This study was done to investigate the abnormalities of vWF related parameters in aggressive haematological malignancies.
The elevated plasma vWF:Ag and activity as well as lowered plasma ADAMTS13 protein level seen in this study were in keeping to similar changes reported in earlier studies on solid tumors. (3-4) Oleksowicz showed that the level of plasma ADAMTS13 protease to be significantly lower in disseminated tumors compared to localized disease. Mean plasma FVIII:C, vWF:Ag and vWF:Rcof were all significantly elevated in patients with advanced stage solid tumors but not in localized disease when compared to normal patients.3 In a separate rather similar study involving Persian population, patients with both disseminated and localized tumors had significantly higher plasma vWF:Ag and lower ADAMTS13 protein compared to normal controls. The ADAMTS13 protein was shown to inversely correlated with vWF:Ag level (r=-0.4).4 It is possible that increased consumption of ADAMTS13 as demonstrated by high vWF antigen and activities in these cases have resulted in low ADAMTS13 protein.
We made use of manufacturer’s reference normal values and grouped the subjects into two groups; acute leukaemias or lymphoma to gain reasonable numbers for comparative analysis. Plasma cell leukaemia is not an acute leukaemia but was arbitrarily grouped together due to it’s dispersive and clinically aggressive nature. The leukaemias are naturally more disseminated compared to lymphomas and are expected based on previous results to have higher vWF:Ag, vWF activity, and vWF:CBA. On the contrary the result of this study was the exact reversed. The lymphomas showed significantly higher level of vWF activities compared to the leukaemias. Similar to the previous study we also demonstrated reduced ADAMTS13 protein level with 76.7% of all subjects having levels below the reference range. However the protease levels were not significantly different between the two groups.Unlike the previous study, there was no correlation between ADAMTS13 protein levels with vWF-related parameters.
The relatively higher vWF-related parameter levels among lymphomas compared to acute leukaemias provide a possible explanation to a marginal higher rate of venous thromboembolism seen among lymphomas compared to the latter (local data not included). It is difficult to compare the various rates derived from different population and different diagnostic criteria. Epidemiological data from the Californian Cancer Registry showed that the 2-years cumulative rates for venous thromboembolism (deep vein thrombosis or pulmonary embolism) was 3.6, 3.7 and 4.7 in acute myeloid leukaemia, acute lymphoblastic leukaemia and aggressive lymphomas respectively.7, 8
Measures were taken to remove patients with sepsis from this study sample yet the depicted vWF-related parameters have similar profile to those shown during severe sepsis (elevated plasma vWF antigen, activity, vWF:CBA and reduced plasma ADAMTS13 protein) suggesting possible sharing of pathophysiological mechanism between neoplasm and inflammation.9 In addition to lowered ADAMTS13 synthesis in the liver, it was shown that sepsis lead to increase ADAMTS13 catabolic digestion by various cleaving protease among them, such as granulocyte elastase.5
In TTP, acquired anti-ADAMTS13 antibodies contribute to low ADAMTS13 protease. These antibodies has since also been identified in other diseases i.e sepsis, inflammatory diseases etc. We showed that there was a high prevalence with almost two third of patients with acute leukaemias and agressive lymphomas having detectable IgG anti-ADAMTS13 antibodies. However these detected IgG antibodies do not appear to contribute in lowering plasma ADAMTS13 protein level or affecting the vWF:CBA. None of the subjects were found to have clinical features of TTP in this study. There are several possibilities to explain these findings. We did not assess the sensitivity of the reagents and perform local validation studies. It is also possible that these are non-inhibitory antibodies targeting on less significant domains. Autoantibodies derived from plasma of patients with clinical TTP are most commonly directed against the cystein-rich spacer (cys-rich/spacer) domain of ADAMTS13. Activities against various other domains have also been registered at lesser frequencies.10 In a study evaluating patients with immunopathology other than TTP, low titers of IgG anti-ADAMTS13 antibodies (measured using ELISA assay) were found in 3.6% ,13% and 5% of healthy donors, patients with systemic lupus erythromatosis and antiphospholipid syndrome respectively. The ELISA technique was found to have more sensitive detection compared to the ADAMTS13 neutralizing inhibitor technique. In that study too there was no correlation between antibody levels and plasma ADAMTS13 protease activity.6
Presence of anti-ADAMTS13 IgG antibodies was common among the aggressive types of hematological malignancies (76.7%). The presence of these antibodies among AML patients was an unexpected finding. Though the presence of autoantibodies is rather explainable in lymphoid malignancies, in AML the mechanism of its development requires further exploration. The persistence positivity of auto IgG is more important to exclude false positive results due to transient circulating antibodies of unknown clinical significance. The titre level may also indicate the clinical significance of the antibody thus requiring further confirmation.
In the recent guideline on diagnosing TTP cases11, severely reduced ADAMTS13 activity < 5% ± the presence of an inhibitor or IgG antibodies, confirms the diagnosis. However none of the cases in this study had typical clinical manifestation of TTP.
It would have been beneficial if this study also looked into vWF multimeric composition analysis and ADAMTS13 activities rather just the protein. Increased proteolysis of ADAMTS13 was associated with reduced high molecular weight vWF multimers. vWF multimer analysis may further characterise the vWF changes in aggressive haematological malignancies. In future, anti-ADAMTS13 antibodies detection should be combined with neutralizing technique to confirm their functional effect, as this test is more specific.