Anemia, thrombosis and adaptive therapy
In this entity, the risk of thrombosis is similar to ET where overall
survival is impacted by presence of SF3B1 but not JAK2mutations and/or prior history of thrombosis 16. The
mechanism of increased thrombotic predisposition is not clear and
requires further studies. However similar to ET a relative loss of
endothelium derived relaxing factor (EDRF or nitric oxide) by platelet
uptake may be involved. The result is vasomotor symptoms such as
migraines, palpitation, erythromelalgia along with vascular stasis with
arterial and venous thrombosis17,18 . At an extremely
high platelet counts (>1000 x 109/L) a
therapeutic quandary may exist where some patients can develop an
acquired von Willebrand’s disease and hemorrhage. This is presumably
also due to abnormal platelet uptake and factor destruction. In absence
of a high platelet count and increased risk of bleeding, low dose
aspirin may be beneficial in treating arterial thromboses along with a
significant decrease in vasomotor symptoms . In the setting of a
contraindication to aspirin, other antiplatelet agents (clopidogrel,
prasugrel, ticagrelor etc.) work similarly 19-21.
Proper evaluation for acquired von Willebrand’ s includes measuring von
Willebrand antigen, ristocetin cofactor activity and multimers
analysis22 . With concomitant anemia the use of
cytoreductive therapy is nuanced and may exacerbate the existing anemia.
Consequently, its use must be justified against a significant increase
in risk of thrombosis. Specifically, if cytoreductive therapy is
indicated, hydroxyurea or second line agents such as, lenalidomide,
interferon alpha or busulfan have been used and are effective against
acquired Von Willebrand with improvement in bleeding symptoms23,24. The management of anemia is similar to
treatment of lower risk MDS and includes transfusion support and the use
of erythropoietin stimulating agents (ESA) 25,26 . In
normal erythropoiesis, the binding of TFG beta superfamily ligand to
activin receptor type IIB causes phosphorylation of downstream SMAD 2/3
with overall inhibition of erythroid maturation and cellular
regeneration. Luspatercept, is a recently FDA approved fusion protein
partly made up of modified extracellular domain of activin receptor type
IIB and human IgG1 Fc domain. This molecule can effectively trap the TGF
beta superfamily ligand making it unavailable for signal transduction.
The end effect is promotion of erythroid maturation and effective
erythropoiesis 27. Reserved for refractory or
progressive cases, and confounded by graft versus host disease and
non-relapse mortality, allogeneic stem cell transplantation is the only
curative therapy 28.