Congenital Deficiency of Vitamin K-Dependent Clotting Factors

Clinical Manifestation

VKCFD commonly presents in infancy and early childhood. Neonatal intracranial hemorrhage may occur, presenting a clinical scenario that is similar to hemorrhagic disease of the newborn associated with acquired vitamin K deficiency. Mucocutaneous bleeding, neonatal umbilical bleeding, and bruising may also present very early in life. Most cases of VKCFD2 have presented early in life, and almost a third of cases of VKCFD1 presented with bleeding in the first year.8,24 Another third of VKCFD1 patients presented with bleeding after the first year and another third have laboratory evidence of VKCFD but have not manifested a bleeding phenotype before or after vitamin K supplementation. After menarche in female patients, menorrhagia can be problematic. Severe gastrointestinal hemorrhage and hemarthrosis have been described in children and adults. The combination of affected clotting factors results in deficient activity of both TF/FVIIa-mediated and platelet phospholipid/tenase complex-mediated thrombin generation. As a result, almost all types of spontaneous or trauma-induced bleeding may be observed. Although the total number of cases is too low to power statistically significant conclusions, a more severe bleeding phenotype may be associated with GGCX homozygous mutations or compound heterozygous mutations affecting the same protein domain (as compared to compound heterozygous mutations that affect separate domains).24

One case report has suggested that an incidental finding of old cerebral infarct on a head CT scan may indicate a thrombotic tendency (presumably resulting from deficient activity of the anticoagulant proteins).9 This association, however, has not been established and VKCFD is primarily a bleeding diathesis that is best managed with vitamin K supplementation.

Special Considerations in Women

In addition to menorrhagia, women may experience pregnancy complications. Severe postpartum hemorrhage has been reported. In addition, a small number of reports suggest that fetal wastage may occur at an increased rate. This clinical outcome is similar to events documented in mice carrying defects in the GGCX gene.26,30,33 ,34

Additional Manifestations Beyond Coagulation (Dermatologic, Opthalmic, Osseous, and Cardiac)

Soon after the description of VKCFD, it was recognized that some affected individuals displayed phenotypic features outside of the coagulation system, in particular skeletal abnormalities and dysmorphic features, including features that resemble warfarin embryopathy. Only one patient with VKCFD2 (VKOR mutation) has documented undercarboxylation of non-coagulant VKDP and non-bleeding phenotypic features (finger hypoplasia and skeletal stippling).35

In contrast, the accumulation of phenotypic data on a significant number of patients with GGCX mutations along with advances in the understanding of potential physiologic roles of non-coagulant VKDPs reveal emerging patterns of skin, eye, heart, and bone abnormalities co-incident with clotting factor deficiencies in many VKCFD1 patients. The most frequent association is that of GGCX mutations and skin manifestations of elastic fiber mineralization and fragmentation, leading to skin loosening and loss of elasticity (cutis laxa), along with yellow skin papules; ocular manifestations may also occur. The skin and ocular manifestations resemble pseudoxanthoma elasticum (PXE), an autosomal recessive ectopic mineralization disorder that results from biallelic mutations of the ABCC6 gene. The so-called “PXE-like” condition has been associated with 11 different mutations in the GGCX gene. With the exception of one kindred, the coagulation protein deficiencies coincide with the PXE-like phenotype.5,36 Importantly, while the coagulation abnormalities may develop as early as the neonatal period, the skin lesions most commonly develop in the second decade of life. The VKDP MGP and OC are both potent mineralization inhibitors and accumulation of uncarboxylated MGP and OC have been demonstrated in PXE-like disorder with VKCFD.37 In regards to the management of VKCFD1, even if the bleeding diagnosis is made early in life, monitoring into adulthood for the development of PXE-like manifestations is warranted; if possible, serial monitoring should demonstrate the efficacy of vitamin K supplementation to correct the carboxylation defect of both coagulation and non-coagulation VKDP. At least 6 VKCFD1 patients (expressing 6 different GGCX mutations) have also presented with ophthalmologic manifestations of angioid streaks, with or without peau d’orange, always seen with PXE-like skin symptoms.

Up to 1/3 of VKCFD1 patients may have abnormal bone phenotype, which has been associated with 13 different GGCX mutations. Interestingly, specific features (including brachytelephalangy of the fingers) characteristic of Keutel syndrome, an autosomal recessive disorder caused by mutations in MGP, have been described, evidently due to defective GGCX-mediated carboxylation of MGP. The skeletal phenotype involved with GGCX mutations and VKCFD1 may include facial dysmorphisms (midfacial hypoplasia, flat nasal bridge, short nose), reduced bone mass, chondodysplasia punctata and other deformities of the digits. Finally, a variety of cardiac structural or conduction defects have been described in some VKCFD1 patients. In light of the importance of carboxylation to the function of OC (bone formation), MGP (tissue mineralization) and Gas6 (cell proliferation), it is of interest to consider whether distinct GGCX functional domains could be specific to carboxylation of specific VKDP. To date, all individuals with osseous and cardiac defects have inherited at least one mutation within the so-called horizontally transferred transmembrane domain that is encodes the GGCX TMD 1-4.

Information on whether clinical symptoms occur spontaneously, after trauma or surgery, and special issues in women are addressed in the section “Clinical History.”