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Published by GerardLum

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Published by: GerardLum on Jun 07, 2010
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ThrombophiliaThrombophilia/ Hypercoagulable States
Inherited or Acquired Haemostatic disorders↑ Risk of developing Thrombotic complications (compared with general)
History of RecurrentThrombosisThrombosis atearly ageFamilialTendencyThrombosis atunusual sites Underlying disease/ conditions associated with thrombo-embolic disorder
Solid masses/ plugs formed in circulation from blood constituentsPlatelets, Fibrin – Form basic structure
Ischaemia from local vascular obstructionDistant Embolization
MI(Myocardial Infarction)Cerebro-Vascular diseasePeripheral Artery Disease(Arterial Thrombosis)Venous ThrombosisThrombophilia/ Hypercoagulable state – Venous Thrombosis(unless otherwise stated)
Blood Coagulation Pathway↑ Risk of Thrombosis (Venous)
Haemostatic balancebetween procoagulant, anticoagulant forcesshift in favour of coagulation 
 city of ncoagulant echanism leads to
↑ lood clot formaonThrombosisIf caused by Inherited defect, resulting hypercoagulable stateis a lifelong ↑ risk of thrombosis
Haemostatic BalanceProcoagulant nticoagulant
PAI-I Protein SAntiplasmin Protein CTissue Factor TFPIClotting Factor Fibrinolytic systemAT III
Regulation of Blood Coagulation
Require strict regulation (considerable biological potential)Plasma proteins, Protein-cell interactions – involved in constant sensoring
Efficient control
CirculatingInhibitors Fibrinolyticpathway
Deep Vein Thrombosis (DVT) of the legs (common site)Pulmonary Embolism – outcome of distal thrombosis
Depends on site of Thrombosis
Lower LimbDVT– Pain, Swelling of Lower Limb (+ve*Homan’s sign) Abdomen– Intra-abdominal thrombosis(mesenteric thrombosis, bowel ischaemia) – Pain in abdomenChest Pain– Pulmonary Embolism
Consequent of DVT
Chronic Leg UlcerPost Phlebitic Limb Syndrome(limb - discoloration, pain, swelling)(Post-Thrombotic Syndrome)*Homan’s sign – Forceful Dorsiflexion of Foot will cause pain in Calf 
ThrombosisDVT of legsUnusual sites
Upper extremity thrombosisCerebral veinAdrenal infarctionudd-Chiari syndromeRenal vein thrombosisVisceral vein thrombosisRetinal vein thrombosisPriapism
VirchowCauses of Thrombosis (3 main groups)
↓ lood FlowChange invessel wall(vessel wall damage)Change inblood composition(hypercoagulability)
ost risk factors for enous thrombosis
StasisChanges in overall totalblood coagulabality (Arterial Thrombosis – Vessel wall Damage)
echanisms/ Pathogenesis of Thrombosisbnormal Blood Flow bnormal Vasculature bnormal Coagulation
Sickle cell diseas Hyperlipidemia ATCCF Atherosclerosis Protein C deficiencyObesity DM Protein S deficiencyHyperviscosity Vasculiti Nephrotic syndromeTrauma
rterial ThrombosisPathogenesis
Atherosclerosis (AS)Plaque RuptureEndothelial Injurylood Exposure(Subendothelial Collagen,TF) Formation of Platelet Nidus, Adhere, Aggregation Platelet DepositionRelease PDGFProliferation of smooth muscle, fibroblasts(in Arterial Intima)Thickening of lood Vessel
Risk Factors
Family HistoryMaleHyperlipidemiaHyperhomocysteinaemia↓ Serum Folate, 12, 6HPT, DM, GoutPolycythemiaCigarette smokingCollagen vascular disease
Venous Thrombosiscquired Risk Factors Inherited Risk Factors
Advanced agFactor V Leiden mutationHeart disease, Myocardial infarct PT20210A (Abnormal Prothrombin)ImmobilityAntithrombin deficiencyLupus AnticoagulantsProtein C deficiencyMalignancyProtein S deficiencyObesity Fibrinolytic disorders AbnormalPlasminOral contraceptives (oestrogen)Pregnancy, PuerperiumTrauma, SurgeryVaricose VeinNephrotic syndromeHyperhomocysteinaemiaHyperviscosity stateMyeloproliferative diseasesParoxysmal NocturnalHaemoglobinuriaehcet’s syndrome
(↑ Common than Inherited)
Acquired Risk Factors for Venous Thrombosis
(↑ common in our region than Caucasian)
< 40 y/o – 1:10,000 people/year>75 y/o – 1:100 people/year
Solid TumourLymphomaMucin Secreting AdenocarcinomoasTroussseau syndrome– Migrating nature of venous thrombosis
Cancer patients
Procoagulant materialproduced by tumour (AML-M3)Mechanical effectsdue to venous obstruction by tumourGeneral effect of an acute phase reactants↓ Mobility, Direct effect of treatment↓ Protein C, Protein S
Prolonged bed rest(from complicated operative procedures)Long haul airline travel(cramped seating – economy class travel)Mechanism
Interfering of function of calf muscles in pumping blood upstreamthrough veins
Lead to prolonged stasis, excessive activation of coagulation system(in relatively static areas associated with valve cusps)
Nephrotic Syndrome
Loss of AT III (Antithrombin) in urine
Haemolytic Disorders
Paroxysmal Nocturnal Haemoglobinuria(defect in red cell membrane – prone to haemolysis when blood pH changes)
Heparin induced Thrombocytopenia Thrombosis
Complication of Heparin therapy Paradoxically, associated withThrombocytopenia 
Acquired Hypercoagulable statesOCP, HRT
(Oral Contraceptive Pill)(Hormone Replacement Therapy)VII,VIII,XII,VWF,Fibrinogen  Plateletchanges3
generation OCP - ↑ risk of thrombosis
Myeloproliferative Disorders
Blood viscosity↑ Platelet count, activity↑ Haematocrit levels (hyperaggregability of platelets, ↑ blood viscosity) 
Antiphospholipid Syndrome (APS)
(Common Acquired Cause of Thrombosis)
Can be diagnosed as
Arterial/ Venous ThrombosisIsolated ThrombocytopeniaRecurrent miscarriages1° or 2° toauto-immune disease(eg. SLE)AcquiredThrombophilia/ Thrombosis (common cause)
Anti-phospholipid antibodies comprise of a family of antibodies
Lupus Anticoagulant (LA) Anticardiolipin Antibodies
APTT ↑Mixing Test – Not CorrecteProceed to confirmatory test(eg. Lupus Anticoagulant study)[PL = Phospholipid]
 Mechanism of Thrombogenesis in LA
Inhibition of Endothelial activation of Protein CInhibition of Endothelial cell release or production of prostacycline ↓ Protein SImpairedFibrinolyticCapacity(In Vivo disturb anticoagulant activity)
Prolongs clotting time (in vitro)
In vivo effects of this antibody
Suppression of FibrinolysisDisturbed Protein C systemDisturbed Endothelial functionLead to Thrombosis
InheritedFactor V Leiden (FVL)
(Common – Whites)Hereditary resistanceto activated protein C
Defect in Factor V
Render itunable to be degradedby activatedprotein C  Associated with primarilyVenous Thrombosis 
2-15% of normal population (white), 40-60% of all hypercoagulable statesRare in Malaysia
Prothrombin Gene Mutation
Mutation in PT gene : 20210G → AMight be involved inArterial disease 
Mutation is present in 1-2% normal populationPerhaps 10-20% in patients with hypercoagulable states
Protein C Deficiency
Protein when activated will degradeF VIIIa,F Va  Primarily will causeVenous Thrombosis 
Incidence in population – 1:2005-10% of Hypercoagulable statesWarfarinInducedSkin Necrosis  Purpura Fulminansin Neonates
Skin NecrosisProtein S Deficiency
Protein S = cofactor for Protein C
Deficiency of free Protein S can lead to
Hypercoagulable state (unbound to C4b)Primarily causesVenous Thrombosis 
Incidence in population – 1:?50005-10% of Hypercoagulable states
Antithrombin DeficiencyAntithrombin Inhibits Activated Factors
(Thrombin, 7,9,10,11)ThrombinF XIaF IXaF XaF VIIaImportant Serine Protease Inhibitor (Serpin) in regulation of blood coagulation
1-3% of Hypercoagulable states

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