Most thrombotic events in ALL occur initially during induction phase of treatment due to intense treatment especially during the use of asparaginase in combination with corticosteroids5.
Surprisingly, our patients had thrombotic event in the form of left sigmoid and transverse sinus thrombosis before the diagnosis of ALL as evidenced by normal BM at 1st admission. Of interest, De Stefano et al, reported that increased thromboembolic events can take place even prior to the diagnosis of acute leukemia, similar to the situation seen in solid tumors, indicating that a prothrombotic state is present even at the earliest phase of leukemia 6. In our patient, it might be an aplastic phase of leukemia was there at 1st admission that is why the BM didn’t show blast cells.
During infection, inflammatory cells, and mediators, can induce the expression of tissue factor on monocytes and endothelial cell surfaces which is a major activator of coagulation, this can lead to widespread intravascular fibrin deposition7.
Also, enhanced fibrin formation is caused by tissue factor-mediated thrombin generation. In addition to depression of inhibitory mechanisms, such as the protein C and S system and impairment of endogenous thrombolysis secondary to high circulating levels of Plasminogen activator inhibitor 1.
Taken together, a state of imbalance between procoagulant and anticoagulant occur during infection that might overwhelm the balance of hemostasis and result in microthrombi8.
Our patient developed thromboembolic manifestations in absence of infectious causes.
In view of this thrombotic event the child developed, thrombophilia gene mutations were done, and the child was positive for MTHFR A1298C at homozygous state and factor V Leiden mutation at heterozygous state.
To date, several studies have attempted to correlate the association of genetic variants of inheredit thrombophilia and the risk of childhood ALL but has yielded discordant reports.
Kałużna et al,9 studied the relation between inheritance of MTHFR C677T and A1298C polymorphisms, and risk of ALL development in a population under 18 years of age of Caucasian ancestry. They reported that The MTHFR 677T allele alone or in combination with the MTHFR 1298C allele significantly increases the risk of development of ALL (two-folds compared to control).
Also, Roy Moulik et al,10 examined this association in north Indian children with ALL and they found that Polymorphisms in the MTHFR gene possibly modulate risk of ALL in north Indian adults but not in children.
Tripathi et al,4 reported a case of 14-year-old boy with ALL who had MTHFR mutation presented with recurrent venous thrombosis in the absence of asparaginase therapy.
However, some studies reported no influence of presence of genetic mutation for hereditary thrombophilia and risk of ALL development. Atashrazm et al11, reported in their studies in pediatric ALL patients that the MTHFR C677T and A1298C gene variants lack a major influence on the susceptibility for pediatric ALL. Also, Sazawal et al12 reported no statistically significant difference was evident between MTHFR C677T and A1298C Polymorphism and susceptibility to ALL in children.
Moreover, Bahari et al,13 documented that MTHFR rs1801131 (A1298C) heterozygous genotype decreased the risk of ALL in comparison with AA homozygous genotype (OR=0.43, 95%CI=0.21-0.90, p=0.037).
We represent a child with acute lymphoblastic leukemia who presented initially with CSVT that can be due to a prothrombotic phase of acute leukemia in addition to the presence of underlying genetic base of inherited thrombophilia as an incriminated factor.
The question to be answered is can we rely on whether hereditary thrombophilia is a genetic risk factor for acute leukemia in our case, or it is just a concomitant association. There is still a need for further studies on different ethnicities about the biological role of these genetic variants in ALL patients and their parents to determine their influence on the patho-mechanisms of ALL development.