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thrombophilias2-111216175316-phpapp02.pdf
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- 2. Thrombophilia orhypercoagulability is the propensity to develop thrombosis (blood clots) due to an abnormality in the system of coagulation
- 3. Abnormal Blood Flow Abnormal Vessel Wall Dr.Rudolph Virchow 1821-1902 The Hypercoagulable State Abnormal Blood
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- 5. Acquired Inherited Mixed/unknown
- 6. Advancing age Prior Thrombosis Immobilization Major surgery Malignancy Estrogens Antiphospholipid antibody syndrome Myeloproliferative Disorders Heparin-induced thrombocytopenia (HIT) Prolonged air travel
- 7. Antithrombin deficiency Protein C deficiency Protein S deficiency Factor V Leiden mutation (Factor V-Arg506Gln) Prothrombin gene mutation (G A transition at position 20210) Dysfibrinogenemias (rare)
- 8. High levelsof factor VIII Acquired Protein C resistance in the absence of Factor V Leiden High levels of Factor IX, XI
- 10. Thrombophilic Defect Prev Antithrombindeficiency 8 – 10 Protein C deficiency 7 – 10 Protein S deficiency 8 – 10 Factor V Leiden/APC resisance 3 – 7 Prothrombin 20210 A muation 3 Elevated Factor VIII 2 – 11 Lupus Anticoagulant 11 Anticardiolipin antibodies 1.6-3.2 Mild hyperhomocysteinemia 2.5
- 11. Risk Incidence/year (%) Normal1 .008 Oral Cont. Pills 4x .03 Factor V Leiden 7x .06 (heterozygote) OCP + Factor V L. 35x .3 Factor V Leiden 80x .5-1 homozygotes
- 12. Thrombophilic Defect Rel.Risk Antithrombin, protein C, 2.5 or protein S deficiency Factor V Leiden mutation 1.4 Prothrombin 20210A mutation 1.4 Elevated Factor VIII:c 6 – 11 Antiphospholipid antibodies 2 – 9
- 13. Idiopathic VTE Residual DVT Elevated D-dimer levels Age
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- 16. Also knownas Antithrombin III Inhibits coagulation by irreversibly binding the thrombogenic proteins thrombin (IIa), IXa, Xa, XIa and XIIa Antithrombin’s binding reaction is amplified 1000- fold by heparin, which binds to antithrombin to cause a conformational change which more avidly binds thrombin and the other serine proteases
- 17. Protein Cis a vitamin K dependent glycoprotein produced in the liver In the activation of protein C, thrombin binds to thrombomodulin, a structural protein on the endothelial cell surface This complex then converts protein C to activated protein C (APC), which degrades factors Va and VIIIa, limiting thrombin production For protein C to bind, cleave and degrade factors Va and VIIIa, protein S must be available Protein C deficiency, whether inherited or acquired, may cause thrombosis when levels drop to 50% or below Protein C deficiency also occurs with surgery, trauma, pregnancy, OCP, liver or renal failure, DIC,or warfarin
- 24. Protein Sis an essential cofactor in the protein C pathway Protein S exists in a free and bound state 60-70% of protein S circulates bound to C4b binding proten The remaining protein S, called free PS, is the functionally active form of protein S Inherited PS deficiency is an autosomal dominant disorder, causing thrombosis when levels drop to 50% or lower
- 25. May bedue to elevated C4bBP, decreased PS synthesis, or increased PS consumption C4bBP is an acute phase reactant and may be elevated in inflammation, pregnancy, SLE, causing a drop in free PS Functional PS activity may be decreased in vitamin K deficiency, warfarin, liver disease Increased PS consumption occurs in acute thrombosis, DIC, MPD, sickle cell disease
- 26. Activated proteinC (APC) is the functional form of the naturally occurring, vitamin K dependent anticoagulant, protein C APC is an anticoagulant which inactivates factors Va and VIIIa in the presence of its cofactor, protein S Alterations of the factor V molecule at APC binding sites (such as amino acid 506 in Factor V Leiden) impair, or resist APC’s ability to degrade or inactivate factor Va
- 27. A G-to-Asubstitution in nucleotide position 20210 is responsible for a factor II polymorphism The presence of one allele (heterozygosity) is associated with a 3-6 fold increased for all ages and both genders The mutation causes a 30% increase in prothrombin levels.
- 29. Defined bythe occurrence of at least one clinical feature and the presence of at least one type of autoantibody known as an antiphospholipid antibody (aPL). Clinical Criteria -Arterial or venous thrombosis -Pregnancy morbidity Laboratory Criteria – confirmed on 2 or more occassions at least 12 weeks apart -IgG or IgM anticardiolipin antibody-medium or high titer -Lupus Anticoagulant - Anti-Beta2 Glycoprotein antibodies
- 30. Thrombosis—arterial orvenous Pregnancy loss Thrombocytopenia CNS syndromes—stroke, chorea Cardiac valve disease Livedo Reticularis Catastrophic APLS – thromboses, thrombocytopenia, MAHA, Widepread organ damage. D/D – TTP, DIC
- 31. DRVVT- venomactivates F. X directly; prolonged by LAC’s APTT- Usually prolonged, does not correct in 1:1 mix Prothrombin Time- seldom very prolonged
- 32. ACAs areantibodies directed at a protein- phosholipid complex Detected in an ELISA assay using plates coated with cardiolipin and B2-glycoprotein
- 33. Patients withthrombosis- anticoagulation, INR 3 Anticoagulation is long-term—risk of thrombosis is 50% at 2 years after discontinuation Women with recurrent fetal loss and APS require LMW heparin and low-dose heparin during their pregnancies
- 35. Abnormality Arterial Venous FactorV Leiden - + Prothrombin G20210A - + Antithrombin deficiency - + Protein C deficiency - + Protein S deficiency - + Lupus Anticoagulant + +
- 36. A caseof VT where no evidence of underlying obvious cause such as surgery, trauma or known malignancy is present. Search for a hypercoagulable state in such conditions
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- 39. Clinical History “Weakly”“Strongly” Age of onset <50 - + Recurrent thrombosis - + Positive family history - +
- 40. Pro Improve understanding ofpathogenesis of thrombosis Identify and counsel affected family members Obviate expensive diagnostic testing (e.g. CT scans) looking for a malignancy Con Infrequent identification of patients with defects whose management would change Potential for overaggressive management Insurance implications Cost of testing
- 41. Routine screeningof patients with VTE for an underlying thrombophilic defect “is not justified” However, the risk of subsequent thrombosis over 5 years in men with idiopathic VTE is 30% Any additional defect adds to risk and to possible need for prolongation of anticoagulation Furthermore, women with a history of VTE who wish to become pregnant will be treated differently if a defect were found
- 42. Test forFactor V Leiden Genetic test for prothrombin gene mutation 20210A Functional assay of antithrombin III Functional assay of protein C Functional assay of protein S Testing for Anti-phospholipid antibody syndrome : Clotting test for lupus anticoagulant ( mixing studies, DRVVT, STACLOT-LA) /ELISA for cardiolipin antibodies. A complete hypercoagulability work – up as above is recommended in strongly thrombophilic patients.
- 43. Test forFactor V Leiden Genetic test for prothrombin gene mutation G20210A Clotting assay for lupus anticoagulant/ELISA for cardiolipin antibodies LIMITED THROMBOPHILIA W/U AS ABOVE IN “Weakly” thrombophilic patients. Eg. for a “weakly” thrombophilic case : one time spontaneous thrombosis in a patient age > 50 years with no family history of thrombophilia.
- 44. Hyperhomocystinemia inThrombophilia In the past, homocysteine levels were recommended in thrombophilic patients. Measurement of fasting total plasma homocysteine is no longer recommended There are no data supporting a change in the duration or type of therapy for a patient with hyperhomocysteinemia and a past history of VTE, since hyperhomocysteinemia may be a marker of thrombotic disease rather than a cause. Results from the Leiden MEGA study indicate that the presence of methylenetetrahydrofolate reductase (MTHFR) mutation which mildly increases homocysteine levels, is not associated with an increased risk for venous thrombosis. Hence, there is no clinical rationale for measurement of plasma homocysteine levels or for assaying for presence of the MTHFR mutation when screening for the risk of VTE.
- 45. Clues – Bilateral DVTs, Arterial and venous thrombosis and Warfarin refractory thrombosis. Follow age – specific screening recommendations and clinical history to select appropriate investigations when cancer associated thromboses are suscpected.
- 46. Heparin ControversialAT-III (heparin vs acute event) Most coagulation based test for APLA ▪ Hexagonal phospholipid not affected Warfarin Protein C and protein S Need to wait 3 weeks before testing protein S Most coagulation based APLA tests
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- 48. Risk Classification Management HighRisk 2 or more spontaneous events Indefinite Anticoagulation 1 spontaneous life-threatening event (near-fatal pulmonary embolus, cerebral, mesenteric, portal vein thrombosis) 1 spontaneous event in association with antiphospholipid antibody syndrome, antithrombin deficiency, or more than 1 genetic defect Moderate Risk 1 event with a known provocative Vigorous prophylaxis in stimulus high-risk settings Asymptomatic
- 49. Risk ofrecurrence depends on type of risk factor. If 1st DVT occurred after a major risk factor, recurrence is 3% where as if it occurred after minor risk factor recurrence is 10% So, stratify pts based on risk factor and then decide duration Major transient risk factors : Major surgery, major medical illness and leg casting. Minor transient risk factors : OC Pills, HRT High risk thrombophilias : Homzygos Prothrombin gene mutation, Homozygos Factor v leiden, antithrombin, protein c and protein s deficiencies and APLA Syndrome Low risk thrombophilias : Heterozygosity for prothrobin gene mutation and Factor V leiden
- 50. Patient Patient characteristics characteristics Risk of recurrence Riskof recurrence (%) (%) - In the year after - In the year after discontinuation discontinuation Duration of Duration of Therapy Therapy a. a.Major transient risk Major transient risk factor factor b. b.Minor risk factor, no Minor risk factor, no thrombophilia thrombophilia d. d.Idiopathic event, no Idiopathic event, no or low risk or low risk thrombophilia thrombophilia e. e.Idiopathic event, Idiopathic event, high risk high risk thrombophilia thrombophilia f. f.More than one More than one idiopathic event idiopathic event g. g.Cancer, other Cancer, other ongoing risk factor ongoing risk factor Ref: NEJM, 2004, 351 Ref: NEJM, 2004, 351 3% 3% <10% if risk factor <10% if risk factor avoided. >10% if avoided. >10% if persistent persistent <10% <10% >10% >10% >10% >10% >10% >10% 3 months 3 months 6 months 6 months Until factor resolves Until factor resolves 6 months 6 months Indefinite Indefinite Indefinite Indefinite Indefinite. Consider Indefinite. Consider long term Rx with long term Rx with LMWH in pts with LMWH in pts with cancer cancer
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- 52. More than1 trillion units heparin used yearly in US; 1/3 of hospitalized exposed (12 million). Unfractionated heparin – 3 - 5% incidence; Heart surgery 2.5% incidence LMWHeparin, Catheter-flushes -- ~0.5% Frequency of thromboemboli : 30%–50% of patients with untreated HIT will have a thrombotic complication within 30 days ( Warkentin TE Am J Med. 1996;101:502–507) Based on increased morbidity and mortality, heparin cessation alone is inadequate in HIT management
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- 54. HIT Two types– HIT type I and Type II. In general, the term HIT is used widely to refer HIT Type II, the immune form. Presence of any of the following : Otherwise unexplained thrombocytopenia Venos or arterial thromboses associated with thrombocytopenia A fall in platelet count of 50% or more from a prior value, even if absolute Thrombocytopenia is not present. Necrotic skin lesions at heparin injection site Acute systemic ( anaphylactoid) reactions occuring after IV heparin bolus.
- 55. Normal plateletcount before commencement of heparin therapy Onset of thrombocytopenia typically 5–14 days after initiation of heparin therapy but can occur earlier Exclusion of other causes of thrombocytopenia (eg, sepsis) Occurrence of thromboembolic complications during heparin therapy
- 56. Sequelae Incidence Thrombosis 30%–50% Amputation20% (arterial thrombosis) Death 22% to 28% .
- 57. • 30%–50% ofuntreated patients with thrombocytopenia progress to thrombosis 4:1 Incidence Ratio Venous to Arterial Arterial Aortic/Ileofemoral Thrombosis Acute Thrombotic Stroke Myocardial Infarction, Mural thrombosis, Thrombi in upper limb, mesenteric, renal and spinal arts. Venous Deep Vein Thrombosis Pulmonary Embolism Cerebral Dural Sinus Thrombosis Adrenal Hemorrhagic Infarction
- 58. HIT Temporal Variants Day1 Day 4 Day 14 Day 30 Delayed-onset HIT (9–40 days) Rapid-onset HIT (hours–days) Typical HIT Mean Day 9 (5–14 days) Heparin (re) Exposure THROMBOCYTOPENIA (± THROMBOSIS)
- 59. Thrombocytopenia Plateletcount fall > 50% and nadir greater than 20k : 2 points Platelet count fall 30 to 50% or nadir 10 to 19k : 1 point Platelet count fall < 30% or nadir < 10k : 0 points Timing of platelet count fall Clear onset b/w days 5 to 10 or platelet count fall at ≤1 day if prior heparin exposure within the last 30 days: 2 points Consistent with fall at 5 to 10 days but not clear (eg, missing platelet counts) or onset after day 10 or fall ≤1 day with prior heparin exposure within the last 30 to 100 days: 1 point Platelet count fall at <4 days without recent exposure: 0 points Thrombosis or other sequelae Confirmed new thrombosis, skin necrosis, or acute systemic reaction after intravenous unfractionated heparin bolus: 2 points Progressive or recurrent thrombosis, non-necrotizing (erythematous) skin lesions, or suspected thrombosis which has not been proven: 1 point None: zero points Other causes for thrombocytopenia present — None apparent: 2 points Possible: 1 point , Definite: zero points The 5th T : The TEST
- 60. A scoreis determined for each of the four above categories, resulting in a total score from zero to 8. Pretest probabilities for HIT are, as follows: ▪ zero to 3: Low probability ▪ 4 to 5: Intermediate probability ▪ 6 to 8: High probability Laboratory tests are ordered to confirm HIT.
- 61. Test Advantages Disadvantages SRASensitivity >95%, Technically demanding Specific > 95% Low predictive value HIPA Rapid, available Variable sensitivity (30% – 80%); Technique-dependent ELISA High sensitivity High cost, less specificity, > 95% 10% false-negative tests There is no Gold Standard in diagnostic testing; HIT requires a clinical diagnosis .
- 62. Stop allHeparin, including heparin flushes. If dialysis, must be Heparin free. Platelet transfusions are relatively contraindicated. ( except in those with overt bleeding). If Intermediate or High pre-test (clinical) probability + Positive ELISA (Anti-PF4 antibody) Start alternative anticoagulant. For low clinical probability, positive ELISA consider false positive ELISA. Obtain Serotonin Release Assay which is more specific. If clinical probability increases over time from a prior value but if initial HIT was negative Repeat HIT antibody (ELISA) (may turn positive. ) Start alternative anticoagulant
- 63. Drug Indications Argatroban FDA-approvedfor HIT (also for PCI) Lepirudin FDA-approved for HIT Bivalirudin (Angiomax) PCI (including HIT patients) Fondaparinux (Arixtra) FDA approved for DVT Prophylaxis in patients with Hip#, Hip or knee replacements. Also used in Rx of VTE. Not yet approved for HIT (Off-label use) Danaparoid Approved for HIT in Canada, Europe, Aust.
- 64. Synthetic DirectThrombin Inhibitor indicated as a prophylactic anticoagulant or for treatment of thromboses in HIT. MOA : Directly inhibits Thrombin, Reversibly binds to the thrombin catalytic site and Active against both free and clot- bound thrombin Rapid Onset of Action In healthy subjects, the pharmacokinetics and pharmacodynamics of Argatroban were NOT affected by renal impairment, age, or gender Dosage adjustment is NOT necessary in renally impaired patients Hepatic impairment decreases Argatroban clearance; therefore, the dosage must be reduced for hepatically impaired patients
- 65. HIT Patients HIT Patients with RenalImpairment HIT Patients with Hepatic Impairment * Not to exceed a dose of 10 µg/kg/min or aPTT of 100 seconds † Due to approximate 4-fold decrease in Argatroban clearance relative to those with normal hepatic function Initiate at 2 µg/kg/min Titrate until steady-state aPTT is 1.5–3.0 times baseline value* No dosage adjustment required Initiate at 0.5 µg/kg/min† Titrate until steady-state aPTT is 1.5–3.0 times baseline value*
- 66. Initiate warfarinonly when platelet count increases above 100k. All direct thrombin inhibitors, including Argatroban, may increase prothrombin time (PT); this must be taken into consideration when converting to warfarin therapy Coadministration of Argatroban and warfarin does produce a combined effect on the laboratory measurement of the INR. Concurrent therapy with Argatroban and warfarin does not exert an additive effect on the warfarin mechanism of action (e.g., factor Xa activity) The previously established relationship between INR and bleeding risk is altered during combination therapy For example, an INR of 4 on co-therapy may not have the same bleeding risk as an INR of 4 on warfarin monotherapy. Continue anticoagulation for 2-3 months in HIT with out thromboses but continue it for 6 months if a thrombotic event occurred.
- 67. If INR isbelow the therapeutic range for warfarin alone, resume Argatroban therapy If INR is >4.0, stop Argatroban infusion Initiate warfarin therapy using the expected daily dose of warfarin while maintaining Argatroban infusion.* A loading dose of warfarin should not be used If INR is within therapeutic range on warfarin alone, continue warfarin monotherapy If INR is ≤4.0, continue concomitant therapy Repeat INR 4-6 hours later Measure INR daily * For Argatroban infusion at ≤2 µg/kg/min, the INR on monotherapy may be estimated from the INR on cotherapy. If the dose of Argatroban >2 µg/kg/min, temporarily reduce to a dose of 2 µg/kg/min 4-6 hours prior to measuring the INR.
- 68. When a patient... ☞experiences a drop in platelet counts ☞ develops thrombosis Consider HIT during/soon after heparin exposure* * Heparin exposure may be through virtually any preparation (including LMWH), any dose, or any route of heparin (including flushes and coated lines)
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