Thrombocytopenic Disorders

Thrombocytopenic disorders include congenital thrombocytopenia, heparin-induced thrombocytopenia (HIT), neonatal alloimmune thrombocytopenia (NAIT), thrombotic microangiopathies (TMA), and idiopathic thrombocytopenic purpura (ITP). The level of medical urgency determines which tests might be ordered and the urgency of ordering those tests (eg, acutely ill patient versus ambulatory patient versus pregnant patient).

Tabs Content

Clinical Overview

Diagnosis

Indications for Testing

Platelet count <100-150 x 10⁹/L

Laboratory Testing

Initial testing
- Confirm thrombocytopenia – repeat CBC with peripheral smear
  - Rule out pseudothrombocytopenia – platelet clumping visible on smear from ethylenediaminetetraacetic acid (EDTA) sample
    - Repeat testing using citrated blood
  - Peripheral smear may give clues as to cause of thrombocytopenia
    - Schistocytes – microangiopathic process
    - Nucleated red blood cells (RBCs) – post splenectomy
    - Spherocytes – hereditary spherocytosis or immune-mediated hemolytic anemia
    - Leukocytosis with bands – sepsis
    - Immature white blood cells (WBCs) – leukemia
    - Multilobed hypersegmented neutrophils – B₁₂ deficiency
- Chemistry and urine testing to evaluate potential hemolysis
- Disseminated intravascular coagulation (DIC) testing if clinically indicated – prothrombin time (PT), partial thromboplastin time (PTT), D-dimer
- Consider drugs that may be causing thrombocytopenia (eg, heparin, cimetidine, amiodarone)
Secondary testing should be performed based on history and clinical presentation
- Neonatal thrombocytopenia – refer to neonatal alloimmune thrombocytopenia
- Thrombocytopenia or thromboses following administration of heparin – refer to heparin-induced thrombocytopenia
- Childhood onset of thrombocytopenia – various studies may be necessary to evaluate the varied causes of congenital thrombocytopenia
- Idiopathic thrombocytopenic purpura suspected – if patient meets clinical diagnostic criteria, testing for direct platelet antibodies aids in confirming diagnosis of autoimmune thrombocytopenia
Other possible testing based on clinical scenario
- HIV testing
- Hepatitis C virus (HCV) testing
- Connective tissue disease evaluation
- Liver disease evaluation

Differential Diagnosis

Refer to Pathophysiology in Background.

Background

Epidemiology

Incidence
- Congenital thrombocytopenia – rare
- Heparin-induced thrombocytopenia (HIT) – 0.5-5% of patients receiving heparin
- Neonatal autoimmune thrombocytopenia (NAIT) – 1/2,000 pregnancies
- Thrombotic microangiopathies (TMA) – 1-2/million
- Idiopathic thrombocytopenic purpura (ITP) – ~2-5/100,000

Pathophysiology

Causes can be subdivided into categories
- Pseudothrombocytopenia – associated with ethylenediaminetetraacetic acid (EDTA) (found in purple top collection tube) initiating platelet clumping and spuriously decreased platelet count
- Decreased platelet production
  - Congenital
  - Bone marrow disorders (eg malignancy, ineffective thrombopoiesis, or bone marrow failure)
  - Chemical or toxin mediated (eg, ionizing radiation, chemotherapy)
  - Infectious (eg, parvovirus B19, adenovirus, Epstein Barr virus [EBV], HIV)
- Increased platelet destruction
  - Immune mediated
    - ITP
    - HIT
    - NAIT
    - Drug induced (eg, amiodarone, cimetidine, digoxin, furosemide, anticonvulsants, sulfonamides, quinidine, penicillins, vancomycin)
    - Connective tissue disease
    - Posttransfusion purpura
  - Nonimmune mediated
    - TMA – thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and atypical HUS (aHUS)
    - Disseminated intravascular coagulation (DIC)
    - Sepsis
    - Cardiac valves
    - HELLP syndrome
- Splenic sequestration
  - Spleen harbors up to 30% of platelets
  - Splenomegaly can reduce count via sequestration
- Dilution
  - Following major surgery
  - Following large transfusion of blood products lacking platelets

Clinical Presentation

Bleeding tendency
Easy bruisability, petechia, purpura
Other signs and symptoms are based on the specific etiology for thrombocytopenia – refer to TMA, HIT, and NAIT topics

ARUP Lab Tests

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Heparin-Induced Thrombocytopenia (HIT) PF4 Antibody, IgG with Reflex to Serotonin Release Assay (Heparin Dependent Platelet Antibody), Unfractionated Heparin 2012181
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Serotonin Release Assay

Recommended Use

Gold standard reflex test for confirming diagnosis of HIT

Reflex pattern – if HIT PF4 antibody, IgG is 0.400 optical density (OD) or greater, serotonin release assay (SRA) is added

Clinical sensitivity/specificity – >90% for SRA

Limitations

Occasional false negatives occur with HIT testing; does not exclude HIT if clinical suspicion is high

Results should always be correlated with clinical findings

Serotonin Release Assay (Heparin Dependent Platelet Antibody), Unfractionated Heparin 2005631
Method: Qualitative Serotonin Release Assay

Recommended Use

Gold standard test for diagnosis of HIT

Clinical sensitivity/specificity – >90%

Limitations

Occasional false negatives occur; does not exclude HIT if suspicion is high

Results should always be correlated with clinical findings

Heparin-Induced Thrombocytopenia (HIT) PF4 Antibody, IgG 2012179
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Recommended Use

Recommended initial screening test for heparin-PF4 antibodies that cause HIT

Confirmation with SRA may be necessary based on clinical presentation

Platelet Associated Antibodies, Direct Assay 0095614
Method: Qualitative Flow Cytometry

Recommended Use

Support diagnosis of autoimmune thrombocytopenia (AITP)

Limitations

Does not distinguish between autoantibodies and alloantibodies

Does not identify specific types of antiplatelet antibodies, such as those against HPA-1a

Platelet Antibodies, Indirect 0051050
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Recommended Use

Not recommended for diagnosis of immune thrombocytopenic purpura (ITP)

Use to detect platelet-specific antibodies in suspected fetal or neonatal alloimmune thrombocytopenia, posttransfusion purpura, or multiplatelet transfusion refractoriness

Platelet Antigen Genotyping Panel 0051308
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Recommended Use

Use in risk assessment for fetal or neonatal alloimmune thrombocytopenia (NAIT)

May be ordered for parental, fetal, or neonatal genotyping

Clinical sensitivity/specificity – unknown

Gene included – HPA

Antigens tested include a and b variants of HPA-1 through -6 and HPA-15

Refer to Additional Technical Information document for further content

Limitations

HPA alleles, other than those tested, are not determined

Bloody amniotic fluid specimens may give false-negative results because of maternal cell contamination

Diagnostic errors can occur due to rare sequence variations

ADAMTS13 Reflex Panel 3000239
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Recommended Use

Reflexive panel to assist in diagnosis of thrombotic thrombocytopenic purpura (TTP) and in distinguishing between inherited and acquired forms of TTP

ADAMTS13 Activity 0030056
Method: Chromogenic Assay

Recommended Use

Assist in diagnosing congenital or inherited thrombotic thrombocytopenic purpura (TTP)

Limitations

Mild to moderate ADAMTS13 deficiency may be seen in a variety of medical conditions

ADAMTS13 Inhibitor 3000228
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Recommended Use

Assist in distinguishing between inherited and acquired forms of thrombotic thrombocytopenic purpura (TTP)

Recommended initial test for the identification of autoantibodies to ADAMTS13; more specific for acquired TTP than ADAMTS13 antibody test

If TTP is suspected but antibodies are not identified by inhibitor test, ADAMTS13 antibody testing is recommended

ADAMTS13 Antibody 3000182
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Recommended Use

Assist in distinguishing between inherited and acquired forms of thrombotic thrombocytopenic purpura (TTP)

Not recommended as the initial test for identification of autoantibodies to ADAMTS13; ADAMTS13 antibody test is less specific for acquired TTP than the inhibitor test

Order when acquired TTP is suspected but antibodies are not identified by the ADAMTS13 inhibitor test

Prothrombin Time 0030215
Method: Electromagnetic Mechanical Clot Detection

Recommended Use

Initial test for suspected bleeding disorder

Partial Thromboplastin Time 0030235
Method: Electromagnetic Mechanical Clot Detection

Recommended Use

Initial test for suspected bleeding disorder

Thrombin Time with Reflex to Thrombin Time 1:1 Mix 0030260
Method: Electromagnetic Mechanical Clot Detection

Recommended Use

Assist in diagnosing dysfibrinogenemia or abnormalities with fibrin polymerization

Screen samples for the presence of heparin or direct thrombin inhibitors

Reflex pattern – if thrombin time (TT) is elevated, then TT 1:1 mix will be added

D-Dimer 0030057
Method: Immunoturbidimetry

Recommended Use

Aid in diagnosing and following disseminated intravascular coagulation (DIC)

Limitations

Presence of rheumatoid factor may lead to false-positive results; test should not be used to rule out venous thromboembolism (VTE)

Fibrinogen 0030130
Method: Electromagnetic Mechanical Clot Detection

Recommended Use

Determine if fibrinogen deficiency is a potential cause of bleeding

Platelet Aggregation Studies 0030160
Method: Qualitative Aggregation

Recommended Use

Evaluate patients with suspected inherited qualitative platelet disorders or patients with lifelong platelet-type bleeding

Limitations

This test is available only for local clients due to short sample stability time

von Willebrand Panel 0030125
Method: Electromagnetic Mechanical Clot Detection/Platelet Agglutination/Microlatex Particle-Mediated Immunoassay

Recommended Use

Recommended panel for the initial workup of suspected von Willebrand disease (VWD)

Panel includes von Willebrand factor (VWF) antigen, ristocetin cofactor activity, and factor VIII activity

Medical Reviewers

Rodgers III, George M., MD, PhD, Medical Director, Hemostasis and Thrombosis at ARUP Laboratories; Professor of Internal Medicine and Adjunct Professor of Clinical Pathology, University of Utah

Smock, Kristi J., MD, Medical Director, Hemostasis/Thrombosis at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

Guidelines

Neunert C, Lim W, Crowther M, Cohen A, Solberg L, Crowther MA, American Society of Hematology. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011; 117(16): 4190-207. PubMed

General References

Arnold DM, Smith JW, Kelton JG. Diagnosis and management of neonatal alloimmune thrombocytopenia. Transfus Med Rev. 2008; 22(4): 255-67. PubMed

Balduini CL, Savoia A. Genetics of familial forms of thrombocytopenia. Hum Genet. 2012; 131(12): 1821-32. PubMed

Chapman K, Seldon M, Richards R. Thrombotic microangiopathies, thrombotic thrombocytopenic purpura, and ADAMTS-13. Semin Thromb Hemost. 2012; 38(1): 47-54. PubMed

Cuker A, Gimotty PA, Crowther MA, Warkentin TE. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood. 2012; 120(20): 4160-7. PubMed

Favaloro EJ, Lippi G, Franchini M. Contemporary platelet function testing. Clin Chem Lab Med. 2010; 48(5): 579-98. PubMed

Geddis AE. Inherited thrombocytopenias: an approach to diagnosis and management. Int J Lab Hematol. 2013; 35(1): 14-25. PubMed

George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med. 2014; 371(7): 654-66. PubMed

Ghanima W, Godeau B, Cines DB, Bussel JB. How I treat immune thrombocytopenia: the choice between splenectomy or a medical therapy as a second-line treatment. Blood. 2012; 120(5): 960-9. PubMed

Heikal NM, Smock KJ. Laboratory testing for platelet antibodies. Am J Hematol. 2013; 88(9): 818-21. PubMed

Nurden AT, Fiore M, Pillois X, Nurden P. Genetic testing in the diagnostic evaluation of inherited platelet disorders. Semin Thromb Hemost. 2009; 35(2): 204-12. PubMed

Nurden AT, Freson K, Seligsohn U. Inherited platelet disorders. Haemophilia. 2012; 18 Suppl 4: 154-60. PubMed

Peterson JA, McFarland JG, Curtis BR, Aster RH. Neonatal alloimmune thrombocytopenia: pathogenesis, diagnosis and management. Br J Haematol. 2013; 161(1): 3-14. PubMed

Sekhon SS, Roy V. Thrombocytopenia in adults: A practical approach to evaluation and management. South Med J. 2006; 99(5): 491-8; quiz 499-500, 533. PubMed

Shenkman B, Einav Y. Thrombotic thrombocytopenic purpura and other thrombotic microangiopathic hemolytic anemias: diagnosis and classification. Autoimmun Rev. 2014; 13(4-5): 584-6. PubMed

Smock KJ, Perkins SL. Thrombocytopenia: an update. Int J Lab Hematol. 2014; 36(3): 269-78. PubMed

Strong NK, Eddleman KA. Diagnosis and management of neonatal alloimmune thrombocytopenia in pregnancy. Clin Lab Med. 2013; 33(2): 311-25. PubMed

Visentin GP, Liu CY. Drug-induced thrombocytopenia. Hematol Oncol Clin North Am. 2007; 21(4): 685-96, vi. PubMed

Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost. 2008; 6(8): 1304-12. PubMed

Wirth SM, Macaulay TE, Armitstead JA, Steinke DT, Blechner MD, Lewis DA. Evaluation of a clinical scoring scale to direct early appropriate therapy in heparin-induced thrombocytopenia. J Oncol Pharm Pract. 2010; 16(3): 161-6. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology^®

Smock KJ. The role of ADAMTS13 testing in the work up of suspected thrombotic thrombocytopenic purpura. American Association for Clinical Chemistry. [Published: Apr 2016; Accessed: Apr 2017]

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	Thrombocytopenic Disorders. ARUP Consult^©. Retrieved May 14, 2018, from: https://arupconsult.com/content/thrombocytopenic-disorders

Thrombocytopenic Disorders

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Reviewers

References

Guidelines

General References

References from the ARUP Institute for Clinical and Experimental Pathology®

References from the ARUP Institute for Clinical and Experimental Pathology^®