Chapter 059. Bleeding and Thrombosis (Part 8)

Screening AssaysThe most commonly used screening tests are the PT, aPTT, and platelet count. The PT assesses the factors I (fibrinogen), II (prothrombin), V, VII and X (Fig. 59-6). The PT measures the time for clot formation of the citrated plasma after recalcification and addition of thromboplastin, a mixture of TF and phospholipids. The sensitivity of the assay varies by the source of thromboplastin. To adjust for this variability, the overall sensitivity of different thromboplastins to reduction of the vitamin K–dependent clotting factors II, VII, IX, and X in anticoagulated patients is now expressed as the International Sensitivity Index...
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Chapter 059. Bleeding and Thrombosis (Part 8) Chapter 059. Bleeding and Thrombosis (Part 8) Screening Assays The most commonly used screening tests are the PT, aPTT, and plateletcount. The PT assesses the factors I (fibrinogen), II (prothrombin), V, VII and X(Fig. 59-6). The PT measures the time for clot formation of the citrated plasmaafter recalcification and addition of thromboplastin, a mixture of TF andphospholipids. The sensitivity of the assay varies by the source of thromboplastin.To adjust for this variability, the overall sensitivity of different thromboplastins toreduction of the vitamin K–dependent clotting factors II, VII, IX, and X inanticoagulated patients is now expressed as the International Sensitivity Index(ISI). An inverse relationship exists between the ISI and thromboplastinsensitivity. The international normalized ratio (INR) is then determined based onthe formula: INR = (PTpatient/PTnormal mean)ISI. Figure 59-6 Coagulation factor activity tested in the activated partial thromboplastintime (aPTT) in red and prothrombin time (PT) in green, or both. HMWK, high-molecular-weight kininogen; PK, prekallikrein; F, factor. While the INR was developed to assess anticoagulation due to reduction ofvitamin K–dependent coagulation factors, it is commonly used in the evaluation ofpatients with liver disease. This measure provides a system for comparing valuesfrom testing performed at different laboratories. However, as progressive liverfailure is associated with variable changes in coagulation factors, the degree ofprolongation of either the PT or the INR only roughly predicts the bleeding risk.Thrombin generation has been shown to be normal in many patients with mild tomoderate liver dysfunction. As the PT only measures one aspect of hemostasisaffected by liver dysfunction, we likely overestimate the bleeding risk of a mildlyelevated INR in this setting. The aPTT assesses the intrinsic and common coagulation pathways, factorsXI, IX, VIII, X, V, II, fibrinogen, and also prekallikrein, high molecular weightkininogen and factor XII (Fig. 59-6). The aPTT reagent contains phospholipidsderived from either animal or vegetable sources that function as a plateletsubstitute in the coagulation pathways and includes an activator of the intrinsiccoagulation system, such as ellagic acid or the particulate activators kaolin, celite,or micronized silica. The phospholipid composition of aPTT reagents varies, which influencesthe sensitivity of individual reagents to clotting factor deficiencies and toinhibitors such as heparin and lupus anticoagulants. Thus, aPTT results will varyfrom one laboratory to another, and the normal range in the laboratory where thetesting occurs should be used in the interpretation. Local laboratories can relatetheir aPTT values to therapeutic heparin anticoagulation by correlating aPTTvalues with direct measurements of heparin activity (anti-Xa or protamine titrationassays) in samples from heparinized patients, although correlation between theseassays is often poor. The aPTT reagent will vary in sensitivity to individual factordeficiencies and usually becomes prolonged with individual factor deficiencies of30–50%. The relationship between defects in secondary hemostasis (fibrinformation) and coagulation test abnormalities is shown in Table 59-4. Table 59-4 Hemostatic Disorders and Coagulation Test Abnormalities Prolonged activated partial thromboplastin time (aPTT) No clinical bleeding –factors XII, high-molecular-weight kininogen,protein kinase Variable, but usually mild, bleeding –factor XI, mild FVIII and FIX Frequent, severe bleeding – severe deficiencies of FVIII and FIX Heparin Prolonged prothrombin time (PT) Factor VII deficiency Vitamin K deficiency – early Warfarin anticoagulationProlonged aPTT and PT Factor II, V or X deficiency Vitamin K deficiency – late Direct thrombin inhibitorsProlonged thrombin time Heparin or heparin-like inhibitors Mild or no bleeding – dysfibrinogenemia Frequent, severe bleeding – afibrinogenemiaProlonged PT and/or aPTT not correct with mixing with normal plasma Bleeding – specific factor inhibitor No symptoms, or clotting and/or pregnancy loss – lupus anticoagulant Disseminated intravascular coagulation Heparin or direct thrombin inhibitorAbnormal clot solubility Factor XIII deficiency Inhibitors or defective cross-linkingRapid clot lysis Deficiency of α2-antiplasmin or plasminogen activator inhibitor 1 Treatment with fibrinolytic therapy