DIAGNOSTIC SCREENING OF CONGENITAL THROMBOTIC SYNDROMES
Authors: Mannuccl P M , Tripodl A 
Published: August 2018

The prevalence of inherited thrombotic syndromes in the general population (1 in 2,500/5,000) appears to be higher than that of inherited bleeding disorders. We have reviewed the problems of their diagnosis and propose a simple screening procedure. The most important candidates far. screening are patients with unexplained venous thromboembolism at ages ofless than 40 years, particularly when thrombotic episodes are recurrent.Screening must start from collectionof the clinical and family history of the propositus and from the exclusion of common acquired forms of thrombophilia. A negative family historydoes not exclude inherited thrombophilia, because the defects have oftena low penetrance and fresh mutationsmay have occurred in the propositi. The test chosen for laboratoryscreening of inherited thrombotic syndromes must be limited in number, easy todo and, more importantly, their results should be clinically relevent Which defects should be screened and what type of methodology should be used? The table is intended to answerthese questions by proposing a two-step screening procedure.

The tests included in the .first step of the screening are aimed at evaluating Laboratory screening of inherited thrombotic syndromes the most frequent and well established causes of inherited thrombophilia, —-antithrombin III, protein C. protein S.plasminogen and fibrinogen.FIRST STEP Antithrombin III (heparin cofactorI chromogenic assay)Protein C (Francis' clotting assay)Protein S(electroimmunoassay of total proteinSantigen)Plasminogen (chromogenic assay)Fibrinogen (clotting assay)SECONSTEP(Tran's functional assay) Plasminogen activator (fibrin plate assay before and after venous stasisor DDAVP)Plasminogen activator inhibitor(chromogenic assay)The tests offirst choice that we propose (see table) are in general functional assaysdetecting both type I and type IIdeficiencies and are simple enough tobecarried out even in non specialized laboratories.For protein S, however,this goal has not been achieved yet and only type I protein S deficiencycan be currently identified with immunoassays measuring total protein S antigen. Since a number of laboratories may still not have the facilities to perform protein C functional assays, they are advised to set up at least an immunoassay, since type I deficiencies are much more frequent than type II deficiencies. The tests included in the second step of the screening are aimed at detectingthe less common or less well established causes of thrombophilia, and should be carried out when the clinical history suggests the existence of inherited thrombophilia and yet the first step has failed to reveal any laboratory abnormality. Defective plasminogen activation can be evaluated by measuring plasminogen activator activity with the simple fibrin plate assay carried out before and after stimuli such as venous occlusion and/or DDAVP infusion. The parallel measurement of plasminogen activator inhibitor allows to distinguish cases of detective plasminogen activation due to high inhibitor levels. The measurement of heparin cofactor II should also be included in this battery of second-step screening tests.

Using this screening procedure in95 propositi with juvenile venous thromboembolism, we have identified 7 kindreds with antithrombin III deficiency (5 type I and 2 type II) (7.5%),7 kindreds with protein C deficiency (1 type II) (7.5%), 5 kindredswith protein S deficiency (5%), 1 withhypoplasminogenemia (1%) and 1 with dysfibrinogenemia Milano II (1). Theremaining undiagnosed cases might bedue to as yet unidentified deficiencies or abnormalities of other antithrombotic mechanisms such as,for instance, endothelial thrombomodulin or the fibrinolysis enhancing property of the protein C-protein S system.