High Platelet Counts, Thrombosis, Bleeding Signs, and Acquired Von Willebrand Syndrome at Diagnosis of Pediatric Chronic Myeloid Leukemia

Background: At diagnosis of chronic myeloid leukemia (CML) patients (pats) may present with elevated platelets (PLT) counts. Generally, high PLT counts may result in thrombosis and/or bleeding complications, the latter being due to binding of von Willebrand factor (VWF) multimers to platelets. Pediatric CML is very rare (Hijiya N, Suttorp M 2019; Blood 33:2374-2384) and no systematic investigation on clinical complications of elevated PLT counts has so far been reported.

Methods: Data on PLT counts and associated thrombo-hemorrhagic complications were retrospectively analyzed in newly diagnosed pediatric pats (0 - 18 yrs old) with CML in chronic phase. Data were pooled from a German pediatric trial (CML-paed II, N= 146 pats; registered as NCT00445822, [Suttorp M, et al. 2018; Leukemia 32:1657-1669], data collection closed Dec 2016) and the International registry for CML in children and adolescents (I-CML- Ped Study, N= 475 pats, registered as NCT01281735, [Millot F, et al. 2017; Haematologica 102:1704-1708], data collection closed June 2019).

Results: A total of 621 pediatric pats with CML in chronic phase could be analyzed. At diagnosis 343/621 (55.2%) pats (median age 13.2 yrs, range 1.3 - 18 yrs) presented with thrombocytosis (>500 000 PLT/µl). PLT ranged from 500 000 - 1 000 000 PLT/µl in 239/621 (38.5%) pats while extremely high PLT counts (>1 000 000 PLT /µl) were present in 94/621 (11.2%) pats. Thrombosis was observed in 2/621 (0.3%) pats including priapism occurring at 655 000 PLT/µl and lower leg venous thrombosis at 1 820 000 PLT/µl. Bleeding signs (bruises, mucosal hemorrhage) being of mild nature (grade 1, grade 2, National Cancer Institute Common Terminology Criteria v3.0) only were described in 38/343 (11.1%) pats with thrombocytosis (>500 000 PLT/µl). Bleeding occurred without correlation to elevated PLT counts but was associated in selected cases investigated with a reduced plasma concentration of large VWF multimers pointing to the diagnosis of acquired von Willebrand syndrome (AVWS). AVWS resolved after initiation of CML treatment with imatinib.

Discussion: In newly diagnosed pediatric pats with CML, pathologically high PLT counts (>500 000 PLT/µL) were detected in >50% of the cohort and extremely high platelet counts in >10%. However, associated thrombo-hemorrhagic complications were rare events affecting less than 10% (40/621= 6.4%) of the pats. Especially thrombosis was a rare (0.3%) complication whereas mild bleeding symptoms formed the majority of hemostaseological complications observed.

Compared to recently published findings in adults (Sora F, et al. 2018; Br J Haematol 181:267-270, N= 1591 pats; Sandal R, et al. 2019; J Clin Oncol (Suppl) abstract #e18546, N= 2350 pats; Liu Z, et al. 2017; Onco Target Ther 10:3515-3520, N= 87 pats) the proportions of adult pats with extremely high platelet counts (Sora F: 5,5%, Sandal R: not listed; Liu Z: 25.3%) is in the same range (5% - 25%) as in pediatric patients (11.2%). Surprisingly, thrombo-hemorrhagic complications were observed more frequently in children (40/621= 6.4%) than in adults (Sora F: 9/1591= 0.5%, Liu Z: 1/85= 0.1%; Sandal R: 66/2350= 2.8%). As a word of caution this comparative analysis is weakened by its retrospective nature and a non-standardized reporting of bleeding signs.

Mild bleeding signs in pats with high PLT counts can be caused by an acquired low plasma concentration of large VWF multimers as could be demonstrated in selected pediatric pats from this cohort. Systematic investigations on AVWS in children with CML have not been published so far and AVWS may be underdiagnosed in pediatric CML.