[Perioperative management for fracture in a child with homozygous congenital protein C deficiency].

Congenital protein C (PC) deficiency is one type of hereditary thrombosis. Patients with hereditary thrombosis are at high risk for thrombosis in the perioperative period, but a standard management strategy has not been established. Here we report a case of perioperative management of a fracture in a child with homozygous congenital PC deficiency. The patient was a 3-year-old boy who was diagnosed with congenital PC deficiency at birth. He sustained a traumatic supracondylar fracture of the right humerus and underwent emergency surgery. To prepare for open surgery for fixation of the fracture, warfarin was discontinued, and an activated PC (APC) concentrate was used in combination with vitamin K antagonism. However, warfarin was administered during the scheduled nail extraction because the operation was minimally invasive. No thrombotic or bleeding complications occurred in either operation. In emergency surgery in patients with congenital PC deficiency, the combination of vitamin K and APC concentrate is considered a maintenance option for PC deficiency. Postoperative PT-INR control was difficult in our patient due to the administration of vitamin K and withdrawal of warfarin, and this issue must be addressed in the future. Further case experience is desirable to standardize perioperative management.

[Extracorporeal Membrane Oxygenation Combined With Interventional Thrombectomy for Treating High-Risk Pulmonary Embolism Caused by Protein C Deficiency:Report of One Case].

Hereditary protein C deficiency is a chromosomal genetic disease caused by mutations in the protein C gene,which can lead to venous thrombosis and is mostly related to mutations in exons 4-9 and intron 8.Fatal pulmonary embolism caused by mutations in the protein C gene is rare,and the treatment faces great challenges.This article reports a case of fatal pulmonary embolism caused by a frameshift mutation in exon 8 of the protein C gene and summarizes the treatment experience of combining extracorporeal membrane oxygenation (for respiratory and circulatory support) with interventional thrombectomy,providing a basis for the diagnosis and treatment of this disease.

Deficiency of protein C or protein S as a possible cause of osteoporosis.

Proteins C and S are vitamin K-dependent anticoagulative factors that also exert a significant influence on bone quality. Clinical studies have linked the deficiency of proteins C and S to lower bone mineral density and the onset of femoral head osteonecrosis in children. Rare foundational studies analyzing this topic have demonstrated that activated protein C, upon binding to the endothelial protein C receptor expressed on the surface of osteoblasts, promotes osteoblast proliferation. It is also established that proteins C and S play crucial roles in proper collagen synthesis and in maintaining the number of osteoclasts and blood vessels. However, the association between protein C and/or S deficiency and the gradual onset of osteoporosis remains largely uninvestigated. Calculations based on data from peer-reviewed journals suggest that approximately one in every 10 individuals may develop osteoporosis due to congenital protein C or S deficiency. Moreover, when secondary causes of protein C and S deficiency are also considered, the proportion likely further increases. In this paper, we discuss the pathophysiological background of the potential relationship between protein C and S deficiency and the genesis of osteoporosis.

Analysis of four hereditary protein C deficiencies associated with vascular thromboembolism.

OBJECTIVE: To analyze the clinical features and gene mutations in four families with hereditary protein C (PC) deficiency and explore their association with vascular thromboembolism. METHODS: The clinical data of four patients with PC deficiency were retrospectively analyzed. Venous blood samples were collected from the four affected patients and their family members, and relevant coagulation indexes and thrombin production and inhibition tests were performed. PCR was used to amplify and directly sequence the PROC gene of the probands. Software analysis was conducted to assess the conservativeness and pathogenicity of the mutated loci. Protein models were constructed to analyze the spatial structure before and after the mutation. RESULTS: Thrombin generation and inhibition assays demonstrated impaired anticoagulation in all four probands. Proband 1 and 4 presented clinically with pulmonary embolism and lower extremity deep vein thrombosis (DVT), Proband 2 with cerebral infarction, and Proband 3 with DVT. Genetic analysis revealed the presence of the following mutations: c.541T > G heterozygous missense mutation, c.577-579delAAG heterozygous deletion mutation, c.247-248insCT heterozygous insertion mutation, c.659G > A heterozygous missense mutation, and a new variant locus c.1146_1146delT heterozygous deletion mutation in the four probands, respectively. In particular, c.1146_1146delT heterozygous deletion mutations not reported previously. Conservativeness and pathogenicity analyses confirmed that most of these amino acid residues were conserved, and all the mutations were found to be pathogenic. Analysis of protein modeling revealed that these mutations induced structural alterations in the protein or led to the formation of truncated proteins. According to the American College of Medical Genetics and Genomics (ACMG) classification criteria and guidelines for genetic variants, c.1146_1146delT was rated as pathogenic (PVS1 + M2 + PM4 + PP1 + PP3 + PP4). CONCLUSION: The identified mutations are likely associated with decreased PC levels in each of the four families. The clinical manifestations of hereditary PC deficiency exhibit considerable diversity.

The clinical and genetic landscape of early-onset thrombophilia in Japan.

OBJECTIVES: To determine the optimal management for early-onset thrombophilia (EOT), the genetic and clinical features of protein C (PC)-, protein S (PS)-, or antithrombin (AT)-deficient patients of ≤20 years of age were studied in Japan. METHODS/RESULTS: Clinical and genetic information of all genetically diagnosed cases was collected through the prospective, retrospective study, and literature review. One-hundred-one patients had PC (n = 55), PS (n = 29), or AT deficiency (n = 18). One overlapping case had PC- and PS-monoallelic variant. Fifty-five PC-deficient patients (54%) had 26 monoallelic or 29 biallelic variant(s), and 29 (29%) PS-deficient patients had 20 monoallelic or nine biallelic variant(s). None of the patients had AT-biallelic variants. The frequent low-risk allele p.K193del (PC-Tottori) was found in five patients with monoallelic (19%) but not 29 with biallelic variant(s). The most common low-risk allele p.K196E (PS-Tokushima) was found in five with monoallelic (25%) and six with biallelic variant(s) (67%). One exceptional de novo PC variant was found in 32 families with EOT. Only five parents had a history of thromboembolism. Thrombosis concurrently developed in three mother-newborn pairs (two PC deficiency and one AT deficiency). The prospective cohort revealed the outcomes of 35 patients: three deaths with PC deficiency and 20 complication-free survivors. Neurological complications were more frequently found in patients with PC-biallelic variants than those with PC-, PS-, or AT-monoallelic variants (73% vs. 24%, p = .019). CONCLUSIONS: We demonstrate the need for elective screening for EOT targeting PC deficiency in Japan. Early prenatal diagnosis of PC deficiency in mother-infant pairs may prevent perinatal thrombosis in them.

Segmental testicular infarction secondary to protein C deficiency.

Protein C deficiency is a rare blood disorder that increases the risk of thromboembolism, resulting in deep vein thrombosis, pulmonary embolisms and strokes. Segmental testicular infarction is also a rare condition with unclear aetiology. This case presents a man in his 50s with protein C deficiency who developed a segmental testicular infarction. The patient was managed conservatively, without surgical intervention. He was monitored with serial ultrasound, which demonstrated progression from normal testis to segmental infarction and eventually resolution. The case highlights that protein C deficiency can cause testicular infarction, and a multidisciplinary approach can help avoid unnecessary surgery with excellent outcomes. Segmental infarction should be considered in patients with pre-existing thrombophilias after excluding malignancy and infection. Conservative management with repeat ultrasonography and follow-up can be appropriate in such cases.

A case of fulminant type 1 diabetes and protein C deficiency complicated by deep vein thrombosis.

A 25-year-old man was diagnosed with diabetic ketoacidosis (DKA) at the onset of fulminant type 1 diabetes. After acute-phase DKA treatment including placement of a central venous catheter, a massive deep vein thrombosis (DVT) and pulmonary embolism (PE) were detected on hospital day 15. His protein C (PC) activity and antigen levels were low even 33 days after completing the DKA treatment, indicating partial type I PC deficiency. Severe PC dysfunction, due to overlapping of partial PC deficiency and hyperglycemia-induced PC suppression, concomitant with dehydration and catheter treatment, may have induced the massive DVT with PE. This case suggests that anti-coagulation therapy should be combined with acute-phase DKA treatment in patients with PC deficiency, even those who have been asymptomatic. As patients with partial PC deficiency should perhaps be included among those with severe DVT complications of DKA, venous thrombosis should always be considered as a potential complication of DKA.

Isolated Protein C Deficiency in a Newborn.

BACKGROUND: Congenital protein C deficiency is a rare hereditary thrombophilia, neonatal purpura fulminans is the most serious form of this deficit. The purpose of this observation is two-fold. The first is the need to make an early diagnosis in order to improve the prognosis. The second, is to discuss the need. In case of extensive purpura fulminans in the neonatal period, the search for a deficiency in anticoagulant factor, in particular the dosage of protein C, in the newborn and in both parents. METHODS: The diagnosis is biological and is based on the quantitative determination of functionally active protein C. We use the Berichrom® Protein C assay on an automated coagulation analyzer from Siemens Healthcare Diagnostics, which allows the chromogenic determination of Protein C activity. RESULTS: We report an observation of cutaneous necrosis in a newborn having developed a purpura fulminans extensive secondary to a total congenital protein C deficiency. In front of this clinical picture, thrombophilia assessment is requested, revealing an isolated deficit in protein C < 1%. CONCLUSIONS: In the case of extensive purpura fulminans in the neonatal period, the search for a deficiency in anticoagulant factor, in particular the dosage of protein C, is essential in the newborn and in both parents.

Idiopathic pulmonary hemosiderosis and stroke secondary to protein C deficiency in a child with Down syndrome: a case report.

BACKGROUND: Patients with Down syndrome are at a higher risk of developing autoimmune disorders such as thyroiditis, diabetes, and celiac disease compared with the general population. Although some diseases are well known to be associated with Down syndrome, others such as idiopathic pulmonary hemosiderosis and ischemic stroke due to protein C deficiency remain rare. CASE PRESENTATION: We report a case of a 2.5-year-old Tunisian girl with Down syndrome and hypothyroiditis admitted with dyspnea, anemia, and hemiplegia. Chest X-ray showed diffuse alveolar infiltrates. Laboratory tests showed severe anemia with hemoglobin of 4.2 g/dl without hemolysis. A diagnosis of idiopathic pulmonary hemosiderosis was confirmed by bronchoalveolar lavage showing numerous hemosiderin-laden macrophages, with a Golde score of 285 confirming the diagnosis of pulmonary hemosiderosis. Concerning hemiplegia, computed tomography showed multiple cerebral hypodensities suggestive of cerebral stroke. The etiology of these lesions was related to protein C deficiency. CONCLUSION: Idiopathic pulmonary hemosiderosis remains a severe disease, which is rarely associated with Down syndrome. The management of this disease in Down syndrome patients is difficult, especially when associated with an ischemic stroke secondary to protein C deficiency.

Kidney Transplantation for a Patient With Protein C Deficiency Using Activated Protein C Concentrate: A Case Report.

BACKGROUND: Thrombophilia causes thrombosis after kidney transplantation (KT). Protein C deficiency is a rare form of hereditary thrombophilia. To our knowledge, there are few reports on KT for patients with protein C deficiency, and there are no reports of KT in patients with protein C deficiency administered with activated protein C concentrate. METHOD: Here we reported the case of a patient with protein C deficiency who underwent KT without the occurrence of any fresh thrombosis after administration of an activated protein C concentrate. The patients was a 49-year-old woman diagnosed with immunoglobulin A nephropathy at 20 years of age. During pregnancy, she experienced deep vein thrombosis of the lower extremities and pulmonary embolism for which she was started on warfarin. After a thorough examination, the patient was diagnosed with protein C deficiency. The patient had end-stage kidney disease and received a preemptive living donor kidney transplant from her mother. RESULTS: To prevent thrombosis, we switched from oral warfarin to continuous heparin 7 days before surgery. Heparin was discontinued 6 hours before surgery, and continuous activated protein C concentrate was administered 12 hours before surgery. Heparin administration was resumed 6 hours after the surgery. Warfarin administration was restarted 3 days after the surgery, and heparin was discontinued 11 days post-surgery. The surgery was performed without complications. After the KT, the patient's renal function steadily improved, and no fresh thrombosis were observed. CONCLUSIONS: Thrombosis can cause graft loss and pulmonary embolism, thus appropriate administration of activated protein C concentrate may help prevent thrombosis.

Compound heterozygous protein C deficiency with pulmonary embolism caused by a novel PROC gene mutation: Case report and literature review.

RATIONALE: Protein C is an anticoagulation agent, and protein C deficiency results in vascular thrombosis disease. Hereditary protein C deficiency is a risk factor for pulmonary embolism in adults. Pathogenic variants of the Protein C, Inactivator Of Coagulation Factors Va And VIIIa (PROC) gene which encodes protein C have been identified as a cause of protein C deficiency. PATIENT CONCERNS: We describe a patient with a novel mutation in the PROC gene who was diagnosed with pulmonary embolism in a Chinese family. DIAGNOSIS: According to the results of the pulmonary computed tomography angiography (CTA) and the level of blood protein C, the patient was diagnosed with pulmonary embolism caused by protein C deficiency. INTERVENTIONS: Whole-exome sequencing (WES) was performed for the molecular analysis. OUTCOME: The results of patient's deoxyribonucleic acid revealed a heterozygous mutation (c.237 + 5G > A) in intron 3 of the PROC gene. His father also harbored the same mutation in the PROC gene. We also reviewed the protein C deficiencies caused by PROC gene mutations in cases. LESSONS: A novel mutation in intron 3 of PROC gene has not been previously reported in patients with pulmonary embolism caused by protein C deficiency. After anticoagulation therapy, the patient recovered, and CT showed resolution of the thrombosis. Pulmonary embolism may be caused by protein C deficiency and the rare compound heterozygous mutation in intron 3 of the PROC gene could cause protein C deficiency via impairment of the secretory activity of protein C.

Pediatric Retinal Detachment in Homozygous Protein C Deficiency: Genetic and Phenotypic Description of a Single Family.

Homozygous protein C deficiency is a rare hypercoagulability disorder. This study describes the ocular manifestations and the genetic background in a family with two affected children. This is a retrospective review of ophthalmic examinations, investigations, genetic testing, and blood work-up of two children with homozygous protein C deficiency from a single family. A family with a positive history of consanguineous marriage was found to have two affected children with homozygous protein C deficiency. Abnormal visual behavior was the presenting symptom. Both children had bilateral total tractional retinal detachments at presentation. Skin manifestations included episodes of discoloration and bruising. Laboratory work-up revealed absent protein C activity. Genetic testing confirmed the presence of a homozygous pathogenic mutation in protein C gene (NM_000312.3: c.1297G>A: p.Gly433Ser). Homozygous protein C deficiency should be considered in the differential diagnosis of early-onset tractional retinal detachment in infancy. Although rare, the ophthalmologist may be the first to encounter the condition, and treatment with protein C replacement or anticoagulants may be life-saving. Examination under anesthesia with fluorescein angiography and laser treatment early in life may be warranted to preserve vision. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:293-296.].

Clinical and genetic features of Chinese pediatric patients with severe congenital protein C deficiency who first presented with purpura fulminans: A case series study and literature review.

INTRODUCTION: Purpura fulminans (PF) is a hematological emergency that can be caused by severe congenital protein C (PC) deficiency. It has been rarely reported in the Chinese population. We aimed to characterize the clinical and genetic features of Chinese pediatric patients with severe congenital PC deficiency who first presented with PF. MATERIALS AND METHODS: Twelve pediatric patients were diagnosed with severe congenital PC deficiency with PF, which was diagnosed based on our hospital records and previous reports from 1988 to July 2021 in China. We evaluated the clinical and genetic features of these patients. RESULTS: Nine patients (9/12, 75%) had onsets that were observed within the first 48 h after birth. Six patients had a family history of thromboembolism. There was no consanguinity. Other symptoms were intracranial thrombosis or hemorrhage (4, 33.3%), ocular lesions (2, 16.7%), gastrointestinal hemorrhage (2, 16.7%) and kidney infarction before birth (1, 8.3%). All but one of the patients (one case not detected) had a plasma PC activity of <10%. The genetic study indicated that in the eight patients with inherited PC deficiency, two were homozygous, five were compound heterozygous and one was heterozygous for PC deficiency. CONCLUSION: This is the first and largest case series of Chinese pediatric patients with severe congenital PC deficiency who first presented with PF. It has been shown that treatment with both fresh frozen plasma and anticoagulants is recommended when PC concentrate is not easily available, especially in developing countries.

A case of polycystic ovary syndrome with inevitable miscarriage and multi-site venous thrombosis caused by hereditary protein C deficiency.

BACKGROUND: Polycystic ovarian syndrome (PCOS) affects up to 18% of reproductive-aged women and raises the risk of venous thromboembolic disease (VTE), due to metabolic features and an apparent fibrinolytic state. Recent studies have shown an increased risk of VTE (1.5- to 2-fold) in patients with PCOS as compared to those without PCOS. Mutations in the Protein C (PC) gene (PROC) lead to deficiency or dysfunction of the protein, Protein C deficiency is the main clotting physiological inhibitor of protein C cofactors, and is a risk factor for venous thrombosis, which can cause a variety of events, including miscarriage. This case report proposes a correlation between PCOS, protein C deficiency, venous thrombosis and inevitable miscarriage. CASE PRESENTATION: A 33-year-old Chinese woman was diagnosed with Polycystic Ovary Syndrome (PCOS) in 2015. During the course of treatment, she took ethinylestradiol and cyproterone acetate tablets for more than one year. In 2016, she was sent to a hospital for emergency care due to explosive thrombosis (thrombosis in multiple parts of the body and pulmonary thrombosis). In 2020, the patient became pregnant via natural means and came to our hospital for treatment. During the second trimester, she experienced an inevitable miscarriage. High-throughput sequencing (NGS) of peripheral blood lymphocytes revealed that the patient had a protein C deficiency resulting from a heterozygous mutation deletion of 572_574 in exon 7. CONCLUSION: PC deficiency in conjunction with PCOS and the concomitant use of oral contraceptive (COC) would increase the risk of VTE, especially in the early stages of COC use.