# The Novel Mechanisms of Thrombosis Formation in Myeloproliferative Diseases

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $618,875

## Abstract

Myeloproliferative neoplasms (MPNs) are pro-thrombotic malignancies resulting from the
clonal expansion of myeloid cells. MPN patients have a hazard ratio for developing an
arterial thrombosis that is similar to cigarette smokers and their risk of developing a
venous thrombosis is comparable to Factor V Leiden heterozygotes. Over 100,000
Americans have a myeloproliferative disorder due to JAK2V617F, an activating mutation of
JAK2 tyrosine kinase. In addition, the JAK2V617F mutation is a driver of clonal
hematopoiesis that may be present in up to 3% of the general population. Even when
patients only have clonal hematopoiesis with normal blood counts, the JAK2V617F mutation
still confers a 12-fold increased risk for developing a myocardial infarction at an early age.
Although notable advances have been made in our understanding of the dysregulation of
hematopoiesis in patients with JAK2V617F driven myeloproliferative diseases, remarkably
little is known about the molecular basis for why patients with the JAK2V617F mutation are
at such high risk for thrombosis. We have found that mice and humans with the JAK2V617F
mutation form thrombi that are structurally and mechanically distinct from normal controls.
Specifically, our preliminary data shows that the JAK2V617F mutation induces larger clots
due to the inability of these clots to compact (i.e. retract) well. Additionally, these clots fail
to stabilize because they cannot cover their surface with fibrin, making the clots more
friable. Because these clots are larger in size, this makes them more likely to occlude
blood flow within blood vessels, and the friable structure of these clots also makes them
more likely to embolize. We have also observed that the loss of the phosphoinositide
adaptor protein, Pleckstrin-2 (Plek2), or its widely expressed paralog Pleckstrin-1 (Plek1),
impair phosphatidylinositol 3-kinase (PI3K) signaling, and thereby reverses many of the
widespread vascular occlusions and lethality of JAK2V617F knockin mice. Based on these
studies, we hypothesize that both Pleckstrin isoforms are critical for thrombus formation
in JAK2V617F driven diseases through phosphoinositide-mediated pathways. The goals of
this Proposal are to: (1) achieve a mechanistic understanding of how JAK2-drives
thrombosis in MPN disorders, and (2) determine how Plek1 and Plek2 mediate the
development of JAK2V617F associated thrombi. A better understanding of the molecular
basis for why patients develop thrombosis should have far reaching impact on both
understanding and treating patients with JAK2V617F driven diseases.

## Key facts

- **NIH application ID:** 10187644
- **Project number:** 5R01HL148014-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** CHARLES S. ABRAMS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $618,875
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10187644

## Citation

> US National Institutes of Health, RePORTER application 10187644, The Novel Mechanisms of Thrombosis Formation in Myeloproliferative Diseases (5R01HL148014-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10187644. Licensed CC0.

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