Hematology – Highyield Topics
<ul><li>Thrombophilia  or hypercoagulability is the propensity to develop thrombosis (blood clots) due to an abnormality i...
Abnormal Blood Flow Abnormal Vessel Wall Dr. Rudolph Virchow 1821-1902 The Hypercoagulable State Abnormal Blood
Thrombosis Hereditary thrombophilia Acquired thrombophilia Surgery trauma Immobility Inflammation Malignancy Estrogens Ath...
<ul><li>Acquired </li></ul><ul><li>Inherited </li></ul><ul><li>Mixed/unknown </li></ul>
<ul><li>Advancing age </li></ul><ul><li>Prior Thrombosis </li></ul><ul><li>Immobilization </li></ul><ul><li>Major surgery ...
<ul><li>Antithrombin deficiency </li></ul><ul><li>Protein C deficiency </li></ul><ul><li>Protein S deficiency </li></ul><u...
<ul><li>High levels of factor VIII </li></ul><ul><li>Acquired Protein C resistance in the absence of Factor V Leiden </li>...
 
<ul><li>Thrombophilic Defect Prev </li></ul><ul><li>Antithrombin deficiency 8 – 10 </li></ul><ul><li>Protein C deficiency ...
<ul><li>  Risk Incidence/year (%) </li></ul><ul><li>Normal  1   .008 </li></ul><ul><li>Oral Cont. Pills  4x .03 </li></ul>...
<ul><li>Thrombophilic Defect Rel. Risk </li></ul><ul><li>Antithrombin, protein C,   2.5 </li></ul><ul><li>or protein S def...
<ul><li>Idiopathic VTE </li></ul><ul><li>Residual DVT </li></ul><ul><li>Elevated D-dimer levels </li></ul><ul><li>Age </li...
FXI   FIX FXII FV FVII Prothrombin Thrombin Fibrinogen Fibrin Clot FVIII FX
J Thromb. Haem.1.525, 2003
<ul><li>Also known as Antithrombin III </li></ul><ul><li>Inhibits coagulation by irreversibly binding the thrombogenic pro...
<ul><li>Protein C is a vitamin K dependent glycoprotein produced in the liver </li></ul><ul><li>In the activation of prote...
 
 
 
 
 
 
<ul><li>Protein S is an essential cofactor in the protein C pathway </li></ul><ul><li>Protein S exists in a free and bound...
<ul><li>May be due to elevated C4bBP, decreased PS synthesis, or increased PS consumption </li></ul><ul><li>C4bBP is an ac...
<ul><li>Activated protein C (APC) is the functional form of the naturally occurring, vitamin K dependent anticoagulant, pr...
<ul><li>A G-to-A substitution in nucleotide position 20210 is responsible for a factor II polymorphism </li></ul><ul><li>T...
 
<ul><li>Defined by the occurrence of at least one clinical feature and the presence of at least one type of autoantibody k...
<ul><li>Thrombosis—arterial or venous </li></ul><ul><li>Pregnancy loss </li></ul><ul><li>Thrombocytopenia </li></ul><ul><l...
<ul><li>DRVVT- venom activates F. X directly; </li></ul><ul><li>prolonged by LAC’s </li></ul><ul><li>APTT- Usually prolong...
<ul><li>ACAs are antibodies directed at a protein-phosholipid complex </li></ul><ul><li>Detected in an ELISA assay using p...
<ul><li>Patients with thrombosis- anticoagulation, INR 3 </li></ul><ul><li>Anticoagulation is long-term—risk of thrombosis...
 
<ul><li>Abnormality Arterial Venous </li></ul><ul><li>Factor V Leiden   -   + </li></ul><ul><li>Prothrombin G20210A   -   ...
<ul><li>A case of  VT where no evidence of underlying obvious cause such as  surgery, trauma or known malignancy is presen...
APPROACH
 
<ul><li>Clinical History “Weakly” “ Strongly” </li></ul><ul><li>Age of onset <50   -   + </li></ul><ul><li>Recurrent throm...
<ul><li>Pro </li></ul><ul><li>Improve understanding of pathogenesis of thrombosis </li></ul><ul><li>Identify and counsel a...
<ul><li>Routine  screening of patients with VTE for an underlying thrombophilic defect “is not justified” </li></ul><ul><l...
<ul><li>Test for Factor V Leiden </li></ul><ul><li>Genetic test for prothrombin gene mutation 20210A </li></ul><ul><li>Fun...
<ul><li>Test for Factor V Leiden </li></ul><ul><li>Genetic test for prothrombin gene mutation G20210A </li></ul><ul><li>Cl...
<ul><li>Hyperhomocystinemia in Thrombophilia </li></ul><ul><ul><li>In the past, homocysteine levels were recommended in th...
<ul><li>Clues  –  </li></ul><ul><li>Bilateral DVTs, Arterial and venous thrombosis and Warfarin refractory thrombosis.  </...
<ul><li>Heparin </li></ul><ul><ul><li>Controversial AT-III (heparin vs acute event) </li></ul></ul><ul><ul><li>Most coagul...
<ul><ul><ul><ul><ul><li>? </li></ul></ul></ul></ul></ul>
<ul><li>Risk Classification Management </li></ul><ul><li>High Risk </li></ul><ul><li>2 or more spontaneous events Indefini...
<ul><li>Risk of recurrence depends on type of risk factor. If 1 st  DVT occurred after a major risk factor, recurrence is ...
Patient characteristics Risk of recurrence (%) - In the year after discontinuation Duration of Therapy <ul><li>Major trans...
Diagnosis Management
<ul><li>More than 1 trillion units heparin used yearly in US; 1/3 of hospitalized exposed (12 million). </li></ul><ul><li>...
.
<ul><li>Two types – HIT type I and Type II. In general, the term HIT is used widely to refer HIT Type II, the immune form....
<ul><li>Normal platelet count before commencement of heparin therapy </li></ul><ul><li>Onset of thrombocytopenia typically...
Sequelae Incidence Thrombosis 30%–50%  Amputation 20% (arterial thrombosis) Death 22% to 28% .
<ul><li>30%–50% of untreated patients with thrombocytopenia progress to thrombosis </li></ul>4:1 Incidence Ratio Venous to...
HIT Temporal Variants Day 1 Day 4 Day 14 Day 30 Delayed-onset  HIT  (9–40 days) Rapid-onset HIT  (hours–days) Typical HIT ...
<ul><li>Thrombocytopenia </li></ul><ul><ul><ul><ul><ul><li>Platelet count fall > 50% and nadir greater than 20k : 2 points...
<ul><li>A score is determined for each of the four above categories, resulting in a total score from zero to 8.  </li></ul...
<ul><li>Test Advantages Disadvantages </li></ul><ul><li>SRA Sensitivity >95%, Technically demanding Specific > 95% Low pre...
<ul><li>Stop all Heparin, including heparin flushes. If dialysis, must be Heparin free.  </li></ul><ul><li>Platelet transf...
Drug Indications Argatroban FDA-approved for HIT  (also for PCI)  Lepirudin FDA-approved for HIT Bivalirudin (Angiomax) PC...
<ul><li>Synthetic Direct Thrombin Inhibitor indicated as a prophylactic anticoagulant  or for treatment of thromboses in H...
HIT Patients HIT Patients with Renal Impairment HIT Patients with Hepatic Impairment * Not to exceed a dose of 10 µg/kg/mi...
<ul><li>Initiate warfarin  only when platelet count increases above 100k. </li></ul><ul><li>All direct thrombin inhibitors...
If INR is below the therapeutic range for warfarin alone, resume Argatroban therapy  If INR is >4.0, stop Argatroban infus...
<ul><li>When a patient...   </li></ul><ul><ul><li>experiences a drop in platelet counts </li></ul></ul><ul><ul><li>develop...
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Thrombophilias

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Thrombophilias are hypercoagulable conditions that can be acquired or inherited. Most important hypercoagulable conditions =, testing procedures, duration of anticoagulation will be discussed here. Useful for Internal Medicine Boards and Hematology boards. Some aspects on duration of anticoagulation, HIT are high-yield for USMLE exams.

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  • Heterozygosity is about 5%. Homozygosity of leiden is 1% APC resistance often due to factor V leiden but it can occur due to other mutations in factor V. Acquired APC resistance can be seen in pregnancy.
  • Heparin-Induced Thrombocytopenia (HIT): An Overview Key Point: Broad overview of what the presentation will discuss in detail. The anticoagulant heparin is used in more than 12 million patients per year 1 for treating and preventing thromboembolic disorders in medical and surgical patients. 2 Its importance as an anticoagulant has been well established by its effectiveness, rapid onset of action, ease of laboratory monitoring, and cost. Heparin can cause 2 forms of thrombocytopenia. This slide kit is primarily concerned with immune-mediated thrombocytopenia, or HIT, which occurs in up to 1% to 3% of patients receiving unfractionated heparin and in up to 2% of patients undergoing orthopedic surgery receiving low molecular weight heparin (LMWH). 2 HIT is a serious condition with about 50% of patients at risk of life- or limb-threatening thromboses if they remain untreated. 3 All forms of heparin should be discontinued in the presence of HIT. 4,5 An alternate anticoagulant should be strongly considered to treat HIT as well as the underlying condition. The Food and Drug Administration (FDA) has approved 2 anticoagulants for use in patients with HIT, lepirudin and argatroban. 1. Fahey VA. Heparin-induced thrombocytopenia. J Vasc Nurs . 1995;13(4):112-116. 2. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low- molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332(20):1330-1335. 3. Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med. 1996;101(5):502-507. 4. Warkentin TE, Barkin RL. Newer strategies for the treatment of heparin- induced thrombocytopenia. Pharmacotherapy. 1999;19(2):181-195. 5. Chong BH. Heparin-induced thrombocytopenia. Br J Haematol. 1995;89(3):431-439.
  • HIT is an immune disease resulting in an extremely pro thrombotic state. HIT occurs due to presence of IgG antibodies that recognize heparin-PF4 complexes. Initially, Platelet activation leads to release of platelet factor 4 (PF4) and microparticles. The heparin that is administered forms complexes with PF4  the IgG antibodies that are already present ( from prior sensitization or from de novo formation during this exposure) now react with PF4-heparin complexes to form circulating immune complexes (PF4-heparin-IgG) which then bind to Fc receptors on the platelets thereby, activating the platelets further  leading to further release of microparticles and more PF4 and activation of the coagulation pathways through platelet-derived microparticles thus setting off prothrombotic state
  • HIT is classified as two types HIT Type 1 which is non immune mild TP ( &gt;100k) associated with heparin that occurs with in first five days of heparin. This is not associated with thrombosis or antibody formation and platelet count recovers despite continuing Heparin. This is probably secondary to tiny platelet aggregates.
  • 30 – 50% of patients presenting with HIT experience a thrombotic event within 30 days. Morbidity and mortality are significant in patients with HIT despite discontinuation of heparin therapy. Death can occur in 30% cases if untreated.
  • Venous complications were observed more frequently than arterial events in a ratio of approximately 4:1. 3 The early symptoms of venous thrombosis may not be obvious. The most common venous thrombotic complication was deep vein thrombosis, which was responsible for more than 60% of thrombotic events in one study, followed by pulmonary embolism, which was responsible for 25% of all events. 3, 11 Arterial events are generally evidenced by overt clinical symptoms and may be life or limb threatening. In a single patient, significant clot extensions or multiple sites of thrombosis may occur. 5, 15
  • HIT can be of 3 types based on the time of onset. Early onset HIT can occur with in 5 days of heparin re-exposure and is due to pre-existing circulating anti-PF4 antibodies due to prior recent exposure to heparin in the past 3 months ( the antibodies can exist up to 90 days after initial exposure to heparin). Typical HIT occurs between 5 to 14 days after exposure to heparin. Some patients may have delayed onset HIT which can start as late as 9 days after exposure to heparin and may occur until 40 days after exposure. HIT can occur up until 30 days even after stopping heparin due to circulating antibodies.
  • HIT is a clinical diagnosis. Pre-test probabilty must be estimated by using 4T score. Most laboratory tests have long turnaround time and hence, therapy must not be delayed if pretest is high or intermediate.
  • While these tests are helpful in confirming HIT, the diagnosis remains a clinical one since there is wide variability of, access to, and turnaround time for these assays. There is wide variability in sensitivity and specificity. If SRA is only 95% sensitive, a negative SRA will nor rule out HIT if clinical
  • Direct Thrombin inhibitors : argatroban, lepirudin, bivalirudin. Fondaparinux : Is a INDIRECT inhibitor of Factor Xa. ( does not belong to class of direct thrombin inhibitors) The combination of once-daily subcutaneous administration, predictability of response, and minimal adverse effects makes fondaparinux an appealing alternative anticoagulant for patients with HIT. Although clinical experience with this agent in the setting of HIT is limited, the successful use of fondaparinux in patients with HIT has been reported. To date, one multicenter, blinded, comparative, in vitro study has demon-strated a lack of cross-reactivity between fondaparinux and HIT antibodies. At this time, use of fondaparinux in the setting of HIT is not recommended by the American College of Chest Physicians. Rather, the direct thrombin inhibitors lepirudin and argatroban are recommended as first-line agents. Nevertheless, limited clinical experience suggests that fondaparinux may be an alternative for anticoagulation in patients with HIT. Large, in vivo comparison trials must be performed before fondaparinux can become a standard treatment option in the setting of HIT
  • Dosing for Argatroban is relatively straightforward. 17 The initial dose of Argatroban is 2  g/kg/min; the mean dose during clinical studies was 2  g/kg/min, indicating dose titration for many patients may not be necessary to achieve adequate anticoagulation. No dosage adjustment is necessary in patients with renal impairment. For patients with hepatic impairment, the dose should be reduced to 0.5  g/kg/min.
  • If argatroban infusion rate is &gt;2mcg/kg/min  reduce dose to &lt;2mcg/kg/min first and then, measure inr after 4 hours – now, if INR &gt; 4, can stop argatroban
  • Thrombophilias

    1. 1. Hematology – Highyield Topics
    2. 2. <ul><li>Thrombophilia  or hypercoagulability is the propensity to develop thrombosis (blood clots) due to an abnormality in the system of coagulation </li></ul>
    3. 3. Abnormal Blood Flow Abnormal Vessel Wall Dr. Rudolph Virchow 1821-1902 The Hypercoagulable State Abnormal Blood
    4. 4. Thrombosis Hereditary thrombophilia Acquired thrombophilia Surgery trauma Immobility Inflammation Malignancy Estrogens Atherosclerosis
    5. 5. <ul><li>Acquired </li></ul><ul><li>Inherited </li></ul><ul><li>Mixed/unknown </li></ul>
    6. 6. <ul><li>Advancing age </li></ul><ul><li>Prior Thrombosis </li></ul><ul><li>Immobilization </li></ul><ul><li>Major surgery </li></ul><ul><li>Malignancy </li></ul><ul><li>Estrogens </li></ul><ul><li>Antiphospholipid antibody syndrome </li></ul><ul><li>Myeloproliferative Disorders </li></ul><ul><li>Heparin-induced thrombocytopenia (HIT) </li></ul><ul><li>Prolonged air travel </li></ul>
    7. 7. <ul><li>Antithrombin deficiency </li></ul><ul><li>Protein C deficiency </li></ul><ul><li>Protein S deficiency </li></ul><ul><li>Factor V Leiden mutation (Factor V-Arg506Gln) </li></ul><ul><li>Prothrombin gene mutation (G A transition at position 20210) </li></ul><ul><li>Dysfibrinogenemias (rare) </li></ul>
    8. 8. <ul><li>High levels of factor VIII </li></ul><ul><li>Acquired Protein C resistance in the absence of Factor V Leiden </li></ul><ul><li>High levels of Factor IX, XI </li></ul>
    9. 10. <ul><li>Thrombophilic Defect Prev </li></ul><ul><li>Antithrombin deficiency 8 – 10 </li></ul><ul><li>Protein C deficiency 7 – 10 </li></ul><ul><li>Protein S deficiency 8 – 10 </li></ul><ul><li>Factor V Leiden/APC resisance 3 – 7 </li></ul><ul><li>Prothrombin 20210 A muation 3 </li></ul><ul><li>Elevated Factor VIII 2 – 11 </li></ul><ul><li>Lupus Anticoagulant 11 </li></ul><ul><li>Anticardiolipin antibodies 1.6-3.2 </li></ul><ul><li>Mild hyperhomocysteinemia 2.5 </li></ul>
    10. 11. <ul><li> Risk Incidence/year (%) </li></ul><ul><li>Normal 1 .008 </li></ul><ul><li>Oral Cont. Pills 4x .03 </li></ul><ul><li>Factor V Leiden 7x .06 </li></ul><ul><li>(heterozygote) </li></ul><ul><li>OCP + Factor V L. 35x .3 </li></ul><ul><li>Factor V Leiden 80x .5-1 </li></ul><ul><li>homozygotes </li></ul>
    11. 12. <ul><li>Thrombophilic Defect Rel. Risk </li></ul><ul><li>Antithrombin, protein C, 2.5 </li></ul><ul><li>or protein S deficiency </li></ul><ul><li>Factor V Leiden mutation 1.4 </li></ul><ul><li>Prothrombin 20210A mutation 1.4 </li></ul><ul><li>Elevated Factor VIII:c 6 – 11 </li></ul><ul><li>Antiphospholipid antibodies 2 – 9 </li></ul>
    12. 13. <ul><li>Idiopathic VTE </li></ul><ul><li>Residual DVT </li></ul><ul><li>Elevated D-dimer levels </li></ul><ul><li>Age </li></ul>
    13. 14. FXI FIX FXII FV FVII Prothrombin Thrombin Fibrinogen Fibrin Clot FVIII FX
    14. 15. J Thromb. Haem.1.525, 2003
    15. 16. <ul><li>Also known as Antithrombin III </li></ul><ul><li>Inhibits coagulation by irreversibly binding the thrombogenic proteins thrombin (IIa), IXa, Xa, XIa and XIIa </li></ul><ul><li>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 </li></ul>
    16. 17. <ul><li>Protein C is a vitamin K dependent glycoprotein produced in the liver </li></ul><ul><li>In the activation of protein C, thrombin binds to thrombomodulin, a structural protein on the endothelial cell surface </li></ul><ul><li>This complex then converts protein C to activated protein C (APC), which degrades factors Va and VIIIa, limiting thrombin production </li></ul><ul><li>For protein C to bind, cleave and degrade factors Va and VIIIa, protein S must be available </li></ul><ul><li>Protein C deficiency, whether inherited or acquired, may cause thrombosis when levels drop to 50% or below </li></ul><ul><li>Protein C deficiency also occurs with surgery, trauma, pregnancy, OCP, liver or renal failure, DIC,or warfarin </li></ul>
    17. 24. <ul><li>Protein S is an essential cofactor in the protein C pathway </li></ul><ul><li>Protein S exists in a free and bound state </li></ul><ul><li>60-70% of protein S circulates bound to C4b binding proten </li></ul><ul><li>The remaining protein S, called free PS, is the functionally active form of protein S </li></ul><ul><li>Inherited PS deficiency is an autosomal dominant disorder, causing thrombosis when levels drop to 50% or lower </li></ul>
    18. 25. <ul><li>May be due to elevated C4bBP, decreased PS synthesis, or increased PS consumption </li></ul><ul><li>C4bBP is an acute phase reactant and may be elevated in inflammation, pregnancy, SLE, causing a drop in free PS </li></ul><ul><li>Functional PS activity may be decreased in vitamin K deficiency, warfarin, liver disease </li></ul><ul><li>Increased PS consumption occurs in acute thrombosis, DIC, MPD, sickle cell disease </li></ul>
    19. 26. <ul><li>Activated protein C (APC) is the functional form of the naturally occurring, vitamin K dependent anticoagulant, protein C </li></ul><ul><li>APC is an anticoagulant which inactivates factors Va and VIIIa in the presence of its cofactor, protein S </li></ul><ul><li>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 </li></ul>
    20. 27. <ul><li>A G-to-A substitution in nucleotide position 20210 is responsible for a factor II polymorphism </li></ul><ul><li>The presence of one allele (heterozygosity) is associated with a 3-6 fold increased for all ages and both genders </li></ul><ul><li>The mutation causes a 30% increase in prothrombin levels. </li></ul>
    21. 29. <ul><li>Defined by the occurrence of at least one clinical feature and the presence of at least one type of autoantibody known as an antiphospholipid antibody (aPL). </li></ul><ul><li>Clinical Criteria </li></ul><ul><li>-Arterial or venous thrombosis </li></ul><ul><li>-Pregnancy morbidity </li></ul><ul><li>Laboratory Criteria – confirmed on 2 or more occassions at least 12 weeks apart </li></ul><ul><li>-IgG or IgM anticardiolipin antibody-medium </li></ul><ul><li> or high titer </li></ul><ul><li>-Lupus Anticoagulant </li></ul><ul><li>- Anti-Beta2 Glycoprotein antibodies </li></ul>
    22. 30. <ul><li>Thrombosis—arterial or venous </li></ul><ul><li>Pregnancy loss </li></ul><ul><li>Thrombocytopenia </li></ul><ul><li>CNS syndromes—stroke, chorea </li></ul><ul><li>Cardiac valve disease </li></ul><ul><li>Livedo Reticularis </li></ul><ul><li>Catastrophic APLS – thromboses, thrombocytopenia, MAHA, Widepread organ damage. D/D – TTP, DIC </li></ul>
    23. 31. <ul><li>DRVVT- venom activates F. X directly; </li></ul><ul><li>prolonged by LAC’s </li></ul><ul><li>APTT- Usually prolonged, does not correct in 1:1 mix </li></ul><ul><li>Prothrombin Time- seldom very prolonged </li></ul>
    24. 32. <ul><li>ACAs are antibodies directed at a protein-phosholipid complex </li></ul><ul><li>Detected in an ELISA assay using plates coated with cardiolipin and B2-glycoprotein </li></ul>
    25. 33. <ul><li>Patients with thrombosis- anticoagulation, INR 3 </li></ul><ul><li>Anticoagulation is long-term—risk of thrombosis is 50% at 2 years after discontinuation </li></ul><ul><li>Women with recurrent fetal loss and APS require LMW heparin and low-dose heparin during their pregnancies </li></ul>
    26. 35. <ul><li>Abnormality Arterial Venous </li></ul><ul><li>Factor V Leiden - + </li></ul><ul><li>Prothrombin G20210A - + </li></ul><ul><li>Antithrombin deficiency - + </li></ul><ul><li>Protein C deficiency - + </li></ul><ul><li>Protein S deficiency - + </li></ul><ul><li>Lupus Anticoagulant + + </li></ul>
    27. 36. <ul><li>A case of VT where no evidence of underlying obvious cause such as surgery, trauma or known malignancy is present. </li></ul><ul><li>Search for a hypercoagulable state in such conditions </li></ul>
    28. 37. APPROACH
    29. 39. <ul><li>Clinical History “Weakly” “ Strongly” </li></ul><ul><li>Age of onset <50 - + </li></ul><ul><li>Recurrent thrombosis - + </li></ul><ul><li>Positive family history - + </li></ul>
    30. 40. <ul><li>Pro </li></ul><ul><li>Improve understanding of pathogenesis of thrombosis </li></ul><ul><li>Identify and counsel affected family members </li></ul><ul><li>Obviate expensive diagnostic testing (e.g. CT scans) looking for a malignancy </li></ul><ul><li>Con </li></ul><ul><li>Infrequent identification of patients with defects whose management would change </li></ul><ul><li>Potential for overaggressive management </li></ul><ul><li>Insurance implications </li></ul><ul><li>Cost of testing </li></ul>
    31. 41. <ul><li>Routine screening of patients with VTE for an underlying thrombophilic defect “is not justified” </li></ul><ul><li>However, the risk of subsequent thrombosis over 5 years in men with idiopathic VTE is 30% </li></ul><ul><li>Any additional defect adds to risk and to possible need for prolongation of anticoagulation </li></ul><ul><li>Furthermore, women with a history of VTE who wish to become pregnant will be treated differently if a defect were found </li></ul>
    32. 42. <ul><li>Test for Factor V Leiden </li></ul><ul><li>Genetic test for prothrombin gene mutation 20210A </li></ul><ul><li>Functional assay of antithrombin III </li></ul><ul><li>Functional assay of protein C </li></ul><ul><li>Functional assay of protein S </li></ul><ul><li>Testing for Anti-phospholipid antibody syndrome : </li></ul><ul><li>Clotting test for lupus anticoagulant ( mixing studies, DRVVT, STACLOT-LA) /ELISA for cardiolipin antibodies. </li></ul><ul><ul><li>A complete hypercoagulability work – up as above is recommended in strongly thrombophilic patients. </li></ul></ul>
    33. 43. <ul><li>Test for Factor V Leiden </li></ul><ul><li>Genetic test for prothrombin gene mutation G20210A </li></ul><ul><li>Clotting assay for lupus anticoagulant/ELISA for cardiolipin antibodies </li></ul><ul><li>LIMITED THROMBOPHILIA W/U AS ABOVE IN “Weakly” thrombophilic patients. </li></ul><ul><li>Eg. for a “weakly” thrombophilic case : one time spontaneous thrombosis in a patient age > 50 years with no family history of thrombophilia. </li></ul>
    34. 44. <ul><li>Hyperhomocystinemia in Thrombophilia </li></ul><ul><ul><li>In the past, homocysteine levels were recommended in thrombophilic patients. </li></ul></ul><ul><ul><li>Measurement of fasting total plasma homocysteine is no longer recommended </li></ul></ul><ul><ul><li>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. </li></ul></ul><ul><ul><li>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. </li></ul></ul><ul><ul><li>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. </li></ul></ul>
    35. 45. <ul><li>Clues – </li></ul><ul><li>Bilateral DVTs, Arterial and venous thrombosis and Warfarin refractory thrombosis. </li></ul><ul><li>Follow age – specific screening recommendations and clinical history to select appropriate investigations when cancer associated thromboses are suscpected. </li></ul>
    36. 46. <ul><li>Heparin </li></ul><ul><ul><li>Controversial AT-III (heparin vs acute event) </li></ul></ul><ul><ul><li>Most coagulation based test for APLA </li></ul></ul><ul><ul><ul><li>Hexagonal phospholipid not affected </li></ul></ul></ul><ul><li>Warfarin </li></ul><ul><ul><li>Protein C and protein S </li></ul></ul><ul><ul><li>Need to wait 3 weeks before testing protein S </li></ul></ul><ul><ul><li>Most coagulation based APLA tests </li></ul></ul>
    37. 47. <ul><ul><ul><ul><ul><li>? </li></ul></ul></ul></ul></ul>
    38. 48. <ul><li>Risk Classification Management </li></ul><ul><li>High Risk </li></ul><ul><li>2 or more spontaneous events Indefinite Anticoagulation </li></ul><ul><li>1 spontaneous life-threatening </li></ul><ul><li> event (near-fatal pulmonary </li></ul><ul><li> embolus, cerebral, mesenteric, </li></ul><ul><li> portal vein thrombosis) </li></ul><ul><li>1 spontaneous event in association </li></ul><ul><li> with antiphospholipid antibody </li></ul><ul><li> syndrome, antithrombin deficiency, </li></ul><ul><li> or more than 1 genetic defect </li></ul><ul><li>Moderate Risk </li></ul><ul><li>1 event with a known provocative Vigorous prophylaxis in </li></ul><ul><li> stimulus high-risk settings </li></ul><ul><li>Asymptomatic </li></ul>
    39. 49. <ul><li>Risk of recurrence depends on type of risk factor. If 1 st 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 </li></ul><ul><li>Major transient risk factors : Major surgery, major medical illness and leg casting. </li></ul><ul><li>Minor transient risk factors : OC Pills, HRT </li></ul><ul><li>High risk thrombophilias : Homzygos Prothrombin gene mutation, Homozygos Factor v leiden, antithrombin, protein c and protein s deficiencies and APLA Syndrome </li></ul><ul><li>Low risk thrombophilias : Heterozygosity for prothrobin gene mutation and Factor V leiden </li></ul>
    40. 50. Patient characteristics Risk of recurrence (%) - In the year after discontinuation Duration of Therapy <ul><li>Major transient risk factor </li></ul><ul><li>Minor risk factor, no thrombophilia </li></ul><ul><li>Idiopathic event, no or low risk thrombophilia </li></ul><ul><li>Idiopathic event, high risk thrombophilia </li></ul><ul><li>More than one idiopathic event </li></ul><ul><li>Cancer, other ongoing risk factor </li></ul><ul><li>Ref: NEJM, 2004, 351 </li></ul>3% <10% if risk factor avoided. >10% if persistent <10% >10% >10% >10% 3 months 6 months Until factor resolves 6 months Indefinite Indefinite Indefinite. Consider long term Rx with LMWH in pts with cancer
    41. 51. Diagnosis Management
    42. 52. <ul><li>More than 1 trillion units heparin used yearly in US; 1/3 of hospitalized exposed (12 million). </li></ul><ul><li>Unfractionated heparin – 3 - 5% incidence; Heart surgery 2.5% incidence </li></ul><ul><li>LMWHeparin, Catheter-flushes -- ~0.5% </li></ul><ul><li>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 </li></ul>
    43. 53. .
    44. 54. <ul><li>Two types – HIT type I and Type II. In general, the term HIT is used widely to refer HIT Type II, the immune form. </li></ul><ul><li>Presence of any of the following : </li></ul><ul><ul><li>Otherwise unexplained thrombocytopenia </li></ul></ul><ul><ul><li>Venos or arterial thromboses associated with thrombocytopenia </li></ul></ul><ul><ul><li>A fall in platelet count of 50% or more from a prior value, even if absolute Thrombocytopenia is not present. </li></ul></ul><ul><ul><li>Necrotic skin lesions at heparin injection site </li></ul></ul><ul><ul><li>Acute systemic ( anaphylactoid) reactions occuring after IV heparin bolus. </li></ul></ul>HIT
    45. 55. <ul><li>Normal platelet count before commencement of heparin therapy </li></ul><ul><li>Onset of thrombocytopenia typically 5–14 days after initiation of heparin therapy but can occur earlier </li></ul><ul><li>Exclusion of other causes of thrombocytopenia (eg, sepsis) </li></ul><ul><li>Occurrence of thromboembolic complications during heparin therapy </li></ul>
    46. 56. Sequelae Incidence Thrombosis 30%–50% Amputation 20% (arterial thrombosis) Death 22% to 28% .
    47. 57. <ul><li>30%–50% of untreated patients with thrombocytopenia progress to thrombosis </li></ul>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
    48. 58. HIT Temporal Variants Day 1 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)
    49. 59. <ul><li>Thrombocytopenia </li></ul><ul><ul><ul><ul><ul><li>Platelet count fall > 50% and nadir greater than 20k : 2 points </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Platelet count fall 30 to 50% or nadir 10 to 19k : 1 point </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Platelet count fall < 30% or nadir < 10k : 0 points </li></ul></ul></ul></ul></ul><ul><li>Timing of platelet count fall  </li></ul><ul><ul><ul><ul><ul><li>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 </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>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 </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Platelet count fall at <4 days without recent exposure: 0 points </li></ul></ul></ul></ul></ul><ul><li>Thrombosis or other sequelae  </li></ul><ul><ul><ul><ul><ul><li>Confirmed new thrombosis, skin necrosis, or acute systemic reaction after intravenous unfractionated heparin bolus: 2 points </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Progressive or recurrent thrombosis, non-necrotizing (erythematous) skin lesions, or suspected thrombosis which has not been proven: 1 point </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>None: zero points </li></ul></ul></ul></ul></ul><ul><li>Other causes for thrombocytopenia present  —  </li></ul><ul><ul><ul><ul><ul><li>None apparent: 2 points </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Possible: 1 point , Definite: zero points The 5 th T : The TEST </li></ul></ul></ul></ul></ul>
    50. 60. <ul><li>A score is determined for each of the four above categories, resulting in a total score from zero to 8. </li></ul><ul><li>Pretest probabilities for HIT are, as follows: </li></ul><ul><ul><ul><li>zero to 3: Low probability </li></ul></ul></ul><ul><ul><ul><li>4 to 5: Intermediate probability </li></ul></ul></ul><ul><ul><ul><li>6 to 8: High probability </li></ul></ul></ul><ul><li>Laboratory tests are ordered to confirm HIT. </li></ul>
    51. 61. <ul><li>Test Advantages Disadvantages </li></ul><ul><li>SRA Sensitivity >95%, Technically demanding Specific > 95% Low predictive value </li></ul><ul><li>HIPA Rapid, available Variable sensitivity (30% – 80%); Technique-dependent </li></ul><ul><li>ELISA High sensitivity High cost, less specificity, > 95% 10% false-negative tests </li></ul>There is no Gold Standard in diagnostic testing; HIT requires a clinical diagnosis .
    52. 62. <ul><li>Stop all Heparin, including heparin flushes. If dialysis, must be Heparin free. </li></ul><ul><li>Platelet transfusions are relatively contraindicated. ( except in those with overt bleeding). </li></ul><ul><li>If Intermediate or High pre-test (clinical) probability + Positive ELISA (Anti-PF4 antibody)  Start alternative anticoagulant. </li></ul><ul><li>For low clinical probability, positive ELISA  consider false positive ELISA. Obtain Serotonin Release Assay which is more specific. </li></ul><ul><li>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 </li></ul>
    53. 63. Drug Indications Argatroban FDA-approved for 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.
    54. 64. <ul><li>Synthetic Direct Thrombin Inhibitor indicated as a prophylactic anticoagulant or for treatment of thromboses in HIT. </li></ul><ul><li>MOA : Directly inhibits Thrombin, Reversibly binds to the thrombin catalytic site and Active against both free and clot-bound thrombin </li></ul><ul><li>Rapid Onset of Action </li></ul><ul><li>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 </li></ul><ul><li>Hepatic impairment decreases Argatroban clearance; therefore, the dosage must be reduced for hepatically impaired patients </li></ul>
    55. 65. HIT Patients HIT Patients with Renal Impairment 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*
    56. 66. <ul><li>Initiate warfarin only when platelet count increases above 100k. </li></ul><ul><li>All direct thrombin inhibitors, including Argatroban, may increase prothrombin time (PT); this must be taken into consideration when converting to warfarin therapy </li></ul><ul><li>Coadministration of Argatroban and warfarin does produce a combined effect on the laboratory measurement of the INR. </li></ul><ul><li>Concurrent therapy with Argatroban and warfarin does not exert an additive effect on the warfarin mechanism of action (e.g., factor Xa activity) </li></ul><ul><li>The previously established relationship between INR and bleeding risk is altered during combination therapy </li></ul><ul><ul><li>For example, an INR of 4 on co-therapy may not have the same bleeding risk as an INR of 4 on warfarin monotherapy. </li></ul></ul><ul><li>Continue anticoagulation for 2-3 months in HIT with out thromboses but continue it for 6 months if a thrombotic event occurred. </li></ul>
    57. 67. If INR is below 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  g/kg/min, temporarily reduce to a dose of 2  g/kg/min 4-6 hours prior to measuring the INR.  
    58. 68. <ul><li>When a patient... </li></ul><ul><ul><li>experiences a drop in platelet counts </li></ul></ul><ul><ul><li>develops thrombosis </li></ul></ul>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)
    59. 69. Questions?
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