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NeoQuest May 2022: Newborn with a Skin Lesion and Intracranial Hemorrhage

May 11, 2022

A hemodynamically stable 1-day-old term neonate, born to a mother with an unremarkable prenatal history, presents with a skin lesion on the lower abdomen and pelvic region (Figure 1). Vitamin K was administered in the delivery room. The initial laboratory results are shown in the Table. An infectious evaluation, including blood, urine, and cerebrospinal fluid cultures, was negative. A cranial ultrasound performed two days after birth reveals an intraparenchymal hemorrhage. Dermal microvascular thrombosis and focal areas of necrosis are visualized on skin biopsy.

Figure 1. Abnormal skin findings on physical examination of newborn. Image from: Villacis Calderon DG, Lone D, Boucher A, and Osterholm E. Term infant with bilateral parenchymal brain hemorrhages. Neoreviews. 2022;23(5):e335–e338. 10.1542/neo.23-5-e335

Laboratory Test Result
Infant testing  
White blood cell count 12.1 x 103/µL
Bands 2%
Segmented neutrophils 56%
Lymphocytes 33%
Monocyte 8%
Eosinophil 1%
Hemoglobin 18 g/dL
Platelet 90 x 103/uL
Fibrinogen 105 mg/dL
D-dimer level 65 μg/ml
Prothrombin time 28 seconds
Activated partial thromboplastin time 105 seconds
Maternal testing  
Maternal platelet 320 x 103/µL
Maternal anti-human platelet
antigen antibodies

Table. Initial laboratory evaluation in a neonate with abnormal skin findings


Which of the following interventions will most likely improve this infant’s skin lesion?

  1. Broad spectrum antibiotics, including coverage for Pseudomonas
  2. Fresh frozen plasma transfusion and anticoagulation
  3. Intravenous immune globulin and platelet transfusion
  4. Reassurance that the skin lesion will resolve over time
  5. Vitamin C supplementation


Answer: B. Fresh frozen plasma transfusion and anticoagulation


This term newborn presents with a well-demarcated purpuric skin lesion demonstrating intravascular thrombosis and tissue necrosis confirmed on biopsy in the setting of disseminated intravascular coagulation (DIC) and intraparenchymal hemorrhage—all features consistent with the diagnosis of neonatal purpura fulminans (NPF). NPF is a rare hematologic emergency that presents initially as purpuric lesions and ecchymoses that rapidly progress to skin necrosis within the first few days after birth. This occurs due to a deficiency in Protein C (PC), or less commonly, a deficiency in Protein S or antithrombin III.1

In normal hemostasis, PC is a vitamin K-dependent physiologic anticoagulant synthesized by the liver. Specifically, PC inactivates clotting Factor Va and VIIIa and increases fibrinolysis via upregulation of plasminogen-activator inhibitor-1 activity (Figure 2).1,2 Deficiency of PC results in a prothrombotic state, placing affected individuals at risk of diffuse thromboembolic and bleeding complications with multi-organ involvement. The pathology can be visualized on skin biopsy as cutaneous microvascular thrombi and hemorrhagic skin necrosis, cardinal features confirming the diagnosis of NPF.3 Without a skin biopsy, the diagnosis of NPF can be extremely challenging given the lack of distinct pathognomonic clinical signs. Thus, a high degree of clinical suspicion is required for timely identification and intervention.

Figure 2. Protein C (PC) is a vitamin K-dependent protein involved in downregulating coagulation. After interacting with the thrombin–thrombomodulin complex at the surface of the endothelium, PC is converted to activated PC. In its activated form, PC degrades coagulation factors Va and VIIIa via proteolysis and promotes the activity of plasminogen-activator inhibitor-1 (PAI-1)—critical steps involved in thrombolysis. Image from: Villacis Calderon DG, Lone D, Boucher A, Osterholm E. Term infant with bilateral parenchymal brain hemorrhages. Neoreviews. 2022;23(5):e335–e338. 10.1542/neo.23-5-e335

The etiology of PC deficiency can be hereditary, caused by a mutation of the PROC gene, or acquired from conditions where PC activity is low (eg, sepsis, vitamin K deficiency, vitamin K antagonist exposure, and chronic liver disease).2 As a result, diagnostic testing is extensive and consists of an evaluation of an infectious etiology as well as coagulation studies, including fibrinogen, prothrombin time, activated partial thromboplastin time, and PC, protein S, and antithrombin III activity levels.2–4 In the absence of an identified clinical trigger, a low physiologic anticoagulant activity level warrants a genetic evaluation.2,3 Genetic testing should also be pursued in patients with a family history of consanguinity or thrombophilia (eg, miscarriages or prothrombotic disorders). 2,3 While waiting for confirmation of the diagnosis, fresh frozen plasma (FFP)—made up of clotting factors, fibrinogen, and physiologic anticoagulants including PC, protein S, and antithrombin III—should be provided emergently to address the coagulopathy. Long term, patients with PC deficiency will require frequent FFP or PC concentrate transfusions in conjunction with chronic anticoagulation to ameliorate prothrombotic symptoms and prevent recurrent episodes of NPF (Option B).2,3 To avoid these symptoms completely, a liver transplant is required for cure.2,3

Among the acquired conditions, neonatal sepsis associated with DIC is a common cause of PC deficiency and must be evaluated in any patient with purpura and coagulopathy. Specifically, group B Streptococcus, Staphylococcus species, and gram-negative infections are pathogens most frequently associated with NPF.3 Ecthyma gangrenosum can also present as a purpuric lesion that evolves into a well-defined gangrenous ulcer secondary to a Pseudomonas aeruginosa infection. The negative evaluation for an infectious etiology, including blood, urine, and cerebrospinal cultures, in this hemodynamically stable neonate suggests that broad-spectrum antibiotics, including antibiotics for Pseudomomas coverage (Option A), would not address the underlying diagnosis.

Besides infection, immune-mediated disorders, such as maternal idiopathic thrombocytopenic purpura, maternal systemic lupus erythematosus, or neonatal alloimmune thrombocytopenia, can present with petechiae, purpura, or ecchymoses shortly after birth.6,7 Transplacental passage of maternal antibodies that destroy neonatal platelets is the key mechanism involved in these conditions, resulting in severe neonatal thrombocytopenia with bleeding, petechiae, and purpura. In these scenarios, use of IVIG and platelet transfusions can improve the platelet count and prevent bleeding complications.7 The infant in this vignette is born to a healthy mother with an unremarkable prenatal history and no maternal anti-human platelet antigen antibodies, suggesting that IVIG or platelet transfusions alone may not improve the skin findings (Option C).

Cutis marmorata telangiectatica congenita (CMTC), a rare vascular anomaly, can also present as purpuric lesions that manifest in a reticular pattern involving the extremities and trunk in the absence of illness or coagulopathy. This presentation is not consistent with the findings seen in this case.8 CMTC is also commonly associated with cutaneous atrophy or ulceration, vascular anomaly disorders, and ophthalmic symptoms.8 CMTC resolves by two years of age in majority of cases without any intervention (Option D).

Ecchymoses and other dermatologic symptoms can be seen with vitamin C deficiency, which is also known as scurvy. Vitamin C is an essential nutrient consumed in the diet and plays a significant role in collagen synthesis. Along with dental, bone, and systemic manifestations, vitamin C deficiency leads to poor wound healing and capillary fragility, manifesting as perifollicular hemorrhage, petechiae, ecchymoses, and gingival edema and bleeding.9 Early signs of scurvy present only after 1 to 3 months of inadequate vitamin C intake.9 As a result, vitamin C deficiency is not typically seen in the neonatal period. Given the early timing of cutaneous symptoms soon after birth, this infant’s diagnosis is less likely to be scurvy, and thus, vitamin C supplementation would not be helpful in this situation (Option E).

Did you know?

  • Individuals with hereditary homozygous PC deficiency have high morbidity and can experience serious multi-organ complications, including blindness, retinal detachment, hydrocephalus, ischemic stroke, renal dysfunction, and fluid overload associated with frequent transfusions.2,10

Name a maternal medication used during pregnancy that could lead to neonatal purpura, intracranial hemorrhage, and seizures.
To learn more about this and review bleeding disorders, read the following article: Manco-Johnson M. Bleeding disorders in the neonate. Neoreviews. 2008;9(4):e162–e168.11

NeoQuest May Authors
Neena Jube-Desai, MD, MBA, University of Maryland Medical Center
Shanmukha Mukthapuram, MD, Cincinnati Children’s Hospital Medical Center


  1. Villacis Calderon DG, Lone D, Boucher A, Osterholm E. Term infant with bilateral parenchymal brain hemorrhages. Neoreviews. 2022;23(5):e335–e338. 10.1542/neo.23-5-e335
  2. Dinarvand P, Moser KA. Protein C deficiency. Arch Pathol Lab Med. 2019;143(10):1281–1285
  3. Chalmers E, Cooper P, Forman K, et al. Purpura fulminans: recognition, diagnosis and management. Arch Dis Child. 2011;96(11):1066–1071
  4. Roshan TM, Stein N, Jiang XY. Comparison of clot-based and chromogenic assay for the determination of protein C activity. Blood Coagul Fibrinolysis. 2019;30(4):156
  5. Srinivasan R, Arshid M, Platt MP. Ecthyma gangrenosum in preterm neonate. Arch Dis Child Fetal Neonatal Ed. 2011;96(4):F298
  6. Leung AK, Chan KW. Evaluating the child with purpura. Am Fam Physician. 2001;64(3):419–428 [published correction appears in Am Fam Physician 2002;65(9):1751]
  7. Winkelhorst D, Oepkes D, Lopriore E. Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies. Expert Rev Hematol. 2017;10(8):729–737
  8. Herzlich J, Levy-Mebdelovich S. Case 2: Is it neonatal purpura fulminans? Neoreviews. 2018;19(5):e301–e303
  9. Vitoria I, López B, Gómez J, et al. Improper use of a plant-based vitamin C-deficient beverage causes scurvy in an infantPediatrics. 2016;137(2):e20152781
  10. Oklah M, Parappil H, Al Rifai H, et al. Congenital protein C deficiency with renal vein thrombosis and central retinal venous occlusion in a term neonate due to novel mutation in the PROC gene. J Clin Neonatol. 2017;6:116–20
  11. Manco-Johnson, M. Bleeding disorders in the neonate. Neoreviews. 2008;9(4):e162–e168


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