THROMBOPHILIA Abdulkareem Almomen, MD, FRCPC KSU-MED ( )

THROMBOPHILIA Pre-Thrombotic States, Thrombogenic States, Hypercoagulable States

Hemostasis  Blood must be fluid  Must coagulate (clot) at appropriate time  Rapid  Localized  Reversible Thrombosis = inappropriate coagulation

3 Major systems involved  Vessel wall Endothelium (anti-thrombotic)  Platelets  Coagulation system coagulation fact ors, natural anticoagulants & fibrinolysis

Antithrombotic Thrombogenic Vessel injury (Favors fluid blood)(Favors clotting)

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 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

Procoagulant Anticoagulant

Procoagulant Anticoagulant

Virchow’s Triad  Pathogenesis of a Thrombus Endothelial injury Abnormal blood flow Hypercoagulability  Genetic  acquired

ENDOTHELIAL INJURY ABNORMAL BLOOD FLOW HYPERCOAGULABILITY THROMBOSIS

Signs & Symptoms  DVT:  50% with no clinical signs  ?Edematous extremity  Plethoric,Warm,Painful extremity  PE:  Cough, SOB, Hemoptysis  Tachycardia

FibrinogenFibrin Thrombin Prothrombin Xa Va VIIa TF Extrinsic Pathway IXa VIIIa XIa XIIa Intrinsic pathway XIIIa Soft clot Fibrin Hard clot V VIII

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 pathway  Factor V Leiden  Protein C deficiency  Protein S deficiency  Prothrombin G20210A mutation  Antithrombin deficiency  Hyperhomocystinemia  C677T MTHFR mutation Hereditary Thrombophilias

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

Protein C Pathway C4BP S inactive Thrombin Endothelial surface PC Thrombomodulin S active APC Platelet surface Va Vi VIIIa VIIIi PAIa PAIi

 Mutation in promotor  %  in prothrombin levels  2-3% of Europeans  Heterozygous  autosomal dominant  Homozygous similar to Factor V Prothrombin 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, thromboembolism  Severe – homozygous  1 in 200, ,000  Cystathionine  -synthase  Mild to moderate –  Heterozygotes for C  S mutation  Homozygous for 667C-T MTHFR (11%) Hyperhomocysteinemia

Folate and Homocysteine Metabolic Pathways

Possible mechanism for role in atherogenesis, thrombogenesis Lancet Vol 354, 1999

 Multiple mutations  Most thrombogenic disorder  Type I  Levels and activity  Type II  Activity AT Deficiency

 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  , 0.8 prevalence Protein C / Protein S Deficiencies

Protein C Pathway C4BP S inactive Thrombin Endothelial surface PC Thrombomodulin S active 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 ≥ 10 weeks EGA - ≥ 1 premature birth (≤ 34th week of gestation) due to eclampsia, severe pre-eclampsia, or placental insufficiency - ≥ 3 unexplained consecutive spontaneous <10 weeks EGA Revised Sapporo/Sydney Criteria. JTH 2006;4:

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- β 2 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:

Thrombosis Hereditary thrombophilia Acquired thrombophilia Surgery trauma Immobility 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 (0.5mg)  Monitor anti-factor Xa levels.  In children you need to monitor, unlike adults.  Peak is 2-6hrs after injection SQ.

Low Molecular Weight Heparin Antithro mbin Thrombi n Unfractionated Heparin Pentasaccharid e Antithro mbin Factor Xa LMW Heparin Pentasaccharid e

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= SR )