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Management of thrombophilia

Management of thrombophilia. Dr Galila Zaher MRCPath Consultant Hematologist. BLOOD CLOTTING. Blood clotting interactions Plasma protein clotting factors Vascular endothelium. Platelets. Hemostasis. Hemostasis. Subendothelial matrix. Subendothelial matrix.

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Management of thrombophilia

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  1. Management of thrombophilia Dr Galila Zaher MRCPath Consultant Hematologist

  2. BLOOD CLOTTING Blood clotting interactions Plasma protein clotting factors Vascular endothelium Platelets

  3. Hemostasis Hemostasis Subendothelial matrix Subendothelial matrix Hemostatic plug Hemostatic plug Endothelial cell Endothelial cell WBC WBC WBC WBC Fibrin RBC Platelets Fibrin RBC Platelets

  4. Thrombosis • Reduced Natural anticoagulant • Increased Clotting factors • High platelets count (ET) • Abnormal vascular endothelium • Reduced fibrinolysis

  5. Extrinsic pathway VII + TF ----->VIIa/TF Intrinsic pathway XII ---> XIIa XI---------XIa • IX --------> IXa • + VIII APC PC +PS • Ca +PL • X----------------------> Xa [Common pathway] • V+Ca+PL • Prothrombin -------------> thrombin AT • v • fibrinogen--------------> fibrin

  6. Coagulation Cascade TF VII a IX IXa VIIIa APC Xa X X IIa II AT APC Va FIBRINOGEN FIBRIN

  7. Activation of fibrinolysis damaged cells thrombin inflammation mental/physical stress trauma PAI t-PA extrinsic pathway plasminogen plasmin antiplasmin cross-linked fibrin fibrinogen X-FDP (D-Dimer, cross-linked oligomers, DD/E ...) FDP (X,Y,D,E)

  8. Generation Of Fibrin and D-Dimer D D E D D E E E E E D D D D D D D D D D D D E E E E E E E E E D D D D D D D D E E E E E E E E fibrinogen E thrombin fibrin FpA, FpB fibrin polymer F XIIIa cross-linked fibrin (clot) D-dimer cross-linkage

  9. Incidence Of Venous Thromboembolism • Annual frequency per 100,000 : • Deep vein thrombosis DVT 160 • Symptomatic, non-fatal PE 20 • Fatal, autopsy-detected PE 50 • 250,000 hospitalisations annually due to VTED • Int Angiol 1997

  10. Complications • Risk of recurrence • Fatal PE • Commonest cause of death in pregnancy • Post-phlebitic syndrome Venous ulcers

  11. Thrombophilia • ‘A disorder of the haemostatic mechanism with a predisposition towards thrombosis’ • Many patients with defects remain asymptomatic • >50% patients with TED will have no identifiable laboratory abnormality • Proven thrombophilic defect and a family history of TED • Thrombosis is a multi-factorial disease

  12. Thrombophilia • Physiologic cause: pregnancy • Acquired causes:APL • Genetic Cause • Gene – Gene • Gene - Environment

  13. Physiologic& Acquired Causes

  14. Acquired Factors • Age 1000X. • APS 10X. • Surgery, hospitalization . • Immobilization, trauma & HF • Pregnancy & Puerperium. • Malignancies :18%of DVT. • Obesity. • OCP 4-8x (1ST & 3rd generation) • Previous Thrombosis. • Diet. Obesity • Haemoglobinopathies& MPD

  15. Inherited Thrombophilia • 1965 AT mutation identified [Egeberg et al] • 1967 Dysfunctional fibrinogen [Egeberg et al] • 1981 Protein C [Griffin et al] • 1984 Protein S [Comp et al]] • 1993/4 APCR/FV L [Dalhback/Bertina et al] • 1996 Prothrombin mutation [Poort et al]

  16. Ann Intern Med 2003 Jan 21;138(2):128-34

  17. Antithrombin Deficiency • AT first described in 1939 :AD • The prevalence 1/2000 -1/5000. • Patients with 1ST VTE : 1% • Recurrent VTE 0.5-7% • Carries a 5 X increased risk for VTE • Age 60 Y >70% VTE • Homozygous is not compatible with life

  18. AT Assays • Screening method :Functional assays level <50%. • Repeat testing . • Congenital • Acquired • Best done at least 5d after DC Heparin • It is preferable to avoid acute event .

  19. Acquired AT • Infants have 50% of normal adult levels • Extensive DVT ,diffuse arterial thrombosis & PE • Chronic liver disease& acute hepatitis • Oral contraceptives & HRT. • Proteinuria • Heparin therapy • DIC

  20. Protein C Deficiency • Reported in 1981 AD • The prevalence 0.2 %. • Patients with 1st VTE 3% • Recurrent VTE 1.9% • Warfarin induced skin necrosis • Homozygous neonatal purpura fulminans

  21. Acquired Protein C Defects • Disseminated acute thromboembolic • Severe liver disease. • Hemolytic uremic syndrome. • Thrombotic thrombocytopenia purpura. • OAC warfarin . • Disseminated acute thromboembolic • Extensive DVT ,diffuse arterial thrombosis & PE

  22. Diagnosis Of PC Deficiency • Functional (Amidolytic or Clottable) • Heterozygous: Levels < reference range • Homozygous: extremely low levels. • Acquired causes should be excluded • Testing is best done 30 d off warfarin • It is preferable to avoid acute event • Repeat testing • Family studies +/- to establish a diagnosis

  23. Protein S • First described in 1984 AD. • The prevalence is unknown 0.2-0.5% • Patients with 1ST VTE : 1-3% • Age 60 Y 30 % VTE. • Homozygous neonatal purpura fulminans • Warfarin induced skin necrosis • No defined association with arterial disease.

  24. Protein S • PS assays present a diagnostic challenge Functional • Acquired causes should be excluded • Testing is best done 30 d off warfarin • It is preferable to avoid acute event • Repeat testing • Family studies +/- to establish a diagnosis

  25. FVL Mutation • Reported in 1993. • Dr Jikel & Mrs Hyde. • The prevalence 5% of Caucasians. • Patients with 1st VTE 20% • Recurrent VTE 30-50% • Carries a 5x ,OCP & FVL  150 X • Homozygous : no fulminant thrombotic disorder. • APCR : 90% FVL. • No prolongation APTT on adding APC to plasma. • DNA : heterozygotes from homozygotes.

  26. Prothrombin G20210A mutation • First described 1996 AD • The prevalence 3% • Patients with 1st VTE 18-25% • Three-fold increased risk of thrombosis • Prothrombin levels >115% of normal • No satisfactory screening test • DNA : all are robust and reliable

  27. Inherited Thrombophilia

  28. Anti-phospholipid antibodies

  29. Thrombophilia Whom to test? • VTE below 35-40 Y • Unprovoked VTE • VTE at unusual sites • Life threatening VTE • Recurrent fetal lose syndrome • Recurrent first trimester abortions • Investigating SLE patients • Recurrent thromboses • Family history of thrombosis

  30. Timing Of Testing • Avoid acute presentation • consumption of the natural anticoagulant • Heparin & warfarin interfere with assay • Best time after D/C of warfarin by 2-4 W • Any abnormal results should be repeated 4-6W apart before labeling

  31. Genetic Testing • Reliable and reasonably robust • APCr low: Factor V Leiden mutation confirms • APCr normal: No further testing • Prothrombin Gene Mutation • MTHFR :hyper-homocystinemia

  32. Interpretation • Life threatening episode • 40-50% of patients with VTE have normal results • APS & AT are highly thrombogenic & high recurrence rate. • Double heterozygosity :high incidence of VTE

  33. Prothrombotic Abnormality & OCP • ‘Economy Class syndrome’ 90% have >2 risk factors for thrombosis • Factor V Leiden + OCP RR VTED 35/50-fold increase

  34. Summary • Increasing enthusiasm for thrombophilia testing • Concerns about accuracy and interpretation • Lack of evidence-based data to aid management • Are we providing patients and clinicians with inaccurate information that leads to false reassurance or alternatively creates panic and results in inappropriate treatment?

  35. 4. Fibrin threads (scanning electron micrograph) Fibrin forms rapidly in stagnant blood. Thrombin plays a pivotal role in the polymerisation of the fibrin strands. Red blood cells become trapped in the fibrin network as the thrombus grows.

  36. 4. Venogram showing deep vein thrombosis Some risk factors for venous thrombosis and pulmonary embolism may readily be prevented. A classic example of this is the use of anticoagulant therapy after orthopaedic surgery.

  37. 15. Diagnosis of deep vein thrombosis (venogram) Episodes of deep vein thrombosis are often silent and clinical diagnosis is unreliable, therefore a high level of suspicion is necessary. Venography is considered to be the gold standard for diagnosis. However, investigation using a non-invasive ultrasound technique is often regarded as sufficient.

  38. 3. Thrombus formation in the left auricle (computer graphics superimposed on in-body photograph) The irregular beating of the heart in atrial fibrillation creates ideal conditions for thrombus formation in the left auricle, especially in patients with mitral valve insufficiency.

  39. 5. Fragmentation of the thrombus (computer graphics superimposed on in-body photograph) As the size of the thrombotic mass increases, it becomes more of a threat. Especially if the heart rate is normalised, fragments of the thrombus may break away to be swept into the circulation.

  40. 6. Thrombotic material in the aortic arch(computer graphics superimposed on in-body photograph) Once fragments of the thrombus are in the blood stream they may be carried to any part of the body. Small fragments may result in a transient cerebral ischaemic attack. Larger pieces may have more devastating consequences.

  41. 7. Cerebral thromboembolism (computer graphics superimposed on in-body photograph) 25 percent of the blood flow from the heart is pumped to the brain. Cerebral thromboemboli most frequently affect the middle cerebral artery.

  42. 9. Pulmonary embolus (in-body photograph) When the fragment reaches the lungs, the consequences can be devastating. Here, a thrombotic mass can be seen lodged in a pulmonary vessel. In many cases the underlying deep vein thrombosis is undiagnosed, and may thus strike without any warning.

  43. 11. Diagnosis of pulmonary embolism (perfusion and ventilation scans) In another patient with pulmonary embolism, a perfusion scan shows that an embolus has stopped the blood flow to part of one lung. The ventilation scan shows that this area is ventilated normally.

  44. Surgery and trauma are responsible for what percent of all TED resulting from hypercoagulable state and immobility?A. 10%B. 40%C. 90%D. 75%E. 80%

  45. Increased estrogen occurs in a patient: A. during all stages of pregnancy.B. after elective abortion.C. during treatment with oral contraceptive pills.D. during the first three months post-partum.E. all of the above.

  46. Clinical examination alone is able to confirm what percent of DVT cases?A. 20-30%B. 50%C. 5%D. 60-70%

  47. Radiologists disagree on the interpretation of what percent of venography cases?A. 50%B. Less than 5%C. At least 10%D. 75%

  48. A sonographer can distinguish a fresh clot from an old clot based on:A. collateral flow.B. echogenicity.C. homogeneity.D. all of the above.

  49. Duplex scanning:A. is most sensitive for clots below the knee.B. is less sensitive for clots below the knee.C. detects 30% of distal thrombi.D. is more likely to detect non-occluding thrombi.

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