This systematic review and meta-analysis assesses venous thromboembolism (VTE) risk in adults with hereditary thrombophilia, including Factor V Leiden (FVL) mutation, prothrombin G20210A (FII) mutation, compound heterozygosity, protein C (PC), protein S (PS), and antithrombin (AT) deficiency. Eligibility criteria included studies suitable for quantitative synthesis with extractable information on VTE risk in adults (> 15 years). There were no restrictions on VTE type, location, or occurrence. Two authors reviewed all studies and extracted data from 107 publications, encompassing 107,130 individuals (21,560 experiencing VTE). We used a random effects model and calculated odds ratios (ORs) with 95% confidence intervals (CIs). The highest risk was associated with homozygous FVL (OR 5.58, 95% CI 4.61-6.74), homozygous FII (OR 5.16, 95% CI 3.12-8.52), and compound heterozygosity (OR 4.64, 95% CI 2.25-9.58). In contrast, VTE risk was lowest for FVL heterozygosity (OR 2.97, 95% CI 2.41-3.67) and FII heterozygosity (OR 2.21, 95% CI 1.70-2.87), whereas PC (OR 3.23, 95% CI 2.05-5.08), PS (OR 3.01, 95% CI 2.26-4.02), and AT deficiency (OR 4.01, 95% CI 2.50-6.44) demonstrated an intermediate VTE risk. These results highlight an increased risk of venous thromboembolism in adults with hereditary thrombophilia. However, the risk for patients with PC, PS, and AT deficiency appears to be lower than previously stated, likely due to varying thrombogeneity of the underlying genetic mutations. Further research addressing this aspect of VTE risk in hereditary thrombophilia is imperative to improve patient management. TRIAL REGISTRATION: PROSPERO registration number CRD42022376757.

COVID-19 has been associated with alterations in coagulation. Recent reports have shown that protein C and S activities are altered in COVID-19. This may affect the complications and outcome of the disease. However, their exact role in COVID-19 remains uncertain. The aim of the current study was therefore to analyze all papers in the literature on protein C and S activities in COVID-19. We searched three medical electronic databases. Of the 2442 papers, 28 studies were selected for the present meta-analysis. For the meta-analysis, means ± standard deviations with 95% confidence intervals (CI) for protein C and S activities were extracted. Pooled p values were calculated using STATA software. Protein C and S activities were significantly lower in COVID-19 patients than in healthy controls (pooled p values: 0.04 and 0.02, respectively). Similarly, protein C activities were considerably lower in nonsurviving patients (pooled p value = 0.00). There was no association between proteins C or S and thrombosis risk or ICU admission in COVID-19 patients (p value > 0.05). COVID-19 patients may exhibit lower activities of the C and S proteins, which might affect disease outcome; however, additional attention should be given when considering therapeutic strategies for these patients.

UNASSIGNED: Various inherited traits contribute to the overall risk of venous thromboembolism (VTE). In addition, the epidemiology of thrombophilia in the East-Asian VTE population remains unclear; thus, we aimed to assess the proportion of hereditary thrombophilia via a meta-analysis.
UNASSIGNED: Publications from PubMed, EMBASE, web of science, and Cochrane before December 30, 2022, were searched. Studies from Japan, Korea, China, Hong Kong, Taiwan, Singapore, Thailand, Vietnam, Myanmar, and Cambodia were included. Congenital thrombophilia was described as diseases including protein C (PC) deficiency, protein S (PS) deficiency, antithrombin (AT) deficiency, factor (F)V Leiden (FVL), and prothrombin G20210A mutations. Studies were selected by 2 reviewers for methodological quality analysis. A random-effects model was used for the meta-analysis, assuming that estimated effects in the different studies are not identical.
UNASSIGNED: Forty-four studies involving 6453 patients from 7 counties/regions were included in the meta-analysis. The prevalence of PC, PS, and AT deficiencies were 7.1%, 8.3%, and 3.8%, respectively. Among 2924 patients from 22 studies, 5 patients were carriers of FVL mutation. Among 2196 patients from 10 studies, 2 patients were carriers of prothrombin G20210A mutation in a Thailand study.
UNASSIGNED: The prevalence of PC, PS, and AT deficiencies was relatively high, while a much lower prevalence of FVL and prothrombin G20210A mutations were identified in East-Asian patients with VTE. Our data stress the relative higher prevalence of PC, PS, and AT deficiencies for thrombophilia in the East-Asian VTE population.

Coumarin derivatives are the most used class of oral anticoagulants, and almost 1-2% of adults worldwide take it in the form of warfarin (WA) or acenocoumarol (AC). Cutaneous necrosis is a rare and severe complication of oral anticoagulant therapy. Most commonly, it occurs in the first 10 days, and the incidence peaks between the third and sixth day of starting treatment. Cutaneous necrosis due to AC therapy is underreported in the literature, and studies refer to this condition as \"coumarin-induced skin necrosis\"; however, this term is not totally accurate, as coumarin itself has no anticoagulant properties. We report a case of a 78-year-old female patient with AC-induced skin necrosis, who presented with cutaneous ecchymosis purpura over her face, arms, and lower extremities 3 hours after AC intake.

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BACKGROUND: 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.
METHODS: We describe a patient with a novel mutation in the PROC gene who was diagnosed with pulmonary embolism in a Chinese family.
METHODS: 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.
METHODS: Whole-exome sequencing (WES) was performed for the molecular analysis.
RESULTS: 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.
CONCLUSIONS: 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.

Sepsis, the dysregulated host response to infection, triggers abnormal pro-coagulant and pro-inflammatory host responses. Limitations in early disease intervention highlight the need for effective diagnostic and prognostic biomarkers. Protein C\'s role as an anticoagulant and anti-inflammatory molecule makes it an appealing target for sepsis biomarker studies. This meta-analysis aims to assess the diagnostic and prognostic value of protein C (PC) as a biomarker for adult sepsis.
We searched MEDLINE, PubMed, EMBASE, CINAHL and Cochrane Library from database inception to September 12, 2021. We included prospective observational studies of (1) adult patients (> 17) with sepsis or suspicion of sepsis that; (2) measured PC levels with 24 h of study admission with; and (3) the goal of examining PC as a diagnostic or prognostic biomarker. Two authors screened articles and conducted risk of bias (RoB) assessment, using the Quality in Prognosis Studies (QUIPS) and the Quality Assessment in Diagnostic Studies-2 (QUADAS-2) tools. If sufficient data were available, meta-analysis was conducted to estimate the standardized mean difference (SMD) between patient populations.
Twelve studies were included, and 8 were synthesized for meta-analysis. Pooled analysis demonstrated moderate certainty of evidence that PC levels were less reduced in sepsis survivors compared to non-survivors (6 studies, 741 patients, SMD = 0.52, 95% CI 0.24-0.81, p = 0.0003, I2 = 55%), and low certainty of evidence that PC levels were less reduced in septic patients without disseminated intravascular coagulation (DIC) compared to those with DIC (3 studies, 644 patients, SMD = 0.97, 95% CI 0.62-1.32, p < 0.00001, I2 = 67%). PC could not be evaluated as a diagnostic tool due to heterogeneous control populations between studies.
Our review demonstrates that PC levels were significantly higher in sepsis survivors compared to non-survivors and patients with sepsis but not disseminated intravascular coagulation (DIC). Our evaluation is limited by high RoB in included studies and poor reporting of the sensitivity and specificity of PC as a sepsis biomarker. Future studies are needed to determine the sensitivity and specificity of PC to identify its clinical significance as a biomarker for early sepsis recognition. Trial Registration PROSPERO registration number: CRD42021229786. The study protocol was published in BMJ Open.

BACKGROUND: 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.
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.
CONCLUSIONS: 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.

Objective: To improve the understanding of clinical manifestations, imaging findings, diagnosis and treatment of surfactant protein C gene (SFTPC) mutation associated with familial interstitial lung disease in adults. Methods: Two cases of adult SFTPC gene mutation associated with familial interstitial lung disease diagnosed in the Affiliated Hospital of Medical School of Ningbo University were analyzed retrospectively, and the literature was reviewed. The literatures were retrieved with \"family interstitial lung disease\" \"SFTPC gene\" \"surface protein C gene\" \"SFTPC gene mutation associated with familial international lung disease\" and \"surface protein C gene mutation associated with familial international lung disease\" in PubMed, Embase, Ovid, Wanfang database and China National Knowledge Infrastructure (CNKI). Results: There were two patients with familial interstitial lung diseases(one male and one female) with an average age of 27.5 years. Ⅱ-2 patient had symptoms of dry cough and shortness of breath, and Ⅱ-1 patient had no symptoms. There were multiple cysts and fine reticular shadows in both cases. Ⅱ-2 patient had multiple ground glass opacities in both lower lungs. TheⅡ-2 patient was diagnosed with usual interstitial pneumonia (UIP) by transbronchial lung cryobiopsy. A total of 35 patients were included in this literature review, including 20 males, with an average age of 33.5 years. Of all the patients, the clinical symptoms were described in 30 patients. The main manifestations were shortness of breath (22/30), dry cough (18/30), clubbing finger (12/30), and 30% (9/30) of them were found by chest computerized tomography (CT) without symptoms. There were 17 cases with detailed description of chest CT imaging. The most common chest CT findings were multiple intralobular reticular opacities (17/17), multiple cysts (12/17) and ground glass opacities (7/17). The main histopathological pattern was UIP (24/26). Conclusions: The main clinical manifestations of SFTPC gene mutation associated with familial interstitial lung disease in adults are shortness of breath, dry cough and clubbing fingers. The main manifestations are multiple cysts and intralobular reticular opacities in combination with multiple ground glass opacities. There is no specific drug in the treatment at present and early treatment with hydroxychloroquine may have better curative effect. When the imaging findings show multiple cysts and intralobular reticular opacities in combination with multiple ground glass opacities, especially the age of onset is less than 50 years old, this disease should be considered.
目的： 提高对成人肺表面活性蛋白C（SFTPC）基因突变相关家族性间质性肺疾病的临床表现、影像表现、诊断和治疗的认识。 方法： 回顾分析宁波大学医学院附属医院诊断的2例成人SFTPC基因突变相关家族性间质性肺疾病，结合文献进行复习。以“familial interstitial lung disease”“SFTPC gene”“surfactant protein C gene”“SFTPC gene mutation associated with familial interstitial lung disease”和“surfactant protein C gene mutation associated with familial interstitial lung disease”为检索词在PubMed、Embase及Ovid数据库，以“家族性间质性肺疾病”“SFTPC基因”“肺表面活性物质相关蛋白C基因”“SFTPC基因突变相关家族性间质性肺疾病”及“肺表面活性物质相关蛋白C基因突变相关家族性间质性肺疾病”为检索词在万方数据库及中国期刊网全文数据，检索时间截至2021年3月。 结果： 本组2例家族发病患者1男1女，平均年龄27.5岁，Ⅱ-2患者存在干咳、气促症状，Ⅱ-3无症状，2例影像表现均存在多发囊腔及细网格状影，Ⅱ-2患者存在两下肺多发磨玻璃影，Ⅱ-2患者经支气管镜冷冻肺活检病理诊断为UIP。文献复习共纳入35例患者，其中男20例，平均年龄为33.5岁，主要表现为气促（22/30）、干咳（18/30）、杵状指（12/30），而无症状体检或家族其他成员发现而行胸部CT发现占30%（9/30）。最常见胸部CT表现为双肺多发细网格状影（17/17）及多发囊状影或囊腔（12/17）和磨玻璃影（7/17）。病理主要表现为UIP（24/26）。 结论： 成人SFTPC基因突变相关家族性间质性肺疾病临床主要表现为气促、干咳及杵状指，影像学表现具有一定特征性，主要表现为双肺多发囊腔影及细网格状影伴或不伴两下肺多发磨玻璃影，治疗上目前无特效药，尽早使用羟氯喹可能有较好的疗效。对于影像表现为双肺多发囊腔影伴细网格影及磨玻璃影且发病年龄<50岁时，需要考虑该病可能。.

Sepsis is a dysregulated host response to infection characterised by activation of proinflammatory and procoagulant mechanisms. Protein C (PC)\'s activity as an anticoagulant and antiinflammatory molecule makes it an appealing target for sepsis biomarker studies. To date, there has been no systematic review of PC as a sepsis biomarker.
To evaluate the diagnostic accuracy and prognostic strength of PC as a biomarker for adult sepsis.
Medline, Embase, Cochrane Library, PubMed and Cumulative Index to Nursing and Allied Health Literature (CINAHL) will be searched from inception through 20 January 2021 for prospective observational studies that evaluate the use of PC as a diagnostic or prognostic biomarker for adult sepsis. Title and abstract screening, full-text screening and data extraction will be conducted in duplicate. Risk of bias will be assessed using the Quality Assessment of Diagnostic Accuracy Studies and Quality in Prognostic Studies tools. If sufficient data are available, a meta-analysis will be conducted. The standardised mean difference and 95% CI will be calculated for prognostic and diagnostic studies. If possible, a hierarchical summary receiver operator characteristic curve will be generated to assess overall prognostic and diagnostic biomarker accuracy. I2 statistics will be used to assess heterogeneity. Sensitivity analysis will be performed by removing studies with a high risk of bias and re-examining the meta-analysis results.
Given this is a systematic review and meta-analysis, there is no requirement for ethics approval. Findings will be disseminated through a peer-reviewed publication and social media.
CRD42021229786.