Management of thrombophilia

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Management of thrombophilia

• Dr Galila Zaher
• MRCPath
• Consultant Hematologist

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BLOOD CLOTTING

• Blood clotting interactions
• Plasma protein clotting factors
• Vascular endothelium

Platelets
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Hemostasis
Hemostasis
Subendothelial matrix
Subendothelial matrix
Hemostatic plug
Hemostatic plug
Endothelial cell
Endothelial cell
WBC
WBC
WBC
WBC
Fibrin
RBC
Platelets
Fibrin
RBC
Platelets
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Thrombosis

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

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Intrinsic pathway XII ---gt XIIa
XI---------XIa
IX --------gt IXa
VIII APC PC PS Ca
PL X----------------------gt Xa Common pathway
VCaPL Prothrombin
-------------gt thrombin AT
v fibrinogen--------------gt fibrin
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Coagulation Cascade
TF
VII
a
IX
IXa
VIIIa
APC
Xa
X
X
IIa
II
AT
APC
Va
FIBRINOGEN
FIBRIN
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Activation of fibrinolysis
thrombin
damaged cells
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)
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Generation Of Fibrin and D-Dimer
fibrinogen
E
thrombin
fibrin
FpA, FpB
fibrin polymer
F XIIIa
cross-linked fibrin (clot)
D-dimer cross-linkage
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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

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Complications

• Risk of recurrence
• Fatal PE
• Commonest cause of death in pregnancy
• Post-phlebitic syndrome Venous ulcers

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Thrombophilia

• A disorder of the haemostatic mechanism with a
  predisposition towards thrombosis
• Many patients with defects remain asymptomatic
• gt50 patients with TED will have no identifiable
  laboratory abnormality
• Proven thrombophilic defect and a family history
  of TED
• Thrombosis is a multi-factorial disease

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Thrombophilia

• Physiologic cause pregnancy
• Acquired causesAPL
• Genetic Cause
• Gene Gene
• Gene - Environment

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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
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Acquired Factors

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

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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

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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 gt 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 21138(2)128-34
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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 gt70 VTE
• Homozygous is not compatible with life

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AT Assays

• Screening method Functional assays level lt50.
• Repeat testing .
• Congenital
• Acquired
• Best done at least 5d after DC Heparin
• It is preferable to avoid acute event .

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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

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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

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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

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Diagnosis Of PC Deficiency

• Functional (Amidolytic or Clottable)
• Heterozygous Levels lt 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

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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.

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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

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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.

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Prothrombin G20210A mutation

• First described 1996 AD
• The prevalence 3
• Patients with 1st VTE 18-25
• Three-fold increased risk of thrombosis
• Prothrombin levels gt115 of normal
• No satisfactory screening test
• DNA all are robust and reliable

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Inherited Thrombophilia
Relative risk for VTE Prevalence of recurrent VTE Prevalence of first VTE Prevalence in the general population () Year described Risk factor
5.0 0.5-7 1 0.18 1965 AT deficiency
6.5 1-9 3 0.2 1981 Protein C
2.4 1-13 2 1.3 1984 PS (free)
6.6 50 20 lt15 1993 APC resistance
2.5 - 5 1994 Hyperhomocysteinaemia
4.8 - 11 1995 F VIII levels gt 150 IU/dl
1-2.8 - 18 2.3 1996 Prothrombin gene G20210A variant
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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
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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

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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

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Genetic Testing

• Reliable and reasonably robust
• APCr low Factor V Leiden mutation confirms
• APCr normal No further testing
• Prothrombin Gene Mutation
• MTHFR hyper-homocystinemia

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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

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Prothrombotic Abnormality OCP

• Economy Class syndrome 90 have gt2 risk
  factors for thrombosis
• Factor V Leiden OCP RR VTED 35/50-fold increase

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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?

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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.
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4. Venogram showing deep vein thrombosis Some
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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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• Surgery and trauma are responsible for what
  percent of all TED resulting from hypercoagulable
  state and immobility?A. 10B. 40C. 90D.
  75E. 80

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• 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.

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

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

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

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• Duplex scanningA. 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.

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

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