Severe protein C deficiency in a newborn caused by a homozygous pathogenic variant in the PROC gene: a case report

Background Severe protein C deficiency is a rare and inherited cause of thrombophilia in neonates. Protein C acts as an anticoagulant, and its deficiency results in vascular thrombosis. Herein, we report a case of protein C deficiency with a homozygous pathogenic variant in a term neonate, with good outcomes after proper treatment. Case presentation A four-day-old male newborn was transferred to the Seoul National University Hospital on account of dark red to black skin lesions. He was born full-term with an average birth weight without perinatal problems. There were no abnormal findings in the prenatal tests, including intrauterine sonography. The first skin lesion was observed on his right toes and rapidly progressed to proximal areas, such as the lower legs, left arm, and buttock. Under the impression of thromboembolism or vasculitis, we performed a coagulopathy workup, which revealed a high D-dimer level of 23.05 μg/ml. A skin biopsy showed fibrin clots in most capillaries, and his protein C activity level was below 10%, from which we diagnosed protein C deficiency. On postnatal day 6, he experienced an apnea event with desaturation and an abnormal right pupillary light reflex. Brain computed tomography showed multifocal patchy intracranial hemorrhage and intraventricular hemorrhage with an old ischemic lesion. Ophthalmic examination revealed bilateral retinal traction detachments with retinal folds. Protein C concentrate replacement therapy was added to previous treatments including steroids, prostaglandin E1, and anticoagulation. After replacement therapy, there were no new skin lesions, and the previous lesions recovered with scarring. Although there were no new brain hemorrhagic infarctions, there was ongoing ischemic tissue loss, which required further rehabilitation. Ophthalmic surgical interventions were performed to treat the bilateral retinal traction detachments with retinal folds. Molecular analysis revealed a homozygous pathogenic variant in the PROC gene. Conclusion Severe protein C deficiency can manifest as a fatal coagulopathy in any organ. Early diagnosis and proper treatment, including protein C concentrate replacement, may improve outcomes without serious sequelae.

Case Report: Successful Long-Term Management of a Low-Birth Weight Preterm Infant With Compound Heterozygous Protein C Deficiency With Subcutaneous Protein C Concentrate Up to Adolescence

Homozygous/compound heterozygous forms of congenital protein C deficiency are often associated with severe antenatal and postnatal thrombotic or hemorrhagic complications. Protein C deficiency frequently leads to severe adverse outcomes like blindness and neurodevelopmental delay in children and may even lead to death. The most widely used long-term postnatal treatment consists of oral anticoagulation with vitamin K antagonists (e.g., warfarin), which is supplemented with protein C concentrate in acute phases. Subcutaneous infusions have been described in infants mostly from 2 months of age after severe postnatal thrombosis, but not in newborns or premature infants without thromboembolism. We report the first case of a compound heterozygous protein C-deficient preterm infant, born at 31+5 weeks of gestation to parents with heterozygous protein C deficiency (protein C activity 0.9% at birth). We focus on both prenatal and perinatal management including antithrombotic treatment during pregnancy, the cesarean section, and continuous postnatal intravenous and consecutive subcutaneous therapy with protein C concentrate followed by a change of therapy to direct oral anticoagulants (DOACs) (apixaban). We report successful home treatment with subcutaneous protein C concentrate substitution overnight (target protein C activity >25%) without complication up to 12.5 years of age. We propose that early planned cesarean section at 32 or preferably 34 weeks of gestation limits potential maternal side effects of anticoagulation with vitamin K antagonists and reduces fetal thromboembolic complications during late pregnancy. Intravenously administered protein C and early switch to subcutaneous infusions (reaching about 3 kg body weight) resulted in sufficient protein C activity and has guaranteed an excellent quality of life without any history of thrombosis for 13 years now. In older children with protein C deficiency, as in our case, DOACs could be a new therapeutic option.

Experience of protein C administration in children with acquired deficiency

Тhere is increasing experience of protein C concentrate administration in world practice, but despite that, information of this drug administration in patients with oncohematological diseases and primary immunodeficiency syndromes is lacking. Objective: to study the effectiveness of protein C concentrate administration in pediatric patients with acquired protein C deficiency during the treatment of oncological, hematological or immunological diseases. Medical charts of 12 patients who received inpatient treatment and protein C concentrate administration in the Dmitry Rogachev National Clinical Research Center from 01/01/2012–12/31/18 were analyzed. Depending on the presence or absence of thrombosis, the patients were divided into two groups. Single and daily doses, the number of injections per day, the duration of therapy and the percentage of activity of protein C activity were studied in both groups. Вoth groups included 6 patients, median of a single administrated dose of protein C was lower in the group of patients with thrombosis than in patients without them (20 and 71.4 IU/kg, p < 0.0001), while there were obtained no differences between treatment efficacy (p = 0.45). When comparing the administered dose of the drug in children with unresolved and resolved thrombosis, it was found that the median single dose in patients with ineffective treatment was lower than in those who had effective treatment (8.78 and 71.4 IU/kg, respectively, p < 0.0001); the median daily dose was also lower in the group with ineffective treatment (20 and 71.4 IU/kg, respectively, p < 0.005). Рrotein C administration in children with acquired deficiency for the purpose of antithrombotic prophylaxis can be potentially effective, especially in those patients who already have a thrombosis at the moment of administration. The effectiveness of such prophylaxis may depend on the dose of the injected concentrate. To determine the appropriate dose and mode of administration of the drug in children a prospective study is required. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology.

Purpura fulminans manifesting with Staphylococcus aureus endocarditis: a case report

BackgroundPurpura fulminans (PF) is a haematologic emergency that can occur in the setting of severe septic shock. Its pathophysiology is not well-understood; however, some evidence suggests it may be mediated by excessive protein C consumption.Case summaryIn this case report, we describe a patient with PF secondary to methicillin-resistant Staphylococcus aureus endocarditis. She presented with severe septic shock and, despite haemodynamic improvement, developed a significant purpuric rash. Diagnostic work-up was notable for severely decreased serum levels of protein C. This patient was successfully treated with protein C concentrate and surgical valve replacement.DiscussionWhile PF is rarely associated with S. aureus infection, this presentation may be more frequently encountered among clinicians in the current opioid epidemic. Quick recognition is crucial and a multidisciplinary approach, including intravenous infusion of protein C, may be considered.

A Registry Study on Treatment of Patients with Acquired Protein C Deficiency with a Protein C Concentrate (Human)

The objective of this non-interventional, international registry was to collect and assess data on the indications, safety, and the outcomes of treatment of patients with acquired protein C deficiency with a plasma-derived, human non-activated protein C concentrate (Ceprotin, Baxalta/Shire). Any patient who received treatment with protein C concentrate was eligible for the study; there were no exclusion criteria. This was an observational study with no required predefined visits, medical or laboratory tests, procedures or interventions either at enrollment or during the study. The study was conducted from June 2010 to June 2015. Management of patients was according to the discretion of the investigator. The primary endpoints were the medical diagnoses associated with protein C concentrate treatment, the protein C concentrate treatment regimens (dose, frequency), treatment outcomes and safety information. Here we report the results from 18 patients with severe acquired protein C deficiency (SAPCD - as judged by the treating physician) from 4 European (EU) investigative sites. Protein C concentrate is not currently approved for treatment of acquired protein C deficiency in the EU. The median age at study entry was 1.9 years (range: birth to 73.1 years); 5 [27.8%] patients were <1 month, 4 (22%) from 1 month to <2 years of age, 2 (11.1%) from 2 to <12 years, 2 (11.1%) from 12 to <18 and 5 (27.8%) ≥18 years of age. Eighteen patients were treated with protein C concentrate. At clinical presentation, 15/18 (83.3%) of these patients had sepsis, 2 had necrotizing enterocolitis and 1 had hemolytic uremic syndrome. Thromboembolic disease was present in 8/18 (25.8%) patients, all of whom had purpura fulminans. Of these 8 patients, 2 had disseminated intravascular coagulation (DIC) in addition to other conditions; 1 patient also had arterial thrombosis, and the other patient had macrovascular thrombosis and skin necrosis. The remaining 10 (74.2%) patients had no evidence of thromboembolic disease: of these, 7 patients had sepsis, 2 necrotizing enterocolitis and 1 hemolytic uremic syndrome. Dose level and frequency were variable: the most common dosage was 100 IU/kg and the most common interval between doses was 6 hours. There were no infusions administered for surgical interventions or for prophylaxis. At the time of final analysis 17/18 (94.4%) of patients had at least one follow-up visit. The median duration of study participation was 17.8 months (range 0.4-39.6 months). The mortality rate was 2/18 (11%) patients, including one case of fatal peritonitis, coinciding with protein C concentrate treatment in a 44 day-old, very low birthweight preterm infant and a case of multi-organ failure in a 19 year-old patient. Both deaths were considered not related to protein C concentrate. Ten patients received anticoagulation therapies in addition to protein C including: 4 treatments with antithrombin concentrates, 1 with clopidogrel, 6 with low molecular weight heparin and 7 with unfractionated heparin. Data from historical protein C concentrate treatments which occurred prior to enrollment in the study were collected from 3 patients upon their enrollment into the study (all 3 treatments resulted in halting/reversal of coagulopathy). During the entire study period, 13 adverse events (AEs) were reported in 5 patients with acquired deficiency; among these, 4 were serious adverse events (SAEs). During the period of treatment with protein C concentrate, there were 2 AEs including an SAE of gastroenteritis; neither were considered related AEs. The results of this registry demonstrate that in current clinical practice in the EU, treatment with protein C concentrate was safe with a mortality rate of 11% in patients with acute SAPCD and thrombotic episodes observed in association with sepsis and/or purpura fulminans in this study. Disclosures Knoebl: Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sasse:Baxter/Baxalta/Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding. De Carolis:Baxalta/Baxter: Other: Baxter Investigator for CEPROTIN Registry. Dyck-Jones:Baxter/Baxalta/Shire: Employment, Equity Ownership. Ehrle:Baxter/Baxalta/Shire: Employment, Equity Ownership. Finnerty:Baxalta/Baxter: Employment. Gelmont:Baxter/Baxalta/Shire: Employment, Equity Ownership. Yel:Baxter/Baxalta/Shire: Employment, Equity Ownership. Loghman-Adham:Baxter/Baxalta/Shire: Employment, Equity Ownership. Fischer:Baxter/Baxalta GmBH: Honoraria, Other: 'Weimarer Sepsis Update 2013'; Baxter/Baxalta GmBH: Consultancy, Other: Co-Authorship for E- Book-Preparing (Importance of the Protein C pathway in coagulation disorders and intensive care medicine / Treatment of congenital and acquired protein C deficiency.

Treatment of Patients with Severe Congenital Protein C Deficiency in a Registry Study of Protein C Concentrate (Human)

The objective of this non-interventional, international registry was to collect and assess safety and outcomes of all treatment with protein C concentrate for patients with protein C deficiency in Europe and the United States. Here we report the results from 25 patients with severe congenital protein C deficiency (SCPCD). Any patient who received treatment with protein C concentrate was eligible for the study; there were no exclusion criteria. There were no predefined visits, laboratory tests and/or procedures, or interventions at enrollment or during the study. Management of patients was at the discretion of the investigator. Clinical data collected during the treatment course of these patients are reported here. Twenty-five patients with congenital protein C deficiency from 10 US study sites and 10 study sites in the EU were enrolled into the study. The median age at study entry was 11.12 years (range: 1.3- 43.7 years). No patient was <1 month old, 2 (8.0%) patients were 1 month to <2 years old, 12 (48.0%) patients were 2 to <12 years old, 3 (12%) patients were 12 to <18 and 8 (32%) patients were ≥18 years old. The median duration of study participation was 39.7 months (range: 0.9 to 59.9 months). Thirteen (52%) patients were male and 12 (48%) were female. The initial clinical presentation that led to the diagnosis of SCPCD occurred prior to enrollment into the study (years in some cases). The initial presentations included primarily thromboembolic events (18 [52.9%]) or purpura fulminans (16 [47.1%]). During the study there were 259 treatment regimens with protein C concentrate, including 113 (43.6%) for acute episodes, 29 (11.2%) for short term replacement for surgical procedures, and 117 (45.2%) for long term prophylaxis. There were large variations in protein C treatments prescribed. The most common dose and frequency in patients treated for acute episodes was 60 IU/kg administered once a day. Protein C concentrate was administered at enrollment either intravenously or subcutaneously (SQ). During the study, 217/259 (83.8%) treatment regimens of protein C concentrate were administered intravenously and 42 (16.2%) were administered SQ. Nine patients received SQ infusions prophylactically and three of these 9 patients also used SQ infusions for treatment of an acute episode. Of 25 acute episodes in 7 patients treated with protein C concentrate, 22 (88.0%) resulted in recovery, 2 (8.0%) showed improvement and 1 (4.0%) was unchanged; there was no instance of worsening of an acute episode. Protein C concentrate was effective in prevention of coagulopathy and thrombosis in 23 (100%) short-term replacement treatments for surgery/invasive procedures performed in 13 patients with SCPCD. The median protein C activity level increased from 2.5% (range: 0.0 to 40.0%) at diagnosis (unaugmented) to 41.0% (range: 1.0% to 264.0%) following protein C concentrate infusion. One patient (4.0%) with congenital heart disease died of congestive heart failure, assessed as not related to protein C concentrate. Of 111 AEs in 22 patients, 83 AEs in 17 patients occurred during treatment with protein C concentrate. Of these 83 AEs, only 3 were considered related to protein C concentrate: a single patient had 2 SAEs (abdominal pain and pain in extremity) and 1 nonserious AE (purpura fulminans) that were considered by the investigator to be possibly related to administration of protein C concentrate. The results of this registry provide additional evidence for the use of protein C concentrate as an effective and safe short-term replacement therapy for surgery/invasive procedures and for acute episodes in patients with congenital protein C deficiency. No new safety concerns were identified. Disclosures Manco-Johnson: Bayer: Honoraria, Research Funding; Baxter/Baxalta/Shire: Honoraria; Biogen: Honoraria; NovoNordisk: Honoraria; CSL Behring: Honoraria. Hertfelder:Bayer Healthcare: Consultancy, Honoraria, Other: Support of Congress, Educational and Scientific Meeting Participations; Baxter/Baxalta/Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of Congress Participation; Pfizer: Consultancy, Honoraria, Other: Support of Congress, Educational and Scientific Meeting Participations; Daiichi-Sankyo Germany: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of Congress Participations; NovoNordisc: Other: Support of Congress Participations; Sanofi Aventis: Honoraria, Other: Educational meeting Participations, Speakers Bureau; Octapharma Germany: Other: Support of Congress Participations. Kalfa:Baxter/Baxalta/Shire: Research Funding. Bomgaars:Boeringer Ingleheim: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Membership on DSMB. Shapiro:National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; OPKO: Other: Clinical research protocols; Octopharma: Other: Clinical research protocols; PTC Therapeutics: Other: Clinical research protocols; Bayer healthcare Pharmaceuticals: Other: International network on pediatric hemophilia; Baxter/Baxalta/Shire: Membership on an entity's Board of Directors or advisory committees, Other: Clinical research protocols; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: Clinical research protocols; Daiichi Sankyo: Other: Clinical research protocols; Biogen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical research protocols; Novo Nordisk Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Kedrion Biopharma: Consultancy; ProMetic Life Sciences: Consultancy; American Thrombosis and Hemostasis Network: Other: Medical Director; Selexys: Other: Clinical research protocols; Novartis: Other: Clinical research protocols; CSL Behring: Other: Clinical research protocols. Jacqueline:Baxalta US Inc., now part of Shire: Employment, Equity Ownership. Ehrle:Baxter/Baxalta/Shire: Employment, Equity Ownership. Finnerty:Baxalta/Baxter: Employment. Gelmont:Baxter/Baxalta/Shire: Employment, Equity Ownership. Yel:Baxter/Baxalta/Shire: Employment, Equity Ownership. Loghman-Adham:Baxter/Baxalta/Shire: Employment, Equity Ownership.