Clujul Medical - Iuliu Haţieganu

Clujul Medical 2006 vol. LXXX - nr. 1
x 10 9 /l, and the microscopic investigation emphasized the increase of megakaryoblasts
and micromegakaryocytes in the peripheral blood.
At the family’s request the patient was discharged and died at home, so that
necroptic investigations could not be performed.
Evidence was recently provided about pathogenic factors and mechanisms
relating megakaryoblastic leukemia to myelofibrosis. Actually the expression of the
platelet derived growth factor (PDGF) and of the transforming growth factor beta 1
(TGFβ1), which are both known to be involved in organ fibrosis, was found to be
increased in blast cells of patients with transient myeloprolipherative disorder and acute
megakaryoblastic leukemia (5,6). Noteworthy such growth factors may also be
inappropriately released from monocytes (7).
Another presumptive mechanism involved in organ fibrosis could be
represented by an increased expression and activity of the intracellular factor XIII
subunit A, a transglutaminase mediating crosslinking of fibrin polymers and of
extracellular matrix proteins. Evidence was provided that F XIII subunit A is a reliable
marker for acute myelomonocytic and megakaryoblastic leukemia (8), two pathologic
conditions involved in the development of myelofibrosis (1,2,4). It is also known that by
acting on extracellular matrix proteins such as fibronectin, vitronectin and collagen,
FXIII subunit A contributes to wound healing and tissue repair (9). Interestingly,
immunohistochemical investigations emphasized FXIIIA positivity in pulmonary
fibrotic tissues, suggesting that this transglutaminase might have an important role in
the development of organ fibrosis (10). It is worth mentioning that the activation
mechanisms of FXIIIA subunit differ from those involved in the activation of
circulating plasma factor XIII, in which the enzymatically active subunit A is assembled
and stabilized by the liver secreted subunit B. Therefore plasma factor XIII A2B2
zymogen becomes activated only by a thrombin-mediated limited proteolysis, this
activation being accelerated by the presence of polymerized uncrosslinked fibrin and of
calcium ions, while activation of cellular FXIII subunit A may undergo a slow
spontaneous activation, which does not require fibrin polymers for its acceleration and
occurs at lower concentration of Ca 2+ (11). In other words, the activation of FXIIIA
subunit is regulated to a much lesser extent than plasma FXIII A2 B2 zymogen (11, 12).
When not removed by fibrinolysis, persistent fibrin depositions are penetrated
by fibroblasts and submitted to fibrous transformation. By catalysing the incorporation
of α2 antiplasmin into the fibrin network, fibrin stabilizing factor XIII would limit
fibrinolysis, thereby facilitating the persistence of fibrin depositions (13).
The interrelations between factor XIII, reduced fibrinolysis and fibrosis are
further promoted by the intervention of a fibroblast activation protein acting as an
antiplasmin cleaving enzyme (APCE). It was demonstrated that by enzymatic cleaving
of Methionin α2 antiplasmin (Met-α2AP), the resulting asparagine α2antiplasmin
(Asnα2AP) becomes crosslink to fibrin about 13 times faster than Met-α2AP.
Subsequently, the clot lysis rates are delayed and the progression of fibrosis is promoted
(14).
The above mentioned comments demonstrate that a thorough study of acute
myelofibrosis may contribute to the elucidation of the pathogenic mechanisms involved
in the fibrosis of other organs.
References
1. LEWIS SM, SZUR L: Malignant myelofibrosis. BrMed J 1963; 2: 472-476.
2. ALLEGRA SR, BRODERICK PA: Acute aleukemic megakariocytic leukemia. Am
J Clin Pathol 1971; 55: 197-204.
3. LINMAN JW: Hematology. Physiologic, Pathophysiologic and clinical principles.
McMillan Co Inc New York 1975, p 627.
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