Thrombophilia (hypercoagulability)

Thrombophilia (hypercoagulability)

1. Introduction

   • What is thrombophilia?
     • Its a tendency for an individual's blood to inappropriately form thrombi (clots that occlude blood vessels) or coagulate in the wrong place + time
   • Thrombotic disorders
     • Arterial
       • Myocardial infarction
       • Stroke
       • Peripheral arterial disease
     • Venous
       • DVT
       • Pulmonary embolism (PE)
         • Risk factor = oral contraceptives
         • Vary in size: can be small PE's all the way up to massive PE's
           • Symptoms vary with size (from mild cough with small PE's and pain, haemoptysis (coughing blood) and dyspnoea, fainting, sudden death with massive PEs)
   • Thrombosis = closure of a vessel by a thrombus (clot)
     • Thromboses can fragment or detach and travel in the blood to a second site
       • This travelling form is called an embolus (can also block a tissue vessel -> causes infarction)
         • Infarction = mass cell death due to the occlusion of a supplying blood vessel
     • Types of thrombus
       • Red
         • Mainly RBCs in fibrin mesh
       • White
         • Mainly platelets in fibrin mesh
   • Thrombophilia can be acquired or inherited

2. Factors affecting thrombosis

   • Prothrombotic
     • Vascular damage
     • Platelet activation
     • Activation of the coagulation cascade
   • Antithrombotic
     • Normal blood flow
     • Anicoagulants
     • Fibrinolytic system
     • Normal endothelium
   • Virchow's triad
     • The pathophysiology of thrombosis involves...
       • Changes in the vessel wall
         • Deformities can cause turbulence (see below) and damage exposes ECM
       • Changes in the blood flow
         • Stasis promotes contact between platelets and activated procoagulants and the vessel wall
         • Turbulent blood flow results in damage to the endothelium - exposes ECM
           • Thromboses can occur around venous valves (+++turbulence)
       • Changes in the coagulability of the blood
         • Deficiences of the natural anticoagulants; Protein C, Protein S, antithrombin(III)
         • Acquisition of anti-coagulation factors; Lupus anticoagulant (LA)
     • Important to keep this in mind with thrombosis!

3. Pathaphysiology of thrombosis

   • Blood vessel injury (endothelial damage)
     • Activation of blood coagulation (coagulation cascade)
       • Thrombin
         • Fibrin
       • +
         • Hypercoagulability of blood
     • Platelet activation by subendothelial collagen
       • Platelet factor 3
         • +
       • Thromboxane A2 (TxA2)
         • Thromboxane causes vasoconstriction
         • Platelet activation and aggregation
           • Platelet and fibrin mass (thrombus)
       • ADP
     • +
       • Stasis / turbulence of bloodflow
         • +

4. Causes (acquired vs. hereditary)

   • Hereditary
     • Antithrombin(III) deficiency
     • Prothrombin gene mutation
     • Protein C/S deficiency
     • Elevated factors; XI, VIII
     • Dysfibriginogenemia
     • Tissue plasminogen activator inhibitor (t-PAI) defects
     • Factor V Leiden (activated Protein C resistence)
     • Sticky platelet syndrome
     • Homocystinemia
     • Antiphospholipid Ab'
       • Antiphospholipid syndrome (primary disease; or secondary to lupus)
         • Risk of thrombosis - especially PE or DVT
         • Also causes multiple miscarriages
   • Acquired (risk factors)
     • Prolonged immobilisation (e.g. in hospitals or on long flights)
     • Chronic inflammatory disease
     • Oral contraceptives
       • Oestrogens
     • Nephrotic syndrome
     • Pregnancy
     • Trauma / general surgery
       • Allows exposure of blood to tissue factor
     • CVD
     • Valve disease

5. Natural anticoagulants

   • Antithrombin(III)
     • Activated by heparin and heparin-like molecules (e.g. heperan-sulfate)
     • Function: inactivates thrombin (fIIa), fIXa, fXa and fXIa
   • Protein C
     • Function: decreases the generation of thrombin (fIIa) by inactivating; fVa, fVIIIa and fXa
     • Vit. K dependent, requires endothelial thrombomodulin and activation by protein S
     • Deficicency: in about 4-12% of patients with thrombotic disease
       • Can be heterozygous condition (mild)
       • Can be homozygous; presents early
       • Other conditions; Protein S deficiency, mutated fV (Factor V leiden) and thrombomodulin mutation
         • Factor V Leiden = activated protein C resistence
           • Results in increased thrombin formation
   • Protein S
     • Function: Activates Protein C
     • Vit. K dependent
   • All produced in the liver

6. Hypercoagulable

   • First rule out all other risk factors (surgery, pregnancy, obesity etc.)
   • To label someone as hypercoagulable they must fit a criteria
     • First thrombosis <40yrs
     • Recurrent thrombosis
     • Family history
     • Thrombosis in unusual sites (cerebral veins, hepatic veins, renal veins, mesenteric veins, inferior vena cava
     • Plus positive lab results for any of the mentioned inherited conditions

7. Virchow's triad: Venous vs. arterial thrombosis

   • Venous
     • 1) Vessel walls = normal
     • 2) Blood flow = stasis: low-grade activaion of clotting factors and platelets -> red clots
     • 3) Abnormalities of blood composition
     • Normal vessel wall; flow and shear are low; clot = RBC-rich (red clot)
       • Risk factors = trauma/surgery and cancer
       • Treatment = anticoagulants
   • Arterial
     • 1) Vessel walls = atherosclerosis -> plaque ruptures -> exposes tissue factor -> clotting cascade -> white clot
     • 2) Blood flow = turbulence (high shear)
     • 3) Abnormalities of blood composition
     • Sites of plaque formation; high turbulence and shear rates; clot = platelet rich (white clot)
       • Risk fators = smoking, high BP and cholesterol
       • Treatment = antiplatelet agents

8. Screens for thrombophilic patients

   • Screen for activated protein C resistence by clotting assay
     • activated partial thromboplastin time (aPTT)
       • Intrinsic pathway-based assay - coagulation activated by contact activator of XII
   • Genetic test for prothrombin mutation
   • Immunological assay for free and total protein S
   • Measurement of fasting total plasma homocysteine
     • ELISA assay