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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 45  |  Issue : 1  |  Page : 40-47

Value of assessment of factor XI in patients with myeloproliferative neoplasms with and without thrombotic events


1 Departments of Internal Medicine, Ain Shams University, Cairo, Egypt
2 Departments of Clinical Pathology, Ain Shams University, Cairo, Egypt

Date of Submission26-Oct-2019
Date of Acceptance05-Dec-2019
Date of Web Publication10-Sep-2020

Correspondence Address:
Emad A Abdelhady
10 Ahmed Saman Street, from Makram Ebeid Street, Nasr City Cairo, 1199, Egypt
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejh.ejh_46_19

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  Abstract 


Background Although high levels of factor XI and contact factors have been implicated as a risk factor for deep venous thrombosis and possibly cardiovascular disease in some cancers like prostatic cancer, the relationship between elevated factor XI activity and thrombosis in myeloproliferative neoplasm (MPN) is not established yet.
Aim The aim was to study the possible relation between factor XI in patients with MPNs with and without thrombotic events in comparison with normal controls and the possible effect of its altered level to occurrence of such events.
Patients and methods This is a cross-sectional study conducted in Ain Shams University Hospitals and included 50 patients with MPN. Patients were investigated to assess the relation between level of factor XI and thrombus formation.
Results There was no statistically significant difference between the level of factor XI and thrombotic incidence in patients with MPN.
Conclusion This study focusing on the contribution of factor XI to the thrombotic risk in patients with MPN showed that there was no link between the high levels of factor XI and the thrombotic risk in patients with MPN.

Keywords: factor XI, myeloproliferative, thrombotic


How to cite this article:
Hamed H, Abdelhady EA, Elrazzaz MK, Abdelfatah RG, Hamza MT. Value of assessment of factor XI in patients with myeloproliferative neoplasms with and without thrombotic events. Egypt J Haematol 2020;45:40-7

How to cite this URL:
Hamed H, Abdelhady EA, Elrazzaz MK, Abdelfatah RG, Hamza MT. Value of assessment of factor XI in patients with myeloproliferative neoplasms with and without thrombotic events. Egypt J Haematol [serial online] 2020 [cited 2020 Oct 22];45:40-7. Available from: http://www.ehj.eg.net/text.asp?2020/45/1/40/294784




  Introduction Top


Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are known as Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) [1]. Their diagnosis and management have evolved since the identification of mutations that activate JAK pathway (JAK2, CALR, and MPL mutations) [2].

The most frequent driver mutation is JAK2V617F, found in ∼99% of patients with PV, 55% ET, and 65% PMF. Other driver mutation distributions in ET and PMF are similar with 30% being CALR mutated, and 8% being MPL mutated, whereas 20% of patients might not express any one of the three mutations (i.e. are triple negative) [3].

MPNs are associated with increased risk of thromboembolic events, which is the leading cause of morbidity and mortality [4]. Clinical factors (old age, thrombotic events history, obesity, hypertension, and hyperlipidemia), increase in blood cell counts, CV risk factors, and presence of JAK2V617F contribute to increased risk of venous or arterial or capillary thrombosis in MPN [5],[6].

Factor XI (F-XI) is zymogen of a plasma protease, factor XIa (F-XIa), that contributes to thrombin generation by proteolytic activation of several coagulation factors, most notably, F-IX. F-XI is a homolog of prekallikrein (PK), a component of the plasma kallikrein-kinin system. While sharing structural and functional features with PK, F-XI has undergone adaptive changes that allow it to contribute to blood coagulation [7]. Studies with animal models suggest that activation of F-XI by F-XIIa promotes pathological thrombus formation [8]. F-XII and F-XI have emerged as promising targets, whose inhibition can prevent thrombosis, with no hemostasis disruption [9].


  Aim Top


The aim was to study the possible relation between F-XI in patients with MPN with and without thrombotic events in comparison with normal controls and the possible effect of its altered level to occurrence of such events.


  Patients and methods Top


This is a cross-sectional study conducted in the Hematology Department of Ain Shams University Hospitals, during the period between May 2015 and December 2017. It was conducted in accordance with ethical standards of the Ethical Committee of Faculty of Medicine, Ain Shams University. Informed consent was obtained from all individual participants included in the study.

The study included 50 adult subjects divided into three groups: group A included 22 Philadelphia-negative patients with MPN with thrombotic manifestations. Group B included 18 Philadelphia-negative patients with MPN without thrombotic manifestations. Group C included 10 healthy control subjects matched with patients in age and sex.

All patients were subjected to full history taking and thorough clinical examination, laboratory investigations (including complete blood count, with differential count, and metabolic profile, including liver and kidney function tests), FISH (for BCR/ABL fusion gene), PCR for JAK 2 mutation, bone marrow aspiration and trephine biopsy when indicated, F-XI contact factor assessment by ELISA, as well as imaging studies to confirm presence of thrombotic events according to suspected sites.

Statistical analysis

Data were analyzed using Statistical Program for the Social Sciences version 20.0. Quantitative data were expressed as mean±SD. Qualitative data were expressed as frequency and percentage.

The following tests were done: independent-samples t-test of significance was used when comparing between two means. χ2 test of significance was used to compare proportions between two qualitative parameters. Pearson’s correlation coefficient (r) test was used for correlating data. Receiver operating characteristic curve analysis was used to find out the overall predictivity of the parameters and to find out the best cutoff value with detection of sensitivity and specificity at this cutoff value.

P value less than or equal to 0.05 was considered significant, less than or equal to 0.001 as highly significant, and greater than 0.05 as insignificant.


  Results Top


The present study was conducted in the Hematology Department of Ain-Shams University Hospitals, during the period between May 2015 and December 2017. In our study, we reported the data of 40 patients with MPN (with and without thrombotic events) and a control group of 10 healthy age-matched persons. JAK2 mutation was detected by cytogenetic study in 18 patients, with a percentage of 45%, and negative in 22 patients, with a percentage of 55%.

Patients were investigated for F-XI activity level, which is between 70 and 150. Receiver operating characteristics curve was used to define the bestcut off value of F-XI which was greater than 93, with sensitivity of 45%, specificity of 86%, positive predictive value of 94%, and negative predictive value of 21%, with a diagnostic accuracy of 56% ([Figure 1]).
Figure 1 Receiver operating characteristics curve used to define best cutoff value of F-XI.

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Mean F-XI in patients was 108.74±35.55, with a range of 31.4–178, whereas the mean in control was 120.78±25.55, with a range of 94–155. There was a highly statistically significant difference between patient group and control regarding thrombosis incidence, whereas there was no statistically significant difference regarding F-XI ([Table 1]).
Table 1 Comparison between patients and control according to thrombus event incidence and level of factor XI

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There was no statistically significant difference between F-XI level on one hand and age of patient, type of MPN, thrombotic event, and JAK2 mutation presence on the other hand, but there was a highly statistically significant difference between F-XI level and HCV infection ([Table 2]).
Table 2 Relation between F-XI on one hand and demographic and laboratory data, hepatitis C virus infection, splenomegaly presence in sonar, JAK2, and thrombotic event incidence and type on the other hand

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There was a statistically significant difference between thrombosis event incidence and age of patients as well as presence of JAK 2 mutation, hemoglobin level, and MPN type, with highest incidence of thrombosis detected in patients with PV ([Table 3], [Figure 2]). All the three patients with ophthalmic vein thrombosis were found to have high level of factor XI, ranging between 95 and 150, with a mean of 125.67–28.04 ([Table 4]).
Table 3 Relation between thrombosis event incidence on one hand to demographic, laboratory data, VM, splenomegaly, and JAK-2 mutation presence on the other hand

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Figure 2 Incidence of thrombosis in a relation to the type of myeloproliferative neoplasm.

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Table 4 Relation between type of thrombosis, JAK 2 mutation, and mean level of F-XI

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A scatter plot between F-XI and RBCs showed a positive statistically significant difference between high F-XI level and increase red blood cells count, with P value 0.043 ([Table 5], [Figure 3]).
Table 5 Correlation between factor XI and all parameters, using Pearson’s correlation coefficient in the patient group

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Figure 3 Scatter plot between factor WXI and red blood cells shows a positive statistical significant difference between high level of factor XI and increase count of red blood cell.

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  Discussion Top


In patients with MPNs, thrombotic/thromboembolic and hemorrhagic events are the major determinants of morbidity and mortality. Hence, prediction of such events is essential for proper risk stratification of those diseases [10].

F-XI is the zymogen of a plasma protease F-XIa that contributes to thrombin generation during blood coagulation by proteolytic activation of several coagulation factors, most notably F-IX. F-XI is a homolog of PK, a component of the plasma kallikrein-kinin system. While sharing structural and functional features with PK, F-XI has undergone adaptive changes that allow it to contribute to blood coagulation [7].

Clinical trials and epidemiologic data indicate that F-XI is a key contributor to thromboembolic diseases. Studies with animal models also suggest that the activation of F-XI by F-XIIa promotes pathological thrombus formation [8]. With evidence that contact system is important for thrombus stabilization and growth, F-XI and F-XII have emerged as promising targets for new anticoagulants that may prove to be safer than those that inhibit F-Xa or thrombin [11].

Many studies have reported that elevated levels of F-XI are frequently detectable in patients with thrombosis, especially with malignant tumors, but no studies have tested the clinical relevance of increased F-XI levels in MPN. In our cross-sectional study, we tested the hypothesis that plasma levels of F-XI can be a biomarker of thrombosis risk in patients with MPN.

In the current study, we reported the data of 40 patients with MPN. Their mean age was 50.18±12.81 years, which was aligned with most of MPN studies, such as Barbui et al. [12] and Kaifie et al. [13], which goes with the evident epidemiological statistics of MPN that this group of diseases is common in middle and advanced age adults.

The patient group included 21 patients with ET, 11 patients with PV, and eight patients with MF, with percentages of 52.5, 27.5, and 20%, respectively. This was different from other MPN studies, such as Kaifie et al. [13], in which PV was the most common diagnosis followed by ET and MF, with a ratio of 40, 32, and 28%, respectively. This dominance in the distribution of ET could be owing to the benign entity of ET in terms of survival, progression to MF and transformation to blastic phase, which leads to its prevalence among the patients in our institute, or owing to the random selection of the patients in our study.

HCV was positive in five of our patients, with percentage of 12.5%, which could be related to the endemic nature of the disease in Egypt in comparison with western countries. Splenomegaly was reported in 37 (92.5%) patients, including whose spleen was palpable at less than or equal 5 cm below the costal margin and detected by pelviabdominal ultrasound. This finding was higher than the incidence of splenomegaly in different studies such as Andriani et al. [14] and Haider et al. [15], in which incidence of splenomegaly ranged from 5 to ∼20%. The difference might have been contributed by the difference in the inclusion criteria of patients in our Egyptian study (which included patients with three different MPN subtypes) in comparison with previous studies, which included only patients with ET. This might have led to higher incidence of splenomegaly.

JAK2 mutation was in seen 18 patients, with a percentage of 45%, which was relatively lower than other studies such as De Stefano et al. [16], in which percentage of JAK 2 mutation was 93%. This difference may be owing to many factors as weak power of the tests and the discrepancies between different laboratories in detecting the cytogenetic analysis of JAK 2 mutation in patients, and the possibility of the presence of other driving mutations such as MPL and CALR that may be existing in our patients.

Arterial and venous thrombotic events among the 40 patients with MPN studied were observed in 22 (55%) patients who experienced thrombotic events prediagnosis or following observational period. This result was higher than the incidence of thrombosis in other studies like [13],[17], in which thrombosis incidence was 33%. This discrepancy was because of the presence of patients at different stages of their disease at the time of inclusion.

The most frequent type of thrombotic event was portal and splenic vein thrombosis in eight (20%) patients, followed by six patients with cerebral infarction (14.5%) [five stroke and one transient ischemic attack (TIA)], then five patients with deep venous thrombosis (DVT) (12.5), then three patients with ophthalmic vein thrombosis (7.5%), and lastly, myocardial infarction, pulmonary embolism, and superior mesenteric artery occlusion. This was different from other studies, such as Kreher et al. [18] in which DVT was the most common form of thrombosis, as well as Zhang et al. [19] in which the most frequent type of thrombotic event was cerebral infarction (18.6%), followed by angina pectoris and myocardial infarction (6.8 and 5.1%, respectively). However, it agrees with De Stefano et al. [16] and Appelmann et al. [20] in which splenic thrombosis was in the percentages of 56 and 50%, respectively. Our findings supported that MPN thrombotic events have predilection to unusual sites like splenic venous thrombus and  Budd-Chiari syndrome More Details much more than in general population. This supported the evidence that JAK2 mutation added significant risk for venous thrombosis of unusual sites as proved by other studies such as De Stefano et al. [16].

Our data revealed that there was no statistically significant difference between F-XI level and thrombosis presence in patients with MPN, as it was noticed that among 22 patients with thrombosis, 15 of them had high F-XI level more than 93 and seven patients had low F-XI level less than 93, with P value of 0.499. This suggested that there was no role of high level of F-XI in thrombus formation in patients with MPN, but this result was against other studies, such as Puy et al., Gailani et al., Preis et al., and Weitz et al. [8],[11],[21],[22] and also contradicts other studies, such as Katrin et al. and Nickel et al. [23],[24], which discussed the role of contact factors in thrombosis in other malignancies like prostatic cancer. Our data are as well in contrast with other studies, such as Zhang et al. [19] which revealed the effect of other coagulation factors such as thrombin and other factors such as microparticles in thrombotic promotion in MPNs, suggesting that plasma level of microparticles and thrombin may represent a novel risk factor for thrombosis in MPNs. These discrepancies could be accounted for sample size, therapy, and the length of observation period.

A scatter plot between F-XI and RBCs showed a positive statistical significant difference between high F-XI level and increase red blood cells count, with P value 0.043. Together with the established fact of higher incidence of thrombosis in PV proved by Barbui et al. and Jeryczynski et al. [5],[25], this result denoted the importance of measuring F-XI level in patients with PV to predict any thrombotic incidence even without momentary thrombosis.

Notably, when studying the relation between F-XI level and viral markers of patients, it was noticed that a highly statistically significant difference was found between HCV infection incidence and low F-XI level, with P value 0.005, as it was noticed that 4 patients with HCV infection had lower level of F-XI in contrast to only 1 HCV-infected patient with normal level. These data are in agreement with the study of Huang et al. [26] which demonstrated that an acquired deficiency of F-XI was much more common and severe in patients with HCV and liver cirrhosis. This result suggested that low F-XI levels have a greater discriminatory value for liver damage and possibly for liver regeneration after successful treatment for hepatitis. It is therefore crucial to be aware of the need to measure and monitor F-XI levels in patients with hepatitis C, as F-XI replacement may need to be considered.

Furthermore, it is worth mentioning that there was a relation between MPN type and thrombosis occurrence, in which the highest percentage of thrombotic events was detected in patients with PV followed by those with ET (P=0.011). Moreover, there was a positive relation between thrombosis incidence and high hemoglobin level. These results were aligned with other studies [3],[5],[17],[25] that proved that patients with PV are at an augmented thrombotic risk owing to hyperviscosity associated with the high HCT.

Interestingly, it was noticed that there was no statistically significant difference between high platelet count and thrombosis incidence, which was aligned with Latagliata et al. [27] who showed that extreme thrombocytosis in ET did not, by itself, increase thrombosis risk and might actually be associated with a reduced risk of arterial thrombosis, but in contrast, high count is associated with bleeding diathesis.

A statistically significant difference was found between thrombosis incidence and JAK 2 mutation presence (P=0.048). This was in concordance with many studies, such as Baccouche et al. and Popov et al. [28],[29], which recommended the importance of detecting JAK 2 mutation in MPN diagnosis based on its strong effect and relation with thrombus formation.

Of note, the coexistence between high F-XI level (110.28±47.07) and JAK 2 mutation positivity with thrombosis in patients with MPN suggested the role of F-XI in the liability of patients to thrombosis. Hence, it would be interesting to measure F-XI level in this population in further studies.

Against most western studies, like De Stefano et al. and Michiels et al. [16],[30], which documented high incidence of thrombosis in old patients, it was noticed that thrombosis incidence was inversely proportionate to age of patients, with P value 0.027, as it was noticed that the higher incidence of thrombosis in our study was related to young age, with mean age of 46.18±11.99 years. On the contrary, this results was in concordance with other studies, such as Andriani et al. and Barbui et al. [14],[31] which suggested that ‘advanced age,’ by itself, was a weak risk factor for thrombosis.

Interestingly, our study showed no relation between splenomegaly presence and thrombosis incidence, which was in agreement with Haider et al. [15], which did not identify splenomegaly at diagnosis as a risk factor for thrombosis in ET, although it reported that patients with splenomegaly experienced thrombotic complications earlier than their counterparts without splenomegaly. Both studies were in contrast to Andriani et al. [14], which proved that baseline splenomegaly is significantly associated with thrombotic risk. These discrepancies proved that the role of spleen enlargement on thrombosis pathogenesis and its prognostic relevance remains still unclear.

Moreover, the most striking notice was that all the three patients with ophthalmic vein thrombosis were found to have high F-XI level, with range of 95–150, and a mean of 125.67±28.04. This was followed by patients with DVT in which the range of F-XI was 35–178, and a mean of 116.1±53.15. This result raised the importance of measuring F-XI level in patients with ophthalmic vein thrombosis and DVT in these population in further studies. This was proven by other studies, such as Preis et al. [21], which supported that inhibition, or lower activity levels of F-XI, provides a cardiovascular benefit and a reduced VTE risk.

The longstanding debate of whether high level of F-XI represents a risk factor for thrombosis in patients with MPN remains unresolved, and this may be owing to some limitations in our study: first, the small sample of patient group in contrast to other studies; second, the short duration of follow-up, which did not allow the estimation of the risk of recurrent thrombosis; and third, some patients were under cytoreductive therapy, which reduced the rate of vascular complications and could have influenced the assay results.


  Conclusion Top


Although the role of contact system is dispensable in hemostasis as the contact factors are not required for fibrin generation and clot formation, the role of contact system in thrombosis has regained new interest owing to several observations in animal studies [22]. Recently, striking data point to a role for the contact system in thrombosis. The implications for treatment of thromboembolic diseases are enormous: in vivo inhibition of one of the contact proteins would be ideal because these drugs may be effective against thrombosis and, at the same time, bear no risk of bleeding in contrast to other anticoagulants, which act by inhibiting thrombin [11]

This study focused on the contribution of F-XI to thrombotic risk in patients with MPN showed that there was no link between high F-XI levels and thrombotic risk.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

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