Hereditary combined deficiency of vitamin K-dependent clotting factors (VKCFD) is a rare autosomal recessive disorder characterized by reduced activity of factors II, VII, IX, and X despite normal vitamin K levels. We report a 17-year-old Syrian female who presented with impaired wound healing and haemorrhagic discharge following cervical rib surgery. Laboratory evaluation revealed markedly prolonged prothrombin time and activated partial thromboplastin time both corrected on mixing studies, and selective deficiency of vitamin K-dependent factors. Vitamin K levels were normal, excluding acquired causes. The patient experienced recurrent bleeding episodes including haematuria and epistaxis, successfully managed with plasma and recombinant activated factor VII. The absence of skeletal abnormalities, mild bleeding phenotype, and delayed onset suggest a VKCFD type 2 presentation. This case highlights the importance of early recognition, differentiation from acquired coagulopathies, and targeted replacement therapy to prevent life threatening haemorrhage. Consider vitamin K-dependent clotting factors deficiency in unexplained prolonged prothrombin time/activated partial thromboplastin time with normal vitamin K and combined factor deficiencies.Early recognition prevents catastrophic bleeding; vitamin K and factor replacement are lifesaving.Internists play a pivotal role in differentiating inherited from acquired coagulopathies.

Hereditary combined vitamin K-dependent coagulation factor deficiency (VKCFD) is an extremely rare autosomal recessive genetic disorder characterized by deficiencies in vitamin K-dependent coagulation factors and natural anticoagulants. The condition presents with a spectrum of bleeding symptoms ranging from mild to severe, often beginning in the neonatal period. These bleeding episodes can be particularly severe and even life-threatening, occurring spontaneously or during surgery. In addition to bleeding problems, individuals with VKCFD may experience a variety of non-hemostatic problems, including skeletal deformities, cardiovascular abnormalities, and skin conditions.VKCFD is caused by variants in the genes encoding either γ-glutamyl carboxylase or the vitamin K 2,3-epoxide reductase complex. Both proteins play a critical role in γ-carboxylation, a posttranslational modification that is essential for the proper function of vitamin K-dependent proteins. Timely and accurate diagnosis is essential to differentiate VKCFD from other genetic and acquired disorders, and genetic testing is required to identify the specific variant.The primary treatment for VKCFD is the administration of vitamin K, with transfusions of fresh frozen plasma often required during surgery or in cases of severe bleeding. In certain situations, alternative therapies such as prothrombin complex concentrates (PCCs) or a combination of recombinant activated factor VII and vitamin K may be considered. With appropriate treatment, individuals with VKCFD generally have a good clinical outcome, and the condition has a limited impact on their quality of life. This article presents a comprehensive review of all 57 VKCFD cases documented in the literature, as well as 4 new, unpublished cases from France. Vitamin K comprises a group of fat-soluble compounds. Several vitamin K-dependent proteins are involved in essential processes such as blood clotting, bone metabolism, and cardiovascular health. Vitamin K deficiency can contribute to significant bleeding, poor bone development, osteoporosis, and increased cardiovascular disease. According to the National Academy of Science Food and Nutrition Board, the recommended dietary intake for healthy adults is 120 μg/d for men and 90 μg/d for women. Vitamin K deficiency bleeding (VKDB) in newborns is categorized into 3 groups based on the timing of presentation. Early VKDB manifests within 24 hours after birth, classic VKDB presents within the first week, and late VKDB occurs between 1 week and 6 months of life, with a peak incidence between 2 weeks and 8 weeks. Hereditary combined deficiency of vitamin K–dependent clotting factors (VKCFD) is a rare congenital bleeding disorder that can also manifest during the neonatal period.

Vitamin K dependent coagulation factor deficiency type 1 (VKCFD1) is a rare hereditary bleeding disorder caused by mutations in γ-Glutamyl carboxylase (GGCX) gene. The GGCX enzyme catalyzes the γ-carboxylation of 15 different vitamin K dependent (VKD) proteins, which have function in blood coagulation, calcification, and cell signaling. Therefore, in addition to bleedings, some VKCFD1 patients develop diverse non-hemorrhagic phenotypes such as skin hyper-laxity, skeletal dysmorphologies, and/or cardiac defects. Recent studies showed that GGCX mutations differentially effect γ-carboxylation of VKD proteins, where clotting factors are sufficiently γ-carboxylated, but not certain non-hemostatic VKD proteins. This could be one reason for the development of diverse phenotypes. The major manifestation of non-hemorrhagic phenotypes in VKCFD1 patients are mineralization defects. Therefore, the mechanism of regulation of calcification by specific VKD proteins as matrix Gla protein (MGP) and Gla-rich protein (GRP) in physiological and pathological conditions is of high interest. This will also help to understand the patho-mechanism of VKCFD1 phenotypes and to deduce new treatment strategies. In the present review article, we have summarized the recent findings on the function of GRP and MGP and how these proteins influence the development of non-hemorrhagic phenotypes in VKCFD1 patients.

Hereditary combined vitamin K-dependent clotting factor deficiency (VKCFD) is a rare autosomal recessive congenital bleeding disorder. There are no established guidelines for the care for pregnant women and newborns within the context of VKCFD. A 39-year-old multigravida woman with a family history of VKCFD was referred for high-risk maternal fetal medicine care. Prenatal testing for fetal VKCFD was declined. The patient received vitamin K1 from 36 weeks of gestation and had an uncomplicated vaginal delivery. The baby had normal head ultrasound results, vital signs, and physical examination, with no signs of bleeding: factor levels and coagulation factors were within reference range. Follow-up showed no evidence of VKCFD. A thorough care plan is required for pregnant women whose newborns are at risk for VKCFD.

γ-Glutamyl carboxylase (GGCX) catalyzes the γ-carboxylation of 15 different vitamin K dependent (VKD) proteins. Pathogenic variants in GGCX cause a rare hereditary bleeding disorder called Vitamin K dependent coagulation factor deficiency type 1 (VKCFD1). In addition to bleedings, some VKCFD1 patients develop skin laxity and skeletal dysmorphologies. However, the pathophysiological mechanisms underlying these non-hemorrhagic phenotypes remain elusive. Therefore, we have analyzed 20 pathogenic GGCX variants on their ability to γ-carboxylate six non-hemostatic VKD proteins in an in vitro assay, where GGCX variants were expressed in GGCX-/- cells and levels of γ-carboxylated co-expressed VKD proteins were detected by a functional ELISA. We observed that GGCX variants causing markedly reduced γ-carboxylation of Gla rich protein (GRP) in vitro were reported in patients with skin laxity. Reduced levels of γ-carboxylated Matrix gla protein (MGP) are not exclusive for causing skeletal dysmorphologies in VKCFD1 patients. In silico docking of vitamin K hydroquinone on a GGCX model revealed a binding site, which was validated by in vitro assays. GGCX variants affecting this site result in disability to γ-carboxylate VKD proteins and hence are involved in the most severe phenotypes. This genotype-phenotype analysis will help to understand the development of non-hemorrhagic phenotypes and hence improve treatment in VKCFD1 patients.