Hematology Highyield Topics on Thrombophilia
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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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Hematology Highyield Topics on Thrombophilia
- 1. Hematology – Highyield Topics
- 3. Abnormal Blood Flow Abnormal Vessel Wall Dr. Rudolph Virchow 1821-1902 The Hypercoagulable State Abnormal Blood
- 4. Thrombosis Hereditary thrombophilia Acquired thrombophilia Surgery trauma Immobility Inflammation Malignancy Estrogens Atherosclerosis
- 14. FXI FIX FXII FV FVII Prothrombin Thrombin Fibrinogen Fibrin Clot FVIII FX
- 15. J Thromb. Haem.1.525, 2003
- 37. APPROACH
- 53. .
- 56. Sequelae Incidence Thrombosis 30%–50% Amputation 20% (arterial thrombosis) Death 22% to 28% .
- 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)
- 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.
- 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*
- 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.
- 69. Questions?
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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 ( >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 >2mcg/kg/min reduce dose to <2mcg/kg/min first and then, measure inr after 4 hours – now, if INR > 4, can stop argatroban