Prothrombin liver

Elevated prothrombin time (PT) and International Normalized Ratio (INR) are coagulation derangements that indicate loss of synthetic capacity in the liver and correlate with functional loss of hepatocytes. 

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Prothrombin time PT is performed by adding thromboplastin (tissue) factor and calcium to citrate-anticoagulated plasma, recalcifying the plasma, and measuring the clotting time. The major utility of PT is to measure the activity of the vitamin K-dependent factors II, VII, and X. The PT is used in evaluation of liver disease, to monitor warfarin anticoagulant effect, and to assess vitamin K deficiency. 

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Several substances that contribute to the blood coagulation process are formed in the liver. These include fibrinogen, prothrombin, and several of the blood clotting factors (II, VII, IX, and X). Deficiency in any of these substances leads to impaired blood coagulation. 

Progressive liver damage (shock liver) manifests as elevated serum hepatic transaminases and unconjugated bilirubin. Impaired synthesis of clotting factors may increase prothrombin time (PT), international normalized ratio, and activated partial thromboplastin time (aPTT). 

Contraindications to heparin therapy include hypersensitivity to the drug, active bleeding, hemophilia, severe liver disease with elevated prothrombin time (PT), severe thrombocytopenia, malignant hypertension, and inability to meticulously supervise and monitor treatment. 

Routine liver assessment tests include alkaline phosphatase, bilirubin, aspartate transaminase, alanine transaminase, and y-glutamyl transpeptidase (GGT). Additional markers of hepatic synthetic activity include albumin and prothrombin time. The substances are typically elevated in chronic inflammatory liver diseases such as hepatitis C, but may be normal in others with resolved infectious processes. 

Current nutritional intake Complete blood cell count Serum electrolytes Sodium Potassium Chloride Bicarbonate Magnesium Phosphorous Calcium Serum glucose Serum albumin Markers for organ function Liver function tests Alkaline phosphatase Aspartate aminotransferase Alanine aminotransferase Total bilirubin Prothrombin time or International normalized ratio Renal function tests Blood urea nitrogen Creatinine Fluid balance Input Oral... 

Liver function tests Alkaline phosphatase Aspartate aminotransferase Alanine aminotransferase Total bilirubin Prothrombin time or International normalized ratio (as necessary)... 

Baseline laboratory tests should include complete blood cell count, prothrombin time, activated partial thromboplastin time, liver and renal function tests, and serum carcinoembryonic antigen (CEA). Serum CEA can serve as a marker for monitoring colorectal cancer response to treatment, but it is too insensitive and nonspecific to be used as a screening test for early-stage colorectal cancer. 

The last of the fat-soluble vitamins to be identified was vitamin K, found by Dam to be an anti-hemorrhagic factor for young chicks, distinct from vitamin C. Its structure was determined by Dam in collaboration with Karrer. Interest in the vitamin was intensified when it was discovered (Link, 1941) that dicoumarol, present in spoiled sweet clover, was the agent producing hypothrombinemia (giving prolonged blood-clotting time) in cattle. Since vitamin K is structurally similar to dicoumarol, the vitamin was presumptively implicated in thrombin formation. This has been fully substantiated by recent work on the role of vitamin K in the synthesis of prothrombin in the liver. 

Hematological Effects. Information regarding hematological effects in humans exposed to chloroform is limited. Increased prothrombin time was observed in some patients, following exposure to chloroform via anesthesia (Smith et al. 1973). This effect, however, reflects chloroform hepatotoxicity, because prothrombin is formed in the liver. Decreased erythrocytes and hemoglobin were observed in a patient who was chronically exposed to chloroform in a cough medicine (Wallace 1950). 

PO loading dose 400 mg tid x 15-30 days, then 200-400 mg qd (5-10 mg/l ) pneurrwnitis when dose >400 mg/d elevation of digoxin level, prolongation of prothrombin time (70-100%) with warfarin pultrwnary fibrosis, hepatitis, ocular opacities proarrhythmic monitor thyroid and liver function... 

The most important adverse effect is bleeding. With coumarins, this can be counteracted by giving vitamin Ki. Coagulability of blood returns to normal only after hours or days, when the liver has resumed synthesis and restored sufficient blood levels of clotting factors. In urgent cases, deficient factors must be replenished directly (e.g., by transfusion of whole blood or of prothrombin concentrate). 

Hepatotoxicity manifested by alterations in liver function, including hyperbilirubinemia, and decreased prothrombin activity, is associated with exposure in both animals and humans. ... 

Oral contraceptives have also been reported to produce increases in sulfobromophthalein retention and other liver function tests, as well as in prothrombin time, clotting factors VII, VIII, IX, serum thyroxine, and protein-bound iodine (B8). In a group of 48 women the mean cholesterol value was 206 41 mg/100 ml while they were receiving a variety of oral contraceptives and 179 28 mg/100 ml when they were not receiving the drugs (W19). 

Pharmacokinetics Phytonadione is only absorbed from the Gl tract via intestinal lymphatics in the presence of bile salts. Although initially concentrated in the liver, vitamin K is rapidly metabolized, and very little tissue accumulation occurs. Parenteral phytonadione is generally detectable within 1 to 2 hours. Phytonadione usually controls hemorrhage within 3 to 6 hours. A normal prothrombin level may be obtained in 12 to 14 hours. Oral phytonadione exerts its effect in 6 to 10 hours. 

Monitoring Monitor renal function frequently during amphotericin B therapy. It is also advisable to monitor liver function, serum electrolytes (particularly magnesium and potassium), blood counts, and hemoglobin concentrations on a regular basis. Use laboratory test results as a guide to subsequent dose adjustments. Monitor complete blood count and prothrombin time as medically indicated. 

Acute liver failure, beginning within one or two days of overdosage, can lead to encephalopathy, haemorrhage, oedema and death. Prolongation of prothrombin time is proportional to the degree of liver injury and is the best guide to severity of liver injury. Peak toxicity is seen 3 days after the overdose is taken. 

Twenty to 24 million prescriptions of Coumadin were dispensed in the United States during 2003-2005. Coumadin is an anticoagulant that acts by preventing the synthesis of active vitamin K, a necessary cofactor for synthesizing active clotting factors. Thus, preventing the synthesis of active vitamin K indirectly inhibits the formation of active clotting factors, notably factor II (prothrombin), VII, IX, and X in the liver. Ironically, coumarins, of which Coumadin is a member, are also used as rodenticides. 

Coumarins are competitive inhibitors of vitamin K, which is required for the formation in the liver of the amino acid, gamma-carboxyglutamic acid. This is necessary for the synthesis of prothrombin and factors VII, IX and X (Figure 17.1). After starting treatment the anticoagulant effect is delayed until the concentration of normal coagulation factors falls (36-72 h). The effects can be reversed by vitamin K (slow maximum effect only after 3-6 h) or by whole blood or plasma (fast). Gut bacteria synthesise vitamin K and thus are an important source of this vitamin. Consequently, antibiotics can cause excessive prolongation of the prothrombin time in patients otherwise adequately controlled on warfarin. 

Factor II. Prothrombin is a vitamin K-dependent compound synthesized by the liver. When prothrombin is activated it is cleaved at two sites, resulting in a two-chain molecule linked by a disulfide bond that has a molecular weight of 37,000 daltons. Thrombin is the serine protease that initiates the conversion of soluble fibrinogen into fibrin. 

The most obvious effect of a deficiency in vitamin K in animals is delayed blood clotting, which has been traced to a decrease in the activity of prothrombin and of clotting factors VII, IX, and X (Chapter 12, Fig. 12-17). Prothrombin formed by the liver in the absence of vitamin K lacks the ability to chelate calcium ions essential for the binding of prothrombin to phospholipids and to its activation to thrombin. The structural differences between this abnormal protein and the normal prothrombin have been pinpointed at the N terminus of the 560 residue glycoprotein.e f Tryptic peptides from the N termini differed in electrophoretic mobility. As detailed in Chapter 12, ten residues within the first 33, which were identified as glutamate residues by the sequence analysis on normal prothrombin, are actually y-carboxyglutamate (Gla). The same amino acid is present near the N termini of clotting factors VII, IX, and X. 

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