A PILOT WITH DVTFACTOR V LEIDEN Dr Fiona

A PILOT WITH DVT+FACTOR V LEIDEN Dr Fiona Rennie Emirates Medical Services Dubai

1. DOES HE REQUIRE LIFE LONG ANTICOAGULATION? 2. SHOULD HE BE LICENSED TO FLY ON WARFARIN? • • • OUTLINE Factor V Leiden (FVL) Audit of Emirates Pilots Case History Risk of Recurrence of VTE in FVL Anticoagulation in Aircrew Answers!

Factor V Leiden Mutation • Autosomal Dominant Hypercoaguability Disorder • Discovered in Leiden, Netherlands in 1994 • Most common genetic cause of VTE

Mechanism of Hypercoaguability • Factor V is a co-factor for the activation of thrombin • Activated Protein C is a natural anticoagulant and by cleaving Factor V arrests the clotting pathway because fibrin can no longer be formed • The Factor V Leiden molecule has an abnormal shape making it resistant to APC resulting in a hypercoaguable state.

Risk of VTE in Factor V Leiden Mutation • 4% of population heteroygotes =8 x increased risk of initial VTE (approx 10: 1000 per year) • 0. 16% of population homozygotes =80 x increased risk of initial VTE • Risk is VENOUS only • Up to 30% of diagnosed VTE have FVL mutation

Is This a Concern in The Pilot Population? Cases of VTE in EK pilots reviewed for a 5 year period: • 6 cases of VTE • 50% -Heterozygotes for Factor V Leiden mutation -All 3 had recently travelled as passenger =2 risk factors • 50% -Recent history of surgery or trauma =1 risk factor • Currently 2248 pilots employed by Emirates -There could be up to 89 pilots to be FVL HZ?

AGE SEX YR THROMB SCREEN TRAUMA SURGERY BMI DIAGNOSIS WARFN STAT US 44 M 2004 FVL HZ NO 27 DVT - HOLIDAY TRAVEL 3/12 RTF 2004 FVL HZ NO 25 PE/SUBCLINICAL DVT -SCUBA DIVING HOLIDAY 6/12 RTF 2008 FVL HZ NO 28 DVT – AIR/CAR TRIP 6/12 RTF 2006 NEG YES 27 DVT -GASTROCNEMIUS TEAR 3/12 RTF 2008 NEG YES 27 DVT -ACL (knee) REPAIR 3/12 RTF 2009 NEG YES 28 DVT –Cephalic vein CLAVICLE FRACTURE 3/12 RTF IND 44 M GER 52 M CAN 48 M AUS 50 M CAN 46 M UK

Outcome • None of the 6 have had a second episode • None on long term anticoagulation • Counselled regarding mobility and flight socks for air travel • LMW Heparin recommended for those with FVL for travel as a passenger for flights over 4 hours

Incidence of VTE in Emirates Pilots • • 0. 7 : 1000 per year (Gen Pop 1 -2: 1000 per year) 100% had risk factors 50% had not flown between their injury and VTE unlikely occupationally related CAA Professional Pilots 1990 -2000 (R. Johnston/A. Evans) • Incidence of VTE 0. 21 : 1000 per year • 59% risk factors such as surgery/trauma • Concluded VTE multi-factorial, aircraft cabin does not pose an occupational risk Netherlands Commercial Pilot Study • Incidence of VTE of 0. 3 : 1000 per year

Case History 52 y. o. Canadian B 777 Captain

History • 3 day history -Right thigh, groin, testicular pain & ankle swelling • In the previous 3 weeks: • • Day 1 -Dubai to JFK to Dubai (as pilot) Day 4 -Dubai to Toronto -pax (14 hrs) Day 5 -2 hour flight, 2 hr drive, Day 7 -14 hr car journey (two stops) Day 9 - 5 hr flight (noticed soreness in leg) Day 15 – Vancouver to Toronto to Dubai –pax (20 hrs) Day 17 –Dubai to Toronto to Dubai (as pilot)

Past History 1978 • Age 22 survived a DC 3 crash • Multiple leg fractures • Airlifted to hospital and in cast for 3 months 1983 • Age 27 severe chest pain, elevated cardiac enzymes and abnormal ECG • Diagnosis myocardial infarction • Normal angiography • Loss of medical 5 years Mother “clot in neck” age 40

Investigations • D-Dimer 2443 ng/ml (>500 positive) (96. 4% sensitivity for identifying VTE) • Doppler Ultrasound Scan : RIGHT LEG- “Hypoechoic, homogenous structure visible in all veins from common femoral to peroneal vein. No venous flow in these veins” LEFT LEG –”venous stasis in popliteal, posterior tibial and peroneal veins “ • Thrombotic Screen -Factor V Leiden Heterozygote, -family screened, sister positive

Diagnosis and Management • Right leg DVT confirmed • Right Thrombectomy Day 3 Clot extending from right illiac veins to ankle, 25 g thrombus removed above knee • Warfarin 6 months • Graduated Compression Stockings 2 years • Suspension of Medical License

Risk of VTE Recurrence For This Pilot • Lifetime risk of recurrence was estimated to be 1520% • Risk is highest in first 5 years • Incidence between 2 – 4. 4% per year in first 5 years However 2 meta-analyses (Marchiori 2006, Ho 2007) • Found risk of recurrence to be only slightly greater in FVL pts than those with previous DVT in non FVL. • RR 0. 9 -2. 4 (4 studies , Ho 2006), RR 1. 39 (Marchiori 2006)

Risk Stratification • High risk of recurrence - FVL Heterozygotes as well as Prothrombin 20210 HZ - Factor V Leiden Homozygotes Good evidence life long warfarin after first VTE. • Average Risk of Recurrence -Factor V Leiden heterozygotes Cessation or warfarin at 3 -6 months

Factors Increasing his Recurrence Risk VIRCHOWS TRIAD Hypercoaguability -FVL heterozygote Endothelial Lesion -Damage to leg veins Venous Stasis - Immobility in flight?

Factors Decreasing his Recurrence Risk • Thrombectomy Reduces damage to the vein, but no conclusive evidence that it reduces the risk of recurrence of VTE • Highly motivated individual, Weight loss, exercise, compression stockings and will not be immobile in flight • First recorded episode of DVT Is car journey (+ FVL) the cause?

Does His Work Environment Contribute To Recurrence Risk? Risk of VTE approx doubles after a flight longer than 4 hours due to prolonged seated immobility. (WRIGHT Phase 1) Does this apply to pilots? Risk contributed to by Obesity, Extremes of Height, Oral Contraceptives and Prothrombotic Disorders Maybe aircraft specific factors also? ? ?

Benefits vs Risks of Warfarin • Reduces risk of recurrence of VTE by 80 -95% • But in Aviators consider the risk of INTRACRANIAL bleed • INR values are potent predictors of haemorrhagic complications • Low risk of major bleed if: -INR is maintained between 2. 0 -3. 0 -Risk profile low: Young, >3/12 on Warfarin, no Co-Morbid Conditions

Risks of Warfarin if INR Stable RCT, Non Valvular AF vs Untreated Controls , Young and Otherwise Fit. • Risk of major bleed 1 – 1. 5% per year (Warfarin) 0. 5 – 1. 0% (Controls) 10, 757 pts-Not Stratified for Risk • 2. 5% per year of major bleed Meta Analysis of 29 RCT’s Warfarin Rx for DVT • 2. 2% per year risk of major bleed reducing to 1. 9% after 3/12 on Warfarin , The risk seems acceptable in a multi crew environment

Is Life-Long Anticoagulation Required? 1. Risk of recurrence of VTE 2 - 4. 4 % per year for first 5 years But risk of sudden incapacitation less than 1% 2. Risk of bleeding on anticoagulation 1 – 1. 5% per year with INR 2. 0 -3. 0 (with no other co-morbidities)

Outcome • Reinstated when off Warfarin (6/12) • Weight loss (10 kg), Daily Exercise • Educated regarding prevention -Hydration, Mobility, Flight Socks for work flights > 4 hrs -Prophylactic LMW Heparin NOT required for work flights • Second VTE would require life long Warfarin –DQ

Regulators View on Anticoagulation • United Arab Emirates: No pilots have been licensed on anticoagulation but acceptable for cabin crew. • UK, Australia and New Zealand: Class 1 OML Ø If the underlying indication for Warfarin does not preclude flying Ø Target INR of 1. 8 -2. 5 (UK CAA) Ø 6/12 of stability before relicensing (2/12 INR’s) Ø INR check with personal monitor within 12 hours of flying

Monitoring • Hemosense INRatio®, Coaguchek ®, Pro. Time. Test ® • Coagu. Chek S ® INR Monitor (Australian Rural Study) 88% of dual INR measurements were within 0. 5 INR units of each other

Answers Does he require lifelong anticoagulation after 1 VTE? NO -Recurrence VTE 2 - 4. 4% per year decreasing with time -But risk of sudden incapacitation < 1% per year VS -Risk of bleeding on Warfarin 1. 0 - 1. 5% per year Should he be licensed to fly on warfarin ? YES But only OML because risk close to 2% per year

References… 1. 2. 3. 4. 5. 6. 7. Oral Contraceptives and venous thromboembolism –BMJ Editorial 15 September 2009, Volume 339 WHO research into global hazards of travel (WRIGHT) project –Final report of phase 1 Ho et al. Risk of Recurrent Venous Thromboembolism in Patients with Common Thrombophilia. Arch Intern Med / Vol 166 April 10 2006 Marchiori et al. The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or PT 20210 A mutation. A systematic review of prospective studies. HAEMATOLOGICA 2007; 92(08) Correspondence Dr Paul Gaingrande, Haematologist, Oxford Haemophilia and Thrombosis Centre UK Van Hylckama Vlieg et al; The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 5 September 2009/Volume 339 Linkins LA et al; Major bleeding risk with warfarin for DVT, Cleveland Clinic Journal of Medicine Vol 71 Number 4 April 2004

References (2) 8. 9. 10. 11. 12. 13. 14. 15. 16. Ganfyd; Therapeutic bleeding risk, www. ganfyd. org Kuijer PM; Predicirion of the risk of bleeding during anticoagulation treatment for venous thromboembolism. Arch Intern Med 1999; 159: 457 -60 Factors Affecting Bleeding Risk During Anticoagulant Therapy : Discussion www. medscape. com Harper C, Keeling D. Progestogen Only Contraception for Patients with Thromboembolic Disease. Oxford Radcliffe Hospitals Fitzmaurice D et al. ABC of antithrombotic therapy. Bleeding Risks of antithrombotic therapy. BMJ 2002; 325: 828 -831 Amy JJ, Tripathi V, Contraception for women: an evidence based overview BMJ 15 September 2009, Volume 339 Navathe, Pooshan. Show me the evidence: Atrial Fibrillation in an Airline Pilot CAA NZ. Powerpoint presentation Lidegaard O et al. Hormonal Contraception and risk of venous thromboembolism: national follow-up study, BMJ 15 September 2009, Volume 339 Correspondence Paul Collins-Howgill, UK CAA, Pooshan Navathe CASA, Dougal Watson CAA NZ

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