Homeostasis:The ability or tendency of an organism or cell to maintain internal equilibrium by adjusting its physiological processes
Anticoagulation part 1 (thrombophilia)
ByDR MONKEZ M YOUSIFProfessor of Internal MedicineZagazig University2012Anticoagulationpart 1 (Thrombophilia)
Objectives• Physiology of coagulation• Thrombophilia (Hypercoagulation states)• Venous thromboembolism• Anticoagulants• Case studies
Definition of thrombophiliaA disorder associated with anincreased tendency to thrombosis.
VESSEL WALLENDOTHELPLATELETSPLASMAFACTORS(procoagulation,anti-coagulation)HEMOSTASIS = the arrest of bleedingfrom an injured vesselHemostatic abnormalities can result in procoagulation or/and anti-coagulationconditions
The Role of Platelets in HemostasisCollagen OtherfactorsTFThrombinActivatedplateletActivatedplateletActivatedplateletAdhesionAggregationContractionSecretionPrimaryHemostasis=ActivatedplateletActivatedplateletActivatedplateletActivatedplateletThis plug of activated platelets, localised to the site of injury, provides thephospholipid surface upon which Secondary Hemostasis takes place
Coagulation Cascade:Regulation• Antithrombin (III)– Regulates activity of all serine proteases– Inhibitory activity enhanced by heparin• Protein C and Protein S– Regulate the activity of co-factors of coagulationVa/VIIIa
The Cell-based Model of CoagulationVIIIaIXa+ activates variousfactorsAPC/PSTFPIAntithrombin
What is a Thrombus?Intravascular mass of fibrin and blood cellsArterial thrombi (White thrombi)– High shear rates– Primarily platelet aggregates + fibrin strandsVenous Thrombi (Red thrombi)– Low shear rates– Primarily red cells and fibrin strands (fewplatelets)
LDLLDLMackness MI et al. Biochem J 1993;294:829-834.EndotheliumVessel LumenMonocyteModified LDLMacrophageMCP-1AdhesionMoleculesCytokinesPathophysiology of AtherosclerosisFoamCellHDL Promote Cholesterol EffluxIntimaHDL InhibitOxidationof LDL
Risk Factors for Venous ThrombosisAcquiredPregnancyAdvancing agePrior thrombosisImmobilizationMajor surgeryMalignancyEstrogens (OCP, HRT< SERMs)APA syndromeMyeloproliferative disorders, IBDHITProlonged air travelInheritedAntithrombinDeficiencyProtein C deficiencyProtein S deficiencyFactor V Leiden (FVL)Prothrombin G20210ADysfibrinogenemias(rare)Mixed/UnknownHomocysteineFactor VIII, IX, XIAPC resistance in theabsence of FVLFree TFPIPAI-I, PAI-II
Site of Thrombosis vs. Coag. DefectAbnormality Arterial VenousFactor V Leiden - +Prothrombin G20210A - +Antithrombin deficiency - +Protein C deficiency - +Protein S deficiency - +Hyperhomocysteinemia + +Lupus Anticoagulant + +
Type I (non immune mediated) The more common form, May occur in up to 15% of patients receivingtherapeutic doses of heparin Benign and self limiting side effect. Rarely causes severe thrombocytopenia Usually doesnt require heparin discontinuation.Heparin induced thrombocytopenia(HIT)
Type II (immune type of HIT)Pathogenesis involves the formation of antibodies(usually IgG) against the heparin-platelet factor 4(PF 4) complex. The HIT Abs trigger procoagulanteffect serious arterial and venousthrombosis
The incidence of HIT is about 3-5% inpatients exposed to UFH, the incidence ismuch lower with the use of LMWH.In patients with de novo exposure to heparin afall in the platelet count in those with HIToccurs between day 5 and 14.
Suspicion• Fall in platelet count by 50% following heparinexposureThe clinical spectrum• Isolated HIT• HIT (T), that may be arterial (Stroke, MI, PAD)or venous in nature.