DISCLOSURE. Presented by: Merav Sendowski, MD Oregon Health and Science University

Transcription

1 Thrombophilia!

2 DISCLOSURE Presented by: Merav Sendowski, MD Oregon Health and Science University Created by: Thomas Deloughery, MD Oregon Health and Science University Current Relevant Financial Relationship(s) Speaker Bureau None

3 Key Questions Venous vs arterial clots Hypercoagulable states When to test? What to test for? More specialized testing

4 Is the Thrombosis Venous or Arterial? Venous thrombosis Classic hypercoagulable states Arterial thrombosis Atherosclerosis Embolism Not usually associated with hypercoagulable states

5 When to Consider a Hypercoagulable State Thrombosis at a young age Multiple thromboses Thrombosis at an unusual site Family history of thrombosis

6 Approach Venous or Arterial? Site of Thrombosis? Patient age? Associated risk factors? Family History?

7 Unusual Sites Cerebral vein thrombosis Mesenteric vein thrombosis PNH Myeloproliferative syndromes Upper extremity vein thrombosis Not associated with hypercoagulable states

8 What Is the Age of the Patient? Children unusual to have clots Young adult - inherited hypercoagulable states 50% occur with provocation Older - acquired

9 VTE manifestation age according to the presence and type of thrombophilia

10 Br J Haematol Dec;163(5):

11 Family History Incomplete penetrance Detailed history Aunts, uncles, cousins

12 Inherited Hypercoagulable States TF + VII Antithrombin IX + VIII X + V Protein C (Protein S) II CLOT

13 Inherited Hypercoagulable States Majority involve defects in protein C system Common 10% of people The Big Five Factor V Leiden Prothrombin gene mutation Protein S deficiency Protein C deficiency Antithrombin III deficiency

14 The Big Five Inherited States Normal Hyper Relative Risk Antithrombin III Protein C Protein S Factor V Leiden Prothrombin gene

15 Relative Risk and Annual Incidence of Thrombosis Risk ratio %/year No defect Antithrombin Protein C Protein S F V Leiden No increase in arterial events

16 The "Classics" Antithrombin, Protein C, and Protein S Less common (1-5% of hypercoag states) High risk of thrombosis RR 10 Associated with only venous thrombosis

17 Factor V Leiden Most common risk factor 3-9% population 20% of first DVT s 50-60% of hypercoagulable states Often associated with other risk factors Dramatic increase in risk with estrogens

18 APC PS FVa R306 Slow Full inactivation PS enhances by 20x R506 Rapid Partial inactivation Site of FVL PS enhances by 4-5 fold

19 Protein C (S) V (VIII) + Protein C (S) FVL

20 Factor V Leiden Deep venous thrombosis Cerebral vein thrombosis Not associated with MI or strokes

21 Prothrombin Gene Mutation Mutation of G-->A at position of the prothrombin gene Increases levels of prothrombin Common: 1-5 % of population

22 Prothrombin Gene Mutation: Disease Associations Increased DVT relative risk by 2-3 fold Increased risk of cerebral vein thrombosis 3-10 fold Dramatic elevation of risk with OCP users No increased risk of myocardial infarction

23 Two Types of Hypercoagulable States Defective natural anticoagulants Increased thrombin generation

24 Loss of Function Defects Less common More severe (RR 10-40) Antithrombin Protein C Protein S

25 Gain of Function Defects More common (3-15%) Less severe (RR 1.5-3) Factor V Leiden Prothrombin gene mutation Elevated factor levels (VIII, IX, XI)

26 Acquired Hypercoagulable States Common Complication of underlying disorder Clue to presence of disorder

27 Clues to Acquired State Flurry of thromboses Older age at time of onset Refractory to warfarin Both venous and arterial thrombosis

28 Inherited State Age Acquired State Age

29 Acquired Hypercoagulable States Cancer APLA Estrogen

30 Cancer and Thrombosis Classic association since Trousseau's time Thrombosis can herald cancer Cancer increases risk and decreases success of therapy of thrombosis Worsens prognosis Patients with new DVT and cancer have 4-8 increased risk of dying of their thrombosis In cancer patients with thrombosis, cancer mortality is doubled

31 Probability of death (%) Probability of survival (%) Prognosis with Cancer and Thrombosis year survival Cancer at time of VTE 12% 60 DVT/PE +cancer 60 Cancer without VTE 36% ratio = 2.46 (95% CI: ) 40 cancer DVT/PE no cancer 20 no DVT/PE Number of days after admission Years after diagnosis Levitan N, et al. Medicine. 1999;78: Sorensen HT, et al. N Engl J Med. 2000;343:

32 Cancer and Thrombosis: Epidemiology Cancer increases risk of thrombosis 3-6 fold Cancer diagnosis coincident with DVT diagnosis in 20% of cases Idiopathic DVT: may be a sign of cancer

33 Tumor Type and Thrombosis Cancers most strongly associated with VTE Pancreas Brain Cancers most common in patients with VTE Colorectal Breast* Lung

34 Pancreas Brain Myeloprol Stomach Lymphoma Uterus Lung Esophagus Prostate Rectal Kidney Colon Ovary Liver Leukemia Breast Cervix Bladder Relative Risk of thrombosis in Cancer Patients Thrombosis Risk And Cancer Type Stein PD, et al. Am J Med 2006; 119: 60-68

35 Should Patients with Idiopathic DVT be Screened for Cancer? Randomized Clinic Trials of both CT and PET scan show no benefit to screening

36 Bottom Line No role for aggressive blind screening Recommended approach: 1. Age specific routine screening Chest CT in smokers 2. Follow clues (i.e. colonoscopy in patient with iron deficiency) 3. Consider CT in "worrisome" patients Frustratingly many tumor are metastatic when discovered.

37 Antiphospholipid Antibodies Acquired hypercoagulable state with multiple manifestations Venous thrombosis Arterial thrombosis Pregnancy complications Confusing diagnostic tests

38 Semantics APLA syndrome: APLA + one clinical thing Thrombosis (arterial or venous) Miscarriages Primary APLA Secondary APLA Terminology: Lupus inhibitor or lupus anticoagulant = APLA which prolongs the clotting time

39 Who Gets This? 30-50% SLE patients have APLA Primary APLA: men>>women Up to 30% of normal people have low titer APLA

40 APLA: Venous Thrombosis Most frequent presentation High rates of recurrence Locations Legs Abdominal veins Adrenal glands

41 APLA: Arterial Thrombosis Common cause of strokes in young people Less certain association with MI Predictor of recurrent stroke

42 APLA: Fetal Loss Up to 30% of women with frequent miscarriages have APLA Placental infarctions Higher incidence of pre-eclampsia and HELLP syndrome

43 Placental Infarct path.upmc.edu/cases/case75/micro.html

44 APLA: Other Complications Thrombocytopenia Chorea Cardiac valve disease Catastrophic APLA

45 How to Diagnose APLA Need clinical history Need to demonstrate persistent titer of ACLA or lupus inhibitor

46 Sapporo/Sydney Criteria Clinical event Thrombosis Pregnancy complication Persistently positive APLA test 12 weeks apart 10% false positive rate at time of clot

47 ACLA LUPUS INHIBITORS SYMPTOMS

48 APLA: Testing Anticardiolipin antibodies ELISA assay Coagulation based test: 1. Prolonged clotting test 2. Does not correct with 50:50 mix 3. Phospholipids correct the clotting test

49 Anticardiolipin Antibodies Laboratory dependent Common in older patients Low titer ACLA very common (~20-30%) High titers more predictive of recurrent events Anti-b2 glycoprotein antibodies more predictive

50 b2-gp b2-gp

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52 Blood :

53 ACLA: Burn Points Low titer positivity is common DX: > 99 th percentile or 40 GPL units False positive IgM common + ACLA has less predictive power than + lupus inhibitor

54 Lupus Inhibitors 1. Demonstrate prolongation of coagulation test 2. Demonstrate lack of total correction with normal plasma 3. Demonstrate dependence on phospholipids

55 IXa Ca Ca Ca Ca

56 IXa Ca Ca Ca Ca IXa Ca Ca Ca Ca

57 Lupus Inhibitors Presence of lupus inhibitors more suggestive of hypercoagulable states RR: 3-11 Current tests Hexagonal phospholipid assay Dilute Russell viper venom time

58 APLA: DX Three parts 1. Clinical history 2. Laboratory findings 3. Time!

59 APLA Higher risk for thrombosis Lupus inhibitor High titer IgG ALCA Triple Positive

60 Cumulative incidence of thromboembolic events in patients with antiphospholipid syndrome (APS) and triple laboratory positivity according to treatment with oral anticoagulants during follow-up (OA, oral anticoagulants). Journal of Thrombosis and Haemostasis 8: , 2010

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62 Work-up: First Line Antithrombin III Protein C Protein S Factor V Leiden Prothrombin gene mutation Homocysteine Antiphospholipid antibodies Anticardiolipin antibodies B2Glycoprotein Lupus inhibitors

63 Homocysteine Elevated levels associated with thrombosis However, trials to lower HCY uniformly negative Marker of prothrombotic process Zero utility in checking homocysteine or MTHFR

64 Figure 4. Susceptibility to venous thrombosis is not increased in Tg-I278T Cbs -/- mice. The (A) weight and (B) length of thrombus developed in the IVC after 48 hours of ligation was measured in 20-week-old mice (n mice per group). Values are mean + SE. Figure 5. Elevated methionine in young Tg-I278T Cbs -/- mice does not alter risk for microvessel thrombosis. Plasma levels of (A) thcy and (B) methionine were measured in 3-week-old mice. (C) The time to first occlusion or stable occlusion was examined in mesenteric arterioles after chemical injury. (D) The percentage of mice with a patent mesenteric arteriole as a function of time after chemical injury. Seven mice were studied in each group. Values are mean + SE; **P <.001 and *P <.01 compared with Tg-I278T Cbs -/-mice. Blood Mar 29;119(13):

65 Pregnancy Complications: APLA Test: Pregnancy complications (HELLP,PIH,...) 1 or more fetal death after 10 weeks 1 or more premature birth due to PIH or FUGR 3 or more miscarriages before week 10 RCT shows benefit of heparin/aspirin in preventing complications

66 Pregnancy Complications: Thrombophilia May be associated with adverse pregnancy outcomes RCT data shows no benefit to anticoagulation

67 Work up: Second line PNH screen (flow cytometry) Visceral thrombosis Thrombosis with cytopenias MPS testing (JAK2 mutation assay) Visceral thrombosis Thrombosis with elevated blood counts Fibrinogen If low fibrinogen antigen Thrombin and reptilase time

68 When to Work-up At the time of event and before a/c If able to obtain tests Rapid diagnosis But: Often falsely low values of AT-III, etc.. Falsely low protein S with pregnancy, illness Transient APLA

69 Anticoagulation: Effect on Work-up Heparin Controversial AT-III (heparin vs acute event) Some coagulation based test for APLA Hexagonal phospholipid not affected Warfarin Protein C and Protein S Need to wait 3 weeks before testing protein S

70 DOACS: Effect on Work-up All new anticoagulants interfere with lupus inhibitor testing Falsely increase Protein C and S activity levels Can also affect Antithrombin

71 Work up: Does It Matter?? Increasing evidence that circumstances of thrombosis "trumps" presence of hypercoagulable state for predicting risk of recurrence RR of recurrence ranges

72 Patients with and without thrombophilia during the period from the end of the initial anticoagulation period (90 days) until January 1, The crude hazard ratio of thrombophilia compared with no thrombophilia was 1.3 (95% confidence interval, ); the hazard ratio adjusted for age, sex, and oral anticoagulation as a time-dependent covariate was 1.4 (95% confidence interval, ). JAMA May 18;293(19): Thrombophilia, clinical factors, and recurrent venous thrombotic events.

73 Problems with testing Overestimation of risk from abnormal testing 10% of the general population test positive False assurance from negative testing Misinterpretation of testing results Will it change management? Costs

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75 Does Thrombophilia Testing Change Management? Provoked Not predictive of recurrence Idiopathic Need to be anticoagulated regardless of thrombophilia

76 Arterial disease Two major causes Embolism Atherosclerosis No convincing associations with arterial disease and hypercoagulable states Exceptions: Strokes and lupus inhibitors or high titer APLA

77 Cost Thrombophilia testing ~ $1500 Increasing denials of genetic testing

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79 Explanatory Specific therapy Antithrombin PNH Why Evaluate? Helps in borderline cases Family screening??? Prevent first thrombosis??

80 Thrombophilia Testing Provoked no! Idiopathic Consider APLA Can see other complications Consider PNH/MPS Multiple thrombosis Unusual sites Break through on anticoagulation

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