Familial thrombocythemia: A case report of three Arab siblings with MPL gene mutation p. Pro106Leu and abnormal platelet aggregation studies

Document Type



Paediatrics and Child Health


Background: Familial thrombocythemia is a rare chronic myeloproliferative disorder caused by molecular alterations in the thrombopoietin gene (THPO) or in the gene for the thrombopoietin receptor (MPL). Activating mutations in THPO induces megakaryocytopoiesis due to increased thrombopoietin (TPO) production.
Three germ line mutations in MPL causing thrombocytosis have been described;
1. p.Ser505Asn-associated with autosomal-dominant thrombocytosis.
2. p.Lys39Asn-a functional polymorphism found restricted to African Americans.
3. p.Pro106Leu-frequently found in Arabs
The mutation p.Pro106Leu is thought to be inherited in an autosomal recessive manner. It involves extracellular domain of MPL gene affecting its binding ability to TPO thus reducing its clearance and inducing thrombocytosis.
Objectives: To highlight clinical features and management of patients with MPL Pro106Leu mutations.
Design/Method: Case report and literature review.
Results: Three of five siblings (ages 14, 10, 2 yrs) from a consanguineous Middle Eastern family were evaluated for persistent high platelet count (705,000–991,000/microlitre). Older two siblings had history of epistaxis, easy bruisability and prolonged bleeding with minor surgical procedures such as dental extractions and polypectomies. No thrombotic events were noted. Extensive work up for thrombocytosis was negative except for sequencing of MPL gene which revealed homozygosity for p.Pro106Leu (c.317C > T) mutation in all three patients. Both parents and the two other siblings (brother and sister) were found to be heterozygous carriers and had normal platelet counts. Global platelet aggregation abnormalities were present in all siblings (with high dose ADP, arachidonate, low dose collagen, epinephrine). The eldest sibling underwent dental extraction and good hemostasis was achieved with desmopressin (DDAVP). Prior to the procedure he underwent a DDAVP trial which showed a partial correction of the platelet aggregation studies.
Conclusion: Our cases highlight the importance of considering MPL mutations in patients of Arab descent presenting with thrombocytosis and abnormal platelet aggregation studies given the high rate of consanguinity and carrier rate of 6%. Patients with the MPL Pro106Leu mutations have a predisposition for bleeding diathesis rather than thrombotic events and identification of this mutation may help in clinical management. Larger ethnic specific trials may be needed to understand the pathophysiology of platelet dysfunction associated with this mutation.


This work was published before the author joined Aga Khan University.

Publication (Name of Journal)

Pediatric Blood & Cancer