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Vitamin K-dependent clotting factors, combined deficiency of, type 1(MCFD3; VKCFD1)

MedGen UID:
376381
Concept ID:
C1848534
Disease or Syndrome
Synonyms: FACTORS II, VII, IX, AND X, COMBINED DEFICIENCY OF; FAMILIAL MULTIPLE COAGULATION FACTOR DEFICIENCY III; FMFD III; GLUTAMIC ACID, DEFICIENT GAMMA-CARBOXYLATION OF; MULTIPLE COAGULATION FACTOR DEFICIENCY III; VITAMIN K-DEPENDENT COAGULATION DEFECT
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): GGCX (2p11.2)
 
Monarch Initiative: MONDO:0010187
OMIM®: 277450
Orphanet: ORPHA98434

Definition

Deficiency of all vitamin K-dependent clotting factors leads to a bleeding tendency that is usually reversed by oral administration of vitamin K. Acquired forms of the disorder can be caused by intestinal malabsorption of vitamin K. Familial multiple coagulation factor deficiency is rare. Clinical symptoms of the disease include episodes of intracranial hemorrhage in the first weeks of life, sometimes leading to a fatal outcome. The pathomechanism is based on a reduced hepatic gamma-carboxylation of glutamic acid residues of all vitamin K-dependent blood coagulation factors, as well as the anticoagulant factors protein C (612283) and protein S (176880). Posttranslational gamma-carboxylation of proteins enables the calcium-dependent attachment of the proteins to the phospholipid bilayer of membranes, an essential prerequisite for blood coagulation. Vitamin K1 acts as a cofactor for the vitamin K-dependent carboxylase in liver microsomes, GGCX. Genetic Heterogeneity of Combined Deficiency of Vitamin K-Dependent Clotting Factors Combined deficiency of vitamin K-dependent clotting factors-2 (VKFCD2; 607473) is caused by mutation in the gene encoding vitamin K epoxide reductase (VKORC1; 608547) on chromosome 16p11. [from OMIM]

Clinical features

From HPO
Short distal phalanx of finger
MedGen UID:
326590
Concept ID:
C1839829
Finding
Short distance from the end of the finger to the most distal interphalangeal crease or the distal interphalangeal joint flexion point. That is, hypoplasia of one or more of the distal phalanx of finger.
Joint hemorrhage
MedGen UID:
5479
Concept ID:
C0018924
Pathologic Function
Hemorrhage occurring within a joint.
Cerebral hemorrhage
MedGen UID:
423648
Concept ID:
C2937358
Pathologic Function
Hemorrhage into the parenchyma of the brain.
Epistaxis
MedGen UID:
4996
Concept ID:
C0014591
Pathologic Function
Epistaxis, or nosebleed, refers to a hemorrhage localized in the nose.
Prolonged partial thromboplastin time
MedGen UID:
66815
Concept ID:
C0240671
Finding
Increased time to coagulation in the partial thromboplastin time (PTT) test, a measure of the intrinsic and common coagulation pathways. Phospholipid, and activator, and calcium are mixed into an anticoagulated plasma sample, and the time is measured until a thrombus forms.
Reduced protein C activity
MedGen UID:
96016
Concept ID:
C0398625
Disease or Syndrome
An abnormality of coagulation related to a decreased concentration of vitamin K-dependent protein C. Protein C is activated to protein Ca by thrombin bound to thrombomodulin. Activated protein C degrades factors VIIIa and Va.
Prolonged prothrombin time
MedGen UID:
208879
Concept ID:
C0853225
Finding
Increased time to coagulation in the prothrombin time test, which is a measure of the extrinsic pathway of coagulation. The results of the prothrombin time test are often expressed in terms of the International normalized ratio (INR), which is calculated as a ratio of the patient's prothrombin time (PT) to a control PT standardized for the potency of the thromboplastin reagent developed by the World Health Organization (WHO) using the formula
Abnormal bleeding
MedGen UID:
264316
Concept ID:
C1458140
Pathologic Function
An abnormal susceptibility to bleeding, often referred to as a bleeding diathesis. A bleeding diathesis may be related to vascular, platelet and coagulation defects.
Reduced factor IX activity
MedGen UID:
868754
Concept ID:
C4023159
Finding
Decreased activity of coagulation factor IX. Factor IX, which itself is activated by factor Xa or factor VIIa to form factor IXa, activates factor X into factor Xa.
Reduced factor X activity
MedGen UID:
892449
Concept ID:
C4024702
Finding
Reduced activity of coagulation factor X. The extrinsic and intrinsic pathways converge at factor X (fX). The extrinsic pathway activates fX by means of d factor VII with its cofactor, tissue factor. The intrinsic pathway activates fX by means of the tenase complex (Ca2+ and factors VIIIa, IXa and X) on the surface of activated platelets. Factor Xa in turn activates prothrombin (factor II) to thrombin (factor IIa).
Reduced factor VII activity
MedGen UID:
892851
Concept ID:
C4024722
Finding
Reduced activity of coagulation factor VII. Factor VII is part of the extrinsic coagulation pathway, which is initiated at the site of injury in response to the release of tissue factor (fIII). Tissue factor and activated factor VII catalyze the activation of factor X.
Reduced protein S activity
MedGen UID:
892328
Concept ID:
C4025284
Finding
An abnormality of coagulation related to a decreased concentration of vitamin K-dependent protein S. Protein S is a cofactor of protein C.
Epiphyseal stippling
MedGen UID:
349104
Concept ID:
C1859126
Finding
The presence of abnormal punctate (speckled, dot-like) calcifications in one or more epiphyses.
Elevated circulating hepatic transaminase concentration
MedGen UID:
116013
Concept ID:
C0235996
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Short nose
MedGen UID:
343052
Concept ID:
C1854114
Finding
Distance from nasion to subnasale more than two standard deviations below the mean, or alternatively, an apparently decreased length from the nasal root to the nasal tip.
Ecchymosis
MedGen UID:
8524
Concept ID:
C0013491
Finding
A purpuric lesion that is larger than 1 cm in diameter.
Bruising susceptibility
MedGen UID:
140849
Concept ID:
C0423798
Finding
An ecchymosis (bruise) refers to the skin discoloration caused by the escape of blood into the tissues from ruptured blood vessels. This term refers to an abnormally increased susceptibility to bruising. The corresponding phenotypic abnormality is generally elicited on medical history as a report of frequent ecchymoses or bruising without adequate trauma.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVVitamin K-dependent clotting factors, combined deficiency of, type 1

Recent clinical studies

Etiology

Koenen RR, Gomes L, Tans G, Rosing J, Hackeng TM
Thromb Haemost 2004 Jun;91(6):1105-14. doi: 10.1160/TH04-02-0082. PMID: 15175796

Diagnosis

Ghosh S, Oldenburg J, Czogalla-Nitsche KJ
Int J Mol Sci 2022 Jan 12;23(2) doi: 10.3390/ijms23020798. PMID: 35054981Free PMC Article
Rishavy MA, Hallgren KW, Zhang H, Runge KW, Berkner KL
J Thromb Haemost 2019 Jul;17(7):1053-1063. Epub 2019 Jun 7 doi: 10.1111/jth.14456. PMID: 31009158Free PMC Article
Al Absi HS, Abdullah MF
J Pediatr Hematol Oncol 2019 May;41(4):e224-e226. doi: 10.1097/MPH.0000000000001385. PMID: 30531603
Naz A, Jamal MY, Amanat S, Din Ujjan I, Najmuddin A, Patel H, Raziq F, Ahmed N, Imran A, Shamsi TS
Orphanet J Rare Dis 2017 Apr 7;12(1):66. doi: 10.1186/s13023-017-0620-6. PMID: 28388959Free PMC Article
Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hörtnagel K, Pelz HJ, Lappegard K, Seifried E, Scharrer I, Tuddenham EG, Müller CR, Strom TM, Oldenburg J
Nature 2004 Feb 5;427(6974):537-41. doi: 10.1038/nature02214. PMID: 14765194

Therapy

Todd T, Perry DJ
Haemophilia 2010 Jul 1;16(4):569-83. Epub 2009 Nov 11 doi: 10.1111/j.1365-2516.2009.02118.x. PMID: 19906159
Rost S, Geisen C, Fregin A, Seifried E, Müller CR, Oldenburg J
Blood Coagul Fibrinolysis 2006 Sep;17(6):503-7. doi: 10.1097/01.mbc.0000240927.88177.d1. PMID: 16905958

Prognosis

Al Absi HS, Abdullah MF
J Pediatr Hematol Oncol 2019 May;41(4):e224-e226. doi: 10.1097/MPH.0000000000001385. PMID: 30531603

Clinical prediction guides

Barg AA, Brutman-Barazani T, Avishai E, Budnik I, Cohen O, Dardik R, Levy-Mendelovich S, Livnat T, Kenet G
Blood Cells Mol Dis 2022 Jul;95:102663. Epub 2022 Apr 12 doi: 10.1016/j.bcmd.2022.102663. PMID: 35525014
Ghosh S, Kraus K, Biswas A, Müller J, Forin F, Singer H, Höning K, Hornung V, Watzka M, Oldenburg J, Czogalla-Nitsche KJ
Hum Mutat 2022 Jan;43(1):42-55. Epub 2021 Dec 2 doi: 10.1002/humu.24300. PMID: 34816548
Rishavy MA, Hallgren KW, Zhang H, Runge KW, Berkner KL
J Thromb Haemost 2019 Jul;17(7):1053-1063. Epub 2019 Jun 7 doi: 10.1111/jth.14456. PMID: 31009158Free PMC Article
Czogalla KJ, Biswas A, Rost S, Watzka M, Oldenburg J
Blood 2014 Aug 21;124(8):1354-62. Epub 2014 Jun 24 doi: 10.1182/blood-2013-12-545988. PMID: 24963046
Furutani H
Medinfo 1995;8 Pt 2:909. PMID: 8591581

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