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THROMBOPHILIA
Abdulkareem Almomen, MD, FRCPCKSU-MED 341
17-04- 2011(13-05-1432)
THROMBOPHILIA
Pre-Thrombotic States,Thrombogenic States,
Hypercoagulable States
Hemostasis Blood must be fluid Must coagulate (clot) at appropriate time
Rapid Localized ReversibleThrombosis = inappropriate coagulation
3 Major systems involved
Vessel wall Endothelium (anti-thrombotic)
Platelets Coagulation system coagulation factors,
natural anticoagulants & fibrinolysis
Antithrombotic Thrombogenic
Vessel injury
(Favors fluid blood) (Favors clotting)
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
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
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
ProcoagulantProcoagulant AnticoagulantAnticoagulant
ProcoagulantProcoagulant AnticoagulantAnticoagulant
Virchow’s Triad
Pathogenesis of a Thrombus
Endothelial injuryAbnormal blood flowHypercoagulability
Genetic acquired
ENDOTHELIAL INJURY
ABNORMAL
BLOOD FLOWHYPERCOAGULABILITY
THROMBOSIS
Signs & Symptoms
DVT: 50% with no clinical
signs ?Edematous extremity Plethoric,Warm,Painful
extremity PE:
Cough, SOB, Hemoptysis
Tachycardia
Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway
XIIIa
Soft clot
FibrinHard clot
VVIII
Physiologic Inhibitors of coagulation
Antithrombin Activated Protein C + protein S
Inactivates Va and VIIIa (via proteolysis) Thrombomodulin
Binds to thrombin activate Protein C
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)
Clot removal
Fibrin Fibrin Split Products (FSP)Plasmin
Plasminogen
tPA
Fibrinolysis
Inhibitors of fibrinolysis
Plasminogen activator inhibitors (PAIs)
2-antiplasmin (serpin)
Fate of a Thrombus
Diagram from Robbins Pathologic Basis of Diseases
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
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
Protein C Pathway
C4BPS
inactive
Thrombin
Endothelial surface
PC
Thrombomodulin
Sactive APC
Platelet surface
Va Vi
VIIIa VIIIi
PAIa PAIi
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
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
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
Folate and Homocysteine Metabolic Pathways
Possible mechanism for role in atherogenesis, thrombogenesis Lancet Vol 354, 1999
Multiple mutationsMultiple mutations Most thrombogenic disorderMost thrombogenic disorder Type IType I
Levels and activityLevels and activity Type IIType II
ActivityActivity
AT DeficiencyAT Deficiency
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
Protein C Pathway
C4BPS
inactive
Thrombin
Endothelial surface
PC
Thrombomodulin
Sactive APC
Platelet surface
Va Vi
VIIIa VIIIi
PAIa PAIi
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
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
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
Thrombosis
Hereditarythrombophilia
Acquiredthrombophilia
SurgerytraumaImmobility
Inflammation
Malignancy
Estrogens
Risk Factors for Thrombosis
Atherosclerosis
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.
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
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.
Low Molecular Weight Heparin
Antithrombin
Thrombin
Unfractionated Heparin
Pentasaccharide
Antithrombin
Factor Xa
LMW Heparin
Pentasaccharide
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)
Monitoring PTT PT/INR TT (thrombin time) Heparin level Xa activity No monitoring
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 )