# New approaches to the pathophysiology, diagnosis and management of heparin-induced thrombocytopenia

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $397,500

## Abstract

PROJECT SUMMARY/ABSTRACT
Heparin-induced thrombocytopenia (HIT) is a severe, antibody (ab)-mediated prothrombotic syndrome with
high morbidity and mortality. The biochemical basis of the distinction between “pathogenic” platelet-activating
antibodies and “benign” non-activating HIT antibodies is not well understood. This results in significant
diagnostic challenges and in excessive use of non-heparin alternative anticoagulation that have worse
bleeding profiles than heparin. Outcomes in HIT are suboptimal despite current therapy with direct thrombin
inhibitors: One-third of affected patients develop thrombosis and one in ten patients dies. The proposed studies
will explore key unanswered questions in areas of HIT pathophysiology, diagnosis and treatment. For Aim 1,
we hypothesize the existence of multiple functional classes of HIT antibodies: (1) Pathogenic antibodies that
recognize PF4-treated platelets with or without reactivity to PF4-heparin complexes, and (2) Benign abs that
recognize PF4-heparin but not platelets treated with PF4. We will identify and characterize these antibody
classes by chromatography-based isolation from patient samples and will generate novel HIT monoclonal
antibodies in each of these functional classes. Generated monoclonal antibodies will be tested for
pathogenicity in a HIT mouse model and results will be correlated with their serologic characteristics. Obtaining
and processing normal donor platelets is a major challenge that limits the availability of functional “gold
standard” testing in HIT. In Aim 2, we will develop a rapid HIT diagnostic test using the patient’s own platelets
treated with PF4/heparin. This will facilitate “in-hospital” HIT diagnosis leading to early detection of this
condition. Currently used non-heparin alternative anticoagulants do not address the most proximal event in
HIT: Activation of platelets by HIT antibodies. Given this, breakthrough thrombosis is frequently seen in
patients under treatment and so is unintended bleeding caused by the potent non-heparin anticoagulants used.
In Aim 3, we will use platelet-derived and synthetic chondroitin sulfates of various sulfation levels and
saccharide lengths to evaluate their ability to inhibit HIT-antibody mediated platelet activation in vitro and to
ameliorate thrombocytopenia in a HIT murine model. In Aim 1, we expect to successfully separate and
characterize multiple functional classes of HIT antibodies which will suggest new ways to selectively detect
only the pathogenic ones. Developing and optimizing a diagnostic method using the patient’s own platelets in
Aim 2 will transform platelet-activation based HIT testing by moving it from the reference laboratory
environment to the in-hospital setting. Finally, studies described in Aim 3 will introduce a new class of
therapeutics in HIT, chondroitin sulfates, that will prevent thrombosis, but unlike current therapies, will not
increase the risk of bleeding. In summary, we anticipate that all three...

## Key facts

- **NIH application ID:** 10276062
- **Project number:** 1R01HL158932-01
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Anand Padmanabhan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $397,500
- **Award type:** 1
- **Project period:** 2021-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10276062

## Citation

> US National Institutes of Health, RePORTER application 10276062, New approaches to the pathophysiology, diagnosis and management of heparin-induced thrombocytopenia (1R01HL158932-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10276062. Licensed CC0.

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