15-7022 Quick Guide 115X200 2015.Indd
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H A E M O S T A S tPA FDP I S -1 D-Dimer PAI Plasminogen Plasmin Fibrin T M Fibrinogen IIa PC IIa T A APC PS II PS AP T V C A Activated Va Xa Platelet vWF X A T XI IXa VIIIa APC PS VIII XIa IX T A Activation pathways Inhibition pathways Coagulation PAI-1 AT All rights reserved - 04/2013 Ref. 27646 VIIa AT AGO - Fibrinolysis Xa TFPI T S APC PS Xa TFPI A TF © 2009 DIAGNOSTIC 4614 Diagnostica Stago S.A.S. RCS Nanterre B305 151 409 9, rue des Frères Chausson 92600 Asnières sur Seine (France) AT THE HEART OF HAEMOSTASIS Ph.: +33 (0)1 46 88 20 20 Quick Guide Fax: +33 (0)1 47 91 08 91 [email protected] At the Heart of Haemostasis www.stago.com To Haemostasis Screening assays in Haemostasis Anticoagulant therapy monitoring (1): Vitamin K antagonists Anticoagulant therapy monitoring (2): Heparin Assays for other anticoagulant therapy (3) Disseminated Intravascular Coagulation (DIC) Thrombophilia D-Dimer assay for the exclusion of venous thromboembolism (VTE) Lupus anticoagulants / Antiphospholipid antibodies For more information, visit our website at www.stago.com Screening assays in Haemostasis 1) Questionnaire l Personal and familial history l Treatments l Diseases l Clinical symptoms 2) Physical examination 3) Pre-operative Haemostasis screening assays l Prothrombin time (PT) n Screening test for the extrinsic and common pathways of coagulation (factors II, V, VII, X). Limited sensitivity to fibrinogen. n Usual normal ranges: 12 - 13 sec (may vary between reagents, please refer to manufacturer’s insert) l Activated Partial Thromboplastin Time (aPTT) n Screening test for the intrinsic and common coagulation pathways of coagulation (factors VIII, IX, XI, XII, V and II). Limited sensitivity to fibrinogen. n May be normal in some forms of von Willebrand disease n Usual normal range: ratio patient/reference ≤ 1.2 l Thrombin time n Exploration of fibrin formation n Usual normal range: < 21 seconds (may vary between reagents, please refer to manufacturer’s insert) Effects of coagulation factors and protein levels on clotting assays MINIMUM LEVEL INFLUENCE OF COAGULATION TESTS2 FACTORS NORMAL VALUES FOR LOW BLEEDING RISK PT3 aPTT4 TT5 XII 60 - 150% - N N XI 60 - 150% 20 - 30% N N VIII 60 - 150% 30 - 40% N N IX 60 - 150% 30 - 40% N N VII 55 - 170% 10 - 20% N N X 70 - 120% 30 - 40% N V 70 - 120% 30 - 40% N II 70 - 120% 30 - 40% N Fibrinogen 2 - 4 g/L 0.5 - 1 g/L N or N or VWF 50 - 160% 40% N N or N Antithrombin 80 - 120% - N N N Protein C 70 - 130% - N N N Protein S 60 - 140%6 - N N N 1. Approximate level in the case of a single factor deficiency. These levels may vary according to different clinical settings, e.g. haemophiliacs undergoing surgery will require higher levels of FVIII 2. Results vary as a function of sensitivity of reagents and single or multiple factor levels 3. PT: Prothrombin Time 4. aPTT: activated Partial Thromboplastin Time 5. TT: Thrombin time 6. Sex and age-dependent Screening assays in Haemostasis l Fibrinogen level n Quantitative assay of fibrinogen level n Usual normal range: 2-4 g/L (200-400 mg/dL) n Elevated fibrinogen levels are observed in inflammatory syndrome (acute or chronic) l Platelet count n Number of circulating platelets n Usual normal range: 150-400 G/L 4) Screening assays for Disseminated Intravascular Coagulation (DIC) PT, aPTT and fibrinogen levels, as well as D-Dimers, are generally abnormal in acute DIC but may be normal during chronic and subacute DIC. These screening tests are thus of limited specificity and sensitivity for the diagnosis of DIC (see section on DIC). Recent studies suggest that fibrin monomer may constitute early and more specific markers of DIC. 5) Screening assays for thrombophilia l There are as yet no global tests available to explore all thrombophilia factors. l First-line activity assays are required for monitoring of inhibitors (see Thrombophilia section). 6) Screening tests for Lupus Anticoagulants (LA) l The screening assays are phospholipid-dependent function tests. At least two different tests are required for detection of LA (see Lupus Anticoagulants section). Bibliography: l Simple coagulation tests survival prediction in patients with septic shock. Lissalde Lavigne G et al. J Thromb Haemost 2008, 6:645-653 l Guidelines for the diagnosis and management of DIC. Levi M. et al. Br J Haematol, 2009, 145, 1:24-33 l DIC diagnosed based on the Japanese association for acute medicine criteria is a dependant continuum to overt DIC in patient with sepsis. Gando S. et al. Thromb Res, 2009, 123, 5:715-718 l Conduites pratiques en hémostase, Charles Marc Samama, LFB monograph, 1996 l Hémostase & thrombose, La Simare éditions impression, 1994 l Hemostasis, a case oriented approach, D. A. Triplett, Igaku-Shoin Medical publishers, 1985 l Recommandations pour une juste prescription des examens d’hémostase en pratique médicale courante, M. Gouault-Heilmann, STV, 2006; vol.18, No1, pages 29-42 l Laboratory Techniques in Thrombosis - A Manual, Second revised edition of the ECAT Assay Procedures, Jespersen J, Bertina RM, Haverkate F, 1999, pages 1-308 Anticoagulant therapy monitoring (1) Oral anticoagulant therapy with vitamin K antagonists (VKA*) l Vitamin K antagonists reduce synthesis of both vitamin K-dependent coagulation factors (factors II, VII, IX, X) and some proteins (Protein C and Protein S). The deficiency in factors II, VII, IX and X induced by the absorption of vitamin K antagonists results in prolongation of PT and of aPTT. l The Prothrombin Time is the reference test of choice for monitoring of vitamin K antagonist therapy. It is expressed as a coagulation time, using the ratio between the patient and a control, or as % prothrombin time, leading to wide inter-laboratory result variability due to the use of different analysers/reagents combination. In order to standardise the results obtained for patients on vitamin K antagonists, results are expressed as INR. l PT results expressed as INR (International Normalized Ratio) n The INR is the ratio of PT to the power ISI (International Sensitivity Index). It represents the ratio of PT that would have been obtained if an international thromboplastin reference material had been used for the test. n The ISI is a value calculated for each batch of thromboplastin reagent and varies according to the type of analyser used. ISI values are specific for pairs of reagents and instruments. The international recommendations suggest the use of a reagent with an ISI value of less than 1.7. n The control time is the geometric mean of PT values measured on at least 20 fresh plasma samples from healthy subjects (with no pathology or treatment that might interfere with coagulation). ISI Patient Time (sec) INR = ( Control Time (sec) ) l Anticoagulant therapy monitoring n Heparin followed by vitamin K antagonists l Monitoring of treatment with vitamin K antagonists with the INR (using a reagent insensitive to heparin at therapeutic doses) l Monitoring of heparin treatment - aPTT (indicates the combined effect of vitamin K antagonists and unfractionated heparin) - Specific anti-Xa assay (specific monitoring of anti-Xa activity) l Treatment with heparin and vitamin K antagonists may be given concomi- tantly for 4 to 5 days until the desired therapeutic range is achieved in terms of INR (i.e. two consecutive INR of two consecutive days unchanged and in the therapeutic range). n Stable patients on vitamin K antagonists treatment The INR value should be checked weekly then monthly, and more frequently in the event of a dose change, unbalanced assay results or suspected interference by other factors. *Antivitamins K or vitamin K antagonists Anticoagulant therapy monitoring (1) l N.B.: n Wide inter-patient variability n Interferences due to: l Other treatments (many drugs can interfere with vitamin K antagonists) l Other diseases l Food and drinks rich in vitamin K l Recommended therapeutic ranges (expressed in INR) INR INDICATION ACCP1, BCSH2, GEHT3 Range Target Prophylaxis of venous thrombosis. 2.0 - 3.0 2.5 Treatment for deep venous thrombosis (DVT) and pulmonary embolism (EP). Cardiac valve disease. Myocardial infarction. 2.0 - 3.0 2.5 Atrial fibrillation. Antiphospholipid syndrome associated with recurrent DVT or 3.5 additionnal risk factors. 2.5 - 3.5 1 ACCP: American College of Chest Physicians 2 BCSH: British Committee for Standards in Haematology 3 GEHT: Groupe d’Etude sur l’Hémostase et la Thrombose Bibliography: l Guidelines on oral anticoagulation (warfarin): third edition - 2005 update. Baglin T.P., Keeling D.M., Watson H.G. for the British Commitee for Standards in Haemotalogy. Br J Haematol, 2005; 132: 277-285 l Evidence-Based Management of Anticoagulant Therapy. Antithrombotic Therapy and Prevention of Thrombosis, 9th Ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Holbrook A., Schulman S., Witt D.M., Vandvik P.O., Fish J., Kovacs M.J., Svensson P.J, Veenstra D.L., Crowther M., Guyatt G.H. Chest, 2012; 141: 152S-184S Anticoagulant therapy monitoring (2) Unfractionated Heparin monitoring Unfractionated heparin (UFH) is a heterogeneous mix of polysaccharide chains of variable molecular weight. One-third of the chains have a pentasaccharide pattern that has a strong binding affinity to Antithrombin. Molecular weight: 2,000 to 40,000 Dalton (average: 15,000). They are used for both therapeutic and prophylactic therapy l Limitation: n Short half-life, dose-dependent n Non-specific binding n Random dose-response effect n Major bleeding risk l Sample collection and treatment: n A standardised protocol should be followed for the collection and processing of the samples.