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15.1 Type I antithrombin deficiency occurs when a mutation in the antithrombin gene results in a reduction in the quantity of protein in the circulation. Levels of antithrombin measured with both immunological and functional assays are reduced to about 50% of normal.
Type II antithrombin deficiency occurs when a mutation in the antithrombin gene results in a reduction in the function of the protein, without a reduction in the quantity of protein in the circulation. Levels of antithrombin measured with functional assays are reduced, whilst immunological levels remain normal or near normal.
15.2 Type II RS (reactive site)—mutations in the region of the molecule which binds to thrombin and other serine proteases.
Type II HBS (heparin-binding site)—mutations in the region of the molecule which affect binding to heparin.
Type II pleiotropic—mutations in other regions of the molecule which have varied effects.
15.3 In vivo, protein C is activated by thrombin when thrombin is bound to thrombomodulin. In vitro, protein C may be activated by a fraction from the venom of the Southern Copperhead snake, Agkistrodon contortrix contortrix.
15.4 About 60% of protein S is bound to C4B-binding protein, and doesn’t seem to take part in the natural anticoagulant processes. The remaining protein S in the circulation is free rather than bound, and is an important component of the anticoagulant system.
15.5 About 5–10% of cases of APC resistance (APCr) do not have the FV Leiden mutation; rare FV mutations that confer APC resistance (i.e. FV Cambridge), increased levels of factor VIII, pregnancy, oral contraceptive use, hormone replacement therapy, and lupus anticoagulants can cause APCr in the absence of FV Leiden.
15.6 One or more episodes of arterial, venous or small vessel thrombosis, or pregnancy morbidity, accompanied by the persistent presence of one or more types of antiphospholipid antibody.
15.7 In solid-phase assays, most commonly ELISAs. Variations in reagent composition result in reduced inter-laboratory agreement, such as captured antigen quality.
15.8 The most common presenting symptoms are those outlined in the answer to self-check question 15.6. Patients with LA occasionally present with bleeding due to coexisting antibodies to platelets or specific coagulation factors. Some patients with persistent LA are asymptomatic and only very rarely progress to develop thrombotic disease.
15.9 Prolongation of at least one phospholipid-dependent screening test; evidence that the abnormality is phospholipid-dependent; evidence that the abnormality is inhibitory in nature; need to distinguish results from other coagulopathies that may mask, mimic, or coexist with LA.
15.10 Heterogeneity of LA and marked reagent variation mean that no single assay, or assay type, will detect all LA. Other coagulation abnormalities, whether present in isolation or coexistent with an LA, mean that we must perform tests that confirm phospholipid dependence and inhibition to demonstrate that an abnormal screening test is due to LA.
15.11 Both TTP and HUS have acquired and familial forms. Common features are microangiopathic haemolytic anaemia and thrombocytopenia. ADAMTS-13 levels are reduced in TTP but can be normal in HUS. Renal impairment predominates in HUS but neurological signs predominate in TTP.