Pankaj HANDA Senior Consultant

Int. Med./Vascular Med. & Hypertension Tan Tock Seng Hospital

Virchow’s Triad : Mechanism of Thrombosis - Alteration in Blood Flow ( Stasis) - Vascular Endothelial Injury - Hypercoagulable State Thrombophilia : A disorder of haemostasis in which

there is tendency for occurrence of thrombosis

- Inherited / Acquired

Presenter

Presentation Notes

The most frequent causes of an inherited (primary) hypercoagulable state are the factor V Leiden mutation and the prothrombin gene mutation, which together account for 50 to 60 percent of cases. Defects in protein S, protein C, and antithrombin (formerly known as antithrombin III) account for most of the remaining cases, while a rare cause is one of the dysfibrinogenemia

Normal Healthy Population

Patients With Established VTE

Overall (%) OCP Pregnanacy No Defect 0.01 0.02 0.1 FVL- heterozygous 0.05 0.1 0.2 PGM-heterozygous 0.13 0.07 0.5 Protein C Deficiency 0.7 Unknown 1.7 Protein S Deficiency 0.8 Unknown 6.6 AT Deficiency 1.7 Unknown 3-40 FVL -Homozygous 0.8 Unknown 8-16

FVL+PGM compound(heteroz.) 0.42 0.17 4%

Annual Risk- Family Screening

Unprovoked VTE :Young Age (<50 yr.)

Family history : VTE <50 yr.

Recurrent venous thrombosis

Thrombosis at unusual vascular beds (portal, hepatic, mesenteric, cerebral veins)

History of warfarin-induced skin necrosis, which suggests protein C deficiency

Arterial Thrombosis

Upper Limb Venous Thrombosis

Retinal Vein Thrombosis

Active Malignancy

Myeloproliferative Disorders

Recent Surgery/ Immobilisation

In the 1980s - 1990s thrombophilic testing became a common practice despite no evidence that testing had clinical utility.

It is now apparent that testing for such screening has little value : - Doesn't predict recurrence of VTE in patients with established VTE - Low risk of VTE in asymptomatic relatives

Infrequently identifies patients with defects carrying specific management( multiple thrombophilic or homozygous defects)

Overaggressive management of the patient /asymptomatic affected relatives with complications

Different Clinical Penetrance within families

Cost of testing/consultations can be considerable

Potential for undue anxiety in the patient / family

Presenter

Presentation Notes

Choosing Wisely: medical stewardship and quality improvement initiative by the ABIM Identifies 5 tests and treatments that may not be supported by evidence May involve risk of adverse events and financial costs with low likelihood of benefit

(A) Screening in Established VTE (B) Screening in Asymptomatic Individuals

Objectives - Modify Type/ Duration of Initial Treatment

- Need for Long Term Treatment

No Evidence that thrombophilia influences intensity or duration of initial treatment in patients with VTE Schulman & Tengborn,1992 - No difference in recurrence or extension of thrombosis Kearon et al, 2008 - No evidence that recurrence on oral VKA is more likely in

patients with heritable thrombophilia

Initiation and intensity of anticoagulant therapy following a diagnosis of acute venous thrombosis should be the same in patients with and without heritable thrombophilia (1B).

Ridkar (2003) Schulman (2003)Hron(2006) - no difference in recurrence rates in patients with or without gene mutation/ coagulation protein deficiency, or a positive family history for VTE JAMA 2009 - Meta-analysis

- it is unknown whether testing for gene mutation improves outcomes in adults with VTE or in family members of those with a mutation ACCP (2012) Hereditary thrombophilia – not a major factor to guide duration of anticoagulation for VTE. No Evidence that these factors are major determinants of the risk of recurrence

RISK FACTOR Recurrence : 1st year Recurrence Thereafter Surgical 1%

0.5%

Medical 5%

2.5%

Unprovoked- 1st 10 %

5%

Unprovoked- 2nd 15 % 7.5%

Presenter

Presentation Notes

Timing of screening and effect of anticoagulation Acute thrombosis by itself can transiently reduce antithrombin and occasionally protein C and protein S. Heparin can produce up to a 30 % decline in the plasma antithrombin concentration over several days Warfarin produces a marked reduction in the functional activity of protein C and protein S and a lesser decline in immunologic levels. Warfarin rarely elevates antithrombin concentrations in patients with antithrombin deficiency, sometimes into the normal range.

Objectives

Preventive measures in Positive Cases High Risk Situations- - Combined OCP/HRT - Pregnancy

Unselected population screening is not recommended - low frequency, low penetrance - no safe, cheap, long-term prophylaxis - likely to generate anxiety - Specifically, there are no data that justify the risks of prophylactic anticoagulation in the asymptomatic patient with inherited thrombophilia

General OCP FVL :– ve FH FVL :+ve FH VTE Risk % 0.01 0.02-0.05 0.1-0.2 0.5

1. Most will NOT have VTE even after using OCP for years. 2. Screen10,000 women : Withhold OCP in 500 healthy FVL heterozygotes to prevent 1 VTE 3.Review (Wu 2005 BJH)- All inherited Thrombophilic states – 92000 carries; stop OCP to prevent 1 Death

Women already using OCP- Sudden discovery of a VTE in a first degree relative ?

- OCP related VTE : first 6-12 months of use

Therefore , DO NOT screen women considering use of OCP unless they have a blood relative with VTE ……? caveat Conclusion : General screening before OCP: Not recommended But it may be useful in those with positive FH of VTE

5- to 10-fold increased risk of VTE (1-2/1000 deliveries) Two strongest risk factors for VTE: - previous DVT - thrombophilic states Thrombophilc states also linked with - fetal loss - intrauterine growth retardation - pre eclampsia etc.

Routine testing Not recommended ( low frequency ,the lack of a safe, cost-effective, long-term method of prophylaxis)

Testing is NOT Justified in HIGH RISK patients: - Previous unprovoked/ recurrent VTE - VTE related to previous pregnancy/COCP

Testing is Justified 1. Provoked VTE (Surgery/# Immobility) if – ve : Low risk; if +ve : may be considered for prophylaxis 2. No prior VTE with BUT 1st degree relative VTE :Both Ante and Post partum prophylaxis High Risk Thrombophilia +ve( AT deficiency; double heterozygous; FVL homozygous) : Only Post Partum prophylaxis : -Low Risk Thrombophilia (FVL heterozygous) in presence of other risk factors -FH of VTE < 50 years

Screen 1. Women with Prior Provoked VTE(surgery/#/etc.) 2. Women with No prior VTE planning a pregnancy who have a first degree relative with VTE or a history of a high-risk thrombophilia. Timing : Patient is not pregnant Not taking anticoagulants/ hormonal Rx

In Asian population; FVL and PGM are the most common thrombophilc disorders

Screening general population for inherited thrombophilia is NOT recommended

All cases of unprovoked VTE should be screened for thrombophilic disorders

Hx of previous VTE has no bearing on recurrence of VTE

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85 YR/Chinese/ female develops Left Lower Limb Proximal DVT 3 days after Knee surgery

- DVT recurrence is likely low

- Thrombophilic screen would help us decide initial

type and intensity of treatment

- Thrombophilic screen would help us decide duration of anticoagulation

- No indication of doing thrombophilic screen

In setting of acute thrombosis- - Levels of protein C & S and AT may increase - FVL and PGM may become undetectable - Warfarin may decrease levels of protein C & S and rarely elevate AT levels - If it is important to check for protein C and S while the patient is still being anticoagulated, it should be done 2 weeks after stopping warfarin.

32 YR/Malay/female using OCP for several years suddenly discovers family Hx of VTE. High risk of VTE associated with OCP mandates that:

- she should stop OCPs immediately

- she should go for thrombophilc screen ASAP

- she be reassured that it is still safe to continue OCP

- she should be warned that she has already incurred high risk of VTE for future

Before considering pregnancy, a women may be considered for thrombophilic screen, if she has

- past Hx of Unprovoked VTE

- past Hx of OCP associated VTE - past Hx of provoked VTE

- positive FH of blood relative with VTE

Inherited thrombophilia screening has been prematurely adopted in medical practice.

Patients with VTE: Little evidence that thrombophilias influence the duration of anticoagulation/recurrence of VTE.

Asymptomatic Relatives: General screening not recommended as it doesn’t lead to improved outcomes

Before OCP/HRT- General screening NOT

recommended. May be useful if a blood relative has VTE

Before Pregnancy- Screening may be recommended - Prior Provoked VTE or No prior VTE but have a relative with VTE