Thrombophilia where angels fear to tread
This presentation is the property of its rightful owner.
Sponsored Links
1 / 29

Thrombophilia Where angels fear to tread PowerPoint PPT Presentation


  • 55 Views
  • Uploaded on
  • Presentation posted in: General

Thrombophilia Where angels fear to tread. Andrew McDonald Division of Haematology GSH. n. CASE 1 40 year old female (physician) 3 years ago: episode of severe diarrhoea / dehydration swollen calf  U/S “calf vein” DVT 2 weeks full dose clexane, then nothing no further events

Download Presentation

Thrombophilia Where angels fear to tread

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Thrombophilia where angels fear to tread

ThrombophiliaWhere angels fear to tread

Andrew McDonald

Division of Haematology

GSH


Thrombophilia where angels fear to tread

n

  • CASE 1

  • 40 year old female (physician)

  • 3 years ago:

  • episode of severe diarrhoea / dehydration

  • swollen calf  U/S “calf vein” DVT

  • 2 weeks full dose clexane, then nothing

  • no further events

  • Tests herself:

  • Homozygous Factor V Leiden (FVL)

  • Would you anticoagulate her?

  • If so, how long?

  • n

NO

Not applicable


Thrombophilia where angels fear to tread

n

CASE 2

52 year old female from a family with VTE history

Heterozygous FVL, no personal history of thrombosis

Asymptomatic daughter tested pre OC use:

– heterozygous FVL positive

Would you have done this?

Do you advise longterm anticoagulation?

She falls pregnant – do you anticoagulate?

Would you test her 2 asymptomatic brothers?

  • n

Probably not

NO

NO

NO


Thrombophilia where angels fear to tread

n

CASE 2

Her 26 year old bother develops insidious onset dyspnoea

CT shows massive multiple pulmonary emboli

Pulmonary hypertension is present – resolves on anticoagulation

Was the decision not to test him wrong?

How long would you anti-coagulate?

Would you now test him for FVL?

Would you now test the other brother?

  • n

NO

Lifelong

NO

NO


Thrombophilia where angels fear to tread

n

CLINICAL

Thrombophilia:

“an inherited or acquired disorder which increases the risk of Venous Thrombo-embolism”

VTE is the DISEASE

NOT thrombophilia

  • n


Thrombophilia where angels fear to tread

n

  • CLINICAL MANIFESTATIONS of THROMBOPHILIA

  • Family history of VTE

  • Spontaneous VTE at younger age

  • Recurrent VTE

  • Unusual sites (splanchnic, cerebral venous sinus, upper limb)

  • Warfarin skin necrosis

  • Neonatal purpura fulminans

  • Resistance to therapy

  • [Obstetric complications (fetal loss, GPH / HELLP, IUGR)]

  • [Arterial thrombosis]

  • n


Thrombophilia where angels fear to tread

n

CLINICAL RISK FACTORS

  • n

  • ACUTE

  • Immobility (>3 days)

  • Surgery

  • Pregnancy

  • Medical diseases (TB)

  • Indwelling catheters

  • Medical diseases (CCF, Stroke, COPD exacerbation, HIV)

  • CHRONIC

  • Obesity

  • OC and HRT

  • Hypertension

  • Smoking

  • Cancer +/- therapy


Thrombophilia where angels fear to tread

n

THROMBOPHILIA

Genetic

AT deficiency

PC deficiency

FVL

Prothrombin 20210A

FV Cam / HK

FV HR2 haplotype

FVII 10976A

FXIII Val34Leu

Fibrinogen mutations

TAFI 438A

TM 127A

ACE intron 16

FSAP 1601A

PAI-1 polymorphisms

tPA intron h

Apolipoprotein E polymorphism

Mixed / Unknown

PS deficiency

APC resistance

 FVIII

 IX

 XI

 Fibrinogen

Elevated homocysteine (MTHFR C677T)

Sticky platelet syndrome

Acquired

APLS

PNH

MPD / JAK2V617F

  • n


Thrombophilia where angels fear to tread

n

What is the most prevalent “thrombophilic” risk factor?

  • n

Heit et al 2001


Thrombophilia where angels fear to tread

n

Relative risk of VTE

  • n


Thrombophilia where angels fear to tread

n

Absolute risk of VTE in asymptomatic carriers

  • n


Thrombophilia where angels fear to tread

FVL

X

FVL + X

FVL

X

n

EVENTS

VTE event multifactorial:

gene-gene interaction

gene-environment interaction

50-80% “thrombophilic events” have a laboratory abnormality

  • n


Thrombophilia where angels fear to tread

n

RISK FACTOR ANALYSIS

ARTERIALVENOUS

Risk factor predictive of events YESYES

“Exclusion” other causes YES NO

Risk factor modifiable YESNO

Modifies prevention strategy YES ?

Modifies disease therapy YES NO

  • n


Thrombophilia where angels fear to tread

n

Decision analysis post VTE event

Post first VTE event, does the presence of a thrombophilic defect influence the:

intensity of therapy?

NO

duration of therapy?

NO, except: AT deficiency

homozygous FVL?

APLS ??

  • n


Thrombophilia where angels fear to tread

n

LEIDEN THROMBOPHILIA STUDY

  • n

Christiansen et al 2005


Thrombophilia where angels fear to tread

n

RISK STRATIFICATION for VTE RECURRENCE

Provoked VTE – 0-1% recurrence Baglin 2003

Stop after 3-6 months (Grd 1A)

Idiopathic VTE

Dfn:No recent surgery (within 3 months)

No plaster cast

No malignancy in past 5 years

No immobilisation for 3/7

Usual therapy with OAC for 6-12 months

Recurrence rates:

5-10% first year

5% second year

2-3% / year thereafter

  • n


Thrombophilia where angels fear to tread

n

  • n


Thrombophilia where angels fear to tread

n

RISK STRATIFICATION for VTE RECURRENCE

Catch up effect Agnelli 2001

- OAC Rx

- Early stop

- Late stop

Stratify: 3% recurrence risk = acceptable

>9% recurrence risk = unacceptable

  • n


Thrombophilia where angels fear to tread

n

RISK STRATIFICATION for VTE RECURRENCE

Clinical Decision Rules for stopping therapy

Risk Stratification:

D-dimer – good at PPV, but not NPVPaoreti 2002, 2006

Residual DVT – proven

but difficultPrandoni ISTH 2007

Male gender – OR 1.6 for recurrence

Elevated FVIII

Age

Thrombophilia

  • n


Thrombophilia where angels fear to tread

n

RISK STRATIFICATION for VTE RECURRENCE

REVERSE[REcurrent VEenous thromboembolism Risk Stratification Evaluation]

Clinical findings of

Hyperpigmentation

Edema

Redness

MEN: HER+ 21% annual recurrence rate,

HER- 7.9% recurrence risk

WOMEN: Also factor in

d-dimer, obesity (BMI>30), age >65 years, ( chol)

HER DOO 0 or 1 score 1.6% recurrence risk (half of all women)

HER DOO 2 or more 14.1% annual recurrence rate

Kovacs et al ISTH 2007

  • n


Thrombophilia where angels fear to tread

n

Screening Asymptomatic Individuals

Screen first degree family members of an index case?

No evidence for long term prophylaxis prior to VTE

Bleeding risk outweighs incidence rate of VTE events

FATAL 0.25% / year

SERIOUS1% / year

Short term prophylaxis

Standard indications and strategy similar

? More aggressive prophylaxis in “low risk” situations

  • n


Thrombophilia where angels fear to tread

n

Family history

Family history:

EDITH study – case control in 1st VTE event

Family history  OR for VTE of 2.7 (95%CI 1.8-3.8)

FVL / II 20210A mutation OR 3.6 (1.2-4)

No mutation OR 2.6 (1.7-3.8)

Positive family history increases risk for DVT irrespective of 2 common mutations Noboa et al 2008

Treat all patients with family history as high risk, irrespective of thrombophilic status

  • n


Thrombophilia where angels fear to tread

n

Screening Asymptomatic Individuals

Universal screening prior to longer term risk situations?

  • n

N.Baartman - personal communication 2008


Thrombophilia where angels fear to tread

n

  • OC and Thrombophilia

  • OC  risk of thrombosis by 3-4x

  • Combination with “thrombophilic” defect synergistic

  • FVL + OC  risk ~30x

  • Studies confirm increased risk

  • No indication to screen general population for thrombophilia (FVL) prior to OC initiation

  • TREATS

  • ICER £202 402 for universal screening pre OC

  • Wu et al 2005

  • Prevent 1 in 200 000 deaths by screening

  • n


Thrombophilia where angels fear to tread

n

  • OC and Thrombophilia

  • OR 4.9 (1.92-12.6 95%CI) for VTE event in women with lowest quartile of APC function (all negative for FVL and other mutations) Legnani et al 2004

  • Screen first degree relatives of known carriers?

  • May prevent DVT

  • BUT consider:

  • Anxiety

  • False reassurance of negative test

  • Other contraceptives not as good

  • Insurance

  • n


Thrombophilia where angels fear to tread

n

FVL and Insurance

Asymptomatic FVL+ve

<30 years

75% load re mortality

no income protection / critical illness / lumpsum disability.

>30 years

50% load on mortality

no income protection

Positive VTE and FVL

No cover

O’Mahoney 2008 – personal communication

  • n


Thrombophilia where angels fear to tread

n

Traveler’s thrombosis:

  • n


Thrombophilia where angels fear to tread

n

  • Practical testing tips

  • DON’T test functional assays during acute event or inflammatory process

  • No antithrombin (and ?LAC) on UF heparin / LMWH

  • No Protein C and S (and ?LAC) on warfarin (washout 2-4 weeks)

  • Repeat all abnormal functional assays (high cv)

  • Serological and clotting assays for APLS

  • - Repeat positive APLS studies after 12 weeks

  • Do ALL appropriate tests

  • n


Thrombophilia where angels fear to tread

n

  • SUMMARY

  • CURRENT

  • Utility of thrombophilia testing largely questionable

  • Consider cost-benefit ratio

  • Do in context of:

    • Trials

    • Changing management strategy

  • FUTURE

  • New global coagulation tests for screening?

  • Newer anticogulants?

  • n


  • Login