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Charles Greenberg: What If D-dimer Isn’t ‘Non-Specific’ At All?

Charles Greenberg/MUSC Health

Mar 5, 2026, 15:28

Charles Greenberg: What If D-dimer Isn’t ‘Non-Specific’ At All?

Charles Greenberg, Professor of Medicine at Medical University of South Carolina, shared a post on LinkedIn:

”After studying D-dimer biology for many years, I’ve started to wonder if we’ve been misunderstanding one of the most common tests in medicine.

What if D-dimer isn’t ‘non-specific’ at all?

For decades we’ve used D-dimer mainly for one purpose:
ruling out venous thromboembolism.

If the level is normal and the clinical probability is low, we safely exclude DVT or pulmonary embolism. In that role the test performs remarkably well.

But when D-dimer is elevated, clinicians often dismiss it:

Infection
Inflammation
Cancer
Trauma
Pregnancy
Aging

In other words: ‘non-specific’

But the biology tells a different story.

D-dimer appears only when cross-linked fibrin is broken down.

And that cross-linking step is controlled by Factor XIII, which stabilizes fibrin architecture and determines how resistant a clot is to fibrinolysis.

So the D-dimer signal actually integrates several biological systems:

Fibrin architecture — Factor XIII crosslinking
Inflammation — endothelial injury and coagulation activation
Genetic susceptibility — emerging polygenic thrombotic risk
Disease biology — cancer, sepsis, COVID, systemic stress

The COVID-19 pandemic highlighted this clearly.

Patients with severe disease often had markedly elevated D-dimer levels, sometimes without clear thrombosis on imaging, yet those levels strongly predicted clinical outcomes.

Seen this way, D-dimer may not simply be a clot marker.

It may be a systems-level biomarker of fibrin turnover reflecting the interaction between coagulation, inflammation, and tissue injury.

As genomics and multi-omics frameworks evolve, laboratory markers we once labeled ‘non-specific’ may actually be reporting complex biological networks that we are only beginning to understand.

D-dimer might just be the first example.

Discussion

Are we underestimating what so-called ‘non-specific’ biomarkers are actually telling us about systemic disease biology?

References

Adam SS et al. Blood. 2009
Righini M et al. JAMA. 2014
Tang N et al. J Thromb Haemost. 2020
Ay C et al. Blood. 2012
Muszbek L et al. Physiol Rev. 2011”

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