Case Report: ANXA2 Associated Life-Threatening Coagulopathy With Hyperfibrinolysis in a Patient With Non-APL Acute Myeloid Leukemia

Abstract

Patients with acute promyelocytic leukemia (APL) often present with potentially life-threatening hemorrhagic diathesis. The underlying pathomechanisms of APL-associated coagulopathy are complex. However, two pathways considered to be APL-specific had been identified: 1) annexin A2 (ANXA2)-associated hyperfibrinolysis and 2) podoplanin (PDPN)-mediated platelet activation and aggregation. In contrast, since disseminated intravascular coagulation (DIC) is far less frequent in patients with non-APL acute myeloid leukemia (AML), the pathophysiology of AML-associated hemorrhagic disorders is not well understood. Furthermore, the potential threat of coagulopathy in non-APL AML patients may be underestimated. Herein, we report a patient with non-APL AML presenting with severe coagulopathy with hyperfibrinolysis. Since his clinical course resembled a prototypical APL-associated hemorrhagic disorder, we hypothesized pathophysiological similarities. Performing multiparametric flow cytometry (MFC) and immunofluorescence imaging (IF) studies, we found the patient’s bone-marrow mononuclear cells (BM-MNC) to express ANXA2 - a biomarker previously thought to be APL-specific. In addition, whole-exome sequencing (WES) on sorted BM-MNC (leukemia-associated immunophenotype (LAIP)1: ANXAlo, LAIP2: ANXAhi) demonstrated high intra-tumor heterogeneity. Since ANXA2 regulation is not well understood, further research to determine the coagulopathy-initiating events in AML and APL is indicated. Moreover, ANXA2 and PDPN MFC assessment as a tool to determine the risk of life-threatening DIC in AML and APL patients should be evaluated.

Impaired fibrinolysis and increased clot strength are potential risk factors for thrombosis in lymphoma

“… 20 Other studies have reported increased tPA and uPA concentrations, 43 , 44 however, we found these parameters to be within the reference range. Annexin II was also associated with hyperfibrinolytic coagulopathy and bleeding diathesis in a recent case report of a patient with acute myelomonocytic leukemia (AMML), 45 and, moreover, Olwill et al found that annexin II was highly expressed in APL, AMML, and erythroid leukemia cell lines. 45 , 46 Several case reports spanning multiple decades have also associated AMML with disseminated intravascular coagulation and hyperfibrinolysis 47 , 48 , 49 Thus, annexin II–associated hyperfibrinolysis does not seem to be exclusive to APL.…”

Investigation of Biomarkers Associated with Low Platelet Counts in Normal Karyotype Acute Myeloid Leukemia

“…The CLEC-mediated platelet adhesion to PDPN is important in the development and dissociation of lymphatics from blood vessels, in supporting the integrity of the blood-lymphatic vessel junctions, in preventing blood cell efflux into lymphatics and in maintaining vascular integrity during inflammation [ 23 ]. There were reports that PDPN related to platelet aggregation and annexin A2 (ANXA2) related to hyperfibrinolysis were related to life-threatening coagulopathy in acute promyelocytic leukemia (APL) and non-APL, respectively [ 25 , 26 ]. The JAK-STAT pathway is involved in immune response, inflammation and tumorigenesis [ 27 , 28 ].…”