The Anatomy of Recurrent Thrombosis and Its Risk Factors in Myeloproliferative Neoplasms

Background:

The main objective of current treatment in both essential thrombocythemia (ET) and polycythemia vera (PV) is to prevent thrombotic complications, specifically in high-risk patients. The most reliable predictor for such complications is a similar previous event. The current study considered the central importance of thrombosis history in predicting future events in ET and PV and, therefore, focused only on patients presenting with a history of thrombosis; the objective was to identify additional risk factors and assess the impact of anti-thrombosis treatment documented at the time of diagnosis.

Methods:

Study patients were selected from our institutional database of MPN, based on documentation of thrombosis history at or before the time of diagnosis, made according to WHO criteria (Arber et al. Blood 2016;127:2391). Statistical analyses considered clinical and laboratory data collected at the time of diagnosis. Thrombosis-free survival (TFS) was calculated both by considering all vascular events (arterial + venous) as well as by separately analyzing arterial vs venous TFS.

Results:

i) Presenting features:

A total of 290 patients with ET (n=175) or PV (n=115) presented with history of thrombosis, either "at" (n=146; 50%) or "before" (n=194; 67%) the time of diagnosis. The respective arterial vs venous distribution of events was 35% vs 15% "at" and 49% vs 21% "before" the time of diagnosis. When ET and PV were analyzed separately, the respective incidences of thrombosis history (arterial + venous) were 19% vs. 25% (p=0.02) "at" and 64% vs 71% (p=0.19) "before" the time of diagnosis; the respective figures for arterial thrombosis were 44% vs 21% (p=0.0002) "at" and 50% vs 44% (p=0.75) "before" time of diagnosis and for venous thrombosis 12% vs 18% (p=0.13) "at" and 18% vs 23% (p=0.12) "before" time of diagnosis.

ii) Treatment documented at time of diagnosis:

Treatment at time of diagnosis was documented in 95% of the patients and included cytoreductive therapy in 82%, anti-platelet therapy in 61% and systemic anticoagulation in 26%, with no significant difference between ET and PV; the most frequent combination therapies were cytoreductive + anti-platelet therapy (42%), cytoreductive therapy alone (19%) and cytoreductive + systemic anticoagulation (13%); 9% of the patients received combination of all three treatment modalities.

iii) Post-diagnosis events:

Median follow-up was 9 years and was longer for ET (10 years) compared to PV (7 years; p=0.002); during this period, 146 (50%) deaths, 10 (3%) leukemic transformations, 17 (6%) fibrotic progressions, and 86 (30%) thrombotic events were recorded. Among the latter, 72 (25%) were arterial and 22 (8%) were venous. The incidence of post-diagnosis arterial (p=0.2) or venous (p=0.9) events was not significantly different between ET and PV.

iv) Risk factors for thrombosis-free survival (including both arterial and venous):

In univariate analysis, significant risk factors for arterial + venous TFS included male sex (HR 1.9; 95% CI 1.3-3.0), diabetes history (HR 1.8, 95% CI 1.01-3.2) and use of coumarins (HR 1.7, 95% CI 1.1-2.7). During multivariable analysis, male sex and use of coumarins remained significant.

v) Risk factors for arterial vs venous thrombosis-free survival:

In univariate analysis, significant risk factors for arterial TFS included older age, male sex and history of arterial thrombosis; male sex (HR 1.7, 95% CI 1.1-2.7) and arterial thrombosis history (HR 2.6, 95% CI 1.3-5.3) remained significant during multivariable analysis. Significant risk factors for venous TFS included history of venous thrombosis (HR 4.9, 95% CI 1.9-12.3) and use of coumarins (HR 5.3, 95% CI 2.2-12.9); both remained significant during multivariable analysis.

Conclusions:

The significant association between thrombosis history and future vascular events in patients with ET or PV is major vessel-specific in its distribution (i.e. arterial vs venous) and the current study identifies male sex and use of coumarins as additional independent risk factors for arterial and venous events, respectively. The unexpected association between coumarin use and recurrent venous thrombosis might be related to a higher underlying risk in the patients chosen to receive such therapy or detrimental drug effect; prospective studies are needed for further clarification.