Evaluation of D‑dimer and lactate dehydrogenase plasma levels in patients with relapsed acute leukemia
- Authors:
- Published online on: June 1, 2016 https://doi.org/10.3892/ol.2016.4657
- Pages: 591-596
Abstract
Introduction
Acute leukemia (AL) is a clonal disease that progressively produces novel sub-clones, which exhibit altered phenotypic and cytogenetic traits. AL is divided into acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). AML is the most common type of leukemia in adults. Acute promyelocytic leukemia (APL) is a distinct subtype of AML characterized by coagulopathy and signs of disseminated intravascular coagulation (1,2). It is not known whether coagulation results are associated with AL except in APL. Therefore, the comparison of certain clinical parameters of AL patients, including activated partial thromboplastin time (aPTT), prothrombin time (PT), D-dimer and fibrinogen (FIB) should be eliminated due to interference from the APL cohort. Despite high sensitivity to standard chemotherapy, which leads to increased rate of complete remission (CR) in the two subtypes of AL, ~1/3 of AL patients subsequently relapse (3–6). AL relapse following standard chemotherapy remains a significant therapeutic challenge (7–10). AL continues to have a low survival rate compared to other cancers (11). Disease-free survival rates are 5–15% in older adults and 25–40% in younger patients (12).
Metabolic changes occur as part of oncogenesis and tumor progression. A better understanding of AL relapse and the careful monitoring of clinical parameters following chemotherapy may aid clinicians in determining the best treatment options on an individual patient basis. As a result of local activation of intravascular coagulation at the onset of some forms of malignancy (13,14), the fibrinolytic marker D-dimer increases and accumulates (14). LDH exists in numerous cell systems and, subsequent to tissue or cell damage, serum LDH levels may increase (15). Although it is generally understood that there is a poor outcome for adults with AL that develop bone marrow relapse (16) and various risk factors predicting outcome are continuously analyzed, there are few studies concerning LDH and D-dimer in these types of patients. The present study was performed to determine whether D-dimer and LDH levels during treatment are associated with relapse in patients with AL.
Materials and methods
Patients
The present study evaluated data from 204 patients that were newly diagnosed with AL at the The First Affiliated Hospital of Wenzhou Medical University (Wenzhou, China) between February 2010 and October 2014, several of whom relapsed. At the initial onset, 204 patients were treated uniformly for AML or ALL. AL was classified according to the FAB criteria (17). In total there were 40 ALL patients and 164 AML patients (M1, 44; M2, 26; M3, 32; M4, 36; M5, 20; M6, 6). AML patients only were treated with daunorubicin (45 mg/m2 per day on days 1–3) and cytarabine (150 mg/m2 per day for 7 days) according to the 3 plus 7 regimen. APL patients were treated based on an all-trans retinoic acid (20 mg/m2 per day on days 1–15) plus anthracycline (idarubicin; 8 mg/m2 per day on days 1–3) protocol. The induction chemotherapy in ALL patients included vincristine (2 mg per day on days 1, 8, 15 and 22) and daunorubicin (40 mg/m2 per day on days 1–3), prednisone]1 mg/kg per day on days 1–14 and 15–28 (2/3 dose)] and L-asparaginase (6,000 IU/m2 per day on days 11, 14, 17, 20, 23 and 26). The AL patients were free from any systemic, cardiovascular or inflammatory illnesses. The Ethics Committee at The First Affiliated Hospital of Wenzhou Medical University approved the present study. Written informed consent was obtained from the patients.
Blood collection
Blood samples were taken from the antecubual vein and placed in plastic tubes containing 3.8% trisodium citrate (9 volumes of blood and 1 volume of 0.1 M trisodium citrate) or ethylenediaminetetraacetic acid (EDTA)·K2 anticoagulant. For plasma separation, blood was centrifuged at 2,500 × g for 15 min at 4°C; blood samples were obtained prior to the initiation of any treatment for AL. The present study adhered to the tenets of the Declaration of Helsinki.
Data collection
Blood counts were performed using an XE 2100 Sysmex™ automated hematology analyzer (Sysmex, Kobe, Japan). aPTT, PT, D-dimer and FIB were measured using a STAGO Coagulation analyzer (Diagnostica Stago, Asnières, France). The STA®-Liatest® D-Di kit (Diagnostica Stago) is intended for use with analyzers of the STA® line suitable with these reagents for the quantitative determination of D-dimer in plasma by immuno-turbidimetric method. The STA®-fibrinogen kit (Diagnostica Stago) is intended for use with STA-R® analyzers for the quantitative determination of FIB levels in plasma using the clotting method of Clauss. The STA®-néoplastine Cl Plus and STA®-APTT kits (Diagnostica Stago) are intended for use with STA-R® analyzers for the determination of PT and aPTT in plasma by the clotting method, respectively. Lactate dehydrogenase (LDH) plasma levels were measured using the LDH substrates method (Beckman Coulter Experiment System Co., Ltd., Suzhou, China). Markers were compared against normal ranges, which were as follows: White blood cell (WBC) count, 3.5–9.5×109/l; platelet (PLT) count, 125.0–350.0×109/l; hemoglobin (Hb), 115.0–175.0 g/l; PT, 11.6–14.9 sec; aPTT, 29.0–43.0 sec; FIB, 2.0–4.0 g/l; D-dimer, 0.0–0.5 mg/l; and LDH, 0.0–247.0 units (U)/l. The laboratory data were collected promptly at the initial onset of AL, CR and in patients with relapsed AL.
Response evaluation
The diagnostics were comprised of cytomorphology, cytochemistry, cytogenetics, molecular genetics and immunophenotyping of bone marrow or peripheral blood. Bone marrow aspirate smears were applied to assess the therapeutic effect of AL. The morphological diagnosis and classification were performed according to the WHO 2008 diagnostic criteria (18).
Statistical analysis
The results were graphed using line charts depicting medians and range. The data were analyzed using the Wilcoxon matched pairs test. Spearman's rank correlation coefficient was used to analyze correlations between serum D-dimer or LDH level and selected blood routine parameters. P-values of <0.05 were considered to indicate a statistically significant difference. Data were analyzed using SPSS version 13.0 for Windows (SPSS, Chicago, IL, USA).
Results
Clinical parameters of AL patients at various stages of disease
Laboratory data in patients with initial onset, CR and relapsed AL are shown in Table I. The WBC count was significantly different at the initial onset of AL (P=0.002) and during relapsed AL, compared with patients in the CR group (P=0.009). Hb levels (P<0.001 and P=0.003) and PLT counts (P=0.001 and P<0.001) were significantly reduced in the initial onset and relapsed AL groups. compared with the CR group. D-dimer (P=0.005 and P=0.007) and LDH levels (P=0.007 and P=0.008) were also significantly increased in the two groups compared with the CR group (Figs. 1 and 2). In addition, these levels were significantly different across the two groups compared with AL in CR, regardless of whether APL patients were included. Plasma PT and FIB levels were significantly (P=0.020) increased in the initial onset and relapsed AL groups compared with patients achieving CR. Plasma FIB levels were significantly decreased in the initial onset (P=0.008) and relapsed AL groups (P=0.009) compared with patients achieving CR. Plasma aPTT levels were not significantly different between patients with initial onset or relapsed AL and AL in CR. When coagulation data results were eliminated in patients with APL, plasma levels of aPTT were elevated, but plasma PT, aPTT and FIB levels were not significantly different between patients with relapsed AL and AL in CR.
Plasma levels of D-dimer and LDH levels in all subtypes of AL at various stages of disease
In the AML-M1 group (Table II), LDH (P=0.030) and D-dimer (P=0.020) plasma levels were significantly increased at the initial onset of AL compared with during CR. The plasma levels of D-dimer and LDH were significantly increased in the relapsed group compared with the CR group (P=0.010 and P=0.020, respectively), which were higher during relapse compared with at initial onset of AL. In the AML-M2 group, LDH (P=0.008 and P=0.010) and D-dimer (P=0.008 and P=0.007) plasma levels were significantly increased in the initial onset and relapsed groups compared with CR; LDH plasma levels were increased in patients with initial onset of M2 compared with relapsed patients. The highest values of D-dimer were observed in AML-M3 patients. D-dimer plasma levels were significantly increased at initial onset of APL compared with during CR, and significantly increased during relapse compared with CR. Plasma LDH levels were significantly greater in patients at the initial onset and in patients with relapsed AL compared with patients achieving CR (P=0.009 and P=0.007, respectively). In the AML-M4 patients group, D-dimer plasma levels were significantly increased in patients with initial onset and patients with relapsed AL (P=0.010 and P=0.030, respectively), but not with CR. LDH levels in AML-M4 patients were significantly increased at initial onset and in relapsed AL compared with at CR. In the AML-M5 patients group, D-dimer (P=0.030 and P=0.040) and LDH (P=0.020 and P=0.040) plasma levels significantly increased in the relapsed group and initial onset of disease compared with the CR group. In the AML-M6 patient group, D-dimer plasma levels increased during relapsed AL (P=0.030), but not at initial onset of AL compared with patients with CR. Plasma LDH levels were significantly greater in patients with initial onset and relapsed AL compared with CR (P=0.030 and P=0.020, respectively). In the ALL patient group, D-dimer plasma levels were significantly increased in the initial onset and relapsed groups compared with the CR group, but were higher at the initial onset of ALL compared with during relapse. LDH plasma levels significantly increased at initial onset and during relapse compared with patients achieving CR (P=0.005 and P=0.002, respectively).
Serum LDH levels were elevated in the majority of AL patients following initial diagnosis and in relapsed patients; however, there does not appear to be a correlation between increased LDH levels and blood routine parameters in AL patients. Increased D-dimer concentrations demonstrated no correlation with any blood routine parameters in AL patients.
Discussion
Despite the outstanding advances made over the past decade regarding our knowledge of AL, AL relapse following routine conventional-dose chemotherapy remains to be associated with a dismal prognosis (3–6,8,10). D-dimers are a sensitive measure of endogenous fibrinolysis and are used to screen for deep vein thrombosis (19–24). Elevated LDH levels have frequently been observed in animal and human malignancies (15,25,26); in addition, there appears to be a strong correlation between disease activity and tumor mass (27). The association, pathogenesis and significance of D-dimers and LDH levels with relapse within the subtypes of AML and ALL are currently unknown. A clear understanding of the associations between these parameters and relapsed AL patients requires additional research.
Coagulation disorders are frequently observed in APL and can also occur in other AL subtypes (28–30). The pathogenic mechanism underlying the blood coagulation disorder in these patients is complex. The levels of D-dimer complex generally reflect the functional state of the clotting and fibrinolysis systems and support the existence of a hypercoagulable state (19,20,31,32).
In the present study, during the initiation of AL, PT was found to be significantly prolonged (P=0.020), plasma levels of FIB were significantly decreased (P=0.009), the levels of D-dimer were elevated in all subtypes of AML and ALL, and the highest levels of D-dimer were found in AML-M3 (Tables I and II); however, there was no significant difference in aPTT between patients with initial onset and those with CR, or between relapse and CR. When coagulation data results were eliminated in patients with APL, plasma PT, aPTT and FIB levels were not significantly increased at the initial onset of AL or during AL relapse compared to patients with CR. The results of the present study indicate that the determination of D-dimer levels may be useful for predicting the probability of relapse during chemotherapy, as the PT, aPTT and FIB tests were not reliable markers of AL relapse.
Increased D-dimer levels at initial onset, which further increased during relapse, strongly suggest a hypercoagulable state, with secondary activation of fibrinolysis in the majority of patients (33,34). Activation of coagulation and secondary activation of fibrinolysis are likely to occur continuously and simultaneously throughout circulation (20,24,34). The activation of coagulation is most likely associated with the leukemic cells circulating in the blood, which may contain procoagulants, and the content of these substances depends on the leukemia subtype (35,36). These substances may be released into the blood from disintegrating cells during relapse.
Tanaka et al (35) confirmed that the development of disseminated intravascular coagulation in patients with AL prior to chemotherapy is associated with the presence of tissue factor (TF) on the surface of the leukemic cells. TF is a major procoagulant that initiates blood coagulation in vivo and is the membrane protein receptor for factor VII. The resulting factor VIIa activates factors IX and X, leading to thrombin generation and fibrin formation (35,37,38). The TF gene is expressed in cells from patients with AL.
In the present study, cells from AML patients expressed particularly high VII activity; these levels become essentially undetectable when patients are in CR. Other procoagulant mediators, including tumor necrosis factor α (39,40), cysteine proteinase (41), interferon-γ (40), asinterleukin-1 (42) and vascular permeability factor (43), are regarded as indirect procoagulants as they initiate coagulation by inducing TF in endothelial cells and monocytes (44). In addition, natural apoptosis may contribute to thrombogenesis in AL via the release of microparticles from the damaged leukemic cells (35). Coagulation disorders may also occur due to leukemia-associated complications, including infection or organic impairment (45).
Notably, for patients that achieved CR following the induction of chemotherapy, D-dimer levels did not return to a normal value. The increased D-dimer levels during CR following chemotherapy treatment suggest a hypercoagulable state with secondary activation of fibrinolysis. Velasco et al (46). Observed an increase in the D-dimer level during treatment in patients with AML. In the present study, the results showed that the LDH levels were moderately elevated in the majority of AL patients with the exception of the CR phase, irrespective of cell type. Significantly elevated levels were recorded in the majority of patients with ALL but there was no significant difference in serum LDH levels between AML and ALL patients during relapse; in addition, no significant difference was found at initial onset of AL and during relapse.
In patients with increased levels of LDH at diagnosis, AL relapse was not found to lead to significant elevation. LDH activity reflects increased glycolysis in the cytoplasm of malignant cells accompanied by a high metabolic rate (15,25). The increase of serum LDH activity may be due to thrombotic microangiopathy, intravascular hemolysis or tumor lysis (25,26). Certain values from the ALL patients were remarkably high (Table II), and the majority of these patients had a high WBC counts during relapse. This phenomenon is likely due to the correlation between LDH levels and the number of circulating ALL blasts during relapse (47). Cumulative evidence indicates that serum LDH levels can be a good and reliable prognostic marker of ALL patients (48–50), suggesting an association between LDH levels and relapse.
Although D-dimer and LDH levels have been shown to be elevated in all subtypes of AML and ALL, none of these parameters provide diagnostic specificity. In the present study, a significant change in routine hematological parameters was indicated in patients with relapsed AL, which is consistent with previous findings (51,52). The most important and most common associated risk factors for the hematological relapse of AL are thrombocytopenia, leukocyte count and lower hemoglobin, which is associated with the proliferating leukemic clone (53,54). Ambulatory monitoring of D-dimer, LDH, and routine hematological parameters are recommended for the assessment of relapse in AL patients.
In conclusion, the present study demonstrated that D-dimer and LDH plasma levels were significantly increased at initial onset and during relapse in AL patients compared to those with CR. D-dimer and LDH levels may be useful for predicting AL relapse; therefore, the present study recommends that monitoring D-dimer and LDH for the assessment of AL relapse.
Acknowledgements
The authors gratefully acknowledge the patients for participating in the present study, and thank Dr Xiao Bo Nie for the critical reading of this manuscript.
References
|
Deschler B and Lübbert M: Acute myeloid leukemia: Epidemiology and etiology. Cancer. 107:2099–2107. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Lo-Coco F, Ammatuna E, Montesinos P and Sanz MA: Acute promyelocytic leukemia: Recent advances in diagnosis and management. Semin Oncol. 35:401–409. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Inagaki J, Fukano R, Noguchi M, Kurauchi K, Tanioka S and Okamura J: Hematopoietic stem cell transplantation following unsuccessful salvage treatment for relapsed acute lymphoblastic leukemia in children. Pediatr Blood Cancer. 62:674–679. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Cui L, Gao C, Zhang RD, Jiao Y, Li WJ, Zhao XX, Liu SG, Yue ZX, Zheng HY, Deng GR, et al: Low expressions of ARS2 and CASP8AP2 predict relapse and poor prognosis in pediatric acute lymphoblastic leukemia patients treated on China CCLG-ALL 2008 protocol. Leuk Res. 39:115–123. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Arakawa Y, Koh K, Aoki T, Kubota Y, Oyama R, Mori M, Hayashi M and Hanada R: Clofarabine-based combination chemotherapy for relapse and refractory childhood acute lymphoblastic leukemia. Rinsho Ketsueki. 55:2316–2319. 2014.PubMed/NCBI | |
|
Bruedigam C, Bagger FO, Heidel FH, Kuhn Paine C, Guignes S, Song A, Austin R, Vu T, Lee E, Riyat S, et al: Telomerase inhibition effectively targets mouse and human AML stem cells and delays relapse following chemotherapy. Cell Stem Cell. 15:775–790. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Ilyas AM, Ahmad S, Faheem M, Naseer MI, Kumosani TA, Al-Qahtani MH, Gari M and Ahmed F: Next generation sequencing of acute myeloid leukemia: Influencing prognosis. BMC Genomics. 16(Suppl 1): S52015. View Article : Google Scholar : PubMed/NCBI | |
|
Itzykson R, Thépot S, Berthon C, Delaunay J, Bouscary D, Cluzeau T, Turlure P, Prébet T, Dartigeas C, Marolleau JP, et al: Azacitidine for the treatment of relapsed and refractory AML in older patients. Leuk Res. 39:124–130. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Rashidi A and Cashen AF: A cytogenetic model predicts relapse risk and survival in patients with acute myeloid leukemia undergoing hematopoietic stem cell transplantation in morphologic complete remission. Leuk Res. 39:77–81. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Martelli MF, Di Ianni M, Ruggeri L, Falzetti F, Carotti A, Terenzi A, Pierini A, Massei MS, Amico L, Urbani E, et al: HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse. Blood. 124:638–644. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, Pettenati MJ, Patil SR, Rao KW, Watson MS, et al: Cancer and Leukemia Group B (CALGB 8461): Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: Results from Cancer and Leukemia Group B (CALGB 8461). Blood. 100:4325–4336. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Thakkar SG, Fu AZ, Sweetenham JW, McIver ZA, Mohan SR, Ramsingh G, Advani AS, Sobecks R, Rybicki L, Kalaycio M and Sekeres MA: Survival and predictors of outcome in patients with acute leukemia admitted to the intensive care unit. Cancer. 112:2233–2240. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Benyo M, Flasko T, Molnar Z, Kerenyi A, Batta Z, Jozsa T and Harsfalvi J: Follow-up of thrombin generation after prostate cancer surgery: Global test for increased hypercoagulability. PLoS One. 7:e512992012. View Article : Google Scholar : PubMed/NCBI | |
|
Diao D, Zhu K, Wang Z, Cheng Y, Li K, Pei L and Dang C: Prognostic value of the D-dimer test in oesophageal cancer during the perioperative period. J Surg Oncol. 108:34–41. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Kachel P, Trojanowicz B, Sekulla C, Prenzel H, Dralle H and Hoang-Vu C: Phosphorylation of pyruvate kinase M2 and lactate dehydrogenase A by fibroblast growth factor receptor 1 in benign and malignant thyroid tissue. BMC Cancer. 15:1402015. View Article : Google Scholar : PubMed/NCBI | |
|
Park HY, Suh GY, Jeon K, Koh WJ, Chung MP, Kim H, Kwon OJ, Kim K, Jang JH, Jung CW, et al: Outcome and prognostic factors of patients with acute leukemia admitted to the intensive care unit for septic shock. Leuk Lymphoma. 49:1929–1934. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR and Sultan C: Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7). A report of the French-American-British Cooperative Group. Ann Int Med. 103:460–462. 1985. View Article : Google Scholar : PubMed/NCBI | |
|
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellström-Lindberg E, Tefferi A and Bloomfield CD: The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood. 114:937–951. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Danese E, Montagnana M, Cervellin G and Lippi G: Hypercoagulability, D-dimer and atrial fibrillation: An overview of biological and clinical evidence. Ann Med. 46:364–371. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Lee K, Kim JE, Kwon J, Kim I, Yoon SS, Park S, Han KS and Kim HK: Poor prognosis of hypocoagulability assessed by thrombin generation assay in disseminated intravascular coagulation. Blood Coagul Fibrinolysis. 25:241–247. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Sartori M, Migliaccio L, Favaretto E, Cini M, Legnani C, Palareti G and Cosmi B: D-dimer for the diagnosis of upper extremity deep and superficial venous thrombosis. Thromb Res. 135:673–678. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
van der Hulle T, Tan M, den Exter PL, Mol GC, del Iglesias Sol A, van de Ree MA, Huisman MV and Klok FA: Selective D-dimer testing for the diagnosis of acute deep vein thrombosis: A validation study. J Thromb Haemost. 11:2184–2186. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Yoon CW, Kim SJ, Bang OY, Chung CS, Lee KH and Kim GM: Premorbid warfarin use and lower D-dimer levels are associated with a spontaneous early improvement in an atrial fibrillation-related stroke. J Thromb Haemost. 10:2394–2396. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Sartori M, Cosmi B, Legnani C, Favaretto E, Valdré L, Guazzaloca G, Rodorigo G, Cini M and Palareti G: The Wells rule and D-dimer for the diagnosis of isolated distal deep vein thrombosis. J Thromb Haemost. 10:2264–2269. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Han X, Sheng X, Jones HM, Jackson AL, Kilgore J, Stine JE, Schointuch MN, Zhou C and Bae-Jump VL: Evaluation of the anti-tumor effects of lactate dehydrogenase inhibitor galloflavin in endometrial cancer cells. J Hematol Oncol. 8:22015. View Article : Google Scholar : PubMed/NCBI | |
|
Augoff K, Hryniewicz-Jankowska A and Tabola R: Lactate dehydrogenase 5: An old friend and a new hope in the war on cancer. Cancer Lett. 358:1–7. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Dowling P, Pollard D, Larkin A, Henry M, Meleady P, Gately K, O'Byrne K, Barr MP, Lynch V, Ballot J, et al: Abnormal levels of heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) in tumour tissue and blood samples from patients diagnosed with lung cancer. Mol Biosyst. 11:743–752. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Choudhry A and DeLoughery TG: Bleeding and thrombosis in acute promyelocytic leukemia. Am J Hematol. 87:596–603. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Chang H, Kuo MC, Shih LY, Dunn P, Wang PN, Wu JH, Lin TL, Hung YS and Tang TC: Clinical bleeding events and laboratory coagulation profiles in acute promyelocytic leukemia. Eur J Haematol. 88:321–328. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Asakura H, Takahashi H, Tsuji H, Matsushita T, Ninomiya H, Honda G, Mimuro J, Eguchi Y, Kitajima I and Sakata Y: Post-marketing surveillance of thrombomodulin alfa, a novel treatment of disseminated intravascular coagulation-safety and efficacy in 1,032 patients with hematologic malignancy. Thromb Res. 133:364–370. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Mego M, Zuo Z, Gao H, Cohen EN, Giordano A, Tin S, Anfossi S, Jackson S, Woodward W, Ueno NT, et al: Circulating tumour cells are linked to plasma D-dimer levels in patients with metastatic breast cancer. Thromb Haemost. 113:593–598. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Gomes M and Khorana AA: Risk assessment for thrombosis in cancer. Semin Thromb Hemost. 40:319–324. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Yanada M, Matsushita T, Suzuki M, Kiyoi H, Yamamoto K, Kinoshita T, Kojima T, Saito H and Naoe T: Disseminated intravascular coagulation in acute leukemia: Clinical and laboratory features at presentation. Eur J Haematol. 77:282–287. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Hess EP and Sztajnkrycer MD: Images in emergency medicine. Acute leukemia with blast crisis, disseminated intravascular coagulation, and intraparenchymal hemorrhage. Ann Emerg Med. 46:314–322. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Tanaka M and Yamanishi H: The expression of tissue factor antigen and activity on the surface of leukemic cells. Leuk Res. 17:103–111. 1993. View Article : Google Scholar : PubMed/NCBI | |
|
Jácomo RH, Santana-Lemos BA, Lima AS, Assis PA, Lange AP, Figueiredo-Pontes LL, Oliveira LO, Bassi SC, Benício MT, Baggio MS, et al: Methionine-induced hyperhomocysteinemia reverts fibrinolytic pathway activation in a murine model of acute promyelocytic leukemia. Blood. 120:207–213. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Marchetti M, Russo L, Balducci D and Falanga A: All trans-retinoic acid modulates the procoagulant activity of human breast cancer cells. Thromb Res. 128:368–374. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Marchetti M, Diani E, ten Cate H and Falanga A: Characterization of the thrombin generation potential of leukemic and solid tumor cells by calibrated automated thrombography. Haematologica. 97:1173–1180. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Ohkawara H, Ishibashi T, Sugimoto K, Ikeda K, Ogawa K and Takeishi Y: Membrane type 1-matrix metalloproteinase/Akt signaling axis modulates TNF-α-induced procoagulant activity and apoptosis in endothelial cells. PLoS One. 9:e1056972014. View Article : Google Scholar : PubMed/NCBI | |
|
Poovassery JS, Sarr D, Smith G, Nagy T and Moore JM: Malaria-induced murine pregnancy failure: Distinct roles for IFN-gamma and TNF. J Immunol. 183:5342–5349. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
de Menezes YA, Félix-Silva J, da Silva-Júnior AA, Rebecchi IM, de Oliveira AS, Uchoa AF and Fernandes-Pedrosa Mde F: Protein-rich fraction of Cnidoscolus urens (L.) Arthur leaves: Enzymatic characterization and procoagulant and fibrinogenolytic activities. Molecules. 19:3552–3569. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Gansler J, Preissner KT and Fischer S: Influence of proinflammatory stimuli on the expression of vascular ribonuclease 1 in endothelial cells. FASEB J. 28:752–760. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Zucker S, Mirza H, Conner CE, Lorenz AF, Drews MH, Bahou WF and Jesty J: Vascular endothelial growth factor induces tissue factor and matrix metalloproteinase production in endothelial cells: Conversion of prothrombin to thrombin results in progelatinase A activation and cell proliferation. Int J Cancer. 75:780–786. 1998. View Article : Google Scholar : PubMed/NCBI | |
|
Hawiger J, Veach RA, Liu XY, Timmons S and Ballard DW: IkappaB kinase complex is an intracellular target for endotoxic lipopolysaccharide in human monocytic cells. Blood. 94:1711–1716. 1999.PubMed/NCBI | |
|
Ma J, Duffy MR, Deng L, Dakin RS, Uil T, Custers J, Kelly SM, McVey JH, Nicklin SA and Baker AH: Manipulating adenovirus hexon hypervariable loops dictates immune neutralisation and coagulation factor X-dependent cell interaction in vitro and in vivo. PLoS Pathog. 11:e10046732015. View Article : Google Scholar : PubMed/NCBI | |
|
Velasco F, Torres A, Rojas R, Alvarez MA, Gomez P and Castillo D: Increase in the D-dimer levels during treatment in patients with acute myelogenous leukemia. Haemostasis. 22:117–123. 1992.PubMed/NCBI | |
|
Cortelazzo S, Ponzoni M, Ferreri AJ and Hoelzer D: Lymphoblastic lymphoma. Crit Rev Oncol Hematol. 79:330–343. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Rao D, Ghalaut VS, Ghalaut PS and Rao S: Case series: CSF LDH, proteins and electrolyte levels in patients of acute lymphocytic leukemia. Clin Chim Acta. 413:1045–1048. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Thomas X, Danaïla C, Le QH, Sebban C, Troncy J, Charrin C, Lhéritier V, Michallet M, Magaud JP and Fiere D: Long-term follow-up of patients with newly diagnosed adult acute lymphoblastic leukemia: A single institution experience of 378 consecutive patients over a 21-year period. Leukemia. 15:1811–1822. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Yeh CH, Tseng R, Hannah A, Estrov Z, Estey E, Kantarjian H and Albitar M: Clinical correlation of circulating heat shock protein 70 in acute leukemia. Leuk Res. 34:605–609. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Suvajdžić N, Cvetković Z, Dorđević V, Kraguljac-Kurtović N, Stanisavljević D, Bogdanović A, Djunić I, Colović N, Vidović A, Elezović I and Tomin D: Prognostic factors for therapy-related acute myeloid leukaemia (t-AML)-a single centre experience. Biomed Pharmacother. 66:285–292. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Litzow MR, Othus M, Cripe LD, Gore SD, Lazarus HM, Lee SJ, Bennett JM, Paietta EM, Dewald GW, Rowe JM, et al: Failure of three novel regimens to improve outcome for patients with relapsed or refractory acute myeloid leukaemia: A report from the Eastern Cooperative Oncology Group. Br J Haematol. 148:217–225. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Shiozawa Y, Takita J, Kato M, Sotomatsu M, Koh K, Ida K and Hayashi Y: Prognostic significance of leukopenia in childhood acute lymphoblastic leukemia. Oncol Lett. 7:1169–1174. 2014.PubMed/NCBI | |
|
Hossain MJ, Xie L and Caywood EH: Prognostic factors of childhood and adolescent acute myeloid leukemia (AML) survival: Evidence from four decades of US population data. Cancer Epidemiol. 39:720–726. 2015. View Article : Google Scholar : PubMed/NCBI |
