Journal of Applied Hematology

ORIGINAL ARTICLE
Year
: 2021  |  Volume : 12  |  Issue : 1  |  Page : 10--16

Rates of bleeding, thrombosis, and survival in patients who underwent hematopoietic cell transplantation at king abdulaziz medical city, Riyadh, Saudi Arabia


Sultan Alqahtani1, Ahmed Alragea2, Basil Alqahtani2, Nawaf Alhoshan2, Ibrahim Aljasser2, Abdulaziz Alobaied2, Mohammed Alassiri3, Emad Masuadi4, Mohsen Alzahrani5,  
1 Department of Basic Medical Sciences, King Saud bin Abdulaziz University for Health Sciences; King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
2 Department of College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
3 King Abdullah International Medical Research Center; Department of Basic Sciences, College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
4 Department of Medical Education, Research Unit, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
5 King Abdullah International Medical Research Center; Department of Oncology, Division of Stem Cell Transplantation and Cellular Therapy, King Abdulaziz Medical City, Riyadh, Saudi Arabia

Correspondence Address:
Dr. Sultan Alqahtani
Department of Basic Medical Sciences, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh
Saudi Arabia

Abstract

BACKGROUND: Bleeding tendency and thrombosis are two major hematological complications observed in patients after hematopoietic cell transplantation (HCT). Although these complications are well reported in western communities, they are not well established in Saudi Arabia. OBJECTIVES: This retrospective study investigated the rates of bleeding, thrombosis, and survival in Saudi and non-Saudi patients who underwent HCT at King Abdulaziz Medical City, Riyadh, Saudi Arabia, from 2010 to 2017. METHODS AND MATERIALS: A total of 372 Saudi and non-Saudi patients of both sexes with leukemia, anemia disorders, lymphoma, and other types of pathological disorders who underwent autologous or allogeneic HCT were included in this study. Patient data including age, sex, nationality, type of cancer, transplant type, coagulation profile, date of operation and discharge, treatment, and other outpatient notes were collected and analyzed using the Chi-square test. RESULTS: The majority of our patients undergoing allogeneic transplantation had leukemia and other types of anemia disorders including aplastic anemia, sickle cell anemia, and β-thalassemia (79%). However, the majority of patients undergoing autologous transplantation (73.4%) had lymphoma and other types of pathological disorders, including liver cell carcinoma, nephroblastoma, neuroblastoma, myelodysplastic syndromes, and primitive neuroectodermal tumors. Among patients with leukemia, anemia disorders, lymphoma, and other pathological disorders, 2.2%, 1.4%, 1.4%, and 2.8% suffered from thrombosis (overall, 1.9%) and 9.5%, 8.6%, 5.6%, and 11.2% suffered from bleeding, respectively (overall 8.9%). Moreover, the 7-year survival rate among those patients was 82.5%. CONCLUSION: Bleeding occurred at a higher rate after HCT, and the overall 7-year survival rate was relatively high.



How to cite this article:
Alqahtani S, Alragea A, Alqahtani B, Alhoshan N, Aljasser I, Alobaied A, Alassiri M, Masuadi E, Alzahrani M. Rates of bleeding, thrombosis, and survival in patients who underwent hematopoietic cell transplantation at king abdulaziz medical city, Riyadh, Saudi Arabia.J Appl Hematol 2021;12:10-16


How to cite this URL:
Alqahtani S, Alragea A, Alqahtani B, Alhoshan N, Aljasser I, Alobaied A, Alassiri M, Masuadi E, Alzahrani M. Rates of bleeding, thrombosis, and survival in patients who underwent hematopoietic cell transplantation at king abdulaziz medical city, Riyadh, Saudi Arabia. J Appl Hematol [serial online] 2021 [cited 2021 Apr 20 ];12:10-16
Available from: https://www.jahjournal.org/text.asp?2021/12/1/10/311327


Full Text



 Introduction



Hematopoietic cell transplantation (HCT) involves an intravenous infusion of hematopoietic stem and progenitor cells to restore normal immune, hematologic, and metabolic functions.[1],[2] HCT is used to treat many inherited and/or acquired benign and neoplastic disorders of the hematopoietic system, including hematologic malignancies such as leukemia, lymphoma, and myeloma, nonmalignant acquired bone marrow disorders such as aplastic anemia, and other genetic disorders associated with abnormal hematopoiesis, including thalassemia and sickle cell anemia.[1],[2],[3]

There are two major types of HCT – autologous and allogeneic. Autologous HCT uses hematopoietic progenitor cells from the same patient whereas allogeneic HCT uses hematopoietic progenitor cells from a donor.[4] Although both treatments are currently used to treat most hematologic cancers, treatment choice depends on cancer type, diagnosis, type of donor, and health of the patient at diagnosis and at the time of transplantation and the status and stage of cancer at the time of transplantation.[2],[4] Patients undergoing autologous HCT are less likely than those undergoing allogeneic HCT to develop graft-versus-host diseases (GVHD).[5]

Despite achievements in advanced clinical procedures and significant progress in histocompatibility matching, donor selection, GVHD, conditioning regimens, sources of hematopoietic stem cells, and peri- and post-transplant care, patients undergoing HCT develop disease relapses and several serious early and late infectious, organ-specific, immunologic, and hemostatic complications, which reduce survival rates and contribute to significant long-term morbidity and mortality.[5],[6],[7] A multifactorial risk of bleeding tendency due to prolonged thrombocytopenia, acquired hepatic dysfunction, and specific end-organ toxicities including hemorrhagic cystitis, diffuse alveolar hemorrhage, and GVHD-associated gastrointestinal bleeding were observed after autologous and allogeneic HCT.[5],[8],[9],[10],[11] Different types of venous thrombosis, including catheter-related thrombosis, venous thromboembolic (VTE) events, sinusoidal obstructive syndrome, veno-occlusive disease (VOD), and transplant-associated thrombotic microangiopathy, have been observed after HCT.[10],[12],[13],[14],[15]

Nonetheless, during the last year, hematologic cancer incidence has rapidly increased in the Kingdom of Saudi Arabia, with a prevalence of 70% in Saudi men and women.[16] HCT is frequently used as an effective therapy for different types of cancers among children and adults.[17],[18] Among 82 patients with acute lymphoblastic leukemia visiting King Faisal Specialist Hospital and Research Center (Riyadh, Saudi Arabia), overall 5-year survival rate was 58.8%, whereas event-free survival rate was 54.3%. Interestingly, patients' age at the time of diagnosis, sex, source of stem cells (transplant), donor's human leukocyte antigen status, and complete remission status after HCT did not affect survival rates.[17] This suggests that neglecting hematologic complication status after HCT may improve survival rates and reduce mortality.

To our best knowledge, data on the prevalence of bleeding and/or thrombosis in Saudi patients with hematological disorders after HCT is lacking for most areas of Saudi Arabia. Therefore, in this study, we aimed to investigate the prevalence of bleeding and thrombotic events in Saudi patients with hematologic disorders and to determine the related risk factors including age, sex, and type of cancer at diagnosis.

 Subjects and Methods



This study was a retrospective analysis of the data of patients visiting the oncology department in King Abdulaziz Medical City (KAMC), Riyadh from 2010 to 2017. KAMC is a tertiary care center and one of the biggest hospitals in Saudi Arabia in which the oncology department receives approximately 500 patients suffering from all types of cancer and performs approximately 50–100 HCTs every year. The study included Saudi and non-Saudi male and female patients with hematologic disorders (leukemia, anemia [sickle cell anemia, aplastic anemia, and β-thalassemia] and lymphoma) and other pathological disorders including liver cell carcinoma, nephroblastoma, neuroblastoma, myelodysplastic syndromes, and primitive neuroectodermal tumors who underwent HCT surgery between 2010 and 2017. All the patients were included, irrespective of the diagnosis, transplant type (autologous or allogeneic), and donor source. The patient data collected included age, sex, race, cancer diagnosis, type of hematopoietic stem cell transplant, time of admission, discharge and operation, duration of hospitalization, treatment, hospital discharge summary, outpatient clinic notes, and survival. In addition, different hematologic laboratory test data including prothrombin time, activated partial prothrombin time, platelet count, bleeding time, and international normalized ratio were collected. These hematological data were analyzed and used to identify bleeding and thrombotic events in all patients after HCT. The exclusion criteria were the presence of other complications such as GVHD, VOD, the use of immune modulators such as cyclosporine, corticosteroids, etc.), and viral infections such as cytomegalovirus infections. Additionally, the patients with any other comorbid chronic disorders were excluded. The Ethical Research Committee of King Abdullah International Medical Research Center (KAIMRC), KAIMRC approved this study (IRB number SP18/422/R).

Data analysis

All data were analyzed using Statistical Package for the Social Sciences (SPSS) version 20 (IBM Corp, USA). The differences among different variables were assessed using the Chi-square test. P < 0.05 was considered significant different. Data are presented as mean ± standard deviation.

 Results



In this study, we included 372 patients, including men and women, with hematologic and other pathological disorders who underwent HCT at KAMC, Riyadh. Among these, we had 156 (41.9%) female and 261 (58.1%) male patients, aged between 5 and 80 years; patient details are presented in [Table 1]. Accordingly, we had 75 patients below the age of 5 years; 65 patients aged 6–14 years; 81 patients aged 15–-25 years; 71 patients aged 26–40 years; and 80 patients aged 40–80 years. In addition, 339 patients resembled the majority of the patients included in this study (91.1%); we had only 33 (8.9%) non-Saudi patients [Table 1].{Table 1}

The initial diagnoses of the 372 patients included in this study were as follows: leukemia (147 patients, 39.5%), anemia disorders (i.e., sickle cell anemia, aplastic anemia, and β-thalassemia; 70 patients, 18.8%), lymphoma (84 patients, 22.6%), and other pathological disorders, including liver cell carcinoma, nephroblastoma, neuroblastoma, myelodysplastic syndromes, and primitive neuroectodermal tumor (71 patients, 19.1%) [Table 2]. The majority of our patients undergoing allogeneic transplantation had a diagnosis of leukemia and anemia disorders (79%). However, the majority of patients undergoing autologous transplantation (73.4%) were diagnosed with lymphoma and other types of pathological disorders [Table 2]. Among the patients with leukemia, 109 patients (74%) underwent allogeneic and 38 (25%) underwent autologous HCT, respectively [Table 2]. Likewise, the majority of the patients with anemia disorders (66 patients, 94.3%) underwent allogeneic HCT, whereas only 4 patients underwent allogeneic HCT [Table 2]. In contrast, 64 patients with lymphoma (59.3%) and 53 patients with other pathological disorders (74.2%) underwent autologous HCT whereas 20 patients with lymphoma (41.7%) and 19 patients with other pathological disorders (26.7%) underwent allogeneic HCT [Table 2]. Overall, 214 patients of the study population (57.5%) underwent allogeneic HCT whereas 158 patients underwent autologous HCT (42.5%) [Table 2].{Table 2}

Among them, three patients with leukemia; 1 with anemia disorders; 1 with lymphoma; and 2 with other pathological disorders suffered from post-HCT thrombosis, representing an overall percentage of 1.9% [Table 3]. In contrast, 14 patients with leukemia; 6 with anemia disorders; 5 with lymphoma; and 8 with other pathological disorders suffered from bleeding; thus, the proportion was 8.9% [Table 3]. These data indicate that the proportion of patients with no events was high (89%) and the major hematological post-HCT complication in patients was bleeding, which occurred in approximately 9% of the patients [Table 3].{Table 3}

Further analysis revealed that among the seven patients who suffered from thrombosis, 4 and 3 underwent allogeneic and autologous HCT, respectively, thereby indicating an equal proportion of 1.9% among their groups [Table 4]. In contrast, among the patients who suffered from bleeding, 11 patients underwent allogeneic HCT (5.1%) and 22 (13.9%) underwent autologous HCT [Table 4]. From these data, we can conclude that patients undergoing autologous HCT were at a higher risk of bleeding.{Table 4}

The data collected from the study showed that 65 patients died (63 Saudi and 2 non-Saudi) between 2010 and 2017 after HCT, thus giving a survival rate of 82.5% [Table 1] and [Table 5]. The survival curve for these patients is shown in [Figure 1]. The majority of deaths occurred among male patients (54 patients) whereas only 20 females died. The death rates in males and females with hematologic disorders were 12.1% and 5.4%, respectively, and the overall death rate was 17.5% [Table 4]. Furthermore, death occurred in three patients under the age of 5 years (4%), eight patients (13.3%), 6–14 years; 16 patients (19.8), 15–25 years; and nine patients (12.7%), 26–40 years; the death rate was highest and significant only in patients aged 40–80 years (36.2%) [Table 5].{Table 5}{Figure 1}

No deaths occurred among the patients with anemia disorders [Table 6]. However, 11 patients with lymphoma (13.1%); 12, other pathological disorders (16.9%); and 42, leukemia (28.6%) died within 5 years after HCT [Table 6]. Interestingly, 36 patients who underwent allogeneic HCT died (16.8%) whereas 29 patients who underwent autologous HCT died [Table 6]. Concerning post-surgery complications, one patient with thrombosis and nine patients who suffered from bleeding died (27.3%). In addition, 55 patients died without any evidence of any hematological complications (16.6%) [Table 6].{Table 6}

 Discussion



The prevalence of bleeding and thrombosis and the survival rate among patients with hematologic and pathological disorders who undergo HCT are not established in Saudi Arabia. This retrospective study determined the blood-related complications among 372 patients undergoing HCT of different ages in Riyadh, the capital of Saudi Arabia, thus representing the first and largest analysis in the Kingdom of Saudi Arabia. The major findings indicate that bleeding was commonly seen among those patients (9%) whereas thrombosis occurs at lower rates (2%). Moreover, the 7-year survival rate among those patients was found to be 82.5%.

The majority of our patients undergoing allogeneic transplantation had a diagnosis of leukemia and other types of anemia disorders including sickle cell anemia, β-thalassemia, and aplastic anemia (79%). However, the majority of the patients undergoing autologous transplantation (73.4%) had lymphoma and other pathological disorders including liver cell carcinoma, nephroblastoma, neuroblastoma, and myelodysplastic syndromes, and primitive neuroectodermal tumors. Bleeding, a frequent complication after allogeneic and autologous HCT, was associated with poor survival.[8] In previous cross-sectional studies in western countries, it was observed that more than 25% patients experienced at least one bleeding episode in the first 10 years after HCT.[8],[11],[12],[18],[19],[20] In the USA, a cohort study on hemostatic disturbance after HCT had shown that 11.3%, 12%, and 5% of the patients suffered from moderate, severe, and fatal bleeding, respectively.[18] The common causes of bleeding were gastrointestinal and genitourinary hemorrhage after allogeneic HCT whereas hemorrhages in alveolar and intracranial locations may be involved after autologous HCT.[8]

In this study, among the 147 patients with leukemia, bleeding was observed in 14 patients (9.5%). In addition, bleeding was observed in 6, 5, and 8 patients among the 70, 84, and 71 patients with anemia, lymphoma, and other types of pathological disorders, in proportions of 8.6%, 5.6%, and 11.2%, respectively. In addition, 11 of the 214 patients (5.1%) undergoing allogeneic transplantation suffered from bleeding. On the other hand, 22 of the patients (13.9%) who underwent autologous HCT suffered from bleeding. However, the overall rate of bleeding among patients undergoing both allogeneic and autologous transplantations was approximately 9%. These data indicate that bleeding occurred at lower rates than those reported in the western populations (25%)[8] and at a higher rate after autologous HCT among our study patients in Saudi Arabia.

The patients' records indicated that thrombocytopenia was evident among all patients at the time of diagnosis of bleeding (data not shown). In addition, some patients suffered from GVHD. This could, at least, explain the reason for bleeding among those patients. In fact, thrombocytopenia and severe acute GVHD are life-threatening risk factors for bleeding and are correlated with bleeding severity after HCT.[8,12,13,18,20] Other risk factors for bleeding among patients undergoing allogeneic and autologous transplantation include umbilical cord transplantation, hepatic VOD, use of antithymocyte globulin, anticoagulant therapy, and myeloablative conditioning.[8] However, whether these factors contributed to the observed high proportion of bleeding complications in the study population could not be determined due to a lack of evidence and warrants further attention in future research. Moreover, investigation on the severity of bleeding in the Saudi population after HCT is needed.

On the other hand, VTE is a common complication among patients with hematologic malignancies that was shown to occur at a rate of 6%–12% in patients with lymphoma and leukemia, respectively.[13],[21],[22],[23],[24] Moreover, thrombosis occurred at a rate of 35% in patients with multiple myeloma and those undergoing thalidomide-based therapy.[25] The risk factors for VTE after HCT included prolonged hospitalization, indwelling vascular catheters, infection, GVHD, cytotoxic chemotherapy, obesity, and use of immune modulators.[13],[26],[27],[28],[29],[30],[31] Gerber et al.[13] have shown that VTE occurred in 4.6% of patients undergoing autologous and allogeneic HCT and is predominantly catheter-associated. Likewise, Pihusch et al.[11],[12] noted catheter thrombosis in 3.6% of patients, and DVT and/or pulmonary embolism in 2.2% of patients during the first 100 days after transplantation.

Similarly, the percentage of thrombosis in our patients was significantly low at 2%. However, this rate is lower than those reported by Gerber et al.[13] and Pihusch et al.[10],[12] Herein, we observed that 2.2% 1.4%, 1.4%, and 2.8% patients with leukemia, anemia disorders, lymphoma, and other types of pathological disorders had thrombosis. In addition, the rates of thrombosis (1.9%) were equal among patients undergoing allogeneic and autologous transplantation. However, we did not capture data on the risk factors of VTE to precisely identify the major risk factors associated with thrombosis, and this should be considered in future studies.

Nevertheless, it has been reported that death is rarely seen (<10%) in patients after HCT, except if bleeding is due to alveolar and intracranial hemorrhage.[8] In contrast, the death rates in our study among patients undergoing allogeneic and autologous transplantations were 16.8% and 18.4%, respectively, with an overall death rate of 17.5%, which exceeds the international ratio. However, the highest death rate was seen in patients older than 40 years (36.2%). In addition, the death rate was higher in patients with leukemia (28.6%). Moreover, we observed that only one patient with thrombosis died, whereas nine patients with bleeding died during the 5 years after transplantation. Such a high death rate could be due to bleeding in vital organs such as the lungs and brain probably related to disease relapse, and not drugs, comorbidities, and other complications such as infection. However, we could not obtain patients' records for the organ-specific location of the hemorrhage or the time of occurrence after HCT in these patients. Besides, we have no other evidence regarding the comorbidities, infection profiles, and postmortem reports of these patients to precisely determine the cause of death. This could be a limitation of this study.

 Conclusion



Our study was the first in Saudi Arabia to report the prevalence of bleeding and thrombosis in patients after HCT. These data enhance the awareness of the hematological complications among those patients, which will help to decrease the complications and mortalities among those patients. However, we are of the opinion that further larger studies and large multicenter registers with more patient data are required to precisely determine the cause of death in these patients in an endeavor to improve their survival. Additionally, further investigation is needed to clarify the risk of life-threating bleeding and thrombosis after HCT. Based on our observations, we recommend continuous screening and follow-up of HCT survivors for prevention of complications and appropriate management.

Acknowledgment

The authors would like to thank the Oncology department in King Abdulaziz Medical City for the full access of all patients data included in this study and would like to thank King Abdullah International Medical Research Center, Riyadh, KSA for their help to the current study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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