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Quantitative Platelet Disorders. LabM 419 Clinical Coagulation Fall 2009 ©C. Calvo, MS, MT(ASCP), SH(ASCP) – UW, 2009. Learning Objectives – Upon completion of required reading, after careful study, and following this lecture the student will be able to:.

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    1. Quantitative Platelet Disorders LabM 419 Clinical Coagulation Fall 2009 ©C. Calvo, MS, MT(ASCP), SH(ASCP) – UW, 2009.

    2. Learning Objectives – Upon completion of required reading, after careful study, and following this lecture the student will be able to: • Define the key terms black-bolded or italicized on pages 630 – 649 of the course text. • Contrast clinical symptoms and coagulation profiles of the quantitative platelet disorders discussed in lecture with clotting factor deficiency disorders. • Explain the primary pathophysiologic processes of thrombocytopenia. • Classify quantitative disorders of platelets according to primary pathophysiologic etiology. • Describe immunologic and non-immunologic mechanisms by which drugs induce thrombocytopenia. Provide specific examples to illustrate. • Explain the pathophysiology of and recognize the lab test results’ profile associated with Thrombotic Thrombocytopenic Purpura (TTP), Immune Thrombocytopenic Purpura (ITP), Heparin-Induced Thrombocytopenia (HIT), Neonatal Alloimmune Thrombocytopenia (NAIT), and hemolytic-uremic syndrome. • List lab tests useful in detecting and differentiating the platelet disorders identified in objective 6. • Contrast the serotonin release and the immunoassay test for HIT. • Differentiate acute and chronic immune thrombocytopenia. • Distinguish neonatal isoimmune from neonatal autoimmune thrombocytopenia. • Compare and contract primary and reactive thrombocytosis. • Interpret lab data, correlate it with patient information, and synthesize knowledge of the quantitative platelets disorders to correctly respond to test questions and solve subject-matter related case studies.

    3. Checkpoint Primary Hemostasis • It’s about vasculature • It’s about platelets • It’s about maintaining blood in a fluid state within the blood vessels and preventing excessive blood loss after vascular injury Bottomline Platelet Abnormalities – QUANTITAIVE OR QUALITATIVE result in bleeding Graphic accessed URL http://www.uv.es/~vicalegr/CLindex/CLvasculitis/vasleu11.jpg , 2005.

    4. Primary Skin petechiae purpura ecchymoses Mucous membranes nose bleeds sclera gums Secondary Tissues Joints Clinical ManifestationsPrimary v.s. Secondary Disorders of Hemostasis http://heme-coag.uthscsa.edu/wwwbleed97/22apet.gif

    5. Identify the cause of bleeding physical exam medical history Prescribe appropriate treatment Important information Age of onset younger = inherited etiology umbilicus/circumcision bleeding secondary hemostasis problem Severity and persistence of symptoms Family History inherited condition Health status secondary causes of bleeding malignancy liver disease Drug history aspirin anticoagulants chemotherapeutics Exposure to toxins industrial agents pharmaceuticals Physician’s Eye View

    6. Laboratory Perspective • Platelet counts • Function test • Bleeding time • Aggregation studies • Coagulation studies • Prothrombin time (PT) • Activated partial thromboplastin time (aPTT) • Thrombin time (TT) • Fibrinogen (Fi)

    7. Inherited Abnormal synthesis of subendothelial connective tissue components Telangectasia Ehlers-Danlos Marfan Syndrome Rare Limited Lab Test Importance Acquired Abnormal cells Scurvy Paraproteins Amyloidosis Multiple myeloma Vasculitis infections Drugs Primary clinical manifestaton: Purpura Common Vascular-based Disorders

    8. Platelet-Associated Disorders • Quantitative – Numbers game • Increased = thrombocytosis • >450K/ml • Decreased = thrombocytopenia • <100K/ml http://www.mcl.tulane.edu/classware/pathology/Krause/ET/RM1.html http://lifesci.rutgers.edu/~babiarz/Histo/Blood/Smear2.jpg http://www.ispub.com/xml/journals/ijid/vol3n2/vivax-fig1.jpg

    9. Bleeding Clinical Correlation - PLT Numbers BT prolongation proportional to PLT count IF no complicating factors. Graphic accessed URL http://home13.inet.tele.dk/gloerud/red_l.gif, 2004.

    10. Significant Lab Data in Defects of Primary Hemostasis

    11. Thrombocytopenia

    12. Congenital – lack of adequate BM Megakaryocytes Fanconi Anemia Wiskott-Aldrich Syndrome Bernard Soulier Syndrome May-Hegglin Anomaly Rare, Autosomal Dominant Dohle Bodies Big PLTS PLT Aggregation = NL Acquired – suppressed or ineffective megakaryopoiesis Neonatal Hypoplasia Viral infection (CMV) In utero drug exposure Chlorothiazide Tolbutamide Drugs Chemotherapy Alcoholism Interferon Estrogen Chloramphenicol B12 deficiency Impaired or Decreased PLT Production

    13. Increased Platelet Destruction Categories • Immune-mediated destruction • ITP • Acute • Chronic • Alloimmune • Drug-induced • Non-immune destruction/ consumption • DIC • Thrombotic Thrombocytopenic Purpura (TTP) • Hemolytic Uremic syndrome (HUS) • Dilution or Distribution Disorders Thrombocytopenia results when production and replacement of PLTS can’t keep up with rate of destruction

    14. Immune (Idiopathic) Thrombocytopenic Purpura = ITP • Cause -antibodies against viral epitopes or antibodies against platelet membraneglycoproteinsIIb-IIIa or Ib-IX, and are of the IgG type • RES system clears sensitized PLTs • Acute – children • Viral Infection • <20K/ml counts • 1 – 3 weeks post infection • Spontaneous remissions common • Treatment • no specific treatment • IVIG • PLT transfusions • Splenectomy • Chronic – adults • PLT antibodies • 30-80K/ml counts • Remissions rare • 2/3rds recover • Treatment • IVIG • Prednisone • Splenectomy Graphic accessed URL http://z.about.com/d/pediatrics/1/G/N/Q/bruises.JPG, 2007.

    15. Clinical Picture – Acute/Chronic ITP

    16. Neonatal Alloimmune Thrombocytopenia (NAIT) • Analogous to HDN • Mom lacks PLT-specific Ag that fetus inherited from father • HPA – 1a: found on GPIIIa (Caucasian populations) • HPA-3a: found on GPIIb (Asian populations) • Fetal Ags may pass into maternal circulation • Maternal IgG AB cross placenta and attack fetal PLTs • Diagnosis by exclusion • Need to recognize early and treat appropriately NAIT – Autoimmune version: ITP or SLE in mom is prerequisite – passive AB transfer from mom – fetus is incidental target

    17. Rare Develops 1 week after PLT-containing product(s) transfusion AB – preformed Anamnestic immune response AB target = HPA-1a Affected population more often multi-parous women Previously transfused men Post-Transfusion Purpura Graphic accessed URL http://www.coldbacon.com/mdtruth/pics/hsp.jpg, 2009.

    18. Immune Drug-Induced ITP Drugs of Interest • Analgesics • Salicylates • Acetaminophen • Antibiotics • Cephalothin • Penicillin • Rifampin • Sulfa Drugs • Quinidine • Sedatives • Phenobarbital • Meprobamate • Carbamazepine • Oral hypoglycemics • Chlorpropamide • Heavy Metals • Bismuth • Mercury • Insecticides Figure 43-04.   Immunoglobulin binds a platelet membrane antigen or antigen and drug combination. Macrophage Fc receptors bind the Fc portion of the immunoglobulin. This may result in platelet removal and thrombocytopenia. (From Rapaport SI: Introduction to Hematology, 2nd ed. Philadelphia: JB Lippincott, 1987:489.) Graphic accessed URL http://coursewareobjects.elsevier.com/objects/elr/Rodak3e/IC/jpg/Chapter43/043004.jpg, 2008.

    19. Heparin Induced Thrombocytopenia • Common side effect of UFH Therapy (1-5% patients) • Delayed onset with never-before-heparin-exposure • Follows immune response rate: symptoms @ 7- 10 days • Acute onset with previous exposure • Symptoms @ 1 – 3 days Graphic accessed URL http://coursewareobjects.elsevier.com/objects/elr/Rodak3e/IC/jpg/Chapter43/043005.jpg, 2008.

    20. Type I Benign Mild, transient thrombocytopenia Counts >100K Counts return to ‘normal’ if heparin is continued Type II Clinically significant Moderate –severe thrombocytopenia Counts<100K Counts return to normal only if heparin is discontinued Heparin Induced Thrombocytopenia

    21. HIT Testing Figure 43-06.   The serotonin release assay for heparin-induced thrombocytopenia (HIT). Donor platelets in platelet-rich plasma are labeled with tritiated (3H) serotonin, washed, and suspended in patient plasma. Heparin in therapeutic and saturating doses is added to 2 aliquots. Release of radioactive serotonin in the therapeutic aliquot in combination with no release in the supra-therapeutic system indicates HIT. Graphic accessed URL http://coursewareobjects.elsevier.com/objects/elr/Rodak3e/IC/jpg/Chapter43/043006.jpg, 2008.

    22. HIT Testing Figure 43-07.   Enzyme immunoassay for HIT. The solid-phase target antigen is a complex of PF4 and heparin or a heparin surrogate. Antiheparin/PF4 in patient serum binds the antigen and is bound by enzyme-labeled antihuman antibody, a sandwich assay. The enzyme catalyzes the release of a chromophore from its substrate. Graphic accessed URL http://coursewareobjects.elsevier.com/objects/elr/Rodak3e/IC/jpg/Chapter43/043007.jpg, 2008.

    23. Non-Immune PLT Destruction • CAUSES • PLT exposure to non-endothelial surfaces • Mechanical heart valve • Activation of coagulation • DIC • PLT consumption by endovascular injury • TTP • HUS

    24. Thrombotic Thrombocytopenic Purpura (TTP) Graphics accessed URL http://evolvels.elsevier.com/section/default.asp?id=1138_ccalvo7_0001,, http://www.coolhealthtips.com/coolimages/causes.jpg, & URL http://www.childrenshospital.org/az/Site1209/Images/ei_1884.gif 2008.

    25. TTP Mechanism ULVWF multimers are normally digested by von Willebrand cleaving protease, ADAMTS13. In TTP, the absence of ADAMTS13 allows release of ULVWF, triggering platelet activation. TTP, thrombotic thrombocytopenic purpura; ULVW, unusually large von Willebrand factor. ‘ADisintegrin-like And Metallprotease with ThromboSpondin’ Graphic accessed URL http://evolvels.elsevier.com/section/default.asp?id=1138_ccalvo7_0001, 2008.

    26. TTP Clinical Presentation • Abdominal pain • Visual defects • Heart failure • Headaches • Seizures • Confusion • Renal dysfunction • Jaundice Graphic accessed URL http://www.uwhealth.org/images/ewebeditpro2/upload/4318_Figure_1.jpg, 2009.

    27. TTP: Lab Data & Therapy • Moderate Anemia • MCV variable, MCHC normal • Reticulocytes increased • NRBC on PB smear • Marked schistocytosis on PB smear • Leukocytosis w/left shift • Profound thrombocytopenia • Coag profile normal • Plasma exchange • Use FFP or cryo • Supply the deficient protease • Remove multimers • Corticosteroids • Splenectomy • Immunosuppressive agents

    28. Hemolytic Uremic Syndrome • Self-limiting • Bacterial toxins in blood stream damage renal capillary endothelia • Release ULVWF • Adult form associated w/immunosuppressive agents or chemotherapeutics • Dialysis usually required Graphics accessed URLs http://www.climatechoices.org.uk/images/jumpHEX.jpg, http://www2.umdnj.edu/mimmweb/hemeweb/session%202/schistocytes400.jpg, 2008.

    29. HUS Clinical & Lab Findings • Pallor • Abdominal pain • Bloody Diarrhea • Hypertension • Bruising • Jaundice • Oliguria • Renal failure • Lethargy • Seizures • Moderate-severe N/N anemia • Marked schistocytes on PB smear • NRBC • Polychromasia • Leukocytosis w/left shift • Moderate-profound thrombocytopenia • PT Normal – sl prolonged • PTT Normal • FDPs elevated

    30. HUS Therapy • Supportive • Observation • Transfusions • PRC • PLT • FFP/ Plasma exchange • Fluids/electrolyte replacement • Dialysis

    31. Thrombocytopenia Distribution/Dilution Disorders • Spleen sequestration • Extracorporeal circulatory devices • Massive transfusions Graphic accessed URL http://news.cnet.com/i/ne/p/2008/0703_Army_inventions/Army_invntns_15_550x550.jpg, 2008.

    32. Thrombocytosis Reactive Thrombocytosis Splenectomy Post hemorrhage Post therapeutic phlebotomy Malignancy Drug therapy epinephrine TPO Primary Thrombocytosis Essential Thrombocytosis Idiopathic myelofibrosis Chronic myelogenous leukemia Polycythemia Vera • Platelet counts greater than upper reference range • Reactive process (Counts usually don’t exceed > 750 x109/L) • Rare hemorrhage or thrombotic episodes • PLT morphology normal • BM megakaryocytes may be increased • Primary T or Myeloproliferative disorders (Counts often exceed 1000 x109/L • Common hemorrhage or thrombotic episodes • Abnormal PLT morphology • Large in size • Dysplastic appearance • BM megakaryocytes increased

    33. ThrombocytosisA = ?; B= ? Graphic accessed http://pathcases.com/Image27.gif, 2009. A Graphic accessed URL http://www.aamdsglossary.co.uk/i/c/1_normal_bone_marrow.jpg, 2009. B Graphic accessed http://www.som.tulane.edu/classware/pathology/Krause/ET/RM1.jpg, 2009. Graphic accessed URL http://www.healthsystem.virginia.edu/internet/hematology/hessimages/secondary-thrombocytosis-100x-website.jpg, 2009.

    34. References • Rodak, BF, Fritsma, GA & Doig, K (2008). Hematology Clinical Principles & Applications. Saunders Elsevier. Chapter 43. • Lab Tests On-line at URL http://www.labtestsonline.org/understanding/analytes/platelet/test.html • Silverman, MA. ITP (2007) at eMedicine URL http://www.emedicine.com/emerg/TOPIC282.HTM • Symonette, D. TTP (2008) at eMedicine URL http://www.emedicine.com/emerg/TOPIC579.HTM • Hemolytic Uremic Syndrome. National Kidney Foundation, NIH Publication No. 06–4570, December 2005. • Hemolytic Uremic Syndrome Commentary, CDC URL ftp://ftp.cdc.gov/pub/EID/vol1no4/adobe/cameron.pdf, 2009.