vitamin-k-semiquinone-radical and Syndrome

Vitamin K antagonists (warfarin, syncumar, phenylin, etc.) are commonly used to treat and prevent thrombotic diseases. The risk for varying degrees of hemorrhagic syndrome (intracranial hemorrhage in particular) is the most important problem in the use of drugs from this group. The rapid neutralization of the effects of used anticoagulants, which is verified by correcting the international normalized ratio (INR), is required in these cases and when emergency surgical interventions are needed. Transfusions of prothrombin complex concentrates (PCCs) in combination of vitamin K preparations are optimal for this purpose. The reason for the rational use of PCCs to promptly correct INR is the balanced composition of this transfusion medium (a combination of blood coagulation factors and biological anticoagulants). This regimen for emergency correction of INR minimizes the risk of thrombotic events.

Topics: Anticoagulants; Blood Coagulation Factors; Hemorrhage; Humans; International Normalized Ratio; Intracranial Hemorrhages; Syndrome; Time Factors; Vitamin K

Accomplishing a successful percutaneous coronary intervention in a patient with a suspected or diagnosed heparin-induced thrombocytopenia (HIT) requires the selection of an appropriate alternative anticoagulant and a thorough assessment of bleeding and thrombotic risks. In this review, we suggest an evidence-based management algorithm that takes into account the clinical phase of HIT (acute, recent, and remote HIT) and the associated risk when patients present with acute coronary syndrome. The algorithm also integrates preventive measures directed at decreasing the bleeding risk associated with the antithrombotic and invasive therapies used for HIT and percutaneous coronary intervention.

Topics: Algorithms; Angioplasty, Balloon, Coronary; Anticoagulants; Arginine; Chondroitin Sulfates; Comorbidity; Dermatan Sulfate; Drug Therapy, Combination; Fibrinolytic Agents; Fondaparinux; Heparin; Heparinoids; Heparitin Sulfate; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Syndrome; Thrombocytopenia; Vitamin K

Topics: Adolescent; Diabetes Mellitus, Type 1; Diagnosis, Differential; Facies; Female; Hepatomegaly; Humans; Hypoglycemic Agents; Insulin; Liver; Liver Diseases; Puberty, Delayed; Syndrome; Ultrasonography; Vitamin K; Vitamins

Venous limb gangrene (VLG) can occur in cancer patients, but the clinical picture and pathogenesis remain uncertain. We identified 10 patients with metastatic cancer (7 pathologically proven) who developed severe venous limb ischemia (phlegmasia/VLG) after initiating treatment of deep-vein thrombosis (DVT); in 8 patients, cancer was not known or suspected at presentation. The patients exhibited a novel, clinically distinct syndrome: warfarin-associated supratherapeutic international normalized ratio (INR; median, 6.5) at onset of limb ischemia, rising platelet count during heparin anticoagulation, and platelet fall after stopping heparin. Despite supratherapeutic INRs, patient plasma contained markedly elevated thrombin-antithrombin (TAT) complex levels (indicating uncontrolled thrombin generation) and protein C (PC) depletion; this profile resembles the greatly elevated TAT/PC activity ratios reported in patients with warfarin-associated VLG complicating heparin-induced thrombocytopenia. Analyses of vitamin K-dependent factors in 6 cancer patients with available serial plasma samples showed that variations in the INR corresponded most closely with changes in factor VII, with a highly collinear relationship between VII and PC. We conclude that venous limb ischemia/gangrene is explained in some cancer patients by profoundly disturbed procoagulant-anticoagulant balance, whereby warfarin fails to block cancer-associated hypercoagulability while nonetheless contributing to severe PC depletion, manifest as a characteristic supratherapeutic INR caused by parallel severe factor VII depletion.

Topics: Aged; Anticoagulants; Antithrombin III; Blood Coagulation Factors; Blood Platelets; Female; Follow-Up Studies; Gangrene; Heparin; Humans; International Normalized Ratio; Ischemia; Leg; Male; Middle Aged; Neoplasms; Peptide Hydrolases; Prognosis; Protein C Deficiency; Syndrome; Venous Thrombosis; Vitamin K; Warfarin

Soft-tissue mineralization is a tightly regulated process relying on the activity of systemic and tissue-specific inhibitors and promoters of calcium precipitation. Many of these, such as matrix gla protein (MGP) and osteocalcin (OC), need to undergo carboxylation to become active. This post-translational modification is catalyzed by the gammaglutamyl carboxylase GGCX and requires vitamin K (VK) as an essential co-factor. Recently, we described a novel phenotype characterized by aberrant mineralization of the elastic fibers resulting from mutations in GGCX. Because of the resemblance with pseudoxanthoma elasticum (PXE), a prototype disorder of elastic fiber mineralization, it was coined the PXE-like syndrome. As mutations in GGCX negatively affect protein carboxylation, it is likely that inactive inhibitors of calcification contribute to ectopic mineralization in PXE-like syndrome. Because of the remarkable similarities with PXE, we performed a comparative study of various forms of VK-dependent proteins in serum, plasma (using ELISA), and dermal tissues (using immunohistochemistry) of PXE-like and PXE patients using innovative, conformation-specific antibodies. Furthermore, we measured VK serum concentrations (using HPLC) in PXE-like and PXE samples to evaluate the VK status. In PXE-like patients, we noted an accumulation of uncarboxylated Gla proteins, MGP, and OC in plasma, serum, and in the dermis. Serum levels of VK were normal in these patients. In PXE patients, we found similar, although not identical results for the Gla proteins in the circulation and dermal tissue. However, the VK serum concentration in PXE patients was significantly decreased compared with controls. Our findings allow us to conclude that ectopic mineralization in the PXE-like syndrome and in PXE results from a deficient protein carboxylation of VK-dependent inhibitors of calcification. Although in PXE-like patients this is due to mutations in the GGCX gene, a deficiency of the carboxylation co-factor VK is at the basis of the decreased activity of calcification inhibitors in PXE.

Topics: Adult; Aged; Animals; Calcinosis; Calcium-Binding Proteins; Extracellular Matrix Proteins; Humans; Matrix Gla Protein; Mice; Mice, Knockout; Middle Aged; Mixed Function Oxygenases; Mutation; Proteins; Pseudoxanthoma Elasticum; Syndrome; Vitamin K; Vitamin K Deficiency; Vitamin K Epoxide Reductases

Topics: Drug Eruptions; Fatal Outcome; Female; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Injections, Intramuscular; Leg Ulcer; Male; Necrosis; Syndrome; Treatment Outcome; Vitamin K

Trousseau described spontaneous, recurrent superficial migratory thrombophlebitis associated with occult cancers, and this was later correlated with disseminated microangiopathy (platelet-rich clots in small blood vessels). Trousseau syndrome often occurs with mucinous adenocarcinomas, which secrete abnormally glycosylated mucins and mucin fragments into the bloodstream. Since carcinoma mucins can have binding sites for selectins, we hypothesized that selectin-mucin interactions might trigger this syndrome. When highly purified, tissue-factor free carcinoma mucin preparations were intravenously injected into mice, platelet-rich microthrombi were rapidly generated. This pathology was markedly diminished in P- or L-selectin-deficient mice. Heparin (an antithrombin-potentiating agent that can also block P- and L-selectin recognition of ligands) ameliorated this platelet aggregation, but had no additional effect in P- or L-selectin-deficient mice. Inhibition of endogenous thrombin by recombinant hirudin also did not block platelet aggregation. Mucins generated platelet aggregation in vitro in hirudinized whole blood, but not in platelet-rich leukocyte-free plasma nor in whole blood from L-selectin-deficient mice. Thus, Trousseau syndrome is likely triggered by interactions of circulating carcinoma mucins with leukocyte L-selectin and platelet P-selectin without requiring accompanying thrombin generation. These data may also explain why heparin ameliorates Trousseau syndrome, while vitamin K antagonists that merely depress thrombin production do not.

Topics: Adenocarcinoma, Mucinous; Animals; Antifibrinolytic Agents; Blood Platelets; Comorbidity; Fibrinolytic Agents; Heparin; Humans; L-Selectin; Lung; Mice; Mice, Inbred C57BL; Mucins; Neoplasm Transplantation; P-Selectin; Paraneoplastic Syndromes; Platelet Activation; Syndrome; Thrombin; Thrombophlebitis; Thrombosis; Transplantation, Heterologous; Tumor Cells, Cultured; Vitamin K

Intracoronary thrombosis is fundamental in the pathogenesis of acute coronary syndromes, although the causes of thrombosis are still unclear. As thrombin generation is crucial for thrombus formation, the inhibition of thrombin is a primary aim to prevent the evolution of an initial repair process into a pathological thrombus. Thrombin inhibition can be achieved by several drugs. Heparin is the principal antithrombin drug currently used in acute syndromes; it acts mainly by binding to antithrombin III and increasing its inhibitory effect on thrombin and other coagulation factors. The heparin-antithrombin III complex, however, does not inhibit thrombus-bound thrombin; moreover, iv heparin requires frequent laboratory monitoring and dose adjustments. Despite these limitations, continuous infusion of i.v. heparin has been found to be effective in unstable angina and in myocardial infarction, especially when treated with accelerated rt-PA. New antithrombin drugs that selectively and directly inhibit thrombin are hirudin, its synthetic derivate hirulog, and argatroban. These drugs have several theoretical advantages over heparin: greater stability of the aPTT--with the need for less laboratory monitoring--and greater efficacy--associated mainly with its capacity to inhibit clot-bound thrombin. Clinical pilot studies seem to indicate a greater antithrombotic efficacy compared with heparin, but a greater number of hemorrhagic events in patients with acute myocardial infarction receiving thrombolysis. In conclusion, the use of heparin is certainly indicated in patients with unstable angina and persistent ischemia and in acute myocardial infarction treated with accelerated rt-PA. The use of new antithrombin drugs, although promising, requires further clinical evaluation.

Topics: Acute Disease; Angina, Unstable; Coronary Thrombosis; Fibrinolytic Agents; Heparin; Humans; Myocardial Infarction; Syndrome; Thrombin; Thrombolytic Therapy; Vitamin K

We report on a male infant with X-linked ichthyosis, X-linked Kallmann syndrome, and X-linked recessive chondrodysplasia punctata (CPXR). Chromosome analysis showed a terminal deletion with a breakpoint at Xp22.31, inherited maternally. This patient confirms the localization of XLI, XLK, and CPXR to this region of the X chromosome and represents an example of a "contiguous gene syndrome." A comparison of the manifestations of patients with CPXR, warfarin embryopathy, and vitamin K epoxide reductase deficiency shows a remarkable similarity. However, vitamin K epoxide reductase deficiency does not appear to be the cause of CPXR. We propose that CPXR may be due to a defect in a vitamin K-dependent bone protein such as vitamin K-dependent bone carboxylase, osteocalcin, or matrix Gla protein.

Topics: Chondrodysplasia Punctata; Chromosome Deletion; Chromosome Mapping; Genetic Linkage; Humans; Hypogonadism; Ichthyosis; Infant; Male; Mixed Function Oxygenases; Olfaction Disorders; Olfactory Bulb; Sulfatases; Syndrome; Vitamin K; Vitamin K Epoxide Reductases; X Chromosome

Topics: Humans; Hypoprothrombinemias; Infant; Infant, Newborn; Milk, Human; Syndrome; Vitamin K; Vitamin K 1; Vitamin K Deficiency

We describe a brother and sister with amelogenesis imperfecta, nephrocalcinosis and impaired renal concentrating ability. This is the second sibship reported, further substantiating autosomal recessive inheritance of this condition. There is lack of enamel, lifelong nocturnal enuresis, progressive punctate nephrocalcinosis, and decreased calcium and phosphate excretion over 24 hours and after an acute load. Increased serum osteocalcin and decreased urine delta-carboxyglutamic acid suggest involvement of vitamin K-dependent calcium binding proteins, although this may represent a secondary finding. No other evidence of abnormal calcium metabolism was found. Renal function is stable in the early teens, but the previously reported patients went on to renal failure.

Topics: 1-Carboxyglutamic Acid; Amelogenesis Imperfecta; Biopsy; Calcium Metabolism Disorders; Calcium-Binding Proteins; Child; Female; Genes, Recessive; Humans; Kidney; Kidney Concentrating Ability; Male; Nephrocalcinosis; Osteocalcin; Radiography; Syndrome; Tooth; Vitamin K

An outbreak of a haemorrhagic diathesis in cattle fed home produced hay is described. A similar syndrome was reproduced experimentally in calves by feeding them the hay. The experimental disease was characterised by increased prothrombin and partial thromboplastin times while the leucocyte and erythrocyte counts remained normal until the terminal haemorrhage. The calves ate well and grew well until the rapid onset of progressive weakness, stiff gait, mucosal pallor, tachycardia, tachypnoea and haematomata ending in sudden death. The absence of blood coagulation was seen at necropsy while petechial, ecchymotic and free haemorrhages were found in most organs. Particularly striking were massive ecchymotic haemorrhages on the peritoneal surface of the rumen, a bloody, gelatinous mass enveloping each kidney and extensive bruising, haemorrhage and haematomata in the subcutis of the limbs. In a second feeding trial the effects of various preparations of vitamin K1 and vitamin K3 were investigated. Oral administration of large quantities of vitamin K1 reduced the elevated prothrombin time; vitamin K3 acted less consistently. Analysis of the hay for trichothecene mycotoxins was negative but floral analysis revealed that sweet vernal grass (Anthoxanthum odoratum) comprised about 80 per cent of the hay. Dicoumarol was detected in the hay and in the serum and ruminal contents of the experimental calves. The diagnosis, treatment, control and importance of this syndrome in the United Kingdom are discussed.

Topics: Animal Feed; Animals; Cattle; Cattle Diseases; Dicumarol; Disease Outbreaks; Female; Hemorrhagic Disorders; Plant Poisoning; Prothrombin Time; Syndrome; United Kingdom; Vitamin K

Topics: Adult; Female; Hemorrhage; Humans; Infant, Newborn; Male; Partial Thromboplastin Time; Persistent Fetal Circulation Syndrome; Phenytoin; Pregnancy; Pregnancy Complications; Prothrombin Time; Seizures; Syndrome; Vitamin K

A bleeding syndrome due to severe prothrombin complex deficiency is reported in 93 infants. Most were breast fed (98 per cent), aged 2 weeks to 1 year and there were no serious preceding or associated diseases. Hemorrhagic diathesis, pallor and mild hepatomegaly were the major manifestations. The incidence of intracr anial bleeding was strikingly high (63 per cent) particularly with subdural and subarachnoid hemorrhage. Acute onset, short course and rapid clinical and laboratory improvement after vitamin K therapy were observed. Mortality rate was 35 per cent but has been reduced to 17 per cent since 1969. The location of bleeding, prompt diagnosis and early treatment are the major factors affecting prognosis. Severe prothrombin complex deficiency due to vitamin K deficiency accounted for the pathogenesis of bleeding. Possible causes of vitamin K deficiency were discussed but definite conclusions could not be drawn.

Topics: Cerebral Hemorrhage; Female; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Hypoprothrombinemias; Infant; Infant, Newborn; Male; Subarachnoid Hemorrhage; Syndrome; Vitamin K; Vitamin K Deficiency

Topics: Adrenal Cortex Hormones; Anabolic Agents; Blood Coagulation Disorders; Estrogens; Hemorrhage; Humans; Syndrome; Vitamin K

Topics: Animals; Chlortetracycline; Dietary Carbohydrates; Female; Glucose; Heart Diseases; Hemorrhage; Male; Prothrombin Time; Rats; Salicylates; Sucrose; Swine; Swine Diseases; Syndrome; Vitamin K

Topics: Blood; Corrinoids; Folic Acid; Gastrointestinal Diseases; Humans; Riboflavin; Syndrome; Urine; Vitamin A; Vitamin B 12; Vitamin K; Vitamins

Topics: Osteosclerosis; Syndrome; Vitamin A; Vitamin D; Vitamin K; Vitamins