vitamin-k-semiquinone-radical and Factor-X-Deficiency

Congenital bleeding disorders of the vitamin K-dependent coagulation factors represent only about 15-20% of all congenital bleeding disorders. However, they played an important role of the history of blood coagulation. Prothrombin was the first entity dealt with. Subsequently, in the late 1940s or early 1950s, the discovery of factor IX allowed the separation of hemophilia into two groups, A and B. In the 1950s, the discovery of factors VII and X allowed the formulation of a logic and plausible explanation for the clotting mechanism. The subsequent discovery of vitamin K-dependent proteins with an inhibitory effect on blood coagulation has further enhanced the importance of the vitamin K-dependent clotting factors. Recently, the study of families with multiple defects of the prothrombin complex has spurred the interest in vitamin K metabolism and the gamma-carboxylation system. The relevance of these studies had also an important role in the understanding the mechanism of action of other noncoagulation-related proteins. The vitamin K-dependent clotting factors represent a homeostatic mechanism at the basis of the hypercoagulability (thrombosis)-hypocoagulability (hemorrhagic) system, namely, to a mechanism that is vital for survival. The different bleeding condition will be dealt with separately, namely, prothrombin or Factor II, Factor VII, Factor IX (hemophilia B), and Factor X deficiencies. An additional heading deals with the combined defect of the prothrombin complex, namely, combined deficiency of Factor II, Factor VII, Factor IX, and Factor X. Since, sometimes, a hemorrhagic role has been attributed to Protein Z deficiency, another vitamin K-dependent protein, this defect will also be dealt with, even though briefly. Each deficiency has been approached in a global manner, namely, with adequate reference to history, background, prevalence, classification, hereditary pattern, biochemistry and function, molecular biology, clinical picture, updated laboratory diagnosis, prognosis, and therapy. Particular emphasis has been placed on the significance of cases with "true" deficiency [cross-reacting material (CRM negative)] and cases with abnormalities (CRM positive). The genetic, clinical, and laboratory implications of these two forms have been extensively discussed in every instance. The importance of a multiple, combined diagnostic approach that has to include whenever possible clotting, chromogenic, immunological, and molecular biology studies has bee

Topics: Blood Coagulation Disorders; Blood Proteins; Factor VII Deficiency; Factor X Deficiency; Hemophilia B; Humans; Hypoprothrombinemias; Prognosis; Vitamin K

Topics: Amino Acid Sequence; Animals; Antithrombin III; Blood Coagulation; Blood Coagulation Factors; Cattle; Factor V; Factor Va; Factor X; Factor X Deficiency; Factor Xa; Feedback; Heparin; Humans; Liposomes; Molecular Weight; Oligosaccharides; Phospholipids; Protein Conformation; Protein Processing, Post-Translational; Prothrombin; Substrate Specificity; Thrombin; Vitamin K

Topics: Disseminated Intravascular Coagulation; Factor IX; Factor VII; Factor VIII; Factor X; Factor X Deficiency; Half-Life; Hemophilia B; Hemostasis; Hepatitis B; Hepatitis, Viral, Human; Humans; Infant, Newborn; Prothrombin; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Airway Obstruction; Antifibrinolytic Agents; Blood Coagulation Factors; Ecchymosis; Factor X Deficiency; Factor XI Deficiency; Female; Hematoma; Humans; Laryngoscopy; Middle Aged; Treatment Outcome; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Animals; Anticoagulants; C-Reactive Protein; Cell Line; Endocytosis; Factor X; Factor X Deficiency; Gene Expression; HEK293 Cells; Humans; Kinetics; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Organ Specificity; Protein Binding; RNA, Small Interfering; Scavenger Receptors, Class A; Vitamin K

Four factor deficiency is variably associated with mild to fatal bleeding. We describe a 3-month-old boy, born of consanguineous parents, who presented with a right subdural haematoma and a clotting screen showing a prothrombin time (PT) > 100 s, an activated partial thromboplastin time (aPTT) > 150 s, a fibrinogen of 0.4 g/l, and fibrinogen degradation products < 1 microg/ml. He was given 300 U of factor IX concentrate (containing factors II and X) and 1 mg of vitamin K intravenously. Forty-five minutes later, clotting tests showed a PT of 24 s, an aPTT of 31 s and a fibrinogen of 2.6 g/l. The patient was found to be deficient in all the vitamin K-dependent factors: factors II, VII, IX and X, protein C and protein S. A 14-base deletion was found in intron 1 (bases 1056-1069) of the gamma-carboxylase gene. The patient and his elder sister were homozygous for this deletion, whereas both parents were heterozygous. The deletion destroys a reverse palindromic sequence (TTGAGGCAA) of the type often associated with cis-acting elements. Our results suggest that this element may be involved in the regulation of gamma-carboxylase expression. Expression studies are being completed so that this region can be definitively ascribed as a cis-acting element involved in gene regulation.

Topics: Blood Coagulation Factors; Blood Coagulation Tests; Carbon-Carbon Ligases; Consanguinity; Factor VII Deficiency; Factor X Deficiency; Female; Hematoma, Subdural; Hemophilia B; Humans; Hypoprothrombinemias; Infant; Introns; Male; Protein C Deficiency; Protein Processing, Post-Translational; Protein S Deficiency; Sequence Deletion; Thrombophilia; Vitamin K

A flock of Rambouillet sheep experienced unexpected lamb mortality associated with excessive bleeding at the time of parturition. Most lambs died of blood loss through the umbilicus or into subcutaneous tissues. Subsequently, nine ewes which had previously delivered lambs that bled to death were bred to the suspected sire of the previous bleeding lambs. Fifteen lambs were born alive the following Spring, and three males and one female bled clinically. These lambs had markedly decreased factor IX (< 16%) and factor X (< 4%) activities, with variably decreased factor II (11-36%) and factor VII (20-37%) activities. Protein C chromogenic activity was also markedly decreased (< 1%) in these lambs. The results from crossed immunoelectrophoresis and 'protein-induced-in-vitamin-K-absence' determination of the plasma of affected lambs, with antiserum directed against coagulation factor X, protein C or proteins S, suggested that these proteins were not carboxylated normally. Examination of liver from one lamb in the first batch and the four subsequent lambs did not reveal a known vitamin K antagonist. The breeding data suggested that the coagulopathy in these sheep was inherited as an autosomal recessive trait. The genetic or molecular defect that exists in these lambs is unknown, but possibilities include abnormal gamma-glutamyl carboxylase activity or abnormal metabolism of vitamin K.

Topics: Animals; Blood Coagulation Factors; Coagulation Protein Disorders; Counterimmunoelectrophoresis; Factor VII; Factor X Deficiency; Female; Genes, Recessive; Hemophilia B; Liver; Male; Partial Thromboplastin Time; Protein C; Protein S; Prothrombin; Sheep; Sheep Diseases; Thrombin Time; Vitamin K

Severe congenital deficiency of factor X was diagnosed in a 3-year-old castrated male domestic shorthair cat with clinical signs of generalized seizures and prolonged bleeding after venipuncture. Heritability of factor X deficiency was suspected because of a prolonged Russell's viper venom time in the dam and reductions in factor X activity in the dam and 1 sibling. To our knowledge, factor X deficiency in cats has not been reported previously. Definitive diagnosis for animals with clinical signs of coagulopathy may require repetition of coagulation screening tests using different assay methods or specific coagulation factor analyses.

Topics: Animals; Blood Coagulation; Cat Diseases; Cats; Factor X; Factor X Deficiency; Male; Partial Thromboplastin Time; Prothrombin Time; Vitamin K

Topics: Adolescent; Anticonvulsants; Blood Coagulation; Drug Combinations; Factor X Deficiency; Female; Gingivectomy; Hemorrhage; Humans; Phenytoin; Prothrombin Time; Valproic Acid; Vitamin K

A patient is described with serious bleeding due to a transient selective deficiency of factor X. Crossed immunoelectrophoresis of patient's plasma with anti-factor X antibody revealed an abnormal factor X arc suggestive of the presence of plasma factor X/anti-factor X immune complexes. A similar abnormal arc was obtained on adding the patient's IgG to normal plasma. Immunoblotting of factor X after reduced SDS-PAGE revealed that the patient's IgG bound to the light chain of intact factor X but not Gla-domainless factor X. The patient's IgG inhibited activation of factor X by VIIa/tissue factor (TF), by IXa/VIIIa/phospholipid complex, and by Russell's viper venom. The IgG failed to inhibit the proteolytic activity of factor Xa towards a chromogenic substrate. However, under reaction conditions of limited factor Xa availability, the IgG could be shown to impair hemostatic functions of factor Xa that require the participation of its light chain: activation of prothrombin by prothrombinase; activation of factor VII bound to TF; and inhibition of VIIa/TF activity by factor Xa/tissue factor pathway inhibitor complexes. A few earlier patients have been described with transient, selective factor X deficiency and serious bleeding, but in only one was evidence obtained of an antibody against factor X. It will be of interest to learn whether use of the techniques described in this report will permit the identification of immunoglobulin with similar binding and functional properties in future patients with this rare syndrome.

Topics: Aged; Autoantibodies; Autoimmune Diseases; Blood Coagulation Tests; Enzyme Activation; Factor X Deficiency; Factor Xa Inhibitors; Hemorrhage; Humans; Immunoelectrophoresis, Two-Dimensional; Immunoglobulin G; Lipoproteins; Male; Plasma; Protein Structure, Tertiary; Recombinant Proteins; Vitamin K

Topics: Aged; Cefotetan; Factor V Deficiency; Factor X Deficiency; Female; Humans; Hypoprothrombinemias; Premedication; Vitamin K

Topics: Age Factors; Child; Cortisone; Drug Eruptions; Factor X Deficiency; Female; Humans; Infusions, Parenteral; Vitamin K

Hereditary combined deficiency of vitamin K-dependent factors is a rare entity. We report a 7-year-old girl of Arab origin with hereditary deficiency of the procoagulants factors II, VII, IX and X and the natural anticoagulants proteins C and S. The patient is the tenth offspring of a consanguinous marriage and presented at 6 weeks with spontaneous intracerebral haemorrhage. Symptoms improved following plasma infusion. A sibling died at 5 d from uncontrollable umbilical bleeding. Blood coagulation work-up at 6 years showed: factor II:C (activity) 12 U/dl, factor II:Ag (antigen) 40 U/dl; factor VII:C 12 U/dl; factor IX:C 36 U/dl, factor IX:Ag 57 U/dl; factor X:C 17 U/dl, factor X:Ag 54 U/dl; protein C activity 43 U/dl; protein C:Ag 45 U/dl; protein S:Ag 34 U/dl; levels of factors V:C and VIII:C were normal. Assays of coagulation factors in the parents and five of the siblings were within the normal range. Following acute infection and dilantin therapy procoagulant activity levels were reduced further and were partially increased after vitamin K infusion. Crossed immunoelectrophoresis of prothrombin in the presence of calcium lactate revealed a population of des-carboxyprothrombin. Serum vitamin K epoxide levels were undetectable. The data suggest that the defect in our patient stems from abnormal carboxylation of the vitamin K-dependent proteins and that the mode of inheritance is autosomal recessive.

Topics: Blood Coagulation Disorders; Child; Factor VII Deficiency; Factor X Deficiency; Female; Glycoproteins; Hemophilia B; Hemorrhagic Disorders; Humans; Hypoprothrombinemias; Male; Pedigree; Protein C Deficiency; Protein S; Vitamin K; Vitamin K 1

A coagulopathy attributable to a deficiency of vitamin K-dependent clotting factors (II, VII, IX, and X) was diagnosed in 3 Devon Rex cats. There was no evidence for exposure to vitamin-antagonist-related rodenticides. The cats did not have evidence of hepatic disease, gastrointestinal disease, or fat malassimilation. Oral treatment with vitamin K1 resulted in normalization of clotting factor concentrations. However, when treatment was discontinued in 2 cats, prothrombin and activated partial thromboplastin values became prolonged again, although the cats did not have clinical signs of a bleeding disorder.

Topics: Animals; Blood Coagulation Disorders; Breeding; Cat Diseases; Cats; Factor VII Deficiency; Factor X Deficiency; Female; Hemophilia B; Hypoprothrombinemias; Male; Partial Thromboplastin Time; Pedigree; Prothrombin; Prothrombin Time; Vitamin K; Vitamin K Deficiency

Combined deficiency of coagulant activity of the vitamin K-dependent factors was found in a 14-year-old boy suffering from severe hemorrhages. Immunoassays revealed the presence of acarboxyprothrombin. The bleedings could be controlled, but the coagulation defects persisted during more than 2 years' follow-up and could not be corrected by oral or parenteral vitamin K. No intoxication or underlying disease was found. The abnormality was considered a congenital disorder of the carboxylation of prothrombin.

Topics: Adolescent; Blood Coagulation Factors; Factor VII Deficiency; Factor X Deficiency; Follow-Up Studies; Hemophilia B; Hemorrhagic Disorders; Humans; Hypoprothrombinemias; Male; Protein Processing, Post-Translational; Prothrombin; Vitamin K

A Saudi Arabian infant with severe factor X deficiency who had had two intracranial haemorrhages is described. Attempts to raise his factor X level and improve his prothrombin time (PT) and partial thromboplastin time (PTT) by using vitamin K, oestradiol and danazol have failed. New therapeutic trials are necessary for patients with severe forms of this rare disorder.

Topics: Blood Transfusion; Cerebral Hemorrhage; Child, Preschool; Danazol; Estradiol; Factor X Deficiency; Humans; Hypoprothrombinemias; Male; Partial Thromboplastin Time; Prothrombin Time; Vitamin K

A patient congenitally deficient in factors II, VII, IX, and X has been further investigated after a follow-up of 15 yr. At birth, these factors, when determined by clotting assays, were undetectable. Following therapy with vitamin K1, the clotting activity of these factors rose but never exceeded 18% of normal. Immunologic assays revealed much higher levels of these factors than did clotting assays, thus suggesting that the vitamin-K-dependent factors were present in abnormal forms. Two-dimensional crossed immunoelectrophoresis showed that at least two forms of prothrombin were present in the patient's plasma. One form was similar to normal prothrombin; the other had the same mobility as acarboxyprothrombin. In addition, the majority of this fast-migrating peak was not adsorbable onto insoluble barium salts. These observations suggested that some molecules of the patient's prothrombin lacked the normal complement of gamma-carboxyglutamic acid residues. This observation was confirmed by a specific assay for gamma-carboxyglutamate. Since malabsorption of vitamin K, warfarin intoxication, and hepatic dysfunction were excluded as causes of this patient's syndrome, this rare congenital abnormality could represent either a defective gamma-carboxylation mechanism within the hepatocyte or faulty vitamin K transport.

Topics: Adolescent; Blood Coagulation Tests; Chromatography, Thin Layer; Factor X Deficiency; Female; Hemophilia B; Humans; Hypoprothrombinemias; Immunoelectrophoresis, Two-Dimensional; Neutralization Tests; Vitamin K

A case of severe haemorrhagic diathesis due to acquired deficiency of factor X (both immunologically and in procoagulant activity) is presented. The clinical and serological features of this case indicated mycoplasma pneumonial infection. Factor X in the peripheral blood did not appear to be influenced by administration of vitamin K, prothrombin-complex concentrate, fresh plasma or fresh whole blood. Circulating inhibitors of blood coagulation were absent and systemic amyloidosis could not be demonstrated. After 20 d, factor X spontaneously returned to normal. In view of the absence of other known causes of factor X deficiency, a possible relationship with mycoplasma pneumonial infection is suggested.

Topics: Blood Transfusion; Factor X Deficiency; Hemorrhagic Disorders; Humans; Hypoprothrombinemias; Male; Middle Aged; Pneumonia, Mycoplasma; Prothrombin; Remission, Spontaneous; Vitamin K

Topics: Administration, Oral; Animals; Anticoagulants; Biomarkers; Blood Coagulation Disorders; Blood Proteins; Cattle; Cold Temperature; Factor VII; Factor VII Deficiency; Factor X; Factor X Deficiency; Humans; Hypoprothrombinemias; Kaolin; Protein Precursors; Prothrombin; Prothrombin Time; Rabbits; Thromboplastin; Vitamin K

Topics: Animals; Antibody Specificity; Antigen-Antibody Complex; Antigens; Blood Proteins; Cattle; Factor IX; Factor X; Factor X Deficiency; Hemophilia B; Hypoprothrombinemias; Immunoelectrophoresis; Prothrombin; Rabbits; Vitamin K

Topics: Blood Coagulation Factors; Chromatography, DEAE-Cellulose; Edetic Acid; Factor IX; Factor VII; Factor VII Deficiency; Factor X; Factor X Deficiency; Hemophilia A; Hemophilia B; Hemorrhage; Humans; Hypoprothrombinemias; Infant, Newborn; Prothrombin; Vitamin K

Topics: Acute Disease; Adolescent; Adult; Factor V Deficiency; Factor VII Deficiency; Factor X Deficiency; Humans; Hypoprothrombinemias; Middle Aged; Muscle Spasticity; Paraplegia; Quadriplegia; Spinal Cord Injuries; Vitamin K

Topics: Blood Coagulation Tests; Coumarins; Factor VII Deficiency; Factor X Deficiency; Humans; Hypoprothrombinemias; Plasma; Thromboplastin; Vitamin K