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17.1 To prevent the growth of an existing thrombus and reduce the risk of a new clot developing.
17.2 In the deep veins of the calf, associated with stasis of blood in the lower limbs. It can on occasions form above the knee and in very rare cases form in the arm. If the thrombus is extensive or anticoagulant therapy is delayed, parts of the clot can break off and move through the circulation to the lungs forming a life-threatening pulmonary embolus.
17.3 It is used in conjunction with a clinical risk score as a negative predictive indicator to identify patients at low risk of a VTE, and reduces the need for radiological investigation and anticoagulant cover until the diagnosis is confirmed.
17.4 The formation of a thrombus in an artery is associated with the rupture of an atherosclerotic plaque, which is a build up of cholesterol under the vessel wall of the artery. Platelets adhere to the exposed plaque, aggregate, and lead to a thrombus which can break free of the surface leading to heart attack or stroke.
A venous thrombosis normally forms in a deep vein in a leg. Although events leading up to a VTE are not fully established, blood stasis is known to be a major contributor. Blood clots in the veins are composed mainly of fibrin and coagulation factors with a smaller platelet component.
17.5 Warfarin inhibits the re-cycling of vitamin K by blocking the action of the enzyme vitamin K reductase. The hydroquinone form of vitamin K is an essential coenzyme for the vitamin K-dependent clotting factors (II, VII, IX, and X) to be converted to the carboxylated forms, hence warfarin reduces the concentration of biologically active vitamin K-dependent clotting factors.
17.6 Unfractionated heparin has to be given IV and monitored, and has a high incidence of HIT. LMWH is given SC, in most situations it does not need monitoring, has a lower incidence of HIT, and can be self-administered by the patient thus enabling home use.
17.7 Aspirin reduces normal platelet function by inhibiting the arachidonic acid pathway within the platelet. This is essential for the generation of thromboxane A2 which is a potent activator of platelets causing aggregation.
17.8 INR = (Patient PT(s)/GMNPT (s))ISI
17.9 A multicentre exercise is used, utilizing large numbers of normal and warfarinized donors for PT determinations. An orthogonal regression line is used to plot the natural logarithms of PTs with the new IRP against those with existing IRPs. The slope of the calibration line is used to calculate the ISI.
17.10 The exercise is performed in at least two laboratories. The new reagent must be calibrated against the IRP for the corresponding species and a regression line generated as for an IRP. Pooled plasmas can be used.
17.11 Plasmas are supplied with known PT values assigned via an IRP thromboplastin. PTs are performed using the local system and the ISI calculated from a regression line. Plasmas can also be supplied with known INR values.
17.12 From the PTs of a minimum of 20 fresh plasmas from normal adult donors from both sexes, analysed over a period of several days, for each local system. It can be calculated from the PT and INR of a lyophilized or frozen pooled normal plasma obtained for the ISI calibration exercise, as shown below, as long as it has been previously established that the local system gives equivalent results between fresh and frozen or lyophilized plasma:
Theoretical GMNPT = PT of normal pooled plasma (s)/INR of normal pooled plasma.
17.13 Automated INR POCT INR
Sample Always plasma Usually native whole blood
Reagent Liquid Dry
Analysis Fully automated Semi-manual
ISI Locally calibrated Manufacturer assigned
Portability No Yes
17.14 Reagent variability in sensitivity to heparin means that the therapeutic range must be locally derived in relation to assays that measure heparin concentration. APTT results are affected by other aspects of the patient’s haemostasis. The short half-life of UFH means that APTT should be analysed within 2 hours of phlebotomy. UFH can be partially neutralized by PF4 if the sample is not cooled, centrifuged, and analysed within 2 hours.
17.15 Heparin in the patient sample (UFH or LMWH) is reacted with either an excess of exogenous AT or the patient’s circulating AT and forms a heparin–AT complex. This complex is reacted with an excess of exogenous FXa. In the chromogenic assay, residual FXa is reacted with a chromogenic substrate—the residual factor Xa that reacts with the chromogenic substrate is inversely proportional to the UFH concentration. In the clotting assay, the residual FXa is reacted with bovine plasma, phospholipid, and calcium ions and the time taken to clot is directly proportional to the heparin concentration.
17.16 Immunological assays such as ELISA, ELIFA, and FLIFA capture HIT antibodies and subject them to different measurement techniques. Platelet activation assays utilize the platelet activating properties of PF4–heparin–antibody complexes and then measure platelet activation via different methods such as aggregometry or release assays.
17.17 Because for each individual patient the dosage can vary widely due to a number of substances that interact with warfarin. These include diet, alcohol, and additional prescription medications. The issues relating to poor control can be very serious, including life-threatening haemorrhage or thrombosis.