Which clotting factors are vitamin k dependent

Cervical vertebral anomalies are a relatively common finding in warfarin embryopathy and in the related Binder syndrome In an editorial on variants of vitamin K-dependent coagulation factors, Bertina et al.

At least one variant of factor VII Padua is also known. A homozygous mutation in the GGCX gene Bertina, R. Variants of vitamin K dependent coagulation factors. Editorial Acta Haemat. Brenner, B. A missense mutation in gamma-glutamyl carboxylase gene causes combined deficiency of all vitamin K-dependent blood coagulation factors. Blood , Hereditary deficiency of all vitamin K-dependent procoagulants and anticoagulants. Chung, K. Furie, B.

Molecular basis of vitamin K-dependent gamma-carboxylation. Goldsmith, G. Studies on a family with combined functional deficiencies of vitamin K-dependent coagulation factors. Hall, J. Maternal and fetal sequelae of anticoagulation during pregnancy. Howe, A. Severe cervical dysplasia and nasal cartilage calcification following prenatal warfarin exposure.

Johnson, C. Khau Van Kien, P. Vitamin K deficiency embryopathy. Letter Am. McMillan, C. New Eng. Menger, H. Vitamin K deficiency embryopathy: a phenocopy of the warfarin embryopathy due to a disorder of embryonic vitamin K metabolism. Newcomb, T. Congenital hemorrhagic diathesis of the prothrombin complex.

There is no bleeding diathesis but a venous thrombosis. A brother is similarly affected but asymptomatic. The mother is a carrier and asymptomatic. The clinical significance of this mutation in the pathogenesis of inherited thrombosis is limited, since the abnormality seems rare.

The prolongation is particularly evident when an ox-brain tissue thromboplastin is used in the assay system. Hemophilia B Leiden is characterized by an increase in FIX activity as the age of the patient increases. Protein C is another vitamin K-dependent clotting protein. Its absence or abnormality is associated with the appearance of a hypercoagulable or thrombophilic state.

Protein S acts a cofactor in aPC function. Deficiency or abnormalities of protein C or protein S are associated with a thrombophilic state and thrombosis, mainly venous. No genetic abnormality of either protein C or protein S gene has shown reversal of its biological action, which is anticoagulant.

Protein Z deficiency should also be mentioned here, since a few sporadic observations or articles have suggested but not proven the possibility that this factor plays a role in blood coagulation. It is synthesized in the liver under the coding of a gene located at chromosome 13q34, close to the genes encoding for FVII and FX. It has 8 exons and a structure similar to those encoding for other prothrombin complex PC factors.

The possibility that protein Z might be involved in bleeding diathesis arose from the observations of decreased protein Z levels in patients with a variable bleeding tendency but without other clotting defects that the diathesis could be attributed to.

Other studies have not confirmed the findings and shown a great variability in protein Z levels even in the normal population.

Isolated cases with a severe deficiency have also never been reported. For example, recent studies on the protein Z-dependent protease inhibition might clarify the pattern. In fact, since the activity of this inhibitor seems directed toward FXa, this could supply some support to a bleeding role of this protein, at least an indirect one. However, even in this area, results are not univocal and therefore do not seem conclusive.

Therefore, protein Z is still a clinically functional orphan glycoprotein. Needless to say, future studies might clarify the pattern. The ties of another protein, protein Z with blood coagulation, is less evident or still poorly defined. Prothrombin abnormalities due to Arg substitution have been reported so far to be associated with venous thrombosis.

This is one of the most important homeostatic systems in blood coagulation. There is no other similar system in blood coagulation. The phylogenetic significance of it is unknown. Did the procoagulant factors appear first as a defense from bleeding, and the antithrombotic components appear later as a defense from thrombosis?

On the contrary, in FVII deficiency, both venous and arterial thromboses have been reported although the majority of events involve the venous system. The mutations associated with venous thrombosis in FVII deficiency are mostly AlaVal and ArgGln 11 These are both type 2 disorders with low activity but normal or near-normal antigen.

However, the correlation between mutation and thrombosis in this case is not so strict as that observed for FII and FIX. In fact, venous thrombosis has also been seen, although rarely, in patients with other mutations.

There is no available report that mutations in these 2 antithrombotic proteins might turn them into prohemorrhagic entities. Can this be excluded? Obviously not. The same was true for prothrombin before the first case of ArgGln. Mutation was discovered in It is worth noting that there is no direct relation between Vitamin K-dependent coagulation proteins.

Due to the structural similarities existing between FV and FVIII, it is no surprise that a protein C with the help of protein S may inhibit or downregulate both of them. There are also useful clinical and laboratory implications involved. The occurrence of venous thrombosis at a young age is important. Similarly, important is the observation that venous thrombosis may be present in a family in association with decreased prothrombin activity as seen in dysprothrombinemias.

It remains now to be seen whether other clotting factors, for example, FX and Protein Z, might show similar features. These studies have considerably widened the spectrum and significance of blood coagulation studies. Keywords: bleeding; prothrombin complex; thrombosis; vitamin K. The scientific literature in this area is composed of single case reports and small clinical series described in Africa, Asia, Europe and North America.

Racial distribution, ethnic predilection and carrier incidence are therefore unpredictable. Clinical symptoms of VKCFD vary according to procoagulant protein levels which depend on the availability of vitamin K.

The severity of the bleeding pattern is therefore influenced by both dietary intake of vitamin K and functional status of the gut microflora, as well as by the penetrance of the genetic defect which is widely variable. Accordingly, in the most severe cases, onset of symptoms occurs in newborns while a delayed recognition of the disorder is possible in milder cases.

Despite a modest propensity to thrombosis hypothesized in milder cases due to the deficiency of natural anticoagulants, VKCFD is characterized by a cluster of different, often life threatening, bleeding symptoms occurring both spontaneously and in a surgical setting. Reviewing the scientific literature on this disease, the spectrum of bleeding symptoms appears to range from mild to severe and usually involves skin and mucosae. Easy bruising is common. Muco-cutaneous bleeding, such as gastrointestinal bleeding, may also appear spontaneously or after antibiotic therapy, because of the decreased vitamin K production by gut bacteria.

Bleeding from the umbilical cord is reported [ 6 , 8 ]. Hemarthrosis is rarely described [ 8 ]. VKCFD can sometimes cause fatal intracranial haemorrhage in the first weeks of life, which is similar to the haemorrhagic disease the newborns that results form acquired vitamin K deficiency [ 6 , 7 , 16 ].

The case of a woman with persistent menorrhagia, but whose worst bleeding episodes occurred mainly in a surgical scenario, such as post-partum haemorrhage and haemoperitoneum following ovarian cyst rupture, has been described [ 17 ]. Antibiotic and anticonvulsivant therapy administration must be carefully evaluated as these drugs can worsen the bleeding pattern [ 8 ]. Developmental and skeletal abnormalities resembling those seen in warfarin embryopathy are striking non-haemostatic features, consisting in stippling of the long bones epiphyses and shortness of finger distal phalanges [ 7 , 11 ].

Osteoporosis without the classical serum circulating markers of bone rearrangement [ 11 , 17 ] and pseudoxanthoma elasticum-like disorders [ 18 ] have been reported. As a consequence of the bone impairment during embryogenesis, an increased rate of foetal loss has been suggested by some authors.

The exact incidence is still difficult to calculate because of the rarity of the defect [ 11 , 19 ]. Carboxylation, necessary for their normal activity in the coagulation system, involves Glu residues located in a homologous ' Gla domain' which spans approximately 45 amino acids.

Gla residues enable these proteins to adapt to calcium-dependent conformation allowing their binding to phospholipids [ 20 ]. Carboxylated proteins are then transported to the Golgi for secretion and the propeptide sequence is then removed [ 21 , 22 ].

Vitamin K is an essential cofactor for GGCX and when a carbon dioxide is added to Glu to form Gla , the reduced form of vitamin K vitamin K hydroquinone is oxygenated to form vitamin K 2,3 epoxide. Three forms of vitamin K are known: i vitamin K1 Phylloquinone which is abundant in green and leafy vegetables and is produced by plants and algae; ii vitamin K2 Menaquinones which is a mixture of molecules produced by the microbial intestinal flora and differs from K1 by unsaturated side chains of isoprenoid units with different length; iii vitamin K3 Menadione which is a synthetic form and is more water-soluble.

In both cases the disorder leads to under-carboxylation and comparable reduction in the activities of several proteins including vitamin K-dependent clotting factors. GGCX was isolated in by forward genetics and to date several point mutations have been detected [ 23 , 24 ]. One exception is a 14 bp deletion in intron 1, which is supposed to be involved in the protein expression [ 13 ].

VKOR was identified 34 years ago [ 28 ] but its biochemistry has been difficult to understand because of refractoriness to purification. Both isolation and characterization of VKOR were performed only in by reverse genetics and expression cloning [ 29 ]. The wider knowledge of this protein has amplified the interest of the scientific community in this rare disease. Remarkably, mutations other than the Arg98Trp influence the response to vitamin K intake during oral anticoagulation, encoding for resistance to warfarin treatment [ 32 ].

VKCDF is therefore a natural model that resembles oral anticoagulation with vitamin K antagonists and treatment of this disease can be used to test different modalities to reverse warfarin overdose, whose most feared and dramatic complication is intracranial haemorrhage.

Most non-haemostatic manifestations that complete the clinical picture in individuals affected by VKCFD are explained by defective synthesis of these proteins. The last remarkable pathogenetic aspect of this rare coagulation defect is the role that under-carboxylated factors PIVKA may play as signal messengers. Diagnosis of VKCFD requires anamnestic differentiation from acquired forms of the disorder attributable to intestinal malabsorption of vitamin K in the case of inflammatory bowel diseases or celiac disease, severe liver dysfunction during liver cirrhosis or accidental ingestion of warfarins and superwarfarins.

Such conditions must be excluded with certainty before raising the suspect of the disease. A vitamin K assay with a normal result would be useful for screening them but it is usually only performed in selected research laboratories only. The latter is the result of chromosomal abnormalities chr13q deletions as the genes encoding for the two factors are located very close in the chromosome Among acquired bleeding disorders, a distinction from the presence of circulating antibodies with inhibitory function such as acquired haemophilia or the very rare presence of inhibitors against FVII is mandatory.

VKCFD usually becomes evident because of an excessive bleeding pattern compared to the decreased levels of each of the clotting factors involved, but clinical distinction is not always easy and requires precise laboratory assessment as well as genotype confirmation. Laboratory assessment is characterized by prolonged prothrombin time PT and activated partial thromboplastin time aPTT.

The extent to which the PT and aPTT are prolonged may be influenced by the degree to which each individual coagulation factor is decreased.