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Thrombophilia: Practice Aspects Ibrahim Alhijji, MB.BCh., FRCP Head of Clinical Hematology NCCCR HMC Feb. 2015 Contents • • • • Introduction Heritable Thrmbophilia Effect on management Summary Contents • • • • Introduction Heritable Thrmbophilia Effect on management Summary Normal Hemostasis • Vessel wall – Endothelium • • • • Platelets Coagulation factors Fibrinolytic system Natural anticoagulants X TF VIIa prothrombin thrombin VIIa TF thrombin prothrombin IXa VIIIa Xa Va TF-expressing cell IX VIII/vWF V XI Va XIa platelet X IX XIa IXa VIIIa Xa Va Activated platelet Hoffman M et al. Blood Coagul Fibrinolysis. 1998; 9(suppl 1): S61-S65. Bleeding or Thrombosis • Any alterations in hemostatic mechanism may lead to either bleeding or thrombosis Incidence • VTE is affecting 1-2 in 1000/year • Leads to chronic post-thrombotic syndrome (20%) and chronic thrombo-embolic pulmonary hypertension (10%) • 3rd most common cardiovascular disease after MI and CVA ACCP (Bates et al 2012, Kearon et al 2012) NICE (2012) Causes of death in Europe • 543,454 due to VTE • Exceeds combined deaths due to: AIDS 5,860 BC 86,831 PC 63,636 Transport Accidents 53,599 T & H 2007 Circulation 1996 Contents • • • • Introduction Heritable Thrmbophilia Effect on management Summary Virchow’s Triad • Pathogenesis of a Thrombus Endothelial injury Abnormal blood flow Hypercoagulability • Primary (genetic) • Secondary (acquired) Thrombophilias • A heterogeneous group of conditions that predispose individuals to VTE Acquired • Age: largest gradient of risk • Malignancy: prevalence ranges from 3-18% • Surgery: – Orthopedic surgery:30 - 50% – Abdominal surgery: 30% – With anticoagulants: 18% • Major trauma: 50-60% • Immobilization Acquired • Oral contraceptives: 4 X increase in risk • Hormonal replacement therapy: 2-4 X increase • Pregnancy and post-partum: 10 X increase • Antiphospholipid antibodies: 10 X increase Heritable Thrombophilia 1965 AT mutation identified [Egeberg et al] 1967 Dysfunctional fibrinogen [Egeberg et al] 1981 Protein C [Griffin et al] 1984 Protein S [Comp et al]] 1993/4 APCr/FV L [Dalhback/Bertina et al] 1996 Prothrombin mutation [Poort et al] Heritable Thrombophilia • FVL and Prothrombin gene mutation are the most common genetic abnormalities occurring in patients with VTE (Seligsohn et al’ NEJM 2001) • One or more of these abnormalities occur in about 50% of patients with first VTE (Christiansen et al, JAMA 2005) Thrombophilia Prevalence Risk factor Subjects with thrombosis (%) General population (%) Relative Risk of Thrombosis Antithrombin 1 0.2 25-50 Protein C 3 0.3 10-15 Protein S 2-3 0.2 11 Factor V Leiden Hetero 20-50 3-15 3-8/80 Homo Prothrombin 3' UTR mutation Hetero 6 2 3 Multi-Casual Model • The thrombotic event is the result of gene- gene interaction and/or gene-environment interaction. Variable Normal Hyperhomocysteinemia Prothrombin G20210A Oral contraceptives Factor Leiden heterozygote OCT and Factor Leiden Factor Leiden homozygote RR 1 2.5 2.8 4 7 35 80 Annual Incidence% 0.008 0.02 0.02 0.03 0.06 0.3 0.5-1 Thrombophilia screening: first-line tests Coagulation screen APTT, PT, TT Antithrombin activity Chromogenic assay Protein C Chromogenic assay Protein S Immunoreactive (free ± total) Modified APC/SR Predilution in FV-deficient plasma Factor V Leiden PCR Prothrombin G20210A PCR APC/SR, activated Protein C sensitivity ratio; APTT, activated partial thromboplastin time; prothrombin time;TT, thrombin time Lab Evaluation • Risks, benefits and limitations should be discussed • Patient should be consented • It may has uncertain predictive value of recurrence (anxiety) • Negative test does not exclude an increased risk of VTE (false reassurance) • Repeat testing for identification of abnormality is indicated • Interpretation is difficult Lab Evaluation • Timing: – Acute thrombotic event, chronic inflammatory conditions, pregnancy, liver disease, DIC, OCP or anticoagulant therapy will affect the results of functional assays – 14 days after the discontinuation of oral anticoagulation therapy Who Should we Test? (NICE & BJH-2010) • Do not offer testing to patients who have had provoked VTE • Do not offer thrombophilia testing to patients during acute VTE or who are continuing anticoagulation treatment Who Should we Test? (NICE & BJH-2010) • Consider testing in patients (selected) who have had unprovoked VTE, less than 40 yrs and who have a first degree relative who has had VTE if it is planned to stop anticoagulation treatment • Children with purpura fulminans • Skin necrosis due to warfarin Contents • • • • Introduction Heritable Thrmbophilia Effect on management Summary Treatment • Initial management of acute thrombosis is the same for patients with and without inherited thrombophilia – Anticoagulation with warfarin for 3-6 months – There is no evidence that heritable thrombophilia should influence the intensity of therapy (Schulman & Tengborn, TH 1992; Kearon et al, Blood 2008) Recurrent VTE • The risk for recurrent VTE after major factor related VTE is 1-3% patient per year • Slightly higher for minor factor related VTE • For unprovoked VTE the risk is 5-15% per year, up to 30-35% after 5 years (Iorio et al, AIM 2010; Douketis et al, AIM 2010; Eichinger et al, Circulation 2010; Prandoni et al, Hematologica 2007) Cambridge Venous Thromboembolism Study (CVTE) (2003) • Two year Prospective Study: – 570 patients – Recurrence rate was 11% • Lowest incidence after surgery related VTE (0%) • Highest incidence with un-precipitated VTE (19.4%) Cambridge Venous Thromboembolism Study (CVTE) (2003) – 85% of patients were tested for heritable thrombophilic defects→ recurrence rates were not related to presence or absence of heritable thrombophilia. – CONCLUSION: Thrombophilia testing had no predictive value for reoccurrence Baglin et al. The Lancet 2003. Leiden Thrombophilia study (LETS) JAMA 2005 • Prospective follow up study of LETS pts – 447 patients followed for a mean of 7.3 years – Incidence rate of recurrence was highest during the first two years: annual rate of 3.2%; cumulative recurrence of 12.4% at 5 years • Risk of recurrence was 2.7 x higher in men than women (95% CI , 1.8-4.2) • Higher risk of recurrence with idiopathic initial VTE • Lower risk of recurrence with provoked initial VTE • OCT use during follow up had a higher recurrence rate (28 per 1000 pt-yrs vs 12.9 per 1000 pt-yrs) Leiden Thrombophilia study (LETS) JAMA 2005 • Conclusion: – Clinical factors (male sex, use of OCT’s, idiopathic initial VTE) have a more significant role in risk of reoccurrence than lab abnormalities (Christiansen et al, JAMA 2005) Thrombophilia and Recurrent VTE • Retrospective analysis showed detection of natural anticoagulants deficiency in selected patients predicted a risk of recurrence of 6.2% compared to 2.2% in patients with FVL or Prothrombin gene mutation (Lijfering et al, Blood 2009) • In general the risk of recurrence is uncertain and it is low if first event was provoked (Cohn et al, CDSR 2009) Guidelines ACCP 2008 • The presence of hereditary thrombophilia has not been used as major factor to guide duration of anticoagulation for VTE because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence Predicting Disease Recurrence- DASH (Tosetto, JTH 2012) • 1818 with unprovoked VTE treated with warfarin for 3 months analyzed and followed up for 5 years Predicting Disease Recurrence- DASH (Tosetto, JTH 2012) Multivariate Score D-dimer-abnormal 2 Age-less than 50 1 Sex-man 1 Hormonal associated VTE -2 Predicting Disease Recurrence-DASH (Tosetto, JTH 2012) • May be useful to decide whether therapy should be continued indefinitely (if score more than 1) or stopped after 3 months (if score 1 or less) • Independent validation is required in separate population D-dimer to guide the duration of therapy (DULCIS, Blood 2014) • Multicentre prospective study • 1010 patients with unprovoked VTE • 2 years follow up D-dimer to guide the duration of therapy (DULCIS, Blood 2014) D-dimer to guide the duration of therapy (DULCIS, Blood 2014) • D-dimer can be considered as an independent factor of VTE recurrence • Serial measurement is suitable in clinical practice D-dimer • Potential need for gender specific and age specific D-dimer cut points (Legnani et al, IEM 2011) • Additional research is needed Men and HER DOO2 • Prospective cohort of patients with first unprovoked VTE • All men are considered at high risk of recurrence Men and HER DOO2 • For women >=2 factors (comprising lower extremity hyperpigmentation, edema, redness, D-dimer >=250 ng/ml [during therapy], obesity [body mass index >=30 kg/m2] and age over 65 years) identifies women at high risk for recurrent VTE (Le Gal et al, TH 2010; Rodger et al, CMAJ 2008) Residual Vein Occlusion • Lack of a standard definition for RVO and the potential for operator variability in the interpretation of US findings • Detected in at least 40% of patients at 3-6 months treatment • Poor predictor of VTE recurrence JTH 2011 AJH 2011 TH 2011 EJVES 2010 Blood 2014 Risk Factors of VTE Recurrence 1. 2. 3. 4. 5. Mode of initial presentation Patient’s gender D-dimers Age ? Thrombophilia Baglin et al, 2003; Douketis et al, BMJ 2011; DULCIS, Blood 2014 Duration of Therapy • Depends on the presence or absence of risk factors of VTE recurrence • The benefit of continued therapy needs to be balanced against the risk of therapy related bleeding (Schulman et al, Chest 2008) • Annual risk for therapy related bleeding is 13% with 0.3% associated with major hemorrhage (Schulman et al, Chest 2008) Factors that increase the risk of VKArelated bleeding (Scientifica 2012) Treatment related Patient related First 3 months of therapy Advanced age (>75 years) Actual INR values > 4.5 Frequent falls Low quality of anticoagulation monitoring History of major bleeding Uncontrolled hypertension Renal or liver failure Associated antiplatelet therapy Drugs Poor compliance Absence of familial or social support Recent surgery Cancer HAS-BLED score (Lip et al, JACC 2011) Risk factors Score for each risk factor Total score Major bleeding events (% patients) in relation to the total score None / 0 0.9 Hypertension 1 1 3.4 Abnormal renal or liver function 1 each 2 4.1 Stroke 1 3 5.8 Bleeding history or predisposition 1 4 8.9 Labile INR 1 5 9.1 Age > 65 years 1 6 / Drugs/alcohol concomitantly 1 each / / HAS-BLED • HAS-BLED score has been developed for patients with AF who are generally elderly (Pisters et al, Chest 2010) • It needs to be studied in VTE patients Guidelines ACCP 2012 • Recommend at least 3 months treatment for unprovoked DVT • Suggest to evaluate for the risk-benefit ratio of extended therapy Extended Therapy • Periodic reassessment: 1. Patient’s bleeding risk 2. Patient’s values and preferences 3. New research findings Contents • • • • Introduction Heritable Thrmbophilia Effect on management Summary Summary • Inherited thrombophilia can be found in up to 50% of VTE cases • Only selected pts should be tested • Laboratory testing should be done at right time and results should be interpreted with caution Summary • Initial management is not different from non inherited thrombophilia • Risk of recurrence should be identified for unprovoked VTE • Duration of therapy is determined largely by clinical factors and patients preferences Suggested management Clinical condition Management Secondary* isolated distal DVT 6 weeks AC# Unprovoked isolated distal DVT 3 months AC Secondary proximal DVT and/or PE 3–6 months AC Unprovoked first proximal DVT and/or PE 3–6 months AC, then stratify for individual risk of recurrence Life-threatening PE as index event Consider extended£ AC VTE associated to active cancer AC until cancer is no longer active Unprovoked VTE associated with antiphospholipid syndrome or antithrombin deficiency Extended AC Unprovoked VTE associated with other Consider extended AC major thrombophilic alteration (protein C or S deficiency, homozygous factor V Leiden or G20210A prothrombin mutation or double heterozygous) Second unprovoked VTE Extended AC Thank you