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THROMBOPHILIA
Abdulkareem Almomen, MD, FRCPCKSU-MED 341
17-04- 2011(13-05-1432)
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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 ReversibleThrombosis = inappropriate coagulation
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3 Major systems involved
Vessel wall Endothelium (anti-thrombotic)
Platelets Coagulation system coagulation factors,
natural anticoagulants & fibrinolysis
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Antithrombotic Thrombogenic
Vessel injury
(Favors fluid blood) (Favors clotting)
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Antithrombotic Properties of the Endothelium
• Anti-platelet propertiesHealthy endothelium does not bind platelets– Produce PGI-2 (prostacyclin) and NO (Nitric
Oxide), which inhibit platelet binding– Produce ADP-ase which counters the platelet
aggregating effects of ADP
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Antithrombotic Properties of the Endothelium (cont.)
Anticoagulant properties
Produce Heparin-like proteoglycans which activate anti-thrombin Produce Thrombomodulin which make a complex with thrombin (TM.T complex ) 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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ProcoagulantProcoagulant AnticoagulantAnticoagulant
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ProcoagulantProcoagulant AnticoagulantAnticoagulant
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Virchow’s Triad
Pathogenesis of a Thrombus
Endothelial injuryAbnormal blood flowHypercoagulability
Genetic acquired
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ENDOTHELIAL INJURY
ABNORMAL
BLOOD FLOWHYPERCOAGULABILITY
THROMBOSIS
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Signs & Symptoms
DVT: 50% with no clinical
signs ?Edematous extremity Plethoric,Warm,Painful
extremity PE:
Cough, SOB, Hemoptysis
Tachycardia
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Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway
XIIIa
Soft clot
FibrinHard clot
VVIII
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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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Fibrin Fibrin Split Products (FSP)Plasmin
Plasminogen
tPA
Fibrinolysis
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Inhibitors of fibrinolysis
Plasminogen activator inhibitors (PAIs)
2-antiplasmin (serpin)
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Fate of a Thrombus
Diagram from Robbins Pathologic Basis of Diseases
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Protein C pathwayProtein C pathway Factor V LeidenFactor V Leiden Protein C deficiencyProtein C deficiency Protein S deficiencyProtein S deficiency
Prothrombin G20210A mutationProthrombin G20210A mutation Antithrombin deficiencyAntithrombin deficiency Hyperhomocystinemia Hyperhomocystinemia
C677T MTHFR mutationC677T MTHFR mutation
Hereditary ThrombophiliasHereditary Thrombophilias
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Mutation in Factor VMutation in Factor V Protein C/S complexProtein C/S complex Impaired anticoagulationImpaired anticoagulation
5-11% of white Europeans5-11% of white Europeans HeterozygousHeterozygous
Autosomal dominantAutosomal dominant Homozygous rareHomozygous rare
Factor V Leiden MutationFactor V Leiden Mutation
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Protein C Pathway
C4BPS
inactive
Thrombin
Endothelial surface
PC
Thrombomodulin
Sactive APC
Platelet surface
Va Vi
VIIIa VIIIi
PAIa PAIi
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Mutation in promotorMutation in promotor 150-200% 150-200% in prothrombin levels in prothrombin levels
2-3% of Europeans2-3% of Europeans Heterozygous Heterozygous
autosomal dominantautosomal dominant
Homozygous similar to Factor VHomozygous similar to Factor V
Prothrombin G20210A mutationProthrombin G20210A mutation
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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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Atherosclerosis, NTD, Atherosclerosis, NTD, thromboembolismthromboembolism
Severe – homozygousSevere – homozygous 1 in 200,000-355,0001 in 200,000-355,000 Cystathionine Cystathionine -synthase -synthase
Mild to moderate – Mild to moderate – Heterozygotes for CHeterozygotes for CS mutationS mutation Homozygous for 667C-T MTHFR (11%)Homozygous for 667C-T MTHFR (11%)
HyperhomocysteinemiaHyperhomocysteinemia
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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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Multiple mutationsMultiple mutations Most thrombogenic disorderMost thrombogenic disorder Type IType I
Levels and activityLevels and activity Type IIType II
ActivityActivity
AT DeficiencyAT Deficiency
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Protein C deficiencyProtein C deficiency Type I – Type I – number and activity number and activity Type II – Type II – activity activity
Protein S deficiencyProtein S deficiency Type I – Type I – total and free forms total and free forms Type II – Type II – cofactor activity cofactor activity Type III - Type III - free only free only
Autosomal dominantAutosomal dominant 0.2-0.5, 0.8 prevalence0.2-0.5, 0.8 prevalence
Protein C / Protein S DeficienciesProtein C / Protein S Deficiencies
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Protein C Pathway
C4BPS
inactive
Thrombin
Endothelial surface
PC
Thrombomodulin
Sactive APC
Platelet surface
Va Vi
VIIIa VIIIi
PAIa PAIi
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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 @ ≥ 10 weeks EGA
- ≥ 1 premature birth (≤ 34th week of gestation) due to eclampsia, severe pre-eclampsia, or placental insufficiency
- ≥ 3 unexplained consecutive spontaneous abortions @ <10 weeks EGA
Revised Sapporo/Sydney Criteria. JTH 2006;4:295-306
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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 1:1 mix, and correction with excess PL ACLA and/or anti-β2 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 2006;4:295-306
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Thrombosis
Hereditarythrombophilia
Acquiredthrombophilia
SurgerytraumaImmobility
Inflammation
Malignancy
Estrogens
Risk Factors for Thrombosis
Atherosclerosis
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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 <1yr of age 28U/kg/hr Children > 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 <2mo (0.75mg
Q12). >2mo (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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Low Molecular Weight Heparin
Antithrombin
Thrombin
Unfractionated Heparin
Pentasaccharide
Antithrombin
Factor Xa
LMW Heparin
Pentasaccharide
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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 breast milk. New anti-coagulants: Direct anti-thrombin
(Daqbigatran) Anti-Xa (Rivaroxaban)
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Monitoring PTT PT/INR TT (thrombin time) Heparin level Xa activity No monitoring
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Anti dotes (overdose) Stop the anti-thrombotic/anti-coagulant agent, Protamin sulfate (heparin) Plasma/ vitamin K (warfarin) Tranexamic acid (thrombolytic therapy,
fibrinolysis) DDAVP (anti-platelets) rFVIIa ( universal anti hemorrhagic)
( dose= 4000-20000 SR )