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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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Quantitative platelet disorders l.jpg

Quantitative Platelet Disorders

LabM 419 Clinical Coagulation

Fall 2009

©C. Calvo, MS, MT(ASCP), SH(ASCP) – UW, 2009.


Slide2 l.jpg
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.


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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.


Clinical manifestations primary v s secondary disorders of hemostasis l.jpg

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


Physician s eye view l.jpg

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


Laboratory perspective l.jpg
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)


Vascular based disorders l.jpg

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


Platelet associated disorders l.jpg
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


Bleeding clinical correlation plt numbers l.jpg
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.




Impaired or decreased plt production l.jpg

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


Increased platelet destruction l.jpg
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


Immune idiopathic thrombocytopenic purpura itp l.jpg
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.



Neonatal alloimmune thrombocytopenia nait l.jpg
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


Post transfusion purpura l.jpg

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.


Immune drug induced itp l.jpg
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.


Heparin induced thrombocytopenia l.jpg
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.


Heparin induced thrombocytopenia20 l.jpg

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


Hit testing l.jpg
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.


Hit testing22 l.jpg
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.


Non immune plt destruction l.jpg
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


Thrombotic thrombocytopenic purpura ttp l.jpg
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.


Ttp mechanism l.jpg
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.


Ttp clinical presentation l.jpg
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.


Ttp lab data therapy l.jpg
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


H emolytic u remic s yndrome l.jpg
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.


Hus clinical lab findings l.jpg
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


Hus therapy l.jpg
HUS Therapy

  • Supportive

    • Observation

    • Transfusions

      • PRC

      • PLT

      • FFP/ Plasma exchange

    • Fluids/electrolyte replacement

    • Dialysis


Thrombocytopenia distribution dilution disorders l.jpg
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.


Thrombocytosis l.jpg
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


Thrombocytosis a b l.jpg
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.


References l.jpg
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.


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