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Thrombocytopenia

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Thrombocytopenia

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Thrombocytopenia

  1. 1. THROMBOCYTOPENIA DR JIGAR R PADALIA
  2. 2. Thrombocytopenia Normal platelet count : 150,000 to 450,000/microL. Thrombocytopenia is defined as a platelet count less than 150,000/microL . Not usually clinically detected until the platelet count falls to levels below 100,000/microL . 1/3 of platelets are sequestered in the spleen. Half life of a platelet is 8 to 10 days. 15000 to 45000 platelets are produced daily to maintain steady state
  3. 3. Clinical Features  Most conditions are associated with bleeding ( ITP, Drug induced TP, Most other TPs)  Some conditions associated with thrombosis Thrombotic Thrombocytopenia Purpura (TTP) Disseminated Intravascular Coagulation (DIC) Heparin Induced Thrombocytopenia ( HIT)
  4. 4.  Sites of bleeding in thrombocytopenia :  Skin and mucous membranes : Petechiae, Ecchymosis, Hemorrhagic vesicles, Gingival bleeding and epistaxis.  Menorrhagia  Gastrointestinal bleeding  Intracranial bleeding (rarest – but most dreadful complication)  Bleeding in to joints and soft tissues are manifestation of coagulation factor deficiencies rather than thrombocytopenia.
  5. 5. Stratifying levels of thrombocytopenia Why should we evaluate thrombocytopenia…??? 1. To assess the risk of bleeding and 2. To assess the presence of underlying disorders (TTP, HIT etc.) To assess the risk of bleeding  < 20000 - increased risk of spontaneous bleeding  20000 to 50000 - increased risk of bleeding from procedures  50000 to 1 lakh - no increased risk of spontaneous bleeding - no risk of procedural bleeding
  6. 6. Approach to Thrombocytopenia  History  Is the patient bleeding?  Do the sites of bleeding suggest a platelet defect?  Duration - Is thrombocytopenia – acute or chronic?  Is there a history of medications, alcohol use, or recent transfusion ( post-transfusion purpura)?  Are there symptoms of a secondary illness? (neoplasm, infection, autoimmune disease)  Is there a family history of thrombocytopenia?  Heparin exposure – recent or with in past three months (HIT)?  Are there risk factors for HIV infection?  History of liver disease?
  7. 7.  Assess the number of platelets  CBC with peripheral smear :-  RBC  NEUTROPHILS  PLATELETES  Any clumps? Schistocytes? Nucleated RBCs? Any features of nutrional deficiencies (hypersegmented neutrophils), MDS (hyposegmented neutrophils), Myelofibrosis ( tear drop cells) ?  Isolated thrombocytopenia or any other cell line affected?
  8. 8. Typical Platelet Counts in Various Disease States Moderate thrombocytopenia (50–100,000 per μL) Thrombotic thrombocytopenic purpura Heparin-induced thrombocytopenia Disseminated intravascular coagulation Hemophagocytic syndrome Severe thrombocytopenia (< 20,000 per μL) Drug-induced thrombocytopenia Posttransfusion purpura Immune thrombocytopenia
  9. 9. Laboratory tests Peripheral smear Prothrombin time/INR Activated partial thromboplastin time Fibrinogen D-dimer LDH – markedly elevated in TTP and Hantavirus infn. Creatinine BUN
  10. 10. Clinical setting Differential diagnosis Sepsis syndrome DIC, ehrlichiosis, sepsis hemophagocytic syndrome, drug-induced, misdiagnosed TTP, mechanical ventilation, pulmonary artery catheters Pulmonary failure DIC, H1N1, infection hantavirus pulmonary syndrome, mechanical ventilation, pulmonary artery catheters Mental status changes/seizures TTP, ehrlichiosis Renal failure TTP, dengue, HIT, DIC Cardiac failure HIT, drug-induced, pulmonary artery catheter Pregnancy HELLP syndrome, fatty liver of pregnancy, TTP/HUS Acute liver failure Splenic sequestration, HIT, drug-induced, DIC Postsurgery Dilutional, drug-induced, HIT, TTP Cardiac surgery Cardiopulmonary bypass, HIT, dilutional thrombocytopenia, TTP Interventional cardiac procedure Abciximab or other IIb/IIIa blockers, HIT
  11. 11. Classification Can be broadly classified in to five categories based on the mechanism behind reduced platelet count: 1. Pseudo or Spurious Thrombocytopenia 2. Dilutional Thrombocytopenia 3. Decreased Platelet Production 4. Increased Platelet Destruction 5. Altered Distribution of Platelets ( Increased Sequestration) Most common mechanisms are decreased platelet production and increased destruction
  12. 12. Pseudo-thrombocytopenia An artifactual clumping of plateletsin vitro without clinical significance The first step in evaluating any thrombocytopenia is to confirm if it is “true” – diagnosis by peripheral smear. Peripheral smear for platelet clumps which can lead to pseudo-thrombocytopenia.  Various Scenarios : • Inadequate anticoagulation of the blood sample • EDTA dependant platelet auto-antibodies • Abciximab Related Pseudo-Thrombocytopenia.
  13. 13. EDTA Dependant Aggluttinins  Present in 0.1% of normal population.  Unlike true thrombocytopenias, EDTA-PTCP is associated with a NORMAL MEAN PLATELET VOLUME  These patients have naturally occurring platelet antibodies directed towards a normally hidden epitope on platelet membrane GP IIb/IIIa complex  The glycoprotein IIb/IIIa complex must dissociate to expose this epitope (called the cryptantigen or neoantigen) for antibody binding to occur.  EDTA, Drugs such as Abciximab and Mexiletene , pH and temperature can induce dissociation of GP IIb/IIIa and may expose this cryptantigen causing the antibody to bind and resulting in aggluttination ( clumps).
  14. 14. EDTA Dependant Aggluttinins  EDTA – PTCP is diagnosed by examination of peripheral smear for platelet clumping.  If platelet clumping seen, repeat the count in non-EDTA anticoagulant ( heparin or sodium citrate).  If citrate is used, remember to correct the platelet count for dilution caused by amount of citrate solution used. No such correction required for heparin.  Although pseudothrombocytopenia has no pathologic significance failure to recognize it may potentially place a patient in jeopardy for inappropriate discontinuation of the needed drug (eg: abciximab), delay of therapies involving invasive procedures, or initiation of unnecessary therapies, such as platelet transfusion or use of steroids.1
  15. 15. Abciximab- Pseudothrombocytopenia  Thrombocytopenia is a well-recognized adverse effect of abciximab therapy. Two mechanisms : 1. Immune mediated thrombocytopenia ( onset with in minutes to hours of administration rather than days to weeks seen with other drug induced thrombocytopenias). 2. Pseudothrombocytopenia ( 1/3rd of thrombocytopenia found in patients receiving abciximab is due to pseudothrombocytopenia)  Abciximab-PTCP is due to the presence of EDTAas an anticoagulant in the blood-drawing tube. EDTA exposes the cryptantigen in GPIIb/IIIa complex to aggluttination with naturally occuring antibodies. The mechanism of abciximab-associated, EDTA-induced plateletclumping is not clear.  Differentiation of Abciximab-PTCP from True Abciximab-TP and from HIT is extremely crucial. Diagnosis of PTCP will avoid discontinuation of the abciximab infusion and initiationof unnecessary therapies, such as platelet transfusions or anticoagulants (as in HIT).  When thrombocytopeniaoccurs after abciximab treatment, first review peripheral blood film for clumping or obtain platelet count in citrated blood.
  16. 16. Dilutional Thrombocytopenia Large quantities of Packed-RBC transfusion to treat massive haemorrhage can lead to Dilutional TCP. Due to absence of viable platelets in packed RBCs. Usual platelet counts in patients receiving 15 to 20 units of PRBCs in 24 hours is 50k to 100k/µl. Can be prevented by giving platelet concentrates to patients receiving more than 20 units PRBCs in a 24 hour period.
  17. 17. Distributional Thrombocytopenia  Also, referred to as Apparent Thrombocytopenia since total platelet mass is normal.  About 1/3rd of circulating platelets are normally sequestrated in spleen.  Splenic sequestration of platelets may increase to 90% in splenomegaly ( hypersplenism) secondary to portal hypertension or other causes.  Circulating platelet count decreases but total platelet mass and overall platelet survival remain normal.  Hence, these patients can have significant “apparent” thrombocytopenia but rarely have clinical bleeding ( since total available platelet mass is normal)
  18. 18. Decreased Platelet Production  Associated with decreased or ineffective megakaryopoiesis and thrombopoiesis  Marrow Damage: • Aplastic Anemia • Fanconi’s anemia ( defect in DNA repair genes) • Malignancy  Congenital defects ( Congenital thrombocytopenias)  Paroxysmal Nocturnal Hemoglobinuria  Viral infections: Rubella, CMV, EBV, HIV, Hep-C  Ineffective production : • Nutritional Deficiencies: B12, Folate, Severe iron deficiency  Drugs: thiazides, estrogen, chemotherapy , linezolid  Toxins: alcohol, cocaine
  19. 19. Increased Destruction Most common cause of thrombocytopenia. Leads to stimulation of thrombopoiesis and thus an increase in the number, size and rate of maturation of the precursor megakaryocytes. Increased consumption with intravascular thrombi or damaged endothelial surfaces
  20. 20. Increased Destruction NON-IMMUNE Microangiopathy DIC TTP HELLP Hemangiomas VonWillebrand Type2b disease (increased aggregation) IMMUNE  ITP  HIT  SLE, AIDS  Drug Induced Immune TP: heparin, gold, quinidine, furosemide, cephalosporins, H2 blockers
  21. 21. Drug Induced Thrombocytopenias Classified as : Direct Toxicity BM Suppression Immune mediated destruction Pro-hemorrhagic : all other drugs Pro-Thrombotic : Heparin
  22. 22. Classification Mechanism Specific Drugs Autoantibody Drug induces antibody that reacts with autologous platelets in the absence of the drug Gold, procainamide Drug specific antibody Antibody recognizes murine component of chimeric Fab fragment specific for platelet membrane glycoprotein IIIa Abciximab Fiban-type drug Drug reacts with glycoprotein IIb/IIIa to induce a conformational change recognized by antibody Eptifibatide, tirofiban Hapten-dependant Hapten links covalently to membrane protein and induces drug-specific immune response Cephalosporins, piperacillin Immune complex Drug binds to platelet factor 4 to produce an antigenic complex against which antibodies react; resulting immune complexes bind to platelet Fc receptors resulting in platelet activation Heparin and low molecular weight heparin Quinine-type Drug induces antibody that binds to membrane protein in presence of soluble drug Quinine, quinidine, NSAIDs, sulfonamides
  23. 23. Drug Category Individual Agents Analgesics ACETAMINOPHEN, DICLOFENAC , ibuprofen, naproxen Anticonvulsants Carbamazepine, PHENYTOIN, VALPROIC ACID Antimicrobial and antiviral agents ACYCLOVIR, CEPHALOSPORINS, interferon, LINEZOLID, nalidixic acid PIPERACILLIN, rifampin, sulfisoxaxzole trimethoprim-sulfamethoxazole, VANCOMYCIN Antirheumatic agents gold salts, D-penicillamine Cinchona alkaloids Quinine, quinidine Chemotherapeutic agents Oxaplatin, fludarabine Antihypertensive agents Chorothiazide, hydrochlorthiazide, methyldopa Heparins HEPARIN UNFRACTIONATED, HEPARIN LOW MOLECULAR WEIGHT Histamine-2 blockers Cimetidine, ranitidine Immunosuppressants Cyclosporine, rituximab Platelet inhibitors Abciximab, eptifibatide, tirofiban Sedatives Diazepam Sulfonylureas Chlorpropamide Other agents Danazol, procainamide, sulfasalazine
  24. 24. Heparin Induced Thrombocytopenia
  25. 25. Frequency of HIT Perspectives 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 Based on increased morbidity and mortality, heparin cessation alone is inadequate in HIT management
  26. 26. HIT: Pathophysiology . Formation of PF4-heparin complexes IgG antibody Formation of immune complexes (PF4-heparin-IgG) EC injury PF4 release Platelet activation* Microparticle release Fc receptor Platelet Heparin-like molecules Blood vessel PF4 Heparin
  27. 27. 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 • Venous 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.
  28. 28. Diagnosis of HIT Normal platelet count 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
  29. 29. Sequelae Incidence Thrombosis 30%–50% Amputation 20% (arterial thrombosis) Death 22% to 28% Venous thrombosis >> Arterial thrombosis Clinical Sequelae in HIT
  30. 30. 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)
  31. 31. ClinicalSuspicionforHIT The4T’s(Warkentin,2003)Thrombocytopenia Platelet count 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
  32. 32. Interpretation A score is determined for each of the four above categories, resulting in a total score from zero to 8. Pretest probabilities for HIT are, as follows: 0 to 3: Low probability 4 to 5: Intermediate probability 6 to 8: High probability
  33. 33. Laboratory Testing for HIT Test Advantages Disadvantages SRA Sensitivity >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
  34. 34. HIT - Managment Stop all Heparin, 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
  35. 35. Alternative Anticoagulants Drug Indications Argatroban FDA-approved for HIT (also for PCI) Lepirudin FDA-approved for HIT Bivalirudin PCI (including HIT patients) Fondaparinux 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.
  36. 36. Indication Transfusion threshold Most invasive surgery (including post- cardiopulmonary bypass) 50000 Neurosurgery or posterior eye surgery 1 lakh Prevention of bleeding associated with invasive procedures • Lumbar puncture – 50000 • Central-line insertion – 50000 • Liver, renal or transbronchial biopsy – 50000 • Gastrointestinal endoscopy with biopsy - 50000 Spinal anaesthesia 50000 Epidural anaesthesia 80000 Transfusion threshold for Plateletes in various procedures
  37. 37. ManagementofDisseminatedIntravascular Coagulation (DIC):Transfusion The five basic tests of hemostasisa Hematocrit Platelet count Prothrombin time (PT) Activated partial thromboplastin time (aPTT) Fibrinogen level Guidelines for transfusion in patients at high risk of bleeding Platelets < 50,000 per μL: give platelet concentrates or 1 unit of single-donor platelets. Fibrinogen < 80–100 mg/dL: give 10 units of cryoprecipitate Hematocrit below 30%: give red cells INR > twofold the upper limit of normal and aPTT abnormal: give 2–4 units of FFP
  38. 38. HELLP TTP/HUS AFLP Hypertension Always present Sometimes present Sometimes present Proteinuria Always present Sometimes present Sometimes present Thrombocytopenia Always Always Always LDH elevation Present Marked Present Fibrinogen Normal to low Normal Normal to very low Schistocytes Present Present Absent Liver tests Elevated Normal Elevated Ammonia Normal Normal Elevated Glucose Normal Normal Low
  39. 39. Indications and contraindications to platelet transfusion Prophylaxis Procedures Grade >2 bleeding TTP CONTRAINDICATION IF THERE IS AN INCREASED RISK, PREFERABLY AFTER STARTING PLASMA EXCHANGE CONSIDER HUS NO INDICATION CONSIDER INDICATION HELLP NO INDICATION CHILD BIRTH >20000-50000 INDICATION DIC NO INDICATION CONSIDER INDICATION ITP NO INDICATION CONSIDER + IVIG OR PREDNISOLONE INDICATION + IVIG HIT NO INDICATION CONSIDER PROVIDED ALTERNATIVE ANTICOAGULANTS PROVIDED ALTERNATIVE ANTICOAGULANTS
  40. 40. Contraindications to platelet transfusion Thrombotic thrombocytopenic purpura Hemolytic uraemic syndrome Heparin induced thrombocytopenia unless there is life or limb threatening haemorrhage. Congenital IgA defeciency
  41. 41. Plasma exchange Removes large molecular weight substance such as harmful antibodies from plasma. 1 cycle of plasma exchange removes about 66% of intravascular constituent and 2 cycles removes about 85%.
  42. 42. Plasma exchange - indications Category I indications (According to ASFA) TTP ATYPICAL HUS HYPERVISCOSITY SYNDROMES SEVERE/SYMPTOMATIC CRYOGLOBULINEMIA
  43. 43. HEMOLYTIC URAEMIC SYNDROME Triad of renal failure, microangiopathic anemia, and thrombocytopenia. Typical and Atypical Typical mainly seen in childrens Atypical mainly in adults and without preceding gastroenteritis or E. Coli infn. Plasma exchange in Atypical HUS
  44. 44. TTP Thrombocytopenia, microangiopathic hemolytic anemia, renal insufficiency, neurologic phenomena and fever LDH is prognostic factor in TTP Plasma exchange is treatment of choice
  45. 45. Treatment of TTP  Urgent plasmapheresis ( plasma exchange)  Plasma Infusion : Infusion of FFP 30 cc/kg/day until ready for plasma exchange ( serves as emergency initial measure in those who do not have immediate access to Plasma exchange)  Daily plasma exchange with either FFP or cryopoor FFP (45 to 55 cc/kg/day)  Steroids (Prednisone 1 mg/kg/day) ( may help by suppressing anti- ADAMTS13 antibodies).  Red Blood Cell transfusions if needed  Platelet transfusion may worsen the disease and are avoided. Used only if absolutely necessary ( in very rare cases, where severe bleeding is encountered)  Refractory TTP : In patients with worsening disease despite daily plasma exchange + Steroids  Increase plasmpheresis to twice daily exchange.  Poorly responsive or Recurrent TTP  Add Immunosuppressive therapy -Add Rituximab or Cyclosporine
  46. 46. ImmuneMediatedThrombocytopeniaPurpura (ITP) Idiopathic ITP vs. Secondary ITP Idiopathic or Primary ITP : Defined as isolated thrombocytopenia with Platelet count < 100 x 109/L No other cause of thrombocytopenia No clinically evident secondary form of thrombocytopenia. Incidence increases with age Female predominance under the age of 60 but not over the age of 60 May have onset or insidious onset  generally abrupt in onset with children and insidious in adults.
  47. 47. Secondary ITP Post-Infectious : HIV, HEP-C, H.PYLORI Vasculitis : SLE Lymphoproliferative Disorders : CLL, NHL, HD Drug Dependant ITP (DDITP) : Drug induced TP can be sometimes mediated by antibodies eg: quinidine, sulfa containing drugs
  48. 48. Evaluation of ITP  Features consistent with the diagnosis of ITP  Thrombocytopenia with normal or slightly large platelets ( Increased MPV)  Normal RBC morphology and number (may have associated iron def or thallasemia etc.)  Normal white cell number and morphology  Splenomegaly is extremely rare  Features not consistent with the diagnosis of ITP  Giant platelets ( ? Congenital)  RBC abnormalities ie schisotocytes ( ? TTP/HUS, DIC)  Leukocytosis or Leukopenia (? MPD/MDS, Sepsis )
  49. 49. Acute Pharmacologic Management of ITP Steroids Prednisone 1mg/kg/day with taper over 2 to 3 months Solumedrol 30mg/kg/d x 7 days Antibodies IVIG 1 gram/kg/day x 2 days Anti-D 50 mcg/kg IV x1 dose in Rh+ve patients

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