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Acute cerebellar ischemic stroke is a rare disease in children. Typically, patients present with ataxia and cranial nerve palsy. Rarely, some patients show a severe intracranial hypertension syndrome with a life-threatening clinical presentation. We report a case of a 2-year-old male child who was admitted for deterioration of his consciousness level and vomiting. Cerebral imaging revealed a right cerebellar and brainstem infarction with an obstructive hydrocephalus and a tonsillar herniation. Angiography identified an occlusion of the right anterior inferior cerebellar artery. The child was referred to a neurosurgeon for the treatment of acute hydrocephalus and posterior fossa craniectomy. Etiological investigations revealed a protein C deficiency. Initially, the patient was maintained under fluid restriction and received mannitol several times as he had clinical and radiological signs of intracranial hypertension. He was also kept on mechanical ventilation and monitored. However, the evolution was complicated by the occurrence of a thrombosis of the vena cava and the renal vein. [ABSTRACT FROM AUTHOR]

Introduction: The presence of a hypercoagulable state predisposes to venous and arterial thrombi. While the relationship between protein C and S deficiencies with venous thrombus formation is clear, the relationship to arterial thrombi formation is less common. Thromboembolic disease of the renal arteries may result in renal infarction. The development of simultaneous bilateral renal infarction is rare and can lead to significant morbidity and mortality.Case Report: This is a case of a 48-year-old male with known protein C deficiency who presented to the emergency department with sudden onset abdominal pain. A computed tomography angiogram of the abdomen showed bilateral renal infarctions. The patient required significant analgesia and developed acute kidney injury. He was treated conservatively, and dialysis was not required.Conclusion: There are no reports in the emergency medicine literature of bilateral renal infarction secondary to protein C and S deficiency. Prompt evaluation with definitive imaging is necessary for patients who are at high risk for arterial thrombi and present with symptoms suggestive of the diagnosis.

Abstract Background Purpura fulminans (PF) is a rare but severe thrombotic disorder affecting small cutaneous blood vessels. It may present as bruising and discoloration but can rapidly progress necrosis and life-threatening complications if not promptly diagnosed and treated. This paper presents a rare case of neonatal PF associated with protein C and S deficiency, highlighting the importance of prompt recognition and diagnosis. Case presentation A 10-day-old male infant presented with extensive purpura fulminans, microcephaly, and craniofacial abnormalities. Laboratory investigations revealed severe deficiencies in protein C, protein S, and antithrombin III. Treatment involved a multidisciplinary approach including antibiotic therapy, blood transfusions, and anticoagulation. Discussion Neonatal PF poses significant challenges due to its high mortality rate and potential neurological complications. Prompt diagnosis and management are crucial, although outcomes can vary. Long-term care and genetic counseling are essential for families affected by this rare disorder. Conclusion This case underscores the importance of early recognition and intervention in neonatal PF, especially in resource-limited settings. Improved strategies for diagnosis, management, and patient education are necessary to enhance outcomes and support affected families.

Background: Purpura fulminans (PF) is a rare but severe thrombotic disorder affecting small cutaneous blood vessels. It may present as bruising and discoloration but can rapidly progress necrosis and life-threatening complications if not promptly diagnosed and treated. This paper presents a rare case of neonatal PF associated with protein C and S deficiency, highlighting the importance of prompt recognition and diagnosis. Case presentation: A 10-day-old male infant presented with extensive purpura fulminans, microcephaly, and craniofacial abnormalities. Laboratory investigations revealed severe deficiencies in protein C, protein S, and antithrombin III. Treatment involved a multidisciplinary approach including antibiotic therapy, blood transfusions, and anticoagulation. Discussion: Neonatal PF poses significant challenges due to its high mortality rate and potential neurological complications. Prompt diagnosis and management are crucial, although outcomes can vary. Long-term care and genetic counseling are essential for families affected by this rare disorder. Conclusion: This case underscores the importance of early recognition and intervention in neonatal PF, especially in resource-limited settings. Improved strategies for diagnosis, management, and patient education are necessary to enhance outcomes and support affected families. [ABSTRACT FROM AUTHOR]

Severe protein C deficiency (SPCD) is a rare inherited thrombotic disease associated with high morbidity and mortality. In the current study, we established a viable murine model of SPCD, enabling preclinical gene therapy studies. By creating SPCD mice with severe hemophilia A (PROC−/−/F8−), the multi-month survival of SPCD mice enabled the exploration of recombinant adeno-associated viral vector-PC (rAAV8-PC) gene therapy (GT). rAAV8- PC (1012 vg/kg of AAV8-PC) was injected via the tail vein into 6–8-week-old PROC−/−/F8- mice. Their plasma PC antigen levels (median of 714 ng/mL, range 166–2488 ng/mL) and activity (303.5 ± 59%) significantly increased to the normal range after GT compared to untreated control animals. PC's presence in the liver after GT was also confirmed by immunofluorescence staining. Our translational research results provide the first proof of concept that an infusion of rAAV8-PC increases PC antigen and activity in mice and may contribute to future GT in SPCD. Further basic research of SPCD mice with prolonged survival due to the rebalancing of this disorder using severe hemophilia A may provide essential data regarding PC's contribution to specific tissues' development, local PC generation, and its regulation in inflammatory conditions. [ABSTRACT FROM AUTHOR]

Purpose: To describe the ophthalmic presentation and management of a male infant with homozygous protein C deficiency (PCD). Methods: Case report. Observation: An 8-week-old male infant presented with bilateral vitreous hemorrhage and tractional retinal detachment in the right eye. Work up revealed low protein C levels. Whole exome sequencing showed a homozygous likely pathogenic variant in PROC gene. The management included laser photocoagulation to both eyes followed by lens-sparing vitrectomy with membrane peeling to the right eye. Successful outcome was achieved in both eyes. Conclusion and Importance: Congenital PCD is a rare life-threatening disease that usually presents in infancy with purpura fulminans or disseminated intravascular coagulation. However, ophthalmologists should be aware of this condition, as its ocular signs may appear first. Early recognition, laser therapy of the attached ischemic retina and early vitrectomy may be successful in achieving good anatomical and functional outcomes.

Severe congenital protein C deficiency (SCPCD) is a rare disorder associated with life-threatening purpura fulminans and disseminated intravascular coagulation that typically present within hours after birth. Treatment options for patients with SCPCD include replacement therapy with a plasma-derived protein C concentrate. In this targeted literature review, we summarize information on the use of protein C concentrate as long-term prophylaxis (>1 week of treatment) for patients with SCPCD. In total, 18 publications were included in the review, of which 15 were case studies. Treatment with protein C concentrate (Ceprotin; Baxalta US Inc, a Takeda company; Takeda Manufacturing Austria AG) was reported in 11 publications, and treatment with protein C concentrate (Protexel; LFB Biomedicaments) was reported in 2 publications. One publication reported on both Ceprotin and Protexel. Details of protein C concentrate treatment regimens, including the dose, administration frequency, and route of administration, were reported in 11 publications. Dosing regimens varied across all 11 publications, possibly due to different protein C trough levels among patients or the administration of concomitant medications. Seven of the 11 publications reported on patients who initially received intravenous protein C concentrate and subsequently switched to subcutaneous administration. Treatment outcomes with protein C concentrate were generally favorable, including the prevention of coagulopathy and thrombosis and the healing of cutaneous lesions. Three adverse events in 1 publication were identified as being possibly related to Ceprotin administration. Although published data are limited, this review provides valuable insights into the treatment of patients with SCPCD in clinical practice, including protein C concentrate dosing regimens, administration routes, and associated clinical outcomes.

Abstract Background Venous thromboembolism(VTE)is a common multifactorial disease. Anticoagulant protein deficiency is the most usual hereditary thrombophilia in the Chinese people, which includes protein C(PC), protein S and antithrombin deficiencies. Case presentation A retrospective analysis was conducted on clinical manifestations, laboratory tests, genetic information, and other relevant data of siblings diagnosed with VTE in 2020 at the Department of Pediatrics of Shenzhen Second People’s Hospital. The proband, a 12-year-old female, was admitted to the hospital in December 2020 with a complaint of pain in the left lower limb for four days. The examination found that the PC activity was 53%, and B-ultrasound showed bilateral thrombosis of the great saphenous vein in the thigh segment. The proband’s younger brother, a 10-year-old male, was admitted to the hospital in January 2021 due to right lower limb pain for two weeks. PC activity is 40%. B-ultrasound showed superficial venous thrombosis in the left lower limb and upper limb. Both siblings suffered from thalassemia and underwent splenectomy before recurrent thrombosis occurred. The proband’s mother was asymptomatic, and her PC activity was 45%. Both cases were treated with warfarin anticoagulation, and their symptoms improved. The proband’s mother was found to have a heterozygous mutation at this locus through Sanger sequencing. Conclusion Protein C deficiency should be considered for venous thromboembolism in childhood. The heterozygous mutation 1204 A > G in PROC exon 9 in this family is reported for the first time.

Abstract Background We previously conducted a primary survey of pregnant women with hereditary thrombophilia based on national surveillance in Japan, but did not examine their thrombosis-related characteristics. Antithrombin (AT) deficiency, protein C (PC) deficiency and protein S (PS) deficiency are the major types of hereditary thrombophilia in Japan. Methods We examined their detailed information related to thrombosis, and evaluated peripartum outcomes in comparison with control data obtained from the Japan Society of Obstetrics and Gynecology. Results Definite or probable AT deficiency, PC deficiency and PS deficiency were observed in 80, 50, and 317 pregnancies, respectively, from 2014 to 2018 in Japan, with prevalence rates among total deliveries of 0.011%, 0.007%, 0.044%. The number of pregnancies with AT, PC and PS deficiency might have been as many as 27, 17 and 108 every year if complete answers had been provided. In the peripartum period of current pregnancies, 27.5% of women with AT deficiency, 28.0% with PC deficiency and 13.2% with PS deficiency developed thrombosis (p

Background and Objectives: Deficiencies of protein C (PC) or protein S (PS) are rare diseases, characterized by mutations in the PC or PS genes, which encode plasma serine proteases with anti‐coagulant activity. Severe PC or PS deficiencies manifest in early life as neonatal purpura fulminans, a life‐threatening heamorrhagic condition requiring immediate treatment. First‐line treatment involves replacement therapy, followed by maintenance with anti‐coagulants. Replacement therapy with specific protein concentrates is currently only limited to PC, and therefore, a PC + PS concentrate represents a useful addition to therapeutic options, particularly for severe PS deficiency. Further, the production of a PC + PS concentrate from unused plasma fractionation intermediates would impact favourably on manufacturing costs, and consequently therapy prices for patients and health systems. Materials and Methods: Several chromatographic runs were performed on the same unused plasma fractionation intermediates using different supports to obtain a PC/PS concentrate. The best chromatographic mediums were chosen, in terms of specific activity and recovery. A full process of purification including virus inactivation/removal and lyophilization steps was set up. Results: The final freeze‐dried product had a mean PC concentration of 47.75 IU/mL with 11% of PS, and a mean specific activity of 202.5 IU/mg protein, corresponding to over 12,000‐fold purification from plasma. Conclusion: The development of a novel concentrated PC/PS mixture obtained from a waste fraction of other commercial products could be used for its potential therapeutic role in the management of neonatal purpura fulminans pathology. [ABSTRACT FROM AUTHOR]

Acute liver failure is an uncommon presentation in the clinic. Common causes for acute liver failure include viral hepatitis and drug-related hepatotoxicity. However, acute liver failure due to Budd-Chiari syndrome is rare. This case highlights the importance of necessary constrast-enhanced imaging studies to rule out vascular etiologies of acute liver failure, in addition to common causes like viral or drug-induced hepatic failure. We present a case of a male Chinese patient who presented with nausea, vomiting, fatigue, and fever after eating a large amount of fatty food. Six days after hospitalization, the patient developed acute liver failure and hepatic encephalopathy. Contrast-enhanced computerized tomography and ultrasound examinations revealed thromboses in the hepatic veins and inferior vena cava. Further testing also showed decreased protein C activity. Therefore, a diagnosis of Budd-Chiari syndrome secondary to protein C deficiency was made. He received supportive care and a transjugular intrahepatic portal shunt. Hepatic function, coagulation panel results, and clinical presentations gradually returned to normal. Budd-Chiari syndrome from protein C deficiency could be a rare but valid cause of acute liver failure in Chinese patients.

A 43-year-old woman with a recent history of confirmed hepatitis B presented with yellow sclera and dyspnea. Clinically, she had tachycardia and tachypnea as well as signs of jaundice and right upper quadrant pain. She was in sinus rhythm with a normal aspect of cardiac examination. She was treated with corticosteroids and her symptoms were partially relieved, however, her mild fever remained unchanged and a transthoracic echocardiogram (TTE) and transesophageal echocardiography (TEE) were done to rule out embolic or in situ infective endocarditis. Images from the TEE and TTE showed a ping-pong-like clot in the left atrium with a normal cardiac function and a normal mitral valve function. The mitral leaflets appeared to be normal with no regurgitation, and no clot was noted in other chambers or valves, including the atrial appendages. A differential diagnosis of infective vegetations, clots, or tumors was considered. The three subsequent blood cultures were negative. A complete thrombophilia assay revealed a severe reduced protein C factor, however, the IgG anti cardiolipin and lupus anticoagulant were normal. The woman’s anti-nuclear antibody and anti-double-stranded DNA were negative, confirming the diagnosis of acquired protein C deficiency. The patient underwent an open surgical removal of the clot and postoperative treatment with steroids, warfarin, and heparin. The postoperative course was uneventful, and the patient was discharged on the 13th day of operation in good condition. This case was interesting because we did not find any mitral valve pathology such as mitral stenosis, or arrhythmia like atrial fibrillation.

Abstract Background R189W and K193del of protein C (PC) were hotspot mutations in Chinese population with venous thromboembolism (VTE), but almost two-thirds of patients with above mutations coexisting with other genetically or aquiredly prothrombotic risk factors. The aim of this study is to clarify the independent contributions of R189W or K193del to VTE risk. Methods 490 unrelated patients with a personal history of VTE and 410 healthy participants were enrolled in this study. Data of their demographics, family history, genetic and acquired thrombosis risk factors were collected and statistically analyzed. Results PC R189W and K193del were identified in 3/410 (0.7%) and 7/410 (1.7%) healthy controls, and in 27/490 (5.5%) and 43/490 (8.8%) patients with VTE, respectively. Notably, about 70% of these mutant carriers combined with other genetic or acquired thrombophilic factors. After adjustment for age, gender, other inherited and acquired risk factors, we demonstrated that R189W and K193del were associated with 5.781-fold and 4.365-fold increased risk of VTE, respectively, which were significantly lower than the prothrombotic risk of anticoagulant deficiencies induced from rare mutations. Independent R189W or K193del mutation was not associated with earlier first-onset age as well as higher recurrent rate of VTE. However, combination of other genetic or acquired thrombophilic factors had supra-additive effects on those consequences. The more additional risk factors the patients had, the younger first-onset ages and higher risk of recurrence would be. Conclusions As the most frequent mutations for PC deficiency in Chinese population, both R189W and K193del mutations had limited independent contributions to VTE development compared with other rare mutations in PROC gene, but may act in concert with other genetic defects or acquired thrombotic risk factors to produce the final severe phenotype.

Objectives Protein C (PC) is an anticoagulant that is encoded by the PROC gene. Validation for the function of PC was carried out in mouse models. Methods In this study, autosomal recessive PC deficiency (PCD) was selected as the target, and the specific mutation site was chromosome 2 2q13-q14, PROC c.1198G>A (p.Gly400Ser) which targets G399S (GGT to AGC) in mouse models. To investigate the role of hereditary PC in mice models, we used CRISPR/Cas9 gene editing technology to create a mouse model with a genetic PCD mutation. Results The two F0 generation positive mice produced using the CRISPR/Cas9 gene editing technique were chimeras, and the mice in F1 and F2 generations were heterozygous. There was no phenotype of spontaneous bleeding or thrombosis in the heterozygous mice, but some of them were blind. Blood routine results showed no significant difference between the heterozygous mice and wild-type mice (P > 0.05). Prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT) were prolonged in the heterozygous mice, while the level of fibrinogen content (FIB) decreased, suggesting secondary consumptive coagulation disease. The protein C activity of heterozygous mice was significantly lower than that of wild-type mice (P 0.05). H&E staining showed steatosis and hydrodegeneration in the liver of heterozygous mice. Necrosis and exfoliated epithelial cells could be observed in renal tubule lumen, forming cell or granular tubules. Hemosiderin deposition was found in the spleen along with splenic hemorrhage. Immunohistochemistry demonstrated significant fibrin deposition in the liver, spleen, and kidney of heterozygous mice. Conclusion In this study, heterozygotes of the mouse model with a PC mutation were obtained. The function of PC was then validated in a mouse model through genotype, phenotype, and PC function analysis.

Background: The development of new dural arteriovenous fistulas (DAVFs) at another location following endovascular treatment of cavernous sinus DAVFs (CSDAVFs) are extremely rare. Our aim is to review cases of de Novo DAVFs that occurred after treatment of CSDAVFs at our institution and those reported in the literature. Methods: We reviewed all cases of CSDAVFs evaluated by 2 experienced neuroradiologists. A literature search was performed using the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines focusing on De Novo DAVFs following the endovascular treatment of cerebrovascular malformations. Addition articles were searched through the reference lists of the included articles. Results: From June 2004 and September 2019., we identified 3 (2.5%) cases of De Novo DAVFs occurred after endovascular treatment or spontaneous obliteration of CSDAVFs from 119 treated CSDAVFs at our institute. Our review yielded 9 articles involving 12 patients with 15 de novo DAVFs, including our 3 patients. The mean age was 55.08 ± 12.9 years (range 43–69), 83.3% were females (n = 10). The new remote DAVFs occurred after endovascular treatment of CSDAVFs in 10 (83.3%) patients. The de novo DAVFs occurred following spontaneous complete regression in 2 (16.7%) patients. All de novo DAVFs developed after complete obliteration of treated CSDAVFs. Conclusion: Sinus thrombosis and elevated venous pressure may play an important role in the pathogenesis of a de novo DAVF formation. In addition, thrombophilic abnormalities and the use of contraceptives may contribute to sinus thrombosis, leading to the development of the second remote DAVF after treatment of CSDAVFs.

Key Clinical Message: Purpura fulminans is a severe coagulation disorder that often leads to death in neonates. Mutations in the protein C (PROC) gene can cause protein C deficiency, leading to this disorder. This study aimed to investigate a family with a history of coagulopathies, particularly those related to protein C deficiency. The primary objective was to identify any genetic mutations in the PROC gene responsible for the coagulopathies. The study focused on a male neonate with purpura fulminans who ultimately died at 2 months of age. The patient had low protein C activity levels (6%). The entire PROC gene of the patient and his family was analyzed using next‐generation sequencing to identify any genetic mutations. Segregation analysis was conducted to determine if the mutation followed an autosomal dominant inheritance pattern. In silico analysis was also conducted to evaluate the pathogenicity of the identified mutation. Analysis revealed a novel homozygous c.1243T>G variant PROC gene. The mutation resulted in a Phe415Val substitution. The mutation was found in at least three generations of the family. Carrier family members had lower protein C activity levels than wild‐type homozygotes. Additionally, the mutation may account for the observed reduction in protein C enzyme activity. [ABSTRACT FROM AUTHOR]

Bilateral occipital lesions caused by bilateral posterior cerebral artery (PCA) blockage are rare and can present as cortical blindness, which is defined as loss of vision without any ophthalmological cause and retention of normal pupillary light reflexes. Inherited protein C (PC) deficiency may cause thromboembolism, which leads to stroke. We presented a 68-year-old man with bilateral hemianopia, and brain imaging revealed bilateral PCA territory infarcts. PC deficiency was identified, and the symptoms gradually resolved after aspirin and warfarin were administered. The patient's family members underwent laboratory examinations, and his daughter was found to have PC deficiency. [ABSTRACT FROM AUTHOR]

Ascending aorta floating thrombus is a rare entity. Without rapid and specific management this condition has potential catastrophic consequences.

Abstract Background Protein C deficiency is a rare genetic disorder with varying severity of symptoms and disease. The disorder may vary in presentation from a complete symptomless state to a less severe form like venous thromboembolism. The most severe form of disease is a rare condition called neonatal purpura fulminans (NPF) which is characterized with sudden progressive dermal hemorrhage and necrosis due to vascular thrombosis and disseminated intravascular coagulation. In contrast, congenital atrial and ventricular septal defects are the commonest congenital heart diseases found in pediatric population. An infant presenting with systemic vascular thromboembolism secondary to protein C deficiency along with the cardiac septal defects posted for surgery will be a very challenging task to manage in perioperative period. Also, physiological mechanisms during perioperative period and surgery will promote thromboembolism leading to worsening of the situation further. So, perioperative management of such patient pose a great challenge to the anaesthesiologist. Due to rarity of the condition, there is very limited literature available. Case presentation We report the perioperative management of a 2-month-old child suffering with neonatal purpura fulminans with atrial and ventricular septal cardiac defect, scheduled for bilateral foot amputation. The patient was a diagnosed with complete occlusion of abdominal aorta leading to foot gangrene. After initiation of anticoagulant therapy, symptoms were relieved and patient was posted for amputation of gangrenous feet. Conclusions There could be an increased risk of thromboembolism and bleeding due to protein C abnormality along with the chances of shunt reversal, paradoxical embolism, and other cardiac morbidities secondary to septal defects. Wise selection of anaesthetic agents like limiting the use of nitrous oxide, ketamine as much as possible to be considered. Conditions like tachycardia, hypotension, and hypothermia should also be prevented perioperatively as these could increase the chances of thrombosis.

Key Clinical Message Purpura fulminans is a severe coagulation disorder that often leads to death in neonates. Mutations in the protein C (PROC) gene can cause protein C deficiency, leading to this disorder. This study aimed to investigate a family with a history of coagulopathies, particularly those related to protein C deficiency. The primary objective was to identify any genetic mutations in the PROC gene responsible for the coagulopathies. The study focused on a male neonate with purpura fulminans who ultimately died at 2 months of age. The patient had low protein C activity levels (6%). The entire PROC gene of the patient and his family was analyzed using next‐generation sequencing to identify any genetic mutations. Segregation analysis was conducted to determine if the mutation followed an autosomal dominant inheritance pattern. In silico analysis was also conducted to evaluate the pathogenicity of the identified mutation. Analysis revealed a novel homozygous c.1243T>G variant PROC gene. The mutation resulted in a Phe415Val substitution. The mutation was found in at least three generations of the family. Carrier family members had lower protein C activity levels than wild‐type homozygotes. Additionally, the mutation may account for the observed reduction in protein C enzyme activity.

Background and aims: Protein C is a plasma protein, and its active form regulates blood coagulation. The recommended unit of protein C activity is IU/mL; however, some laboratories use percentage. Some deficiencies cannot be detected owing to measurement principles. This study sought to quantify protein C activity levels and overcome the limitations of the current measurements. Materials and methods: Our protein C activity measurement method mimicked the blood coagulation cascade and used a thrombin-specific chromogenic reagent. The control was prepared by adding protein C to the protein C deficient plasma. The calibration curve was plotted as the increase in the absorbance per minute and the concentration of protein C in the control. Statistical tests were performed to compare our method with the current chromogenic method. Results: A calibration curve was constructed (y = −0.0132x + 0.14, R2 = 0.9987, n = 10). The statistical results of our method suggested non-inferiority when compared to the current chromogenic method (α = 0.05). Conclusion: The quantitative measurement was performed using plasma samples. Our method provides the possibility of expressing protein C activity quantitatively and detecting deficiencies that cannot be detected using the current chromogenic method.

Background: R189W and K193del of protein C (PC) were hotspot mutations in Chinese population with venous thromboembolism (VTE), but almost two-thirds of patients with above mutations coexisting with other genetically or aquiredly prothrombotic risk factors. The aim of this study is to clarify the independent contributions of R189W or K193del to VTE risk. Methods: 490 unrelated patients with a personal history of VTE and 410 healthy participants were enrolled in this study. Data of their demographics, family history, genetic and acquired thrombosis risk factors were collected and statistically analyzed. Results: PC R189W and K193del were identified in 3/410 (0.7%) and 7/410 (1.7%) healthy controls, and in 27/490 (5.5%) and 43/490 (8.8%) patients with VTE, respectively. Notably, about 70% of these mutant carriers combined with other genetic or acquired thrombophilic factors. After adjustment for age, gender, other inherited and acquired risk factors, we demonstrated that R189W and K193del were associated with 5.781-fold and 4.365-fold increased risk of VTE, respectively, which were significantly lower than the prothrombotic risk of anticoagulant deficiencies induced from rare mutations. Independent R189W or K193del mutation was not associated with earlier first-onset age as well as higher recurrent rate of VTE. However, combination of other genetic or acquired thrombophilic factors had supra-additive effects on those consequences. The more additional risk factors the patients had, the younger first-onset ages and higher risk of recurrence would be. Conclusions: As the most frequent mutations for PC deficiency in Chinese population, both R189W and K193del mutations had limited independent contributions to VTE development compared with other rare mutations in PROC gene, but may act in concert with other genetic defects or acquired thrombotic risk factors to produce the final severe phenotype. [ABSTRACT FROM AUTHOR]

Key clinical message: In SARS‐CoV‐2 pandemic different disorders in coagulation pathways in COVID‐19 patients were reported. We described a 44‐year‐old female with COVID‐19 and protein C deficiency history. She did not show any coagulation disorder during her disease course. Complete genome sequencing of SARS‐CoV‐2 was performed and some mutations identified and compared with Wuhan strain. Besides hospitalized patients, in COVID‐19 outpatients with low concentration of protein C, early prescription of an anticoagulant such as heparin could be helpful in prevention of venous thromboembolism or pulmonary embolism. [ABSTRACT FROM AUTHOR]

Abstract 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.

Bilateral occipital lesions caused by bilateral posterior cerebral artery (PCA) blockage are rare and can present as cortical blindness, which is defined as loss of vision without any ophthalmological cause and retention of normal pupillary light reflexes. Inherited protein C (PC) deficiency may cause thromboembolism, which leads to stroke. We presented a 68-year-old man with bilateral hemianopia, and brain imaging revealed bilateral PCA territory infarcts. PC deficiency was identified, and the symptoms gradually resolved after aspirin and warfarin were administered. The patient's family members underwent laboratory examinations, and his daughter was found to have PC 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.

Key clinical message In SARS‐CoV‐2 pandemic different disorders in coagulation pathways in COVID‐19 patients were reported. We described a 44‐year‐old female with COVID‐19 and protein C deficiency history. She did not show any coagulation disorder during her disease course. Complete genome sequencing of SARS‐CoV‐2 was performed and some mutations identified and compared with Wuhan strain. Besides hospitalized patients, in COVID‐19 outpatients with low concentration of protein C, early prescription of an anticoagulant such as heparin could be helpful in prevention of venous thromboembolism or pulmonary embolism.

Background: Protein C deficiency is a rare genetic disorder with varying severity of symptoms and disease. The disorder may vary in presentation from a complete symptomless state to a less severe form like venous thromboembolism. The most severe form of disease is a rare condition called neonatal purpura fulminans (NPF) which is characterized with sudden progressive dermal hemorrhage and necrosis due to vascular thrombosis and disseminated intravascular coagulation. In contrast, congenital atrial and ventricular septal defects are the commonest congenital heart diseases found in pediatric population. An infant presenting with systemic vascular thromboembolism secondary to protein C deficiency along with the cardiac septal defects posted for surgery will be a very challenging task to manage in perioperative period. Also, physiological mechanisms during perioperative period and surgery will promote thromboembolism leading to worsening of the situation further. So, perioperative management of such patient pose a great challenge to the anaesthesiologist. Due to rarity of the condition, there is very limited literature available. Case presentation: We report the perioperative management of a 2-month-old child suffering with neonatal purpura fulminans with atrial and ventricular septal cardiac defect, scheduled for bilateral foot amputation. The patient was a diagnosed with complete occlusion of abdominal aorta leading to foot gangrene. After initiation of anticoagulant therapy, symptoms were relieved and patient was posted for amputation of gangrenous feet. Conclusions: There could be an increased risk of thromboembolism and bleeding due to protein C abnormality along with the chances of shunt reversal, paradoxical embolism, and other cardiac morbidities secondary to septal defects. Wise selection of anaesthetic agents like limiting the use of nitrous oxide, ketamine as much as possible to be considered. Conditions like tachycardia, hypotension, and hypothermia should also be prevented perioperatively as these could increase the chances of thrombosis. [ABSTRACT FROM AUTHOR]

Purpose: Congenital protein C deficiency leads to a prothrombotic state that may result in potentially sight- and life-threatening thromboembolic attacks. In this report, we report two cases of infants with compound heterozygous protein C deficiency who underwent lensectomies and vitrectomies for the treatment of traction retinal detachments (TRDs). Observations: One two-month-old and one three-month-old female neonates with leukocoria and purpura fulminans received a diagnosis of protein C deficiency and were referred to ophthalmology. In both cases, the right eye had a total retinal detachment that was considered inoperable, while the left eye had a partial TRD for which surgery was performed. Of the two operated eyes, one resulted in a total retinal detachment, while the other eye has remained stable with no retinal detachment progression three months after surgery. Conclusions: Compound heterozygous congenital protein C deficiency may lead to the rapid development of severe TRDs with poor visual and anatomical prognoses. Early diagnosis and surgery for the treatment of partial TRDs with low disease activity may help prevent progression towards total retinal detachments in these infants.

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. [ABSTRACT FROM AUTHOR]

Background: Thrombophilia due to Protein C deficiency is a rare condition, present in 0.2% of general population. Cerebral venous thrombosis has an incidence of 3-4 cases per million in adults. A combination of both is very uncommon. Patients with these conditions are prone to life-threatening superinfections. Case: A 51-year-old woman presented with pressing frontal headache accompanied with left periorbital edema, fever, diplopia, and disorientation. Laboratory findings showed low protein C levels. Computed tomography demonstrated sphenoidal rhinosinusitis. Magnetic resonance venography revealed cavernous sinus thrombosis. The patient was started on empiric antibiotic treatment (vancomycin, ceftriaxone, and metronidazole) and anticoagulants. Conclusion: This case report emphasizes the importance of early diagnosis and appropriate management of patients with protein C deficiency complicated by septic cavernous sinus thrombosis. Background: Thrombophilia due to Protein C deficiency is a rare condition, present in 0.2% of general population. Cerebral venous thrombosis has an incidence of 3-4 cases per million in adults. A combination of both is very uncommon. Patients with these conditions are prone to life-threatening superinfections. Case: A 51-year-old woman presented with pressing frontal headache accompanied with left periorbital edema, fever, diplopia, and disorientation. Laboratory findings showed low protein C levels. Computed tomography demonstrated sphenoidal rhinosinusitis. Magnetic resonance venography revealed cavernous sinus thrombosis. The patient was started on empiric antibiotic treatment (vancomycin, ceftriaxone, and metronidazole) and anticoagulants. Conclusion: This case report emphasizes the importance of early diagnosis and appropriate management of patients with protein C deficiency complicated by septic cavernous sinus thrombosis.

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. 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. 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. [ABSTRACT FROM AUTHOR]

Direct oral anticoagulants (DOACs) are the first-line anticoagulants for the secondary prevention of venous thromboembolism (VTE). However, patients with severe inherited thrombophilias represent a group in whom the efficiency and safety of DOACs is poorly studied. In this communication, we focus on the utility of DOACs in the secondary prevention of VTE in patients with severe thrombophilia. Current evidence is based only on cohort or single-center studies, and poor data are available on compliance of the patients in the studies. Analysis of the studies suggested that full-dose DOACs and vitamin K antagonists have a similar efficacy and bleeding risk in the secondary prevention of VTE in patients with thrombophilia, with a low hazard ratio for recurrent VTE calculated from cohort studies for DOAC vs warfarin, ranging from 0.3 to 0.75. We wish to highlight that treatment failure is greater in those with severe forms of protein S deficiency (below 20%) and possibly in antithrombin deficiency type II heparin-binding site homozygous Budapest 3. In summary, the current approach to using DOACs in patients with severe thrombophilia is dependent on clinical judgment and experience. Limited evidence suggests that for those with severe thrombophilias, full-dose DOACs have similar utility as vitamin K antagonists. We recommend caution in using low-dose DOACs due to lack of evidence. Ideally, large randomized multicenter studies are required to develop a reliable treatment algorithm., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. All rights reserved.)

Background: Thrombophilia due to protein C deficiency is an unusual condition, present in 0.2% of general population. Cerebral venous thrombosis has an incidence of 3-4 cases per million in adults. A combination of both is very uncommon. Patients with these conditions are prone to acquiring life-threatening superinfections. Case: A 51-year-old woman presented to the Emergency Department with bilateral pressing frontal headache accompanied with nausea and vomiting. Laboratory findings, medical history and physical examination were unremarkable. Computed tomography demonstrated sphenoidal rhinosinusitis. Migraine diagnosis was established and treated with analgesics. No treatment for sphenoidal rhinosinusitis was prescribed. Over the next 2 weeks, headaches worsened, and the patient returned to the Emergency Department showing left periorbital edema, fever, diplopia, and disorientation. Laboratory exams showed low protein C levels, elevated procalcitonin and neutrophilia. Magnetic Resonance Venography revealed cavernous sinus thrombosis. The patient was treated with empiric antibiotic treatment (vancomycin, ceftriaxone, and metronidazole) and long-term direct oral anticoagulants (Dabigatran). After one year of the diagnosis, the patient fully recovered and showed no recurrence of thrombotic events. Conclusion: This case report emphasizes the importance of early diagnosis and appropriate management of patients with protein C deficiency complicated by septic cavernous sinus thrombosis.

There are very few data in the literature describing the occurrence of venous thrombosis in children. This raises the essential problem of late diagnosis, especially in asymptomatic or pauci-symptomatic presentations where this pathology may be unrecognized.The post-traumatic context of venous thrombosis in children, reported in a few cases, should lead to the suspicion of thrombophilia and to a clinical, biological and radiological etiological assessment.We report in our work the observation of a 14-year-old girl admitted in the context of a polytrauma with minimal mechanism in whom the lesion assessment revealed an extensive thrombosis of the inferior vena cava in the supra renal area, with a review of the literature.