JAK2 Mutation and Additional Thrombophilic Markers Predispose to Thrombosis in Myeloproliferative Diseases with Thrombocythemia
Authors: Penka Miroslav , Schwarz Jiri , Doubek Michael , Dulicek Petr , Indrak Karel , Brychtova Yvona , Hlusí Antonin , Kissova Jarmila , Mayer Jiri , Pavlik Tomas 
Published: April 2020

Abstract
OBJECTIVES: Bleeding and thrombotic events are common complications symptoms in myeloproliferative diseases with thrombocythemia (MPD-T). The increased platelet count need not be the only cause of them. In the current study we have evaluated prospectively collected data of 421 Czech patients from an international registry of patients treated with anagrelide (ANG) with the aim to check whether JAK2 V617F mutation or additional thrombophilic states predispose to thrombosis in MPD-T.
PATIENTS: The initial diagnoses (recorded largely according to PVSG criteria) were the following: essential thrombocythemia – 333 (79.1 %), idiopathic myelofibrosis – 40 (9.5%), polycythemia vera – 35 (8.4 %) and chronic myeloid leukemia – 8 (1.9%). The age at diagnosis and at database entry has rankged between 40 – 60 years in more than 50% of patients (mean: 51.0 years). The male/female ratio was 37.5: 62.5%. A large proportion of patients (77.7%) had been already pretreated with thromboreducing drugs: overall, 55 patients had received ANG, 84 had had interferon-alpha, 208 had been treated with hydroxyurea and 59 patients had received another drug. More than one line of previous thromboreductive therapy was recorded in 155 (36.8%) patients. Following registration, 18.0% was receiving another thromboreducing drug in addition to ANG. The median platelet value was 1015 G/l at diagnosis, and 658 G/l (range 140–3325) at database entry. The treatment goal was achieving 600/400 G/l platelets in low-/high-risk patients. High-risk patients had either previous thrombosis, an additional thrombophilic state (mostly inherited; “thrombophilia+”), or JAK2 gene V617F mutation.
RESULTS: Pretreated and unpretreated patients responded to ANG equally well. High-risk patients had lower platelet counts at 3–6–9–12–36 months – 488–400–387–376–323 G/l (n=118) than good-risk ones – 523–441–384–423–455 G/l (n=98) at the given above time points. The mean ANG dose at 3 months was only 1.8 mg/day (median, 1.5 mg/d), whereas onwards, the mean dose was quite stable within 2.2–2.3 mg/day interval (median, 2.0 mg/d). At the time of database entry, 75 (17.8%) patients had a history of a thrombotic event, and 35 (8.3%) had had hemorrhage. During the follow-up after entering the registry, only 11 (3.5%) patients had thrombosis (6 had a major and 5 a minor one). Likewise, there have been very few patients with a bleeding event reported: 2 patients experienced a major and 4 patients a minor event (altogether 1.9% of patients). 282 patients had the JAK2 mutation evaluated. Half of them (51.4% patients) carried the mutation (hetero-/homozygous). Of the 145 patients with the mutation, 40 (27.6%) had thrombosis (before or after registration). Thrombosis was significantly more rare in 137 patients without the mutation, in 11 cases only (8.0%; P = 0.017, Fisher’s test, CI 95%). Of 78 evaluable patients with thrombosis, 20 (25.6%) were thrombophilia+, whereas of 343 patients without thrombosis, a thrombophilia+ state was demonstrated only in 48 cases (14.0%; P = 0.016).
CONCLUSIONS: Our analysis has shown that high-risk MPD-T patients treated with ANG do not achieve the desired level of thromboreduction quite late: after 3–6 months of ANG treatment. However, during ANG treatment, relatively very few hemorrhagic or thrombotic complications were observed. The results confirmed in a large patient cohort that JAK2 mutation or additional thrombophilic states are major risk factors of thrombosis in MPD-T.