Clinical, Laboratory, and Molecular Characteristics of Inherited Vitamin K–Dependent Coagulation Factors Deficiency

Abstract

Vitamin K–dependent coagulation factors deficiency (VKCFD) is a rare autosomal recessive genetic disease characterized by impaired levels of multiple coagulation factors (II, VII, IX, and X) and natural anticoagulants (proteins C and S). VKCFD is part of familial multiple coagulation factor deficiencies, reporting overall 50 affected families thus far. Disease manifestations are quite heterogeneous, bleeding symptoms may vary, and even, although generally mild, some patients may succumb to fatal outcomes. VKCFD diagnosis may be delayed because the disease phenotype simulates the most frequently acquired deficiencies of vitamin K. First-line coagulation assays, prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT), are both prolonged; mixing test typically normalizes the clotting times; and vitamin K–dependent coagulation factors will be variably decreased. Molecularly, VKCFD is associated with mutations in γ-glutamyl-carboxylase (GGCX) or vitamin K epoxide reductase complex subunit 1 (VKORC1) genes. Vitamin K is involved not only in the biosynthesis of coagulation proteins but also in bone metabolism and cell proliferation. Therapeutic options are based on vitamin K supplementation, coagulation factors (prothrombin complex), and fresh frozen plasma, in case of severe bleeding episodes. Two case studies here illustrate the diagnostic challenges of VKCFD: case 1 depicts a woman with a history of bleeding episodes, diagnosed, only in her third decade of life with inherited homozygous GGCX gene mutation. Case 2 shows a man with an acquired vitamin K deficiency caused by Crohn's disease. Better understanding of GGCX and VKORC1 mutations aids in prognosis and treatment planning, with emerging insights suggesting potential limitations in the effectiveness of vitamin K supplementation in certain mutations.

Keywords

VKCFD - γ-Glutamyl carboxylase - VKORC1 - rare bleeding disorders - familial multiple factor deficiencies - vitamin K antagonists

^* These authors contributed equally to this article.

Publikationsverlauf

Artikel online veröffentlicht:
04. November 2024

• References

• 1 Napolitano M, Mariani G, Lapecorella M. Hereditary combined deficiency of the vitamin K-dependent clotting factors. Orphanet J Rare Dis 2010; 5 (21) 21
• 2 Darghouth D, Hallgren KW, Shtofman RL. et al. Compound heterozygosity of novel missense mutations in the gamma-glutamyl-carboxylase gene causes hereditary combined vitamin K-dependent coagulation factor deficiency. Blood 2006; 108 (06) 1925-1931
• 3 Fregin A, Rost S, Wolz W, Krebsova A, Muller CR, Oldenburg J. Homozygosity mapping of a second gene locus for hereditary combined deficiency of vitamin K-dependent clotting factors to the centromeric region of chromosome 16. Blood 2002; 100 (09) 3229-3232
• 4 Zhang B, Ginsburg D. Familial multiple coagulation factor deficiencies: new biologic insight from rare genetic bleeding disorders. J Thromb Haemost 2004; 2 (09) 1564-1572
• 5 Orphanet: Hereditary combined deficiency of vitamin K dependent clotting factors. Accessed October 29, 2023 at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98434
• 6 The GGCX gene homepage - Global Variome shared LOVD. Accessed February 12, 2024 at: https://databases.lovd.nl/shared/genes/GGCX
• 7 Pechlaner C, Vogel W, Erhart R, Pümpel E, Kunz F. A new case of combined deficiency of vitamin K dependent coagulation factors. Thromb Haemost 1992; 68 (05) 617
• 8 Pauli RM, Lian JB, Mosher DF, Suttie JW. Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of the warfarin embryopathy: clues to the mechanism of teratogenicity of coumarin derivatives. Am J Hum Genet 1987; 41 (04) 566-583
• 9 Vicente V, Maia R, Alberca I, Tamagnini GPT, Lopez Borrasca A. Congenital deficiency of vitamin K-dependent coagulation factors and protein C. Thromb Haemost 1984; 51 (03) 343-346
• 10 Bhattacharyya J, Dutta P, Mishra P. et al. Congenital vitamin K-dependent coagulation factor deficiency: a case report. Blood Coagul Fibrinolysis 2005; 16 (07) 525-527
• 11 Oldenburg J, von Brederlow B, Fregin A. et al. Congenital deficiency of vitamin K dependent coagulation factors in two families presents as a genetic defect of the vitamin K-epoxide-reductase-complex. Thromb Haemost 2000; 84 (06) 937-941
• 12 Spronk HM, Farah RA, Buchanan GR, Vermeer C, Soute BA. Novel mutation in the gamma-glutamyl carboxylase gene resulting in congenital combined deficiency of all vitamin K-dependent blood coagulation factors. Blood 2000; 96 (10) 3650-3652
• 13 Brenner B, Sánchez-Vega B, Wu SM, Lanir N, Stafford DW, Solera J. A missense mutation in gamma-glutamyl carboxylase gene causes combined deficiency of all vitamin K-dependent blood coagulation factors. Blood 1998; 92 (12) 4554-4559
• 14 Ghosh K, Shetty S, Mohanty D. Inherited deficiency of multiple vitamin K-dependent coagulation factors and coagulation inhibitors presenting as hemorrhagic diathesis, mental retardation, and growth retardation. Am J Hematol 1996; 52 (01) 67
• 15 Leonar CO. Vitamin K responsive bleeding disorder: a genocopy of the warfarin embryopathy. Proceeding of the Greenwood Genetic Center 1988; 7: 165-166
• 16 Ekelund H, Lindeberg L, Wranne L. Combined deficiency of coagulation factors II, VII, IX, and X: a case of probable congenital origin. Pediatr Hematol Oncol 1986; 3 (02) 187-193
• 17 Goldsmith Jr GH, Pence RE, Ratnoff OD, Adelstein DJ, Furie B. Studies on a family with combined functional deficiencies of vitamin K-dependent coagulation factors. J Clin Invest 1982; 69 (06) 1253-1260
• 18 Puetz J, Knutsen A, Bouhasin J. Congenital deficiency of vitamin K-dependent coagulation factors associated with central nervous system anomalies. Thromb Haemost 2004; 91 (04) 819-821
• 19 Thomas A, Stirling D. Four factor deficiency. Blood Coagul Fibrinolysis 2003; 14 (Suppl. 01) S55-S57
• 20 Mickleson KN, Whyte G. Severe deficiency of vitamin K dependent coagulation factors in an infant. N Z Med J 1979; 90 (645) 291-292
• 21 Johnson CA, Chung KS, McGrath KM, Bean PE, Roberts HR. Characterization of a variant prothrombin in a patient congenitally deficient in factors II, VII, IX and X. Br J Haematol 1980; 44 (03) 461-469
• 22 Fischer M, Zweymuller E. Kongenitaler Mangel der faktoren II, VII und X. Zeitschrift fuer kinderheikunde 1966; 95: 309-323
• 23 Arora R, Hartwig E, Kannikeswaran N. Toddler with unexplained multiple bruises. Pediatr Emerg Care 2014; 30 (09) 646-648
• 24 Al Absi HS, Abdullah MF. Congenital combined deficiency of the vitamin K-dependent clotting factors (VKCFD): a novel gamma-glutamyl carboxylase (GGCX) mutation. J Pediatr Hematol Oncol 2019; 41 (04) e224-e226
• 25 Titapiwatanakun R, Rodriguez V, Middha S, Dukek BA, Pruthi RK. Novel splice site mutations in the gamma glutamyl carboxylase gene in a child with congenital combined deficiency of the vitamin K-dependent coagulation factors (VKCFD). Pediatr Blood Cancer 2009; 53 (01) 92-95
• 26 Chung KS, Bezeaud A, Goldsmith JC, McMillan CW, Ménaché D, Roberts HR. Congenital deficiency of blood clotting factors II, VII, IX, and X. Blood 1979; 53 (04) 776-787
• 27 Darghouth D, Hallgren KW, Issertial O. et al. Compound heterozygosity of a W493C substitution and R704/premature stop codon within the γ-glutamyl carboxylase in combined vitamin K-dependent coagulation factor deficiency in a French family. Blood 2009; 114 (22) 1302-1302
• 28 Lunghi B, Redaelli R, Caimi TM, Corno AR, Bernardi F, Marchetti G. Novel phenotype and γ-glutamyl carboxylase mutations in combined deficiency of vitamin K-dependent coagulation factors. Haemophilia 2011; 17 (05) 822-824
• 29 Jin DY, Ingram BO, Stafford DW, Tie JK. Molecular basis of the first reported clinical case of congenital combined deficiency of coagulation factors. Blood 2017; 130 (07) 948-951
• 30 Guzzardo GM, Ghosh S, Pezeshkpoor B. et al. Novel gamma-glutamyl carboxylase mutation causing hemorrhagic and non-hemorrhagic VKCFD1 phenotypes. Blood 2022; 140 (Suppl. 01) 8480-8482
• 31 Rost S, Fregin A, Koch D, Compes M, Müller CR, Oldenburg J. Compound heterozygous mutations in the γ-glutamyl carboxylase gene cause combined deficiency of all vitamin K-dependent blood coagulation factors. Br J Haematol 2004; 126 (04) 546-549
• 32 McMillan CW, Roberts HR. Congenital combined deficiency of coagulation factors II, VII, IX and X. Report of a case. N Engl J Med 1966; 274 (23) 1313-1315
• 33 Lapecorella M, Napolitano M, Bernardi F. et al. Effective hemostasis during minor surgery in a case of hereditary combined deficiency of vitamin K-dependent clotting factors. Clin Appl Thromb Hemost 2010; 16 (02) 221-223
• 34 Boneh A, Bar-Ziv J. Hereditary deficiency of vitamin K-dependent coagulation factors with skeletal abnormalities. Am J Med Genet 1996; 65 (03) 241-243
• 35 Brenner B, Tavori S, Zivelin A. et al. Hereditary deficiency of all vitamin K-dependent procoagulants and anticoagulants. Br J Haematol 1990; 75 (04) 537-542
• 36 Mathonnet A, Cunat S, Allias F. et al. GGCX-related congenital combined vitamin K-dependent clotting factors deficiency-1: description of a fetus with chondrodysplasia punctata. Am J Med Genet A 2022; 188 (01) 314-318
• 37 Preisler B, Pezeshkpoor B, Banchev A. et al. Familial multiple coagulation factor deficiencies (FMCFDs) in a large cohort of patients - a single-center experience in genetic diagnosis. J Clin Med 2021; 10 (02) 347
• 38 Wen L, Chen J, Duan L, Li S. Vitamin K–dependent proteins involved in bone and cardiovascular health (Review). Mol Med Rep 2018; 18 (01) 3-15
• 39 Kosciuszek ND, Kalta D, Singh M, Savinova OV. Vitamin K antagonists and cardiovascular calcification: a systematic review and meta-analysis. Front Cardiovasc Med 2022; 9: 938567
• 40 Li Y, Chen JP, Duan L, Li S. Effect of vitamin K2 on type 2 diabetes mellitus: a review. Diabetes Res Clin Pract 2018; 136: 39-51
• 41 Liu J, Qin L, Zheng J. et al. Research progress on the relationship between vitamins and diabetes: systematic review. Int J Mol Sci 2023; 24 (22) 16371
• 42 Chen A, Li J, Shen N, Huang H, Hang Q. Vitamin K: new insights related to senescence and cancer metastasis. Biochim Biophys Acta Rev Cancer 2024; 1879 (02) 189057
• 43 Xv F, Chen J, Duan L, Li S. Research progress on the anticancer effects of vitamin K2. (Review) Oncol Lett 2018; 15 (06) 8926-8934
• 44 Perrone S, De Bernardo G, Lembo C. et al. Vitamin K insufficiency and the prophylaxis strategy in term healthy infants: a multicentre study. Eur J Clin Invest 2023;
• 45 Vernia F, Burrelli Scotti G, Bertetti NS. et al. Low vitamin K and vitamin D dietary intake in patients with inflammatory bowel diseases. Nutrients 2023; 15 (07) 1678
• 46 Sultana H, Komai M, Shirakawa H. The role of vitamin K in cholestatic liver disease. Nutrients 2021; 13 (08) 2515
• 47 Wu Q, Wang L, Zhao R. Neglected vitamin K deficiency causing coagulation dysfunction in an older patient with pneumonia: a case report. BMC Geriatr 2022; 22 (01) 628
• 48 Dounousi E, Liakopoulos V. Editorial for the special issue “vitamin K in chronic disease and human health”. Nutrients 2022; 14 (13) 2595
• 49 Yu Z, Chen H. Piperacillin/tazobactam-induced coagulopathy in a patient through a vitamin K-dependent mechanism. Eur J Hosp Pharm 2021; 28 (04) 237-238
• 50 Fotouhie A, Desai H, Parsa NA, King S. Gastrointestinal bleeding secondary to trimethoprim-sulfamethoxazole-induced vitamin K deficiency. BMJ Case Rep 2016; 2016: bcr2016214437
• 51 Tuttolomondo A, Pignatelli P, Pola R. Editorial: Anticoagulation in cardiovascular diseases: evolving role, unmet needs, and grey areas. Front Cardiovasc Med 2023; 10: 1219033
• 52 Watzka M, Geisen C, Scheer M. et al. Bleeding and non-bleeding phenotypes in patients with GGCX gene mutations. Thromb Res 2014; 134 (04) 856-865
• 53 Rydz N, James PD. The evolution and value of bleeding assessment tools. J Thromb Haemost 2012; 10 (11) 2223-2229
• 54 Marchetti G, Caruso P, Lunghi B. et al. Vitamin K-induced modification of coagulation phenotype in VKORC1 homozygous deficiency. J Thromb Haemost 2008; 6 (05) 797-803
• 55 Agnello L, Bellia C, Lo Coco L. et al. Vitamin K deficiency bleeding leading to the diagnosis of Crohn's disease. Ann Clin Lab Sci 2014; 44 (03) 337-340
• 56 Simes DC, Viegas CSB, Araújo N, Marreiros C. Vitamin K as a diet supplement with impact in human health: current evidence in age-related diseases. Nutrients 2020; 12 (01) 138
• 57 Official Journal of the European Union. Commission Directive 2008/100/EC of 28 October 2008 amending Council Directive 90/496/EEC on nutrition labelling for foodstuffs as regards recommended daily allowances, energy conversion factors and definitions. Accessed August 8, 2024 at: https://eur-lex.europa.eu/eli/dir/2008/100/oj/eng
• 58 Pinto E, Viegas C, Martins PV, Nascimento T, Schurgers L, Simes D. New Food Frequency Questionnaire to estimate vitamin K intake in a Mediterranean population. Nutrients 2023; 15 (13) 3012
• 59 Buitenhuis HC, Soute BA, Vermeer C. Comparison of the vitamins K1, K2 and K3 as cofactors for the hepatic vitamin K-dependent carboxylase. Biochim Biophys Acta 1990; 1034 (02) 170-175
• 60 Berkner KL. Vitamin K-dependent carboxylation. Vitam Horm 2008; 78: 131-156
• 61 Hao Z, Jin DY, Chen X, Schurgers LJ, Stafford DW, Tie JK. γ-Glutamyl carboxylase mutations differentially affect the biological function of vitamin K-dependent proteins. Blood 2021; 137 (04) 533-543
• 62 Rishavy MA, Berkner KL. Vitamin K oxygenation, glutamate carboxylation, and processivity: defining the three critical facets of catalysis by the vitamin K-dependent carboxylase. Adv Nutr 2012; 3 (02) 135-148
• 63 Chu PH, Huang TY, Williams J, Stafford DW. Purified vitamin K epoxide reductase alone is sufficient for conversion of vitamin K epoxide to vitamin K and vitamin K to vitamin KH2. Proc Natl Acad Sci U S A 2006; 103 (51) 19308-19313
• 64 Liu S, Shen G, Li W. Structural and cellular basis of vitamin K antagonism. J Thromb Haemost 2022; 20 (09) 1971-1983
• 65 Rost S, Fregin A, Ivaskevicius V. et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004; 427 (6974): 537-541
• 66 Schulman S, Furie B. How I treat poisoning with vitamin K antagonists. Blood 2015; 125 (03) 438-442
• 67 Hand I, Noble L, Abrams SA. Vitamin K and the newborn infant. Pediatrics 2022; 149 (03) e2021056036
• 68 Zhu A, Sun H, Raymond Jr RM. et al. Fatal hemorrhage in mice lacking γ-glutamyl carboxylase. Blood 2007; 109 (12) 5270-5275
• 69 De Vilder EYG, Debacker J, Vanakker OM. GGCX-associated phenotypes: an overview in search of genotype-phenotype correlations. Int J Mol Sci 2017; 18 (02) 240
• 70 Tie JK, Carneiro JDA, Jin DY, Martinhago CD, Vermeer C, Stafford DW. Characterization of vitamin K-dependent carboxylase mutations that cause bleeding and nonbleeding disorders. Blood 2016; 127 (15) 1847-1855
• 71 Vanakker OM, Martin L, Gheduzzi D. et al. Pseudoxanthoma elasticum-like phenotype with cutis laxa and multiple coagulation factor deficiency represents a separate genetic entity. J Invest Dermatol 2007; 127 (03) 581-587
• 72 Czogalla KJ, Biswas A, Rost S, Watzka M, Oldenburg J. The Arg98Trp mutation in human VKORC1 causing VKCFD2 disrupts a di-arginine-based ER retention motif. Blood 2014; 124 (08) 1354-1362
• 73 Brenner B, Kuperman AA, Watzka M, Oldenburg J. Vitamin K-dependent coagulation factors deficiency. Semin Thromb Hemost 2009; 35 (04) 439-446
• 74 Ayyash M, Chitlur M, Oldenburg J, Shaman M. Suspected vitamin K-dependent coagulation factor deficiency in pregnancy: a case report. Case Rep Womens Health 2022; 34: e00416
• 75 Weston BW, Monahan PE. Familial deficiency of vitamin K-dependent clotting factors. Haemophilia 2008; 14 (06) 1209-1213
• 76 Hazim AZ, Ruan GJ, Khodadadi RB, Slusser JP, Marshall AL, Pruthi RK. A single-institution retrospective study of causes of prolonged prothrombin time and activated partial thromboplastin time in the outpatient setting. Int J Lab Hematol 2022; 44 (01) 209-215
• 77 Neutze D, Roque J. Clinical evaluation of bleeding and bruising in primary care. Am Fam Physician 2016; 93 (04) 279-286
• 78 Palla R, Peyvandi F, Shapiro AD. Congenital combined deficiency of the vitamin K-dependent clotting factors (VKCFD): a novel gamma-glutamyl carboxylase (GGCX) mutation. Blood 2015; 125 (13) 2052-2061
• 79 Mumford AD, Ackroyd S, Alikhan R. et al; BCSH Committee. Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors' Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol 2014; 167 (03) 304-326
• 80 Tcherniantchouk O, Laposata M, Marques MB. The isolated prolonged PTT. Am J Hematol 2013; 88 (01) 82-85
• 81 Mathews N, Tasneem S, Hayward CPM. Rare inherited coagulation and fibrinolytic defects that challenge diagnostic laboratories. Int J Lab Hematol 2023; 45 (Suppl. 02) 30-43
• 82 Suttie JW. Vitamin K and human nutrition. J Am Diet Assoc 1992; 92 (05) 585-590
• 83 Shearer M. The assessment of human vitamin K status from tissue measurements. In: Suttie JW. ed. Current Advances in Vitamin K Research. New York, NY: 1985
• 84 Fusaro M, Gallieni M, Rizzo MA. et al. Vitamin K plasma levels determination in human health. Clin Chem Lab Med 2017; 55 (06) 789-799
• 85 Card DJ, Gorska R, Harrington DJ. Laboratory assessment of vitamin K status. J Clin Pathol 2020; 73 (02) 70-75
• 86 Sokoll LJ, Sadowski JA. Comparison of biochemical indexes for assessing vitamin K nutritional status in a healthy adult population. Am J Clin Nutr 1996; 63 (04) 566-573
• 87 Shaw MA, Liu A. Take the shot: a review of vitamin K deficiency. Pediatr Ann 2023; 52 (02) e42-e45
• 88 Loyal J, Shapiro ED. Refusal of intramuscular vitamin K by parents of newborns: a review. Hosp Pediatr 2020; 10 (03) 286-294
• 89 Shao X, Ren Y, Xie N. et al. Effect of cefoperazone/sulbactam on blood coagulation function in infected emergency department patients and the necessity of vitamin K1 (VK1) preventive intervention: a single-center, retrospective analysis. Med Sci Monit 2023; 29: e939203
• 90 Tassew SF, Haile BA, Amera Birlie T. Outcome of rodenticide poisoning and its associated factors among adult patients admitted with rodenticide poisoning at the emergency unit of Debre Tabor Comprehensive Specialized Hospital, Debre Tabor, North Central Ethiopia. Open Access Emerg Med 2023; 15: 189-197
• 91 van Breemen RB, Hafner JW, Nosal DG, Feinstein DL, Rubinstein I. Unmet clinical laboratory need in patients hospitalized for acute poisoning from long-acting anticoagulant rodenticides. Toxicol Commun 2021; 5 (01) 93-96
• 92 Eden RE, Daley SF, Coviello JM. Vitamin K Deficiency. In: StatPearls. StatPearls Publishing; 2024. Accessed February 14, 2024 at: http://www.ncbi.nlm.nih.gov/books/NBK536983/
• 93 Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature 2004; 427 (6974): 541-544
• 94 Wu SM, Stafford DW, Frazier LD. et al. Genomic sequence and transcription start site for the human gamma-glutamyl carboxylase. Blood 1997; 89 (11) 4058-4062
• 95 Wu SM, Morris DP, Stafford DW. Identification and purification to near homogeneity of the vitamin K-dependent carboxylase. Proc Natl Acad Sci U S A 1991; 88 (06) 2236-2240
• 96 Wu SM, Cheung WF, Frazier D, Stafford DW. Cloning and expression of the cDNA for human gamma-glutamyl carboxylase. Science 1991; 254 (5038): 1634-1636
• 97 Hosseini MS, Shams M, Dorgalaleh A, Mansouritorghabeh H. Multiple Coagulation Factor Deficiency. In: Dorgalaleh A. ed. Congenital Bleeding Disorders. Springer International Publishing; 2018: 219-238
• 98 Chen HF, Wu TQ, Jin LJ. et al. Treatment of vitamin K-dependent coagulation factor deficiency and subarachnoid hemorrhage. World J Emerg Med 2011; 2 (01) 73-76
• 99 Zeng L, Choonara I, Zhang L, Li Y, Shi J. Effectiveness of prothrombin complex concentrate (PCC) in neonates and infants with bleeding or risk of bleeding: a systematic review and meta-analysis. Eur J Pediatr 2017; 176 (05) 581-589
• 100 World Health Organization. Global status report on blood safety and availability 2021. Accessed February 14, 2024 at: https://www.who.int/publications-detail-redirect/9789240051683
• 101 Lubetsky A, Hoffman R, Zimlichman R. et al. Efficacy and safety of a prothrombin complex concentrate (Octaplex) for rapid reversal of oral anticoagulation. Thromb Res 2004; 113 (06) 371-378
• 102 Leissinger CA, Blatt PM, Hoots WK, Ewenstein B. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol 2008; 83 (02) 137-143
• 103 Ng HJ, Lee LH. Recombinant activated clotting factor VII (rFVIIa) in the treatment of surgical and spontaneous bleeding episodes in hemophilic patients. Vasc Health Risk Manag 2006; 2 (04) 433-440
• 104 Ghosh S, Kraus K, Biswas A. et al. GGCX mutations show different responses to vitamin K thereby determining the severity of the hemorrhagic phenotype in VKCFD1 patients. J Thromb Haemost 2021; 19 (06) 1412-1424
• 105 Halder M, Petsophonsakul P, Akbulut AC. et al. Vitamin K: double bonds beyond coagulation insights into differences between vitamin K1 and K2 in health and disease. Int J Mol Sci 2019; 20 (04) 896