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Thrombophilia
This document discusses hypercoagulable states (thrombophilia). It presents two case studies of patients presenting with deep vein thrombosis (DVT). It then defines thrombophilia as a disorder associated with an increased tendency to form blood clots. The document reviews hemostasis and coagulation mechanisms, inherited and acquired risk factors for hypercoagulability, and recommends a stepwise approach to thrombophilia testing that considers the clinical scenario and implications of testing.
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Thrombophilia
- 1. By DR MONKEZ MYOUSIF Professor of Internal Medicine Zagazig University 2015 HYPERCOAGULABLEHYPERCOAGULABLE STATES (THROMBOPHILIA)STATES (THROMBOPHILIA)
- 2. Objectives • Revise hemostaticmechanisms • Discuss hypercoaguable states • Focus specifically on the inherited hypercoaguable conditions • Briefly describe the mechanism behind each of the inherited thrombophilias • Review the hypercoaguable workup and when it is appropriately done
- 3. Case 1 • A33-year-old previously healthy man presented with sudden-onset dyspnea and sharp right-sided chest pain. He had noted right leg edema and calf discomfort a week earlier. • He denied recent trauma, surgery, or immobility. His mother had a history of postpartum deep vein thrombosis (DVT). • On physical examination, he has tachycardia with a heart rate of 114 bpm, normotensive with a blood pressure of 102/76 mm Hg, and hypoxemic to 88% on room air. • Contrast-enhanced chest computed tomogram demonstrated bilateral segmental pulmonary embolism. • Right lower-extremity venous ultrasound documented femoral and popliteal DVT.
- 4. Case 2 • A78-year-old woman with hypertension and obesity developed acute left leg edema and pain 2 days after open reduction and internal fixation of a right hip fracture. • On physical examination, the patient had severe edema and tenderness of the left lower leg and thigh. • Left lower extremity venous ultrasound documented left common femoral, distal femoral, and popliteal DVT.
- 5. Definition of thrombophilia Adisorder associated with an increased tendency to thrombosis.
- 7. VESSEL WALL ENDOTHEL PLATELETS PLASMA FACTORS (procoagulation, anti-coagulation) HEMOSTASIS =the arrest of bleeding from an injured vessel Hemostatic abnormalities can result in procoagulation or/and anti-coagulation conditions
- 8. HemostasisHemostasis BV Injury PlateletPlatelet Aggregation Platelet Activation Blood VesselBloodVessel Constriction CoagulationCoagulation Cascade Stable Hemostatic Plug Fibrin formation Reduced Blood flow Damage/contact. Primary hemostatic plug Neural Contact
- 9. The Role ofPlatelets in Hemostasis Collagen Other factorsTF Thrombin Activated platelet Activated platelet Activated platelet Adhesion Aggregation Contraction Secretion Primary Hemostasis = Activated platelet Activated platelet Activated platelet Activated platelet This plug of activated platelets, localised to the site of injury, provides the phospholipid surface upon which Secondary Hemostasis takes place
- 10. Coagulation Cascade XII XIIa XIXIa IX VIII VIIIa X Xa Intrinsic Pathway Extrinsic Pathway Endothelial activation or exposure of subendothelium Tissue Factor VIITF/VIIa Kallikrein HMWK Prekallikrein IIaII Ca2+ PL Va V Organized Fibrin/Platelet thrombus Fibrinogen Fibrin Ca2+ PLCa2+ Cross-linked fibrin polymer XIIIa Ca2+ IXa
- 11. The Cell-based Modelof Coagulation VIIIa IXa Hoffman M & Munroe DM. A cell-based model of hemostasis. Thromb Haemost 2001; 85: 958-965 + activates various factors Initiation Amplification Propagation
- 12. 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 coagulation Va/VIIIa • Fibrinolytic System
- 13. The Cell-based Modelof Coagulation VIIIa IXa + activates various factors APC/PS TFPI Antithrombin Plasmin
- 14. What is aThrombus? Intravascular mass of fibrin and blood cells Arterial thrombi (White thrombi) – High shear rates – Primarily platelet aggregates + fibrin strands – Thrombus associated with vascular abnormalities (atherosclerosis) most often Venous Thrombi (Red thrombi) – Low shear rates – Primarily red cells and fibrin strands (few platelets) – Most often occurs in cases of stasis (inadequate flow) or biochemical abnormalities
- 15. LDLLDL LDLLDL Mackness MI etal. Biochem J 1993;294:829-834. EndotheliumEndothelium Vessel LumenVessel LumenMonocyteMonocyte Modified LDLModified LDL MacrophageMacrophage MCP-1MCP-1 AdhesionAdhesion MoleculesMolecules CytokinesCytokines Pathophysiology of AtherosclerosisPathophysiology of Atherosclerosis FoamFoam CellCell HDL Promote Cholesterol EffluxHDL Promote Cholesterol Efflux IntimaIntima HDL InhibitHDL Inhibit OxidationOxidation of LDLof LDL
- 17. Thromboembolism • Arterial: oftenfragment of thrombus from heart wall or heart valve, travels downstream to smaller vessel - may lead to stroke or MI • Venous: fragment of venous thrombus that breaks off and travels upstream towards the heart, may lead to pulmonary embolism
- 18. Virchow’s thrombosis model Thrombosis Vessel wall injury Slowblood flow (Stasis) Hypercoagulability
- 19. Injury or Activationof Endothelium • Atherosclerosis – Life style - smoking, obesity • Immune mediated – Heparin induced thrombocytopenia – Antiphospholipid Antibody Syndrome (Lupus Inhib) • Trauma • Artificial Surface (vascular graft) • Inflammation/Infection
- 20. Abnormal Blood Flow Decreased mobility Vessel Obstruction Eccomomy class syndrome Pregnancy Malignancy Estrogens Myeloproliferative disorders Hereditary Factors
- 21. Hereditary Risk Factorsfor Venous Thrombosis Antithrombin Deficiency Protein C deficiency Protein S deficiency Factor V Leiden (FVL) Prothrombin G20210A Dysfibrinogenemias (rare) Hyperhomocysteinemia
- 22. Site of Thrombosisvs. Coag. Defect Abnormality Arterial Venous Factor V Leiden - + Prothrombin G20210A - + Antithrombin deficiency - + Protein C deficiency - + Protein S deficiency - + Hyperhomocysteinemia + + Antiphospholipid syndromes + +
- 23. Protein C System •Protein C and Protein S are vitamin K dependent proteins produced in liver • Protein C is activated by thrombin/ thrombomodulin on endothelial cells • Protein S is a co-factor • Activated protein C + protein S destroys factor Va and factor VIIIa - blocking coagulation
- 24. Anticoagulant protein Cpathway Blood Flow Thrombomodulin Protein C APC Anticoagulant effect at the downstream damage ThrombinThrombin Thrombus Thrombosis occurring at the vascular injury
- 25. VIIIai The anticoagulant effectsof protein C Blood Flow VIIIa Va Thrombus Vai APC APC PS PS Factor V Leiden
- 26. Protein C System- 3 abnormalities • Protein C deficiency • Protein S deficiency • Mutation of factor V cleavage site (activated protein C resistance)
- 27. Hereditary Protein Cdeficiency • AD – most patients heterozygous – rare severe homozygous - purpura fulminans • Activity levels 50% of normal • Increased risk of venous thrombosis
- 28. Acquired Protein Cdeficiency Warfarin therapy Ongoing thrombosis Vitamin K deficiency Liver disease Post-operative state
- 29. Protein S • Co-factorof Protein C, produced in hepatocytes, megakarocytes and endothelium • Vitamin K dependent - activity reduced more than antigenic level • 60% bound to C4B-binding protein (inactive)
- 30. Protein S deficiency •AD • Acquired deficiency – Liver disease – Renal disease – Women – especially those on OCPs or pregnant – IBD
- 31. Clinical Picture Increased riskof venous thrombosis (DVT, mesenteric venous occlusion. First episode - 20s to 40s, associated with pregnancy, trauma, surgery Warfarin associated skin necrosis – occurs 24 - 48 hrs after starting warfarin
- 32. APC Resistance -Mutant Factor V (Factor V Leiden) • Activated Protein C (APC) destroys factor Va by cleaving it at arginine 506 • Some patients have a mutated factor V with a glutamine at position 506, this prevents APC from cleaving factor Va and destroying it • Defect is termed Factor V Leiden or APC resistance • Increased risk of venous thrombosis
- 33. APCR aPC A G Cleavage site506 Va aPC Point mutation 506 (Factor V Leiden)
- 34. APC Resistance Assay •Determine aPTT in plasma before and after addition of Activated Protein C. • FVL Genetic assay (PCR)
- 35. Antithrombin deficiencyⅢ • Synthesisin liver & endothelial cells • Activated by binding to heparin-like molecule • Inhibits thrombin, factor a, a, XIa,Ⅸ Ⅹ XIIa • Resistant to unfractionated heparin • Must treat with low-molecular-weight heparin (LMWH).
- 36. Cause of decreasedAntithrombin • Heparin therapy • Nephrotic syndrome • DIC • Hereditary deficiency (AD) – Reduced production – Abnormal molecule
- 37. Antithrombin Clinical • Increasedrisk of venous thromboembolism • First episode typically in 20s to 40s associated with pregnancy, trauma or surgery • Most common sites for thrombosis – Lower extremities – Pulmonary embolus – Mesenteric vein thrombosis – Superior sagittal sinus thrombosis
- 38. Prothrombin G20210A Mutation AVitamin K-dependant protein synthesized in the liver Due to substitution of adenine for guanine Results in 30% higher prothrombin levels This promotes generation of thrombin and impairs inactivation of Factor Va by APC Seen in 6-10% of patients presenting with first episode of unprovoked DVT
- 39. Type I (nonimmune mediated) The more common form, May occur in up to 15% of patients receiving therapeutic doses of heparin Benign and self limiting side effect. Rarely causes severe thrombocytopenia Usually doesn't require heparin discontinuation. Heparin induced thrombocytopenia (HIT)
- 40. Type II (immunetype of HIT) Pathogenesis involves the formation of antibodies (usually IgG) against the heparin-platelet factor 4 (PF 4) complex. The HIT Abs trigger procoagulant effect serious arterial and venous thrombosis
- 41. J Thromb Haem1,1471, 2003
- 42. The incidence ofHIT is about 3-5% in patients exposed to UFH, the incidence is much lower with the use of LMWH. In patients with de novo exposure to heparin a fall in the platelet count in those with HIT occurs between day 5 and 14.
- 43. Suspicion • Fall inplatelet count by 50% following heparin exposure The clinical spectrum • Isolated HIT • HIT (T), that may be arterial (Stroke, MI, PAD) or venous in nature.
- 44. Lab diagnosis • Functionalassays ---heparin induced platelet aggregation, ---serotonin release assay, • Immunoassays ---Ab to heparin-PF 4 complexes.
- 45. Treatment Stopping Heparin and Directthrombin inhibitors Argatorban Platelet transfusion should be avoided Once the platelet count is > 100.000/CC warfarin may be started at low dose.
- 46. Bilateral foot ischemiasecondary to HIT post open heart surgery
- 47. Bilateral foot ischemiasecondary to HIT post open heart surgery
- 48. Arm ischemia secondaryto HIT post open heart surgery
- 49. Antiphospholipid antibody syndrome Most commonof hypercoagulable disorder Characterized by the association of: Thrombosis, obstetric complications and/or thrombocytopenia AND Antibodies against phospholipids or against proteins bound to phospholipids.
- 50. Etiology of APASyndrome Primary: Idiopathic Secondary: SLE Infection Drug reaction Lymphoma
- 51. Antiphospholipid Antibodies 10% ofhealthy donors, 30-50% of SLE patients Lupus Anticoagulant (LA) Antibodies Anticardiolipin (aCL) Antibodies Anti-Beta 2 Glycoprotein I Antibodies (β2GPI)
- 52. Diagnosis - ClinicalCriteria Vascular thrombosis: arterial, venous, or small vessel, in any tissue or organ Pregnancy morbidity: - Unexplained fetal death - Premature birth before 34 weeks gestation - Three or more consecutive spontaneous abortions
- 53. Diagnosis - Laboratorycriteria • Lupus anticoagulant, • Anticardiolipin antibodies (ACA • Anti-beta-2-glycoprotein I antibodies (anti-B2GPI), present on at least 2 occasions, at least 12 wks apart
- 54. When to suspect Hypercoagulability? •Thrombosis < 50 years • Family history • Thrombosis in an unusual site (e.g. mesenteric v. or cerebral v.) • Idiopathic or recurrent thrombosis • Unexplained spontaneous abortions • Massive thrombosis
- 55. Stepwise Approach For Managementof Thrombophilia
- 56. • In fact,testing for an inherited hypercoagulable state is costly & likely to uncover an abnormality in more than 60% of patients presenting with idiopathic VTEs. • Although the remaining 40% will have unremarkable test results, this does not imply a true absence of a hypercoagulable state. Diagnosis
- 57. • In theabsence of validated guidelines, testing for hypercoagulable states should be performed only in selected patients, and only if the results will significantly affect the management.
- 58. Tips for ThrombophiliaTesting • Follow a stepwise strategy for thrombophilia testing that considers: – the clinical scenario (when to test), – the implications of testing (why to test), and then – the overall approach to testing (how to test). • Use a selective strategy that focuses on the highest- yield thrombophilia testing first.
- 59. • Defer testingfor deficiencies of protein C, protein S, and antithrombin because low levels do not necessarily indicate true thrombophilia in the setting of acute thrombosis and anticoagulation. • Remind patients that a negative thrombophilia evaluation does not exclude thrombophilia because there are many hypercoagulable conditions that have yet to be identified and for which testing does not exist.
- 60. A stepwise approachto thrombophilia testing Gregory Piazza Circulation. 2014;130:283-287 Copyright © American Heart Association, Inc. All rights reserved.
- 61. There are nospecific therapies to reverse most hypercoagulable states. Recombinant factor concentrates of antithrombin and APC. Gene transfer to correct a particular genetic defect. Attempts to eliminate APA by plasmapheresis or immunosuppressive therapy have not been very successful. Treatment
- 62. • Initiation oforal anticoagulation for primary VTE prophylaxis in asymptomatic carriers of any hypercoagulable state has not been advised,
- 63. • However, aggressiveVTE prophylaxis should be prescribed to asymptomatic carriers of hypercoagulable states during high-risk situations such as major or orthopedic surgery
- 64. Case 1 • Giventhe patient’s youth, family history of VTE, and unprovoked event, thrombophilia testing was performed after discharge from the hospital. • A lupus anticoagulant was detected and subsequently confirmed on a second test 6 weeks later. • Because of a high risk of VTE recurrence in the setting of a lupus anticoagulant and an unprovoked event, the patient was maintained indefinitely on warfarin anticoagulation with an international normalized ratio of 2 to 3. • At the 1-year follow-up, he had recovered fully and had not experienced another pulmonary embolism or DVT.
- 65. Case 2 • Giventhe patient’s age and the provoked nature of her DVT, thrombophilia testing was not performed. She was treated with 6 months of anticoagulation with Warfarin. • At the 1-year follow-up, she had recovered fully and had not suffered a VTE recurrence.
- 66.
Editor's Notes
- #7 Homeostasis:The ability or tendency of an organism or cell to maintain internal equilibrium by adjusting its physiological processes
- #8 Hemostasis = the arrest of bleeding from an injured vessel - requires the combination of VASCULAR - PLATELETS - PLASMA factors counterbalanced by regulatory mechanisms to limit the accumulation of platelets and fibrin in the area of injury Hemostatic abnormalities can lead to - in procoagulation or/and anti-coagulation (regulatory) mechanisms can lead to a bleeding or thrombosis disorders. Hemostasis is a integral part of inflammatory response
- #10 When a vessel wall is damaged, various signaling molecules are expressed / exposed, including tissue factor and collagen The TF leads to the production of a small local amount of thrombin, which is the initiation step of the coagulation process The exposed signaling molecules attract circulating platelets, which attach themselves to the exposed sub-endothelial tissue (mechanism to be discussed later): this is adhesion These platelets become activated – principally through the presence of the thrombin – and release further attractant chemicals, which attract more platelets: this is secretion These new platelets bind to the adhered platelets (mechanism to be discussed later) and themselves become activated: this is aggregation Through the conformational changes inherent in activation, the loose platelet plug contracts to form a dense, adherent plug: this is contraction Together these steps comprise primary hemostasis, which may well be sufficient to achieve hemostasis if the injury is relatively minor The activated platelets also present a substantial area of negatively-charged phospholipid membrane at the site of the injury, upon which the subsequent processes of coagulation (secondary hemostasis) can occur, if needed
- #12 Initiation of coagulation occurs when sub-endothelial tissue is exposed to the circulation at a site of injury. These tissues express tissue factor at their surface, which binds to endogenous activated FVII This complex binds small amounts of FX and FV to the exposed endothelial surface, which produce small quantities of thrombin The thrombin activates platelets that are attracted to the site by the process, as well as other plasma-borne clotting factors The activated factors (among them FVIII and FIX) enable the binding of activated FX and FV to the surface of platelets whose activation has produce conformational changes in their surface membranes to expose the ‘reaction sites’ necessary for continuation of the process This leads to the ‘thrombin burst’ that is necessary for the large-scale production of fibrin and so the development of an effective clot These three stages are called the initiation, amplification and propagation phases of coagulation
- #14 Initiation of coagulation occurs when sub-endothelial tissue is exposed to the circulation at a site of injury. These tissues express tissue factor at their surface, which binds to endogenous activated FVII This complex binds small amounts of FX and FV to the exposed endothelial surface, which produce small quantities of thrombin The thrombin activates platelets that are attracted to the site by the process, as well as other plasma-borne clotting factors The activated factors (among them FVIII and FIX) enable the binding of activated FX and FV to the surface of platelets whose activation has produce conformational changes in their surface membranes to expose the ‘reaction sites’ necessary for continuation of the process This leads to the ‘thrombin burst’ that is necessary for the large-scale production of fibrin and so the development of an effective clot These three stages are called the initiation, amplification and propagation phases of coagulation
- #19 Pathogenesis - Virchow postulated thathrombi are formed as a result of the one or more abnormalities in: blood vessels blood flow blood coagulability
- #32 Seen in heterozygotes when giving large loading doses of warfarin and heparin not given concomitantly Occurs within days of starting therapy and develops over fatty tissue (thigh, buttocks, breasts) or extremities Begins as a painful erythematous lesion and leads to necrosis Occurs because of the shorter half life of Protein C verses the other vitamin K-dependent proteins As a result, protein C levels decrease rapidly once warfarin therapy has been initiated (reduced to 50% of normal within one day) This effect is even more pronounce in Protein C deficiency Protein C is lost before the anticoagulant effects of warfarin are established and thrombosis develops Treatment: stop warfarin, give heparin, Vitamin K, protein C concentrate Can restart warfarin once skin lesions resolve, restart in low doses and give with heparin
- #33 It is named after the city Leiden (Netherlands), where it was first identified in 1994 by Prof R. Bertina
- #61 A stepwise approach to thrombophilia testing.