Congenital protein C (PC) deficiency is a mostly autosomal dominant hereditary thrombophilia associated with early onset arterial and venous thrombotic diseases. In newborns, PC deficiency results in severe complications such as cerebral hemorrhage, cerebral infarction, and purpura fulminans, leading to death in some cases. We report two cases of deep vein thrombosis diagnosed during pregnancy that prompted genetic testing confirming definitive congenital PC deficiency. One patient with deep vein thrombosis at 30 weeks of gestation underwent anticoagulation therapy with the placement of an inferior vena cava filter. Genetic testing revealed a missense mutation in the PC gene. Another patient developed deep vein thrombosis at 9 weeks of gestation and received anticoagulant therapy, revealing a frameshift mutation in the gene. Genetic testing confirming congenital PC deficiency facilitates tailored postpartum management, including long-term anticoagulation therapy, based on the mother's thrombosis risk. For newborns, early diagnosis allows timely preparation of treatments, such as freshly thawed frozen plasma or PC replacement therapy and ensures closer monitoring through imaging evaluations, enabling early intervention to decrease the severity of potential complications. Given its utility in managing maternal and neonatal outcomes, early genetic testing in suspected cases of maternal PC deficiency is crucial before delivery.

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.

Severe protein C-deficiency is a rare heritable thrombophilia of the newborn. Infants with biallelic PROC mutations present purpura fulminans and intracranial thromboembolism, while the prenatal onset of mutated heterozygotes remains unclear. We herewith present the first case of fetal ventriculomegaly and neonatal stroke associated with heterozygous PROC mutation. The infant was born to a healthy mother at 38 gestational weeks. The fetal growth had been normal, but the routine ultrasound screening had indicated mild hydrocephalus at 28 weeks of gestation. He developed convulsions two days after birth. Computed tomography of the brain revealed multiple hemorrhagic infarctions and ventriculomegaly. Dissociated levels of the plasma activity between protein C (21%) and protein S (42%) reached to determine the heterozygote of PROC c.574_576delAAG, a common thrombophilic predisposition in Asian ancestries. PC-mutant heterozygotes may have a limited high risk of cerebral thromboembolism during the perinatal course.

Peters anomaly is a rare developmental malformation involving the anterior segment of the eye, which culminates in amblyopia or congenital blindness. Multiple ocular and/or systemic malformations have been observed with this anomaly, and novel comorbidities continue to be reported. The probands were monozygotic twin boys (twin I and twin II) born to consanguineous parents at 36 weeks of gestation. Coarse facial features and deep-seated eyes were noted at birth. At 6 months, ophthalmic examination revealed that both twins were unable to blink in response to light, or to fixate and follow a moving object. Both twins had prominent horizontal nystagmus. Slit-lamp examination demonstrated varying degrees of central leukoma (corneal opacity) associated with iridocorneal adhesion, which is characteristic of type I Peters anomaly. No cataractous changes were observed. Normal intraocular pressure and disorganized retina were observed. Pupillary abnormalities included bilaterally underdeveloped pupils and bilateral absence of pupils was noted. Ocular MRI showed bilateral microphthalmia and optic nerve hypoplasia, with a small optic chiasm in both twins. At this age, the diagnosis of Peters anomaly was made. At 16 months of age, both twins developed deep venous thrombosis and purpuric skin lesions. Investigations revealed a hereditary thrombophilia secondary to a homozygous mutation causing protein C deficiency, which is a rare thrombotic condition. Ocular ultrasonography revealed bilateral vitreous hemorrhaging linked to altered coagulation. One twin developed bilateral inguinal hernia and cryptorchidism. The novel concordance of Peters anomaly in these monozygotic twins sharing a mutation in PROC gene provides further evidence that this anomaly has a genetic basis. Hypoplasia of the optic nerves and optic chiasm, along with severe protein C deficiency and bilateral absence of the pupils, are associated comorbidities that have not previously been reported with this anomaly.

Severe congenital protein C (PC) deficiency (SCPCD) is associated with disseminated intravascular coagulation (DIC), purpura fulminans (PF), and vascular thromboembolic events (TE), often leading to organ failure and death. PC replacement therapy offers a safe, effective treatment for thromboembolic complications of SCPCD and secondary prophylaxis for recurrent DIC, PF, and TEs. A prospective, multi-centre, open-label, phase 2/3 study was conducted to demonstrate the safety and efficacy of protein C concentrate for treatment of PF and acute TEs. Fifteen enrolled patients with SCPCD received protein C concentrate; 11 received treatment for acute TEs (PF, 18 events; PF and other coumarin-related vascular thromboembolic events [coumarin-induced skin necrosis; CISN], 1 event; venous thrombosis, 5 events). Pre-defined efficacy criteria for treatment of acute TEs were compared with a historical control arm (i. e. patients receiving conventional therapy without protein C replacement). PF/CISN was demonstrated by pre-defined primary and secondary efficacy ratings. Primary ratings of protein C concentrate-treated episodes were significantly higher (p=0.0032) than in the historical control. For 19 PF/CISN episodes in 11 patients, 94.7 % of treatments were rated effective and 5.3 % effective with complications (not related to protein C concentrate). In a secondary efficacy rating, all treatments were rated effective (68.4 % excellent; 21.1 % good; 10.5 % fair). For 5/24 vascular thrombosis episodes, 80 % of treatments were rated excellent and 20 % were rated good. No treatment-related adverse events or serious adverse events occurred. In conclusion, protein C concentrate provides an efficacious, safe treatment for PF, CISN, and other TEs in SCPCD patients.