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You Make the Call: How would you manage a healthy young adult with asymptomatic elevations in D-dimer levels and atypical chest pain?

December 21, 2021

January 2022

No

Michael Kroll, MDMichael Kroll, MD
Professor of Medicine
Chief of the Section of Benign Hematology

This month, Michael Kroll, MD, discusses management of asymptomatic elevations in D-dimer in a healthy young adult with atypical chest pain.

And don’t forget to check out next month's clinical dilemma – send in your responses for a chance to win an ASH Clinical News-themed prize!


CLINICAL DILEMMA

A 20-year-old patient originally presented to the emergency room with atypical chest pain. She noted sudden onset dysphagia, shortness of breath, and severe anxiety with the chest pain. She tried vaping marijuana after the onset of these symptoms, but then came to the emergency room when her symptoms worsened.

Her D-dimer level was 4,613 ng/dL, with an international normalized ratio of 1.1. Her partial thromboplastin time was 33.5 seconds. A CT angiography of the chest was negative for pulmonary embolism or any other findings to explain the chest pain. Bilateral duplex of the lower extremities was negative for deep vein thrombosis.

She is otherwise healthy with no other past medical history. She is not on oral contraceptive pills and has no history of alcohol abuse or liver disease. She has no recent trauma or surgery, no known autoimmune or inflammatory disorders, and no recent infections including COVID-19. A urine pregnancy test was negative.

Two weeks later, I saw her in the outpatient setting and repeated the D-dimer test with the same result. She has no further chest pain, shortness of breath, nor any other complaints. I also checked her thrombin time, which was 19.9 seconds, while factor XIII and fibrinogen were normal. There is no family history of a bleeding or clotting disorder. She has no personal history of prolonged bleeding or thrombotic events. How do you manage asymptomatic elevations in D-dimer in the absence of any other findings? Is there any role for additional testing here?


EXPERT OPINION

I usually ignore asymptomatic elevations of D-dimer. They are meaningful (predictive) only when there are clinical symptoms or signs of thrombosis, hemorrhage, or coagulopathy. That being said, I have learned something from this case: When elevated D-dimers persist, one should consider looking for a rare bleeding disorder that is often asymptomatic but could emerge during trauma, invasive procedures, pregnancy, and parturition. In this case, the slightly elevated thrombin time identified could be a clue to the mechanism by which the patient’s D-dimers remain elevated and reveal a previously unrecognized mild bleeding disorder due to overactive fibrinolysis from dysfibrinogenemia or deficient plasmin regulatory proteins. To follow this clue, I suggest additional testing looking for systemic hyperfibrinolysis with a thromboelastogram (usually readily available) and the euglobulin clot lysis time. Whatever these results, I also suggest you measure fibrinogen antigen, fibrinogen functional activity, reptilase time, plasminogen activator inhibitor quantity and functional activity, and alpha 2 anti-plasmin quantity and functional activity. Distinguishing dysfibrinogenemia from PAI-1 or alpha 2-antiplasmin deficiency is important, as the former can be associated with thromboses as well as bleeding and therefore one must be cautious if managing bleeding with antifibrinolytic therapy, such as tranexamic acid. Antifibrinolytic therapy is predictably effective and relatively safe when used to prevent or treat hemorrhage from PAI-1 or alpha 2-antiplasmin deficiency, but it could promote thromboses when administered to patients with dysfibrinogenemia.

What do you do if all results return normal? If elevated D-dimers do not normalize, I would remain on guard for a clinically significant bleeding disorder and develop contingency plans with the patient’s health care team for managing surgical, parturitional, or post-partum hemorrhage.

References

Carpenter SL, Mathew P. Alpha2-antiplasmin and its defici-ency: fibrinolysis out of balance. Haemophilia. 2008 Nov;14(6):1250-4.

Casini A, Blondon M, Lebreton A, et al. Natural history of patients with congenital dysfibrinogenemia. Blood. 2015 Jan 15;125(3):553-61.

Casini A, Neerman-Arbez M, Ariëns RA, de Moerloose P. Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management. J Thromb Haemost. 2015 Jun;13(6):909-19.

Franchini M, Mannucci PM. Primary hyperfibrinolysis: Facts and fancies. Thromb Res. 2018 Jun;166:71-75.

Iwaki T, Urano T, Umemura K. PAI-1, progress in understanding the clinical problem and its aetiology. Br J Haematol. 2012 May;157(3):291-8.


NEXT MONTH'S CLINICAL DILEMMA

A 76-year-old woman was referred for anemia. Her hemoglobin level was 8.5 g/dL with a mean corpuscular volume of 88 fL. She had normal white blood cell and platelet counts. There was no evidence of hemolysis, and her ferritin level was 33 ng/mL. She was replete with iron, but her anemia persisted with a hemoglobin level of 10 g/dL. She underwent a biopsy, and her bone marrow was normocellular (60% cellularity) with normal trilineage hematopoiesis and no dyspoiesis. Her iron stores were absent on iron stains of the aspirate. She has a normal metaphase karyotype, and fluorescence in situ hybridization (FISH) was negative for -5/5q31-, -7/7q31-, +8, and 20q12-. Next generation sequencing (NGS) noted several variants: DNMT3A, TET2, U2AF1, IKZF1, and MPL.

In retrospect, I’m not sure what to do with this NGS data, aside from continued observation and repeating bone marrow biopsy if worsening cytopenias develop. Should I have ordered the NGS?

Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.

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