Management of thrombophilia Dr Galila Zaher MRCPath Consultant Hematologist

Management of Management of thrombophiliathrombophilia

Management of Management of thrombophiliathrombophilia

Dr Galila Zaher Dr Galila Zaher

MRCPathMRCPath

Consultant Hematologist Consultant Hematologist

BLOOD CLOTTING Blood clotting interactions

Plasma protein clotting factors

Vascular endotheliumPlatelets

HemostasisSubendothelial matrixSubendothelial matrix

PlateletsPlatelets

Hemostatic plugHemostatic plug

FibrinFibrin

Endothelial cellEndothelial cell

RBCRBCWBCWBC

WBCWBC

HemostasisSubendothelial matrixSubendothelial matrix

PlateletsPlatelets

Hemostatic plugHemostatic plug

FibrinFibrin

Endothelial cellEndothelial cell

RBCRBCWBCWBC

WBCWBC

Thrombosis

Reduced Natural anticoagulant Increased Clotting factors High platelets count (ET) Abnormal vascular endothelium Reduced fibrinolysis

Intrinsic pathway XII ---> XIIa

XI---------XIa

IX --------> IXa + VIII APC PC +PSCa +PL

X----------------------> Xa [Common pathway]

V+Ca+PL

Prothrombin -------------> thrombin AT

vfibrinogen--------------> fibrin

Extrinsic pathwayVII + TF ----->VIIa/TF

Coagulation CascadeTF VII

IX

XaX

IXa

a

IIVaIIa

VIIIa

FIBRINOGEN

FIBRIN

X

AT

APC

APC

Activation of fibrinolysis

plasminogenplasminogen

thrombin

plasmin

damaged cellsdamaged cells

t-PAPAI

cross-linked fibrinfibrinogen

FDP(X,Y,D,E)

X-FDP(D-Dimer, cross-linked oligomers, DD/E ...)

antiplasmin

extrinsic pathway extrinsic pathway

inflammation

traumamental/physical stress

Generation Of Fibrin and D-Dimer

DE

D

E

DDEE

F XIIIa

fibrin

fibrin polymer DDE

DE

D

E

DDE

cross-linkedfibrin (clot)

fibrinogenE

DDE

thrombinFpA, FpB

D-dimer cross-linkage

ED

ED

ED

ED

E

DE

DE

E

DDE

E

D

E

D

E

EDD

E

Incidence Of Venous Thromboembolism

Annual frequency per 100,000 : Deep vein thrombosis DVT 160 Symptomatic, non-fatal PE 20 Fatal, autopsy-detected PE 50 250,000 hospitalisations annually due to VTED

Int Angiol 1997

Complications Risk of recurrence Fatal PE Commonest cause of death in

pregnancy Post-phlebitic syndrome

Venous ulcers

Thrombophilia ‘A disorder of the haemostatic mechanism with a

predisposition towards thrombosis’ Many patients with defects remain asymptomatic >50% patients with TED will have no identifiable

laboratory abnormality Proven thrombophilic defect and a family history of TED Thrombosis is a multi-factorial disease

Thrombophilia Physiologic cause:

pregnancy Acquired causes:APL Genetic Cause Gene – Gene Gene - Environment

Physiologic& Acquired Causes

Physiologic States

Pathological Drugs

Newborn Immediate post- thrombotic

Oral anticoagulants

Early childhood Renal disease Oral Contraceptives &HRT

Pregnancy Liver disease

Post-partum Vit. K deficiency

Acquired Factors

Age 1000X. APS 10X. Surgery, hospitalization . Immobilization, trauma & HF Pregnancy & Puerperium. Malignancies :18%of DVT. Obesity. OCP 4-8x (1ST & 3rd generation) Previous Thrombosis. Diet. Obesity Haemoglobinopathies& MPD

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]

Group 1 disorders Group 2 Disorders

Deficiencies of Natural anticoagulants

High levels or function of coagulation factors

Incidence Less frequent than group 2 At least 5x > group 1

Thrombosis risk is higher Lower

VTE by age 60 years. Many patients Most individuals no thrombosis

Risk of reccurence Yes No

PC deficiency ,PS deficiency, AT deficiency

APCR ,Prothrombin mutation, hyperhomocysteinemia, dysfibrinogenemia & elevated VIII, IX and XI .

Ann Intern Med 2003 Jan 21;138(2):128-34

Antithrombin Deficiency AT first described in 1939 :AD The prevalence 1/2000 -1/5000. Patients with 1ST VTE : 1% Recurrent VTE 0.5-7% Carries a 5 X increased risk for VTE Age 60 Y >70% VTE Homozygous is not compatible

with life

AT Assays Screening method :Functional assays

level <50%. Repeat testing . Congenital Acquired Best done at least 5d after DC Heparin It is preferable to avoid acute event .

Acquired AT Infants have 50% of normal adult

levels Extensive DVT ,diffuse arterial

thrombosis & PE Chronic liver disease& acute hepatitis Oral contraceptives & HRT. Proteinuria Heparin therapy DIC

Protein C Deficiency Reported in 1981 AD The prevalence 0.2 %. Patients with 1st VTE 3% Recurrent VTE 1.9% Warfarin induced skin necrosis Homozygous neonatal purpura

fulminans

Acquired Protein C Defects Disseminated acute thromboembolic Severe liver disease. Hemolytic uremic syndrome. Thrombotic thrombocytopenia

purpura. OAC warfarin . Disseminated acute thromboembolic Extensive DVT ,diffuse arterial

thrombosis & PE

Diagnosis Of PC Deficiency Functional (Amidolytic or Clottable) Heterozygous: Levels < reference range Homozygous: extremely low levels. Acquired causes should be excluded Testing is best done 30 d off warfarin It is preferable to avoid acute event Repeat testing Family studies +/- to establish a

diagnosis

Protein S First described in 1984 AD. The prevalence is unknown 0.2-0.5% Patients with 1ST VTE : 1-3% Age 60 Y 30 % VTE. Homozygous neonatal purpura

fulminans Warfarin induced skin necrosis No defined association with arterial

disease.

Protein S PS assays present a diagnostic

challenge Functional Acquired causes should be excluded Testing is best done 30 d off warfarin It is preferable to avoid acute event Repeat testing Family studies +/- to establish a

diagnosis

FVL Mutation Reported in 1993. Dr Jikel & Mrs Hyde. The prevalence 5% of Caucasians. Patients with 1st VTE 20% Recurrent VTE 30-50% Carries a 5x ,OCP & FVL 150 X Homozygous : no fulminant thrombotic disorder. APCR : 90% FVL. No prolongation APTT on adding APC to plasma. DNA : heterozygotes from homozygotes.

Prothrombin G20210A mutation

First described 1996 AD The prevalence 3% Patients with 1st VTE 18-25% Three-fold increased risk of

thrombosis Prothrombin levels >115% of normal No satisfactory screening test DNA : all are robust and reliable

Inherited Thrombophilia

Risk factor Year described

Prevalence in the general population (%)

Prevalence of first VTE&

Prevalence of recurrent VTE

Relative risk for VTE*

AT deficiency

1965 0.18 1 0.5-7 5.0

Protein C 1981 0.2 3 1-9 6.5

PS (free) 1984 1.3 2 1-13 2.4

APC resistance

1993 <15 20 50 6.6

Hyperhomocysteinaemia

1994 5 - 2.5

F VIII levels > 150 IU/dl

1995 11 - 4.8

Prothrombin gene G20210A variant

1996 2.3 18 - 1-2.8

Anti-phospholipid antibodies

Risk factor Subjects with VTE (%)

General population (%)

RR of Thrombosis

Lupus anticoagulant

3-10 4 11

Anti-cardiolipin antibodies

3-10 4 3.2

OCP 21 6 4.2

Pregnancy

6.2 2.3 2.8

Previous VTED 14 2 8

Thrombophilia Whom to test?

VTE below 35-40 Y Unprovoked VTE VTE at unusual sites Life threatening VTE Recurrent fetal lose syndrome Recurrent first trimester abortions Investigating SLE patients Recurrent thromboses Family history of thrombosis

Timing Of Testing

Avoid acute presentation consumption of the natural

anticoagulant Heparin & warfarin interfere with

assay Best time after D/C of warfarin by 2-4

W Any abnormal results should be

repeated 4-6W apart before labeling

Genetic Testing Reliable and reasonably robust APCr low: Factor V Leiden mutation

confirms APCr normal: No further testing Prothrombin Gene Mutation MTHFR :hyper-homocystinemia

Interpretation

Life threatening episode 40-50% of patients with VTE have

normal results APS & AT are highly thrombogenic

& high recurrence rate. Double heterozygosity :high

incidence of VTE

Prothrombotic Abnormality & OCP

‘Economy Class syndrome’ 90% have >2 risk factors for thrombosis

Factor V Leiden + OCP RR VTED 35/50-fold increase

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?

4. Fibrin threads (scanning electron micrograph)Fibrin forms rapidly in stagnant blood. Thrombin plays a pivotal role in the polymerisation of the fibrin strands. Red blood cells become trapped in the fibrin network as the thrombus grows.

4. Venogram showing deep vein thrombosisSome risk factors for venous thrombosis and pulmonary embolism may readily be prevented. A classic example of this is the use of anticoagulant therapy after orthopaedic surgery.

15. Diagnosis of deep vein thrombosis (venogram)Episodes of deep vein thrombosis are often silent and clinical diagnosis is unreliable, therefore a high level of suspicion is necessary. Venography is considered to be the gold standard for diagnosis. However, investigation using a non-invasive ultrasound technique is often regarded as sufficient.

3. Thrombus formation in the left auricle (computer graphics superimposed on in-body photograph) The irregular beating of the heart in atrial fibrillation creates ideal conditions for thrombus formation in the left auricle, especially in patients with mitral valve insufficiency.

5. Fragmentation of the thrombus (computer graphics superimposed on in-body photograph) As the size of the thrombotic mass increases, it becomes more of a threat. Especially if the heart rate is normalised, fragments of the thrombus may break away to be swept into the circulation.

6. Thrombotic material in the aortic arch (computer graphics superimposed on in-body photograph) Once fragments of the thrombus are in the blood stream they may be carried to any part of the body. Small fragments may result in a transient cerebral ischaemic attack. Larger pieces may have more devastating consequences.

7. Cerebral thromboembolism (computer graphics superimposed on in-body photograph) 25 percent of the blood flow from the heart is pumped to the brain. Cerebral thromboemboli most frequently affect the middle cerebral artery.

9. Pulmonary embolus (in-body photograph)When the fragment reaches the lungs, the consequences can be devastating. Here, a thrombotic mass can be seen lodged in a pulmonary vessel. In many cases the underlying deep vein thrombosis is undiagnosed, and may thus strike without any warning.

11. Diagnosis of pulmonary embolism (perfusion and ventilation scans)In another patient with pulmonary embolism, a perfusion scan shows that an embolus has stopped the blood flow to part of one lung. The ventilation scan shows that this area is ventilated normally.

• Surgery and trauma are responsible for what percent of all TED resulting from hypercoagulable state and immobility?A. 10%B. 40%C. 90%D. 75%E. 80%

• Increased estrogen occurs in a patient: A. during all stages of pregnancy.B. after elective abortion.C. during treatment with oral contraceptive pills.D. during the first three months post-partum.E. all of the above.

• Clinical examination alone is able to confirm what percent of DVT cases?A. 20-30%B. 50%C. 5%D. 60-70%

• Radiologists disagree on the interpretation of what percent of venography cases?A. 50%B. Less than 5%C. At least 10%D. 75%

• A sonographer can distinguish a fresh clot from an old clot based on:A. collateral flow.B. echogenicity.C. homogeneity.D. all of the above.

• Duplex scanning:A. is most sensitive for clots below the knee.B. is less sensitive for clots below the knee.C. detects 30% of distal thrombi.D. is more likely to detect non-occluding thrombi.

• What percent of patients with suspected thrombosis and a negative ultrasound later prove to have proximal DVT?A. 10%B. 25%C. 2-5%D. 40-45%

• Bilateral leg swelling can be caused by:A. liver disease.B. nephrotic syndrome.C. capillary leak syndrome.D. pregnancy.E. all of the above

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