Thrombocytopenia
•Als PPT, PDF herunterladen•
289 gefällt mir•80,947 views
Thrombocytopenia is most frequently encountered Hematological problem in hospitalized patients. The most common causes and differential diagnosis of In-patient and Outpatient presentations of Thrombocytopenia is discussed here. Useful for Internal Medicine Boards . Archer Internal Medicine Board review lectures will be released soon.
![History of the platelet ,[object Object],[object Object],[object Object],[object Object]](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
Empfohlen
Weitere ähnliche Inhalte
Was ist angesagt?
Was ist angesagt? (20)
Ähnlich wie Thrombocytopenia
Ähnlich wie Thrombocytopenia (20)
Mehr von Archer Review USMLE and NCLEX
Mehr von Archer Review USMLE and NCLEX (20)
Kürzlich hochgeladen
Kürzlich hochgeladen (20)
Thrombocytopenia
- 1. Hematology-High Yield Topics For Internal Medicine Boards and Hematology Boards Target Audience: Internal Medicine Residents, Family Medicine Residents, Hematology Fellows, Medical Students, IM Board Recertification exam aspirants Archer Internal Medicine Board Review www.CcsWorkshop.com
- 17. Abciximab – PTCP Time course of automated platelet counts from citrated blood and EDTA blood .
- 23. Discussion Topics: TTP DIC
- 24. Systemic activation of coagulation Intravascular deposition of fibrin Depletion of platelets and coagulation factors Bleeding Thrombosis of small and midsize vessels with organ failure
- 28. Lazarchick, J. ASH Image Bank 2001;2001:100174 Figure 1. Peripheral smear showing microangiopathic hemolytic features with numerous RBC fragments (helmet cells/schistocytes)
- 29. Copyright ©2001 American Society of Hematology. Copyright restrictions may apply. Lazarchick, J. ASH Image Bank 2001;2001:100174 Figure 2. Peripheral smear showing RBC fragmentation consistent with a microangiopathic hemolytic process
- 33. Moake J. N Engl J Med 2002;347:589-600 Proposed Relation among the Absence of ADAMTS 13 Activity in Vivo, Excessive Adhesion and Aggregation of Platelets, and Thrombotic Thrombocytopenic Purpura
- 38. 1. Pivetti S, et al. Br J Haematol. 1996;95:204-211. 2. Pawlotsky JM, et al. J Hepatol. 1995;23:635-639. 3. Sakuraya M, et al. Eur J. Haematol. 2002;68:49-53. 4. García-Suárez J, et al. Br J Haematol. 2000;110:98-103. 5. Rajan SK, et al. Br J Haematol. 2005;129:818-824. Study N Platelet Threshold, x 10 9 /L HCV Positive, n (%) Pivetti et al [1] 33 < 100 12 (36) Pawlotsky et al [2] 139 < 25 14 (10) Sakuraya et al [3] 79 < 10 11 (14) García-Suárez et al [4] 51 < 100 13 (23) Rajan et al [5] 250 < 100 76 (30)
- 43. Discussion: HIT ITP POST-TRANSFUSION PURPURA
- 47. .
- 50. Sequelae Incidence Thrombosis 30%–50% Amputation 20% (arterial thrombosis) Death 22% to 28% .
- 52. 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)
- 57. Alternative Anticoagulants 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.
- 59. Recommended Dosing Guidelines for Argatroban 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*
- 61. Guidelines for Conversion to Oral Anticoagulant Therapy 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.
- 66. Pathophysiology Diagnosis Treatment New advances
- 70. SLE 5% APS 2% CVID 1% CLL 2% Evan’s 2% ALPS, post-tx 1% HIV 1% Hep C 2% H. pylori 1% Postvaccine 1% Misc systemic infection 2% Primary 80% This research was originally published in Blood. Cines DB, et al. Blood. 2009;113:6511-6521. © the American Society of Hematology
- 71. HIV HCV H. pylori
- 76. Timeline: introduction of modern day ITP drug treatment Splenectomy Corticosteroids IVIg Anti-D Rituximab TPO mimetics 1900 1920 1960 2000 1940 1980
- 77. Cines DB, et al. N Engl J Med . 2002;346:995-1008. Pathophysiology of ITP – Intevention Areas
- 95. CONGENITAL TP
- 116. Gene mutation : unknown
Hinweis der Redaktion
- Schematic representation of the origin and development of megakaryocytes : - The pluripotential stem cell produces a progenitor cell committed to megakaryocyte differentiation (Meg-CFC) which undergoes mitosis. The Meg-CFC eventually stops mitosis and enters endomitosis during which neither cytoplasm nor nucleus divides but DNA replication proceeds and gives rise to polyploid immature precursor cells. Upon completion of endomitosis, the immature progenitor cells become large, morphologically identifiable mature megakaryocytes MEGAKARYOCYTE now sheds the platelets. ( non nuclear particles)
- Having said that, it should be remembered that a recent fall in platelet count by 50% even though with in normal range may precede severe clinical issues and must be actively monitored. One good example is HIT.
- Although pseudothrombocytopenia has no pathologic significance and will not increase thrombotic or hemorrhagic risk, failure to recognize it may potentially place a patient in jeopardy for inappropriate discontinuation of the needed drug, delay of therapies involving invasive procedures, or initiation of unnecessary therapies, such as platelet transfusion or use of steroids. 1 , 10 , 12 In the case reported here, olanzapine would not have been discontinued if an early distinction between pseudothrombocytopenia and drug-induced immune thrombocytopenia had been made.
- After abciximab bolus, abciximab PTCP occurs as soon as 2hrs after the bolus and starts normalizing from 3days after the dose. ( Note that even in EDTA blood pseudo-thrombocytopenia recovers 3 days after the bolus as abciximab effect on GP Iib/IIIA wears off). Peripheral smear shows clumps in EDTA blood. Note that in citrate blood, platelet count remains normal in Abciximab related PTCP ( in contrast to true abciximab TP, where platelet clumps are not seen in EDTA smear and platelet counts are low in citrate blood smear as well)
- WHEN REQUIRED PLATELETS COME OUT OF THE SPLEEN
- PNH can lead to drop in all cell lines if the mutation occurs in stem cells instead of red cell precursor alone. Cells deficient in CD55 and CD59 which protects them from complement mediated destruction
- DIC can be better called as consumption coagulopathy – there is activation of entire coagulation cascade with deposition of fibrin thrombi in the vessels that can lead to thromboses of small and mid size vessels multi organ failure and also, MAHA. Consumption of clotting factors will cause prolonged PT, PTT and reduced fibrinogen. Consumption of plats cause thrombocytopenia that can lead to bleeding complications in some cases.
- Most cases of TTP occur because of congenital or acquired deficiency of ADAMT13 or secondary to acquired inhibitor to ADAMTS13 – an enzyme that normally cleaves large VWF multimers
- Figure 2. Proposed Relation among the Absence of ADAMTS 13 Activity in Vivo, Excessive Adhesion and Aggregation of Platelets, and Thrombotic Thrombocytopenic Purpura. In Panel A, in normal subjects, ADAMTS 13 (von Willebrand factor-cleaving metalloprotease) molecules attach to binding sites on endothelial-cell surfaces and cleave unusually large multimers of von Willebrand factor as they are secreted by stimulated endothelial cells. The smaller von Willebrand factor forms that circulate after cleavage do not induce the adhesion and aggregation of platelets during normal blood flow. ADAMTS 13 may use one of its thrombospondin-1-like domains or its arginine-glycine-aspartate (RGD) sequence to attach to the surface of endothelial cells. In Panel B, absent or severely reduced activity of ADAMTS 13 in patients with thrombotic thrombocytopenic purpura prevents timely cleavage of unusually large multimers of von Willebrand factor as they are secreted by endothelial cells. The uncleaved multimers induce the adhesion and aggregation of platelets in flowing blood. A congenital deficiency of ADAMTS 13 activity, or an acquired defect of ADAMTS 13 (such as that caused by autoantibodies or by a change in the production or survival of the protein) can lead to thrombotic thrombocytopenic purpura. Interference with the attachment of ADAMTS 13 to endothelial cells in vivo (for example, as a result of ADAMTS 13-receptor blockade by other types of autoantibodies) may also cause thrombotic thrombocytopenic purpura in patients with normal ADAMTS 13 activity in plasma.
- Steroids must be used as adjuncts in patients whose platelet count does not increase within several days of treatment with plasma exchange or in those who TP recurs when plasmapheresis is being tapered or discontinued.
- Further evidence suggesting that splenomegaly and portal hypertension are not the only factors to explain thrombocytopenia in chronic liver disease is the finding that thrombocytopenia has been shown to endure after surgical portal decompression with transjugular intrahepatic portosystemic shunt (TIPS) in cirrhotic patients.
- Several studies have found increased prevalence of HCV with out overt liver disease in chronic ITP patients between 10 to 30%. Hence, even in the absence of hepatitis or overt liver disease, HCV serology should always be obtained in evaluating the patients with ITP before labelling them as idiopathic ITP . This could turn out to be HCV-related ITP.
- Low baseline platelets < 70k lead to postponement of therapy. Even if the platelets were higher prior to initiation of therapy, they may fall during therapy requiring dose adjustments and hence, less optimal treatment Postponement of treatment due to thrombocytopenia can result in diminished sustained virologic response because of the potential for further progression of liver disease in the absence of treatment. Dose modifications may lower the chances of sustained virological response
- Platelet transfusions are not used just because treatment can be started or treatment can be continued with interruption. Such practice does not help because transfused platelets will not produce a proper response required and also, their life span is not enough to continue prolonged HCV therapy. Multiple platelet transfusions can cause platelet refractoriness ( alloimmunization) and also, other transfusion related complications.
- The study enrolled 74 patients with evidence of liver damage, which was characterized as a liver biopsy indicating chronic hepatitis and cirrhosis or radiographic evidence of cirrhosis or nonbleeding gastroesophageal varices and compensated liver disease (Child-Pugh A). Inclusion criteria included presence of thrombocytopenia at platelet counts of 20,000-70,000 cells/µL, whereas patients were excluded for a history of thrombosis, HIV infection, or active hepatitis B virus infection. Patients received 30, 50, or 75 mg/day eltrombopag or placebo daily for 4 weeks. After 4 weeks, patients were evaluated before initiation of the antiviral treatment phase of the trial. Criteria for initiation of antiviral therapy with peginterferon and ribavirin included platelet counts of > 70,000 cells/µL for patients receiving peginterferon alfa-2a or > 100,000 cells/µL for individuals receiving peginterferon alfa-2b. Patients who met these criteria received antiviral therapy plus eltrombopag for an additional 12 weeks. Results from the initial 4 weeks of this study are presented in the Table. The initial eltrombopag pretreatment resulted in significant increases in platelet counts at Week 4 in all treatment groups. The number of patients able to initiate antiviral treatment ranged from 71% to 91% with eltrombopag vs 22% in the control arm. In total, 65% of patients in the 75-mg dose group, 53% of patients in the 50-mg dosing group, and 36% of patients in the 30-mg dosing group were able to complete the 12-week antiviral therapy phase compared with 6% of placebo-treated patients ( P < .001, P not provided, and P = .003, respectively).
- 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
- Why less than 100k : A prospective cohort of healthy subjects with platelet counts between 100 and 150 x 10 9 /L had a 10-yr probability of developing persistent platelets counts < 100 x 10 9 /L of only 6.9% . Defined in 3 stages: newly diagnosed (< 3 mos), persistent (3-12 mos), and chronic (> 12 mos) [1] Why : Defining patients as acute vs chronic is a retrospective determination; the new stage definitions will allow for better selection of patients for clinical trials
- In the summer of 1950, two hematology fellows working at the Barnes Hospital in St. Louis — William J. Harrington and James W. Hollingsworth — hatched a plan to test their idea that the cause of the idiopathic thrombocytopenic purpura (ITP) in a woman under their care was a factor in the blood that destroyed platelets. They decided that of the two fellows, the one whose blood type matched the patient's would receive 500 ml of her blood. In a flip of the genetic coin, Harrington matched. Within a few hours after receiving the woman's blood, Harrington's platelet count dropped.
- ALPS, autoimmune lymphoproliferative syndrome; APS, antiphospholipid syndrome; CLL, chronic lymphocytic leukemia; CVID, common variable immune deficiency; Hep C, hepatitis C virus; H. pylori, Helicobacter pylori; ITP, immune thrombocytopenia; SLE, systemic lupus erythematosus. Immune thrombocytopenia can occur in conjunction with a number of other disorders. In this figure taken from a paper by Cines and colleagues published in Blood in 2009, primary ITP encompasses about 80% of all ITP; the other disorders listed in the breakout are all causes of secondary ITP. These include systemic lupus erythematosus (5%), antiphospholipid syndrome (2%), common variable immunodeficiency, and chronic lymphocytic leukemia, for example. These are all disorders that are generally immune related and can be associated with an ITP-like syndrome or secondary ITP.
- Some infectious causes of ITP are well recognized such as HIV related ITP, HCV and H.pylori. Rx for HIV-TP is HAART and other modalities of ITP rx. Rx HCV-TP discussed earlier. If H.Pylori antigen detected, may try h.pylori eradication therapy first before using more toxic therapies. CAG A strains of H.Pylori are implicated in ITP.
- B- and T-cell responses in ITP — B cell autoimmune IgG responses in ITP appear to be driven by CD4+ helper T cells reacting to platelet membrane glycoprotein epitopes - possibly involving CD40:CD40L co-stimulation processes , with splenic macrophages as the major antigen-presenting cells.
- In a bleeding patient with ITP, give plt transfusion after IVIG . Steroid added as well. When urgent increase needed always IVIG vs. Anti D