[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.

Analysis of PROC mutations and clinical features in 22 unrelated families with inherited protein C deficiency.

Currently, limited information is available in the literature regarding the relationships between PROC mutations and clinical features in Chinese individuals. We aimed to characterize severe congenital Protein C deficiency in 22 unrelated Chinese families in a tertiary hospital by analyzing its clinical manifestation, associated risk factors, and gene mutations. We measured protein C activity and antigen levels for all participants, screened them for mutations in the PROC gene, and analyzed the clinical features of each family to identify commonalities and differences. The analysis revealed a total of 75 individuals with PCD and 16 different PROC mutations, including 12 missense mutations and 4 deletion mutations. Among them, 11 who were compound heterozygotes or homozygotes for mutations tended to develop symptoms at a younger age without any clear triggers. In contrast, the remaining 64 individuals who were heterozygotes for mutations often had clear triggers for their symptoms and experienced a milder course of the disease. It is worth noting that the mutation c.565C > T occurred most frequently, being identified in 8 out of 22 families (36%). Our team also reported five novel mutations, including c.742-744delAAG, c.383G > A, c.997G > A, c.1318C > T, and c.833T > C mutations. The identification of five novel mutations adds to the richness of the Human Genome Database. Asymptomatic heterozygotes are not uncommon, and they are prone to develop symptoms with obvious triggers. The evidence presented strongly suggest that asymptomatic individuals with family history of protein C deficiency can benefit from mutational analysis of PROC gene.

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.

Recurrent miscarriage: green-top guideline nº 17

The purpose of this guideline is to provide guidance on the investigation and care of women and people with recurrent miscarriage.Within this document we use the terms woman and women's health. However, it is important to acknowledge that it is not only women for whom it is necessary to access women's health and reproductive services in order to main-tain their gynaecological health and reproductive wellbeing. Gynaecological and obstetric services and delivery of care must therefore be appropriate, inclusive and sensitive to the needs of those individuals whose gender identity does not align with the sex they were assigned at birth. The term cou-ple is used to describe two individuals trying to conceive, recognising that in some instances these individuals may not be in a relationship. While every effort is made to ensure the RCOG uses inclusive language there are instances where we have been unable to adhere to this, for example where original research is being referenced the language within the publication is used for accuracy.

[Genetic predisposition to early-onset thrombophilia: a study on challenges in personalized medicine for mothers, infants, and children].

The number of reports on genetic predisposition to pediatric thrombosis is increasing. The risk of thrombosis in childhood varies according to patient age, and the contribution of genetic predisposition also differs. The term early-onset thrombophilia, which occurs until the age of 20 years in patients with genetic diagnosis, was defined. Then, the registry in Japan was established. Further, publications were reviewed comprehensively, and results revealed the genetic and clinical characteristics of patients. Less than 60% of patients presented with protein C (PC) deficiency, and over half of them had PC-gene monoallelic variants. The number of patients with protein S or antithrombin deficiency increased with age. None of them were aged between 6 and 8 years. PC-Tottori and protein S-Tokushima, which are high-frequency and low-risk variants in Japanese, contributed to the development of thrombosis. However, PC-Tottori did not affect the development of severe PC deficiency. One exceptional de novo PC-deficient variant was identified in 32 EOT families, and thrombosis developed concurrently in three pairs of mothers-newborns. Appropriate EOT screening tests targeting PC deficiency are required to prevent maternal and neonatal thromboses.

[Clinical and genetic analysis of a rare fetus with Protein C deficiency due to compound heterozygous variants of PROC gene].

OBJECTIVE: To explore the genetic etiology for a fetus with hydrocephalus and intraventricular hemorrhage. METHODS: Trio whole exome sequencing was carried out. Candidate variants were verified by Sanger sequencing of the fetus and its parents. RESULTS: The fetus was found to harbor c.818G>A (p.W273X) and c.833T>C (p.L278P) compound heterozygous variants of the PROC gene, which were respectively inherited from its mother and father. Based on the guidelines of the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PVS1_Strong+PM2_Supporting+PP4; PM2_Supporting+PM3+PP1+PP3+PP4). CONCLUSION: The fetus was diagnosed with Protein C deficiency due to the c.818G>A (p.W273X) and c.833T>C (p.L278P) compound heterozygous variants of the PROC gene. Above finding has enriched the spectrum of PROC gene variants and enabled genetic counseling and prenatal diagnosis for the family.

Molecular basis of inherited protein C deficiency results from genetic variations in the signal peptide and propeptide regions.

BACKGROUND: Inherited protein C deficiency (PCD) caused by mutations in protein C (PC) gene (PROC) increases the risk of thrombosis. Missense mutations in PC's signal peptide and propeptide have been reported in patients with PCD, but their pathogenic mechanisms, except mutations in R42 residue, remain unclear. OBJECTIVES: To investigate the pathogenic mechanisms of inherited PCD caused by 11 naturally occurring missense mutations in PC's signal peptide and propeptide. METHODS: Using cell-based assays, we evaluated the impact of these mutations on various aspects such as activities and antigens of secreted PC, intracellular PC expression, subcellular localization of a reporter protein, and propeptide cleavage. Additionally, we investigated their effect on pre-messenger RNA (pre-mRNA) splicing using a minigene splicing assay. RESULTS: Our data revealed that certain missense mutations (L9P, R32C, R40C, R38W, and R42C) disrupted PC secretion by impeding cotranslational translocation to the endoplasmic reticulum or causing endoplasmic reticulum retention. Additionally, some mutations (R38W and R42L/H/S) resulted in abnormal propeptide cleavage. However, a few missense mutations (Q3P, W14G, and V26M) did not account for PCD. Using a minigene splicing assay, we observed that several variations (c.8A>C, c.76G>A, c.94C>T, and c.112C>T) increased the incidence of aberrant pre-mRNA splicing. CONCLUSION: Our findings suggest that variations in PC's signal peptide and propeptide have varying effects on the biological process of PC, including posttranscriptional pre-mRNA splicing, translation, and posttranslational processing. Additionally, a variation could affect the biological process of PC at multiple levels. Except for W14G, our results provide a clear understanding of the relationship between PROC genotype and inherited PCD.

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.

Performance of Chromogenic Protein C (PC) Testing.

Protein C (PC) is a vitamin K-dependent zymogen synthesized in the liver that plays a major role in regulating the coagulation pathway. Upon interaction with the thrombin-thrombomodulin complex, PC is converted to its active form, activated PC (APC). APC complexes with protein S and regulates thrombin generation by the inactivation of Factors Va and VIIIa. The role of PC as a key regulator of the coagulation process is highlighted in the deficiency state, in which heterozygous deficiency of PC predisposes to an increased risk of venous thromboembolism (VTE), while in the homozygous deficiency state, potentially fatal complications in the fetus including purpura fulminans and disseminated intravascular coagulation (DIC) can occur. Protein C is often measured with other factors such as protein S and antithrombin as a screen in the investigation of VTE. The chromogenic PC assay, the protocol described in this chapter, quantitates the amount of functional PC in the plasma using an activator of PC with the degree of color change proportional to the amount of PC present in the sample. Other methods, including functional clotting-based assays and antigenic assays, are available; however, protocols for these assays will not be provided in this chapter.

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.

[Analysis of PROC gene variant in a Chinese pedigree affected with hereditary protein C deficiency].

OBJECTIVE: To explore the molecular pathogenesis of a Chinese pedigree affected with inherited protein C (PC) deficiency. METHODS: The protein C activity (PC:A) and protein C antigen (PC:Ag) of the proband and his family members were determined by a chromogenic substrate method and enzyme-linked immunosorbent assay, respectively. The proband was subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing of other members of the pedigree. RESULTS: The PC:A and PC:Ag of proband were reduced to 15% and 11%, respectively. The above parameters of his parents and elder sister were also decreased to approximately 50% of reference values. Next generation sequencing has revealed that the proband has harbored a heterozygous c.572_574delAGA (p.Glu191_Lys192delinsGlu) variant in exon 7 and a missense c.752C>T (p.Ala251Val) variant in exon 8 of the PROC gene. His father was heterozygous for the c.572_574delAGA variant, while his mother and elder sister were heterozygous for the c.752C>T variant. According to the American College of Medical Genetics and Genomics Standards and Guidelines, the c.572_574delAGA (p.Glu191_Lys192 delinsGlu) variant was predicted to be likely pathogenic (PS1+PM4+PP3). c.752 C>T (p.Ala251Val) variant was also likely pathogenic (PS1+PM1+PP3). CONCLUSION: The deletional variant of c.572_574delAGA (p.Glu191_Lys192delinsGlu) in exon 7 and missense variant c.752C>T (p.Ala251Val) in exon 8 of the PROC gene probably underlay the inherited protein C (PC) deficiency in this pedigree. Above finding has enriched the spectrum of PROC gene variants and provided a basis for genetic counseling for this pedigree.