Significance of abnormal blood coagulation in patients with chronic myelomonocytic leukemia

Chronic myelomonocytic leukemia (CMML) is a rare, genotypically and phenotypically heterogenous hematologic malignancy of elderly people, with an intrinsic risk of progression and transformation to secondary acute myeloid leukemia (AML). With regard to the presence of myeloproliferation, CMML was originally subdivided into myeloproliferative disorder (MP-CMML; white blood cell [WBC] count > 13 × 10⁹/L) versus myelodysplastic syndrome (MD-CMML; WBC count ≤ 13 × 10⁹/L MD-CMML) by the FAB criteria [1, 2]. Since CMML is characterized by features of both MDS and MPN, the World Health Organization (WHO) classification of 2002 assigned CMML to the mixed category, MDS/MPN [3]. CMML is further subclassified by the WHO into three groups based on blast equivalents (blasts plus promonocytes) in peripheral blood (PB) and bone marrow (BM) as follows: CMML‑0 if PB < 2% and BM < 5% blast equivalents; CMML‑1 if PB 2–4% or BM 5–9% blast equivalents; and CMML‑2 if PB 5–19% or BM 10–19% blast equivalents, and/or Auer rods are present [4]. CMML patients have a highly variable outcome, suggesting that several factors can determine the course of disease and the causes of death in these patients [5‐9]. There are a number of established prognostic parameters that have been incorporated into several prognostic models [10‐21]. The clinical significance of disturbed plasmatic coagulation in patients with CMML is poorly investigated. Prothrombin time (PT) is a widely used test of overall clotting function. Using the database of the Austrian Biodatabase for Chronic Myelomonocytic Leukemia (ABCMML), we analyzed 104 CMML patients with available information on PT values and other coagulation parameters [22]. This information from a real-life database could be useful in the management of these patients.

Abnormalities of plasmatic coagulation in CMML were described in 1979 in a few patients. In a series of 9 patients, 7 had abnormal coagulation values; in 2 cases, abnormalities were consistent with disseminated intravascular coagulation that correlated with hemorrhagic diathesis [25]. Cells of the human myelomonocytic line RC-2A synthesize tissue factor-like procoagulant and urokinase-type plasminogen activator [26]. Overall, the clinical significance of disturbed plasmatic coagulation abnormalities in patients with CMML is poorly investigated.

In this paper, we show that decreased PT values are an adverse prognostic parameter in CMML. This finding is new and has not been, to the best of our knowledge, reported by others. Interestingly, decreased PT values were not associated with significant bleeding tendency, including the incidence of major bleeding. It has to be noted, however, that the number of CMML patients with information regarding bleeding complications was low. By correlating PT values with laboratory parameters, we found higher leukocyte counts, a higher proportion of circulating blast cells, and lower platelet counts in CMML patients with decreased PT. Moreover, we found that the prognostic significance of PT values was lost in the presence of established prognostic factors such as leukocytosis, anemia, thrombocytopenia, and circulating blasts in multivariate analysis. Altogether, these results suggest that blood coagulation abnormalities in CMML patients may not be an independent prognostic factor but may be associated with more advanced disease. Since blood coagulation parameters are synthesized in the liver, one could speculate that blood coagulation abnormalities may be due to infiltration of the liver by CMML cells. Indeed, it has been shown that in a subgroup of patients with CMML, hepatomegaly can be demonstrated [27]. Moreover, we have seen a correlation of decreased PT values with increased liver parameters, and could demonstrate in single patients with detailed analysis of coagulation factors a reduction of coagulation factors excluding factor VIII, which is a characteristic pattern for impaired liver synthesis. There were 2 patients with subnormal fibrinogen levels and normal PT values. Although not analyzed, one can speculate that in these patients, increased production of urokinase-type plasminogen activator may have contributed to this finding, as was proposed in a previous study [26].

We are aware of the limitations of our study. For example, most of the information used in this study was derived from retrospective real-world data that were not collected systematically or prospectively. Thus, not every parameter was available in all patients. In addition, data from patient records were obtained over many years and from many different centers. Moreover, the patients included in this study represented a relatively heterogenous population regarding the blast cell counts. However, real-world data have recently been recognized as an important way to get insights into routine management and the natural history of rare diseases [28]. CMML is a rare disease, and adequate patient numbers for a systematic and prospective study are not easy to collect within a limited timeframe. Moreover, the ABCMML provides information derived from molecular as well as from functional studies, and therefore allows a more comprehensive view and deeper insight into the complex pathophysiology of this hematologic malignancy [22].