Thrombophilia

1. Thrombophilia Dr Galila Zaher MRCPath Consultant Hematologist

2. Thrombophilia ‘A disorder of the haemostatic mechanism with a predisposition towards thrombosis’ BUT Many patients with defects remain asymptomatic despite multiple challenges AND >50% patients with TED will have no identifiable laboratory abnormality AND proven thrombophilic defect and a family history of TED are at greater risk of TED than individuals with no family history but a similar defect

3. Thrombophilia Patients with spontaneous venous thromboses, or of a severity that is out of proportion to a recognised stimulus

4. Venous Thromboembolic Disease • Common , associated with considerable morbidity and mortality • USA: 1:1,000 pa clinically significant DVTs 250,000 hospitalisations annually due to VTED

5. Complications • Risk of recurrence: 2 years 17.5% 5 years 24.6% • Fatal PE: 1:50,000 pa 20-30% PM • Commonest cause of death in pregnancy • Post-phlebitic syndrome up to 20%

6. Who to test? • Thrombosis at an unusual site • Recurrent thromboses • Family history of thrombosis • Age less than 40 • Recurrent miscarriages

7. Inherited 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]

8. Thrombophilia Prevalence

9. Other Inherited Risk Factors • Hyperhomocysteineaemia • Dysfibrinogenaemias • Factor VII / • Heparin Cofactor II • Factor XII deficiency • Disordered fibrinolysis Elevated PAI-1 Plasminogen deficiency Thrombin Activatable Fibrinolytic Inhibitor (TAFI)

10. Anti-phospholipid antibodies

11. Acquired • Obesity • Immobility (surgery/trauma) • OCP/HRT • Pregnancy/puerperium • Haemoglobinopathies • Myeloproliferative syndromes • Hyperviscosity syndromes • Cardiac failure

12. Acquired • Chronic inflammatory disorders • Klinefelter’s syndrome • Behçets syndrome • Malignancy • Drug induced (e.g. HIT) • TTP/HUS • Nephrotic syndrome • Protein S deficiency • Inflammatory bowel disease

13. Thrombophilia and Laboratory Testing • Diagnostic accuracy • Clinical value of the tests • Interpretation of results • Tests frequently requested (and interpreted) by individuals who are not specialists in this area • Laboratories frequently have no clinical information relating to the patient

14. Genetic Testing • Reliable and reasonably robust • National External Quality Assurance Schemes (NEQAS) • Some incorrectly identified samples • APCr low: Factor V Leiden mutation confirms • APCr normal: No further testing • Risk of VTED modest • Do we seek informed consent for genetic testing?

15. Phenotypic Testing Accuracy • Enormous variability in results: NEQAS/ECAT data supports this • Oral anticoagulants : Protein C/S • Inappropriate to base a diagnosis on a single result but how many times ? • Incorrect information to patients may be falsely reassuring or result in inappropriate treatment

16. Antithrombin deficiency • 24 patients with genotypically proven AT deficiency • Heparin co-factor assay • IIa substrate:Correctly identified all mutations • Xa substrate:Correctly diagnosed only 50% cases • NEQAS thrombophilia Survey March 2000 Functional AT assays showed significant differences depending upon substrate

17. Laboratory Tests 15% heterozygous PC deficient patients had normal PC activity and 5% normal relatives had low PC activity Heterozygotes Normal relatives

18. Immediate Management • No evidence that anticoagulation is less efficient with prothrombotic abnormalities • Antithrombin deficiency : Heparin resistance is rare type I :can be efficiently anticoagulated , antithrombin concentrates is not usually indicated • PC and PS deficiency:Warfarin induced skin necrosis is rare • Screening prior to initiating OAC therapy inappropriate • LA,severe FXII deficiency&elevated Factor VIII levels difficult monitoring UFH

19. Intensity Or Duration Of Anticoagulation • No randomised prospective studies:Current data/experience standard oral anticoagulant protocols • No evidence that more intensive regimes or extended periods of anticoagulation are required • BUT - APL/multiple inherited abnormalities including may be exceptions • Risk of recurrence may be increased and extended periods of treatment may be required • OACs: Mortality 0.3-0.4% Major bleed 2-3%

20. Aggressive Thromboprophylaxis? • RR increased but the absolute risk is small • Thromboprophylaxis : • Asymptomatic :No indication • At-risk individuals & high risk periods: should be given • ‘Economy Class syndrome’ 90% have >2 risk factors for thrombosis

21. Prothrombotic Abnormality & OCP • Thrombosis in women with inherited prothrombotic & OCP is increased • Family studies may be of value in establishing the risk of thrombosis if a genetic risk factor has been identified • POP or progestagen-containing IUDs no increased risk of VTED • Factor V Leiden + OCP • RR VTED 35/50-fold increase

22. Prothrombotic Abnormality & OCP Avoid • In women with history of TED • 1st-degree relative with TED • in women with multiple genetic defects Asymptomatic women with identified genetic risk factors - not absolute contraindication OCP

23. Prothrombotic Abnormality & HRT • HRT increases risk of TED ~3-fold • Risk highest in the initial 12 ms of treatment • Synergy between HRT and thrombophilia • Use with caution in women with a PMH of TED • EVTET study HRT: 10.7% incidence of VTED • Placebo: 2.3% • Asymptomatic women with identified genetic risk factors - not an absolute contraindication to HRT

24. Thromboprophylaxis In Pregnancy • Risk of VTED increased in pregnancy • Genetic risk factor • Multiple pregnancy • Advanced maternal age • Prolonged bed-rest • Previous thrombotic history • Recurrent miscarriages • Routine thromboprophylaxis is not indicated in all women with thrombophilia

25. Thrombophilia & Arterial Disease • No good evidence • Anti-phospholipid syndrome • Hyperhomocysteineaemia • Factor V Leiden/Prothrombin mutation - Possible synergistic interaction with other risk factors

26. Summary • Increasing enthusiasm for thrombophilia testing • Concerns about accuracy and interpretation • Lack of evidence-based data to aid management • Are we providing patients and clinicians with inaccurate information that leads to false reassurance or alternatively creates panic and results in inappropriate treatment?

27. Genetic defect NO TED TED 50% No lab abnormality Lab abnormality +FH >lab with NO FH

28. Other Inherited Risk Factors • Histidine rich glycoprotein • Elevated FVIII/FX/FXI • Thrombomodulin mutations • EPCR mutations • Tissue Factor Pathway Inhibitor (TFPI) • Factor V Cambridge • Factor XIII (Val234Leu) • Platelet glycoprotein receptor polymorphisms

29. Thrombophilia • Thrombosis is a multi-factorial disease • Multiple genetic risk factors increase the risk of TED • In the majority: screen for only the ‘common’ inherited/acquired prothrombotic abnormalities • 50% of patients with TED have no evidence of prothrombotic abnormalities

30. Management of thrombophilia Dr Galila Zaher MRCPath Consultant Hematologist

31. BLOOD CLOTTING Blood clotting interactions Plasma protein clotting factors Vascular endothelium Platelets

32. Hemostasis Hemostasis Subendothelial matrix Subendothelial matrix Hemostatic plug Hemostatic plug Endothelial cell Endothelial cell WBC WBC WBC WBC Fibrin RBC Platelets Fibrin RBC Platelets

33. COAGULOPATHIES Bleeding Thrombosis Clotting factors Natural anticoagulant platelets

34. Clot formation Platelet activation Primary hemostasis No &count (immediate) Fibrin generation plasma clotting Secondary hemostasis factors (delayed)

35. ADP Aggregation Aggregation Aggregation GpIIb/IIIa GpIIb/IIIa GpIIb/IIIa GpIIb/IIIa GpIIb/IIIa GpIIb/IIIa Adrenaline Adhesion Adhesion vWF Endothelium Exposed Collagen Platelet Activation COLLAGEN THROMBIN ADP GpIIb/IIIa Platelet GpIb Adrenaline Adhesion

36. Clotting factor production Liver: source of plasma clotting factors except VWF Factor VIII: produced by liver & endothelium VWF: endothelial cells & megakaryocytes Vitamin K dependent clotting factors are: II, VII, IX, X

37. COAGULATION PATHWAYS Intrinsic & extrinsic pathways “conclude” in the common pathway Intrinsic pathway clotting factors Extrinsic pathway clotting factors Common pathway clotting factors

38. Extrinsic pathway VII + TF ----->VIIa/TF Intrinsic pathway XII ---> XIIa XI---------XIa • IX --------> IXa • + VIII APC PC +PS • Ca +PL • X----------------------> Xa [Common pathway] • V+Ca+PL • Prothrombin -------------> thrombin AT • v • fibrinogen--------------> fibrin

39. Activation of fibrinolysis damaged cells thrombin inflammation mental/physical stress trauma PAI t-PA extrinsic pathway plasminogen plasmin antiplasmin cross-linked fibrin fibrinogen X-FDP (D-Dimer, cross-linked oligomers, DD/E ...) FDP (X,Y,D,E)

40. Generation Of Fibrin and D-Dimer D D E D D E E E E E D D D D D D D D D D D D E E E E E E E E E D D D D D D D D E E E E E E E E fibrinogen E thrombin fibrin FpA, FpB fibrin polymer F XIIIa cross-linked fibrin (clot) D-dimer cross-linkage

41. D-Dimer • D-Dimer is a synonym for a variety of cross-linked fibrin degradation products. • Indicative for dissolution of an existing thrombus. • Evidence of a previous thrombotic event

42. Clinical Application Of D-Dimer • Exclusion of deep vein thrombosis (DVT) • Exclusion of pulmonary embolism (PE) • Supports diagnosis and monitoring of DIC

43. Incidence Of Venous Thromboembolism • Annual frequency per 100,000 : • Deep vein thrombosis 160 • Symptomatic, non-fatal PE 20 • Fatal, autopsy-detected PE 50 • 250,000 hospitalisations annually due to VTED • Int Angiol 1997

44. Complications • Risk of recurrence: 2 years 17.5% • 5 years 24.6% • Fatal PE: 1:50,000 pa • 20-30% PM • Commonest cause of death in pregnancy • Post-phlebitic syndrome 3 years after DVT 35- 69% 5-10 years after DVT 49-100%Venous ulcers

45. Mortality From Pulmonary Embolism • About 1/10 hospital deaths is due to PE • PE is still the leading cause of maternal mortality

46. Diagnosis Of DVT • Compression ultrasound (CUS) Sensitivity ~97%; Specificity ~94% • Problems: Calf vein thrombosis sensitivity Previous thrombosis specificity Combine with D-Dimer and PTP

47. Clinical Prediction Rule • Entire leg tenderness along deep veins • collateral superficial veins • Entire leg swelling • Calf swelling >3 cm difference • Dilated superficial veins • Pitting edema

48. Clinical Prediction Rule • Recent bed ridden >3 days • Major surgery within last 3 ms. • Active cancer within last 6 mo. • Plaster • Paralysis • Presence of alternative Diagnosis -2

49. Diagnostic Strategies for First Attackproximal Deep Venous Thrombosis High probability Moderate-Low probability (>3) (1-2) (0) Doppler US D-Dimers Abnormal Normal Normal High Doppler US Venography Normal Abnormal Normal Abnormal Save to withhold treatment Treat with heparin

50. Diagnostic Strategies for First AttackDistal Deep Venous Thrombosis High probability Moderate-Low probability (>3) (1-2) (0) Doppler US D-Dimers Abnormal Normal High Normal Doppler US Repeat in W or venography Normal abnormal Abnormal Normal Save to withhold treatment withhold treatment Treat with heparin