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 Platelets Coagulation factors Endothelium Platelets Coagulation factors Fibrinolytic system Natural anticoagulants

thrombin X prothrombin VIII/vWF VIIIa TF VIIa Xa Va TF-expressing cell IX XI XIa thrombin prothrombin IXa platelet X IX Xa Va IXa VIIIa XIa 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 Age –largest gradient of risk with 1000 fold difference between very old and very young: Malignancy-The prevalence of cancer among pts with a venous thrombosis ranges from 3 – 18 %thrombogenic effect of cancer due to tumor production of anticoagulants, mechanical (venous obstruction), acute phase reactions Thrombosis occurs in 50 to 60 % of patients with head trauma, spinal injury, pelvic fracture, and femoral fracture. Immobilization: paralysis, bed rest, plaster casts, prolonged travel.

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 The risk of thrombosis in patients with antiphospholipid antibodies (about half of these patients have SLE) is increased by approximately10fold.

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] Prothrombin 3' UTR mutation 1996/7 NEQAS 25,000+ screens for APCr 2002 NEQAS >50,000

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 11 Factor V Leiden Hetero 20-50 3-15 3-8/80 Homo Prothrombin 3' UTR mutation Hetero 6 2

Multi-Casual Model The thrombotic event is the result of gene- gene interaction and/or gene-environment interaction. Variable RR Annual Incidence% Normal 1 0.008 Hyperhomocysteinemia 2.5 0.02 Prothrombin G20210A 2.8 0.02 Oral contraceptives 4 0.03 Factor Leiden heterozygote 7 0.06 OCT and Factor Leiden 35 0.3 Factor Leiden homozygote 80 0.5-1

Thrombophilia screening: first-line tests Coagulation screen APTT, PT, TT Antithrombin activity Chromogenic assay Protein C Protein S Immunoreactive (free ± total) Modified APC/SR Predilution in FV-deficient plasma Factor V Leiden PCR Prothrombin G20210A 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 Thrombo-embolism 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 Thrombo-embolism 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 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 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 1-3% with 0.3% associated with major hemorrhage (Schulman et al, Chest 2008)

Factors that increase the risk of VKA-related 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 / 0.9 Hypertension 1 3.4 Abnormal renal or liver function 1 each 2 4.1 Stroke 3 5.8 Bleeding history or predisposition 4 8.9 Labile INR 5 9.1 Age > 65 years 6 Drugs/alcohol concomitantly

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: Patient’s bleeding risk Patient’s values and preferences 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 major thrombophilic alteration (protein C or S deficiency, homozygous factor V Leiden or G20210A prothrombin mutation or double heterozygous) Consider extended AC Second unprovoked VTE

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