Heparin-Induced Thrombocytopenia Workup

  • Author: Sancar Eke, MD; Chief Editor: Emmanuel C Besa, MD   more...
 
Updated: Mar 6, 2012
 

Laboratory Studies

There are 4 diagnostic tests for heparin-induced thrombocytopenia (HIT): Serotonin release assay (SRA), heparin-induced platelet aggregation assay (HIPA), solid phase immunoassay (H-PF4 enzyme-linked immunosorbent assay [ELISA]), and particle gel immunoassay. The first 2 tests are also referred as functional assays. Most laboratories use HIPA, which is highly specific but which is also reported to be less sensitive than SRA. The availability of SRA is largely restricted to centers where heparin-induced thrombocytopenia (HIT) is a focus of research.

The14 C-SRA is considered the "gold standard" assay for the detection of heparin-dependent antibodies in heparin-induced thrombocytopenia (HIT).[33] Various studies have reported the sensitivity to be as high as 90% and the specificity of SRA to be as high as 100%.[34, 35]

SRA is based on heparin-induced thrombocytopenia (HIT) antibodies causing platelets to aggregate and to release serotonin. The platelet-rich plasma of healthy individuals is incubated with14 C-serotonin and then mixed with patient serum, along with low (therapeutic) and high heparin concentrations. The test is considered positive if the sample caused a greater than 20% serotonin release at a (therapeutic) dosage of 0.1 U/mL heparin.

HIPA is a platelet-activation test in which the patient's serum is mixed with donor platelets in the presence of heparin. Aggregation of the donor platelets indicates the presence of antibodies to the heparin–PF4 complex. A study compared the sensitivity and specificity of14 C-SRA and HIPA.[36] The mean sensitivity of HIPA varied from 39% to 81%, depending on the heparin concentration and the donor of the platelets used. The sensitivity of SRA has ranged from 69% to 94%. The specificities of both tests were high.[36]

The solid phase ELISA is not a functional test. ELISA measures the antibodies to PF4 that is bound to heparin or a polyvinyl sulfonate surface. The experience to date demonstrates that currently available ELISAs indeed have high sensitivity but a relatively low specificity, thereby limiting their usefulness. HIPA proved to be a more sensitive test for laboratory confirmation according to a study that compared HIPA and PF4 ELISA in serum samples from 146 patients examined for heparin-induced thrombocytopenia.[37] A recent study describes a possible confirmatory step when using an ELISA for the diagnosis of heparin-induced thrombocytopenia. The procedure involves the addition of excess heparin to the sample prior to carrying out the ELISA assay.[38]

Particle gel immunoassay is a relatively new test and one method uses special red-dyed, high-density polystyrene particles that are coated with heparin-PF4 complexes. Patient serum– and heparin-PF4–coated microbeads are added to the incubation chamber. A strong positive result is indicated by the agglutinated microbeads.[39] This assay is rapid, technically easy, and offers the promise to become a routine assay for HIT.

Berry et al published a retrospective study that found 81% of patients with clinical suspicion for HIT and a positive PF4 test results were actually heparin-induced thrombocytopenia (HIT) negative. In addition, 8.6 % of patients with Warkentin 4-T scores of 0-3 were positive for heparin-induced thrombocytopenia (HIT), and 57% of patients with Warkentin 4-T scores of 6-8 were heparin-induced thrombocytopenia (HIT) negative. The authors suggested that PF4 and SRA testing and treatment decisions should not be based on Warkentin 4-T scores.

Berry et al questioned the current practice of considering PF4 positive for values of 0.4 and higher because this study found that only 19% of the patients were actually positive. The authors suggested that a PF4 result of 2 optical density (OD) is more predictive of heparin-induced thrombocytopenia (HIT), with a true positive rate of 65% in this study.[40] Despite that, a study published in 2012 reported that higher levels of anti-PF4/heparin antibody are associated with an approximate doubling in thrombosis risk by 30 days among patients with clinically suspected heparin-induced thrombocytopenia.[41]

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Imaging Studies

The major clinical problem associated with heparin-induced thrombocytopenia (HIT) is thrombosis, both venous and arterial. Different vascular imaging studies can be used to document the thrombotic lesions (see the images below).

Ultrasonographic image of a deep vein thrombosis (Ultrasonographic image of a deep vein thrombosis (DVT). Sequential images demonstrate treatment of iliofemSequential images demonstrate treatment of iliofemoral deep venous thrombosis due to May-Thurner (Cockett) syndrome. Far left: View of the entire pelvis demonstrates iliac occlusion. Middle left: After 12 hours of catheter-directed thrombolysis, an obstruction at the left common iliac vein is evident. Middle right: After 24 hours of thrombolysis, a bandlike obstruction is seen; this is the impression made by the overlying right common iliac artery. Far left: After stent placement, image shows wide patency and rapid flow through the previously obstructed region. Note that the patient is in the prone position in all views. (Right and left are reversed.) Ventilation-perfusion scan. Left image: Posterior Ventilation-perfusion scan. Left image: Posterior view of normal findings on ventilation-perfusion scan. Right image: Posterior view of a perfusion scan that reveals a perfusion defect in the left upper quadrant. The defect in the middle of the image is due to the position of the heart. Helical computed tomography scan of the pulmonary Helical computed tomography scan of the pulmonary arteries. A filling defect in the right pulmonary artery is present, consistent with a pulmonary embolism.

Multislice computed tomography (MSCT) scanning is utilized for some reported cases with multiple thrombosis.[42]

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Other Tests

When heparin-induced thrombocytopenia (HIT) is suspected, an investigation for lower limb DVT should be undertaken.

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Histologic Findings

Histologic analysis in an experimental mouse model of heparin-induced thrombocytopenia (HIT)/thrombosis showed fibrin thrombi in the arterioles and capillaries in the heart, liver, and kidneys, as well as platelet/fibrin thrombi in the pulmonary vasculature.[43, 44]

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Staging

Criteria for Diagnosis of HIT

Greinacher Scoring System

Platelet count

  • Decrease in platelet count by 30% to 50% (+1), or
  • Decrease in platelet count by >50% of preheparin value (+2)
  • Normalization of platelet count within 10 days of stopping heparin (+3)

Time of onset

  • After >5 days of heparin, if first exposure (+2), or
  • Within 4 days of heparin, if reexposure (+2)

Thrombosis

  • Thromboembolic complications during heparin treatment (+2) or inflammatory skin reaction at heparin injection site (+1)
  • Other causes of thrombocytopenia or thrombosis

Other

  • Sepsis at time of diagnosis (–1)
  • Recent treatment with cytotoxic drugs (–1)
  • Preexisting thromboembolism (–1)

Clinical group designation of likelihood of heparin-induced thrombocytopenia (HIT)

  • Very likely: score of 6–8
  • Possible: score of 4–5
  • Unlikely: score of 0–3
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Contributor Information and Disclosures
Author

Sancar Eke, MD  Physician in Nephrology and Hypertension, West Virginia

Sancar Eke, MD is a member of the following medical societies: American College of Physicians and Massachusetts Medical Society

Disclosure: Nothing to disclose.

Coauthor(s)

Sarah K May, MD  Consulting Staff, Department of Hematology-Oncology, Caritas Carney Hospital, Commonwealth Hematology-Oncology PC

Disclosure: Nothing to disclose.

Specialty Editor Board

Paul Schick, MD  Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Chief Editor

Emmanuel C Besa, MD  Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

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Ultrasonographic image of a deep vein thrombosis (DVT).
Sequential images demonstrate treatment of iliofemoral deep venous thrombosis due to May-Thurner (Cockett) syndrome. Far left: View of the entire pelvis demonstrates iliac occlusion. Middle left: After 12 hours of catheter-directed thrombolysis, an obstruction at the left common iliac vein is evident. Middle right: After 24 hours of thrombolysis, a bandlike obstruction is seen; this is the impression made by the overlying right common iliac artery. Far left: After stent placement, image shows wide patency and rapid flow through the previously obstructed region. Note that the patient is in the prone position in all views. (Right and left are reversed.)
Ventilation-perfusion scan. Left image: Posterior view of normal findings on ventilation-perfusion scan. Right image: Posterior view of a perfusion scan that reveals a perfusion defect in the left upper quadrant. The defect in the middle of the image is due to the position of the heart.
Helical computed tomography scan of the pulmonary arteries. A filling defect in the right pulmonary artery is present, consistent with a pulmonary embolism.
 
 
 
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