, and documented dual deficiency (Protein C and S) strongly pointed towards hereditary thrombophilia as the primary underlying cause.arents were counselled for hereditary deficiency testing; maternal and paternal samples could not be done due to financial constraints. A comparative analysis of the laboratory parameters of all the above cases is shown in Table 1.
| Investigation | Case no. 1 | Case no. 2 | Case no. 3 |
|---|---|---|---|
| Hb (gm/dL) | 11.6 | 12.7 | 10.5 |
| TLC (cells/cumm) | 35000 | 25600 | 40000 |
| Platelets (cells/cumm) | 79000 | 68000 | 40000 |
| CRP ( mg/L) | 110 | 96 | 126 |
| S. Na+, k+, cl-(meq/L) | 126, 7.5, 109 | 128, 5.6, 107 | 128, 3.2, 104 |
| S. creatinine (mg/dL) | 1.4 | 1.7 | 1.9 |
| S. calcium (mg/dL) | 8.4 | 7.1 | 7.7 |
| PT, Activated PTT, INR (seconds) | 54.6, 49.6, 6.8 | 86.6, 78.5, 9.1 | 85.6, 79.5, 8.1 |
| Blood culture | Negative | Multidrug-resistant Klebsiella pneumoniae | Staphylococcus aureus |
| Protein C* | 8.31% | 9.77% | 9.67% |
| Protein S* | Normal | 0.2 | 0.2 |
Hb: Haemoglobin, TLC: Total leukocyte count, CRP: C-reactive protein, PTT: Partial thromboplastin time, INR: International normalised ratio. *NIH Values
Hb: hemoglobin; TLC: total leukocyte count; CRP: C-reactive protein; PT: prothrombin time; APTT: activated partial thromboplastin time; INR: international normalized ratio.
Protein C and Protein S levels are expressed as percentage activity. Normal reference ranges: Protein C—term neonates: 15–40%; preterm neonates: 10–35%; adults: 70–140%. Protein S—neonates have physiologically reduced levels, particularly free Protein S, with activity typically <40%; adult reference range: 60–120%. Reference ranges may vary according to age and laboratory assay.
Across all three cases, there was no documented maternal history of TORCH infections or recurrent pregnancy losses.
DISCUSSION
In this case series, we reported three neonates with culture-positive sepsis who developed rapidly progressive PF and demonstrated markedly reduced protein C (and protein S in two cases) levels. While these findings were suggestive of an underlying deficiency, we acknowledge that there is limited clarity regarding the basis for confirming congenital protein C deficiency. Physiologically, protein C and S levels in healthy neonates remain significantly lower than adult reference ranges, and only congenital homozygous deficiency presents with absent or nearly undetectable levels. Furthermore, in the absence of parental protein C/S levels or genetic analysis, distinguishing congenital deficiency from acquired reductions, especially in the context of severe culture-proven sepsis in the above cases, remains challenging. Therefore, although hereditary deficiency was considered due to the severity and rapid progression of PF, we recognise that the diagnosis cannot be conclusively established without genetic or familial testing.
The potentially deadly condition known as PF is typified by the abrupt onset of increasing cutaneous bleeding and necrosis brought on by DIC and microvascular thrombosis. Three general categories of PF can be distinguished based on the triggering mechanisms:
PF in neonates
PF idiopathic
PF is an acute infectious disease.
The most prevalent causes of neonatal PF, which often appear within the first 72 hours of life, are homozygous or compound heterozygous deficits of protein C, protein S, or, less frequently, antithrombin III. Idiopathic PF is typically seen in children 7–10 days after a bacterial or viral illness and is linked to temporary decreases in antithrombin III, protein C or protein S levels.[3] The pathophysiology of PF involves endothelial damage and activation of procoagulant pathways, leading to consumption or impaired synthesis of clotting factors. Hepatic dysfunction and sepsis are well-established contributing factors. In neonates, this process is further aggravated by physiologically low levels of plasma protein C activity and antigen, which gradually normalise by 6 months of age.
Infectious causes play a major role in triggering PF. Group B Streptococcus and Gram-negative organisms have been commonly reported in neonates, while N. meningitidis and Varicella infections are more frequent in older children. All three of the neonates in this series developed quickly progressive purpuric and necrotic skin lesions associated with late-onset sepsis and DIC, suggesting acute infectious NPFs. Protein C levels were markedly reduced in all three cases, while protein S levels were normal in the first case and decreased in the later two.
Management in all cases included prompt initiation of supportive therapy with FFP to correct coagulation abnormalities and replenish protein C levels. Protein C concentrate, when available, offers a more specific treatment option and has been shown to improve outcomes. However, its limited availability remains a major challenge in resource-limited settings.[4]
Children with severe hereditary protein C deficiency require lifelong antithrombotic therapy, including protein C replacement and/or anticoagulants, to prevent recurrent episodes of PF. Liver transplantation can offer a permanent cure by restoring endogenous protein C synthesis, but it carries the risks of immunosuppression and development of anti-protein C antibodies.[5,6]
Genetic testing for protein C mutations and family screening are essential for the early diagnosis and prevention of recurrence, but these facilities are often unavailable in most places. Wider accessibility of protein C concentrate and implementation of early diagnostic strategies could substantially improve long-term outcomes. Therefore, a comprehensive, multidisciplinary approach is crucial for the effective management of this devastating condition.[7]
Genetic evaluation and reports
Given the severe clinical presentation, significantly decreased Protein C activity, and early-onset PF in all three instances, genetic evaluation was taken into consideration.
With respect to genetic evaluation:
In Case 1, a borderline low maternal protein C level was found by partial parental screening, which is consistent with heterozygous insufficiency. This biochemical data indirectly supports a genetic aetiology, even though thorough parental protein S assays and molecular testing were not possible due to logistical limitations.
Strong clinical criteria for probable hereditary protein C deficiency were met in Case 2 due to the presence of a prior sibling fatality with an almost identical newborn presentation and a significantly decreased protein C activity in the afflicted neonate. Samples had been stored and sent for PROC gene mutation analysis, later on, which turned out to be present.
In Case 3, a potential combined genetic deficit was suggested by the concurrent depression of protein C and protein S levels. Unfortunately, budgetary constraints, which are a well-known obstacle in environments with low resources, made it impossible to conduct genetic research and parental testing.
Management and monitoring strategy
In the NICU, all newborns were treated as medical emergencies with prompt stabilisation, including inotropic support, fluid resuscitation, and respiratory assistance as needed. Given the substantial correlation between NPFs and severe sepsis, broad-spectrum antibiotics were started early and then adjusted based on culture sensitivity. Repeated FFP infusions and platelet concentrates, depending on serial coagulation profiles (PT, aPTT, and INR) and platelet counts, were used to treat coagulopathy aggressively. When available, protein C concentrate was given in one instance, which led to a partial improvement in both clinical and laboratory outcomes. After the bleeding parameters stabilised, low-molecular-weight heparin was administered, especially if there was growing skin necrosis or proven thrombosis. Daily haematological and coagulation measures, inflammatory indicators, renal function, electrolyte levels, and regular clinical evaluation of skin lesions were all part of the close surveillance. The severity of the disease and changing test trends served as a guide for management options. Results were dismal despite intensive and protocol-based therapy, which is more indicative of the fulminant character of the illness than of management shortcomings or delays.
Lessons Learnt
Neonatal PF can develop abruptly with rapidly spreading purpuric and necrotic skin lesions, often leading to multi-organ involvement and high mortality, as seen in all three cases.
All three newborns had significantly lower protein C levels, which emphasises the significance of early detection and focused replacement treatment in suspected instances.
Intensive supportive care is needed for management, which includes culture-directed antibiotics, FFP or protein C concentrate, ventilatory support, and anticoagulation. Results can be subpar even with the best treatment, which emphasises the need for early detection, family counselling, and preventative measures like genetic screening.
CONCLUSION
Early recognition of NPFs is critical, as prompt diagnosis and initiation of appropriate therapy, such as replacement of deficient anticoagulant proteins and management of DIC, can be lifesaving. Our case series demonstrates how crucial it is to take protein C shortage into account when newborns exhibit coagulopathy and extensive purpuric rashes.
Ethical approval:
The research/study approved by the Institutional Review Board at GMERS MEDICAL COLLEGE GANDHINAGAR, number 21/2022, dated 12 October 2022.
Declaration of patient consent:
The authors certify that they have obtained all appropriate parental consent forms. In the form, the parents have given consent for the patient’s images and other clinical information to be reported in the journal. The parents understand that the patient’s names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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