THROMBOPHILIA

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THROMBOPHILIA
Abdulkareem Almomen, MD, FRCPC KSU-MED 341
March, 2010
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THROMBOPHILIA
Pre-Thrombotic States, Thrombogenic
States, Hypercoagulable States
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Hemostasis

• Blood must be fluid
• Must coagulate (clot) at appropriate time
• Rapid
• Localized
• Reversible
• Thrombosisinappropriate coagulation

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3 Major systems involved

• Vessel wall
• Endothelium
• Platelets
• Coagulation factors

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Vessel injury
Prothrombotic
Antithrombotic
(Favors fluid blood)
(Favors clotting)
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Antithrombotic Properties of the Endothelium

• Anti-platelet properties
• Healthy endothelium does not bind platelets
• Produce PGI-2 (prostacyclin) and NO (Nitric
  Oxide) which inhibit platelet binding
• Produce ADPase which counters the platelet
  aggregating effects of ADP

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Antithrombotic Properties of the Endothelium
Anticoagulant propertiesProduce
Heparin-like proteoglycans which activate
anti-thrombin Produce Thrombomodulin which make
a complix with thrombin and activates protein C
,Produce tPA which activates fibrinolysis by
activating plasminogen to plasmin
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• Prothrombotic Properties of the Endothelium
• Synthesis of von Willebrand factor
• Release of tissue factor
• Production of plasminogen activator inhibitors
  (PAI)
• Membrane phospholipids bind and facilitate
  activation of clotting factors via Ca bridges

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Procoagulant
Anticoagulant
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Procoagulant
Anticoagulant
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Virchows Triad

• Pathogenesis of a Thrombus
• Endothelial injury
• Abnormal blood flow
• Hypercoagulability
• Primary (genetic)
• Secondary (acquired)

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ENDOTHELIAL INJURY
THROMBOSIS
ABNORMAL BLOOD FLOW
HYPERCOAGULABILITY
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Signs Symptoms

• DVT
• Painful, swollen, warm, and Plethoric extremity
  with reduced pulse volume
• PE
• Cough, SOB, Hemoptysis
• Tachycardia

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1. Initiation phase
Injury of vessels wallleads to contact between
blood and subendothelial cells
Tissue factor (TF) isexposed and binds toFVIIa
or FVII which is subsequently converted to FVIIa
The complex between TF and FVIIa activates FIX
and FX
FXa binds to FVa on thecell surface
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Intrinsic pathway
XIIa
Extrinsic Pathway
XIa
TF
Prothrombin
IXa
VIIa
VIIIa
VIII
Xa
V
Va
Soft clot
Thrombin
Fibrinogen
Fibrin
XIIIa
Hard clot
Fibrin
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2. Amplification phase
Activated platelets bind FVa, FVIIIa and FIXa
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Physiologic Inhibitors of coagulation

• Antithrombin
• Activated Protein C protein S
• Inactivates Va and VIIIa (via proteolysis)
• Thrombomodulin
• Binds to thrombin
• activate Protein C

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Non-physiologic inhibitors of coagulation

• Vitamin K antagonists (in vivo only)
• Ca chelators (in vitro only)
• EDTA
• Citrate
• Oxalate
• Heparin (in vivo and in vitro)

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Clot removal
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Fibrinolysis
Plasminogen
tPA
Plasmin
Fibrin
Fibrin Split Products (FSP)
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Inhibitors of fibrinolysis

• Plasminogen activator inhibitors (PAIs)
• a2-antiplasmin (serpin)

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Fate of a Thrombus
Diagram from Robbins Pathologic Basis of Diseases
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Hereditary Thrombophilias

• Protein C pathway
• Factor V Leiden
• Protein C deficiency
• Protein S deficiency
• Prothrombin G20210A mutation
• Antithrombin deficiency
• Hyperhomocystinemia
• C677T MTHFR mutation

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Factor V Leiden Mutation

• Mutation in Factor V
• Protein C/S complex
• Impaired anticoagulation
• 5-11 of white Europeans
• Heterozygous
• Autosomal dominant
• Homozygous rare

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Protein C Pathway
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Prothrombin G20210A mutation

• Mutation in promotor
• 150-200 ? in prothrombin levels
• 2-3 of Europeans
• Heterozygous
• autosomal dominant
• Homozygous similar to Factor V

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MTHFR and Thrombosis

• Hyperhomocysteinemia implicated in both arterial
  and venous thrombosis
• Why is homocysteine thrombogenic? Theories
• Direct toxicity to endothelial cells
• Inhibits Protein C activation
• Promotes endothelial tissue factor expression
• Surpresses endothelial cell surface heparin
  sulfate

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Hyperhomocysteinemia

• Atherosclerosis, NTD, thromboembolism
• Severe homozygous
• 1 in 200,000-355,000
• Cystathionine ? -synthase
• Mild to moderate
• Heterozygotes for C?S mutation
• Homozygous for 667C-T MTHFR (11)

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Folate and Homocysteine Metabolic Pathways
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Possible mechanism for role in atherogenesis,
thrombogenesis
Lancet Vol 354, 1999
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AT Deficiency

• Multiple mutations
• Most thrombogenic disorder
• Type I
• Levels and activity
• Type II
• Activity

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Protein C / Protein S Deficiencies

• Protein C deficiency
• Type I ? number and activity
• Type II ? activity
• Protein S deficiency
• Type I ? total and free forms
• Type II ? cofactor activity
• Type III - ? free only
• Autosomal dominant
• 0.2-0.5, 0.8 prevalence

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Protein C Pathway
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Antiphospholipid Antibody Syndrome

• Autoimmune Acquired Prothrombotic Disorder
• Very High Risk for recurrent thromboembolic
  disease
• both venous and arterial
• Indefinite duration anticoagulation recommended
  /- immunosuppression
• Strict Diagnostic Criteria

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Antiphospholipid Syndrome

• Clinical criteria (1 must be present)
• 1. Vascular thrombosis
• - 1clinical episode of, objectively
  confirmed, arterial, venous, or small vessel
  thrombosis
• 2. Pregnancy morbidity
• - 1 unexplained fetal death _at_ 10
  weeks EGA
• - 1 premature birth ( 34th week of
  gestation) due to eclampsia, severe
  pre-eclampsia, or placental insufficiency
• - 3 unexplained consecutive spontaneous
  abortions _at_ lt10 weeks EGA

Revised Sapporo/Sydney Criteria. JTH
20064295-306
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Antiphospholipid Syndrome

• Laboratory criteria (1 must be present)
• LA () 2 occasions, at least 12 weeks apart,
  according to ISTH guidelines
• prolonged PL-based clotting assay, lack of
  correction with 11 mix, and correction with
  excess PL
• ACLA and/or anti-ß2 glycoprotein-I antibody
• medium or high IgG and/or IgM isotype titer 2
  occasions, at least 12 weeks apart
• Standardized ELISA assays

Revised Sapporo/Sydney Criteria. JTH
20064295-306
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Risk Factors for Thrombosis
Acquired thrombophilia
Hereditary thrombophilia
Atherosclerosis
Thrombosis
Surgery trauma
Immobility
Estrogens
Inflammation
Malignancy
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Therapies/Heparin

• Mechanism catalysis of AT.
• Neonates have lower AT levels.
• Monitoring aPTT
• Problems
• aPTT levels based on adult therapeutic studies.
• Even in adults, therapeutic aPTT may not suggest
  clinically sufficient anti-coag.

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Therapies/Heparin

• Recommended dose 75U/kg loading.
• Maintenance drip dose varies
• Infants lt1yr of age 28U/kg/hr
• Children gt 1yr 20U/kg/hr
• Side effects (besides bleeding)
• Heparin induced thrombocytopenia
• Osteoporosis

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Therapies/ LMWH

• Low Molecular Weight Heparin
• Less monitoring needed, more predictable blood
  levels, less osteoporosis.
• Increase dose needed for age lt2mo (0.75mg Q12).
  gt2mo (0.5mg)
• Monitor anti-factor Xa levels.
• In children you need to monitor , unlike adults.
• Peak is 2-6hrs after injection SQ.

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Therapies/Oral-anticoagulants

• Impairs function of vitamin-K dependent proteins
  (II, VII, IX, X) plus Proteins C S.
• Newborns have reduced levels of vitamin-K
  dependent proteins. (Shot at birth helps.)
• Vitamin K added to formulas.
• Minimal in breastmilk.