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 )