Abstract
Objective
Patients with autoimmune hemolytic anemia (AIHA) are considered to be at an increased risk of thrombosis, and prophylaxis for venous thromboembolism (VTE) is often recommended. However, the occurrence of thrombosis in Asian patients has not been specifically studied. Thrombotic complications and features of Japanese warm AIHA (WAIHA) patients were studied to see if Japanese patients were at an increased risk of thrombosis and should receive prophylaxis for VTE.
Patients and Methods
Forty-seven consecutive patients with warm WAIHA were retrospectively studied. Twenty-nine patients were diagnosed as primary cases and 18 as secondary cases, and 10 patients were diagnosed with Evans syndrome.
Results
No patient presented with thrombosis, and over a median observation period of 15 months, 3 patients had ischemic cerebral vascular accidents. However, all three of those patients had other known risks for thrombosis, with only one taking thrombotic prophylaxis. No venous thrombosis occurred in any patients during the follow-up period. There was no mortality associated with thrombosis. D-dimer levels were often elevated in patients with WAIHA, indicating that the coagulation was activated in a considerable number of patients, but not to such a level as to be associated with clinically overt thrombosis.
Conclusion
Thrombotic complications occur infrequently in Japanese WAIHA patients, and these individuals do not appear to be at a particularly increased risk of thrombosis because of WAIHA. The indication of VTE prophylaxis should be determined individually, considering other risks.
Keywords: autoimmune hemolytic anemia, Evans syndrome, thrombosis, venous thromboembolism, prophylaxis
Introduction
Autoimmune hemolytic anemia (AIHA) is a rare acquired hemolytic disease caused by autoantibodies against one's own red blood cells (RBCs), leading to accelerated destruction and/or shortening of the lifespan of RBCs. AIHA is classified as warm AIHA (WAIHA), cold agglutinin disease (CAD), paroxysmal cold hemoglobinuria, and mixed AIHA based on the thermal range and characteristics of the autoantibodies. It is also divided into primary or secondary disease, according to the presence of underlying disease. Patients in each classification show considerable interindividual heterogeneity in the presenting pictures, response to therapy, and clinical course (1,2).
While the principal symptoms of AIHA are clearly those directly associated with hemolysis and anemia, patients with AIHA are reportedly at an increased risk of thrombotic events, which occur in 11-27% of patients (3-10). Most of these thrombotic events are venous thromboses, especially venous thromboembolism (VTE), and occur typically when hemolysis is active, although arterial thromboses also occur (2-4,6,8,9,11-15). Based on these findings, British guidelines recommend prophylaxis for VTE with low-molecular-weight heparin for AIHA patients during acute exacerbation of hemolysis (2,11). However, reports on AIHA patients from Asia have not particularly addressed this issue, and whether or not Asian patients are similarly at an increased risk of thrombosis is unclear. Furthermore, the needs and indication of VTE prophylaxis for Asian patients have not been explored (16,17).
The observation that the incidence of venous thrombosis in the general population was lower in Japan than in Europe and the United States and the results of a study of paroxysmal nocturnal hemoglobinuria showed a significantly lower prevalence of thrombosis in Japanese patients than in American patients prompted us to study the occurrence of thrombosis in Japanese WAIHA patients and see if VTE prophylaxis is similarly recommended for Asian patients (18,19). We also explored whether or not WAIHA patients have intrinsic prothrombotic conditions associated with the disease by studying the available data on D-dimer, a marker of activated coagulation, and the percentage of immature platelet fraction (IPF%), which reflects the proportion of young and more reactive platelets and functions as a marker of the platelet activity (20).
Materials and Methods
Study design
This was a single-center retrospective study approved by the Ethics Committee of Dokkyo Medical University Saitama Medical Center. Medical records and laboratory data of consecutive patients diagnosed with WAIHA between April 2012 and March 2022 were retrospectively studied.
Materials population
A total of 48 consecutive patients were diagnosed with WAIHA in the 10-year study period. One patient was transferred with cardiopulmonary arrest and excluded from the study, leaving 47 patients as the subjects of this study. The diagnosis of WAIHA was made when a patient had clinical evidence of hemolytic anemia, such as low hemoglobin (Hb) concentration, increased reticulocytes, high serum indirect bilirubin, high lactate dehydrogenase (LDH), and/or low haptoglobin levels as well as a positive direct anti-globulin test (DAT), with other causes of hemolysis excluded. Patients with immune thrombocytopenia (ITP) preceding or diagnosed simultaneously with WAIHA were diagnosed with Evans syndrome. ITP was diagnosed when the platelet count was below 100×109/L and other causes of thrombocytopenia were excluded. Patients who had underlying conditions known to be associated with WAIHA were diagnosed with secondary WAIHA or Evans syndrome (21).
Laboratory analytical methods
The complete blood count findings and IPF% were determined by XE-5000Ⓡ (until January 2016) or XN-9000Ⓡ (since February 2016) automated hematology analyzer (Sysmex, Kobe, Japan). Polyspecific and monospecific DATs were studied with the standard tube method, and the column agglutination test was conducted with ORTHO VISIONⓇ (Ortho Clinical Diagnostic, Raritan, USA).
Statistical analyses
Median values and lower and upper ranges were the descriptive statistics used. Spearman's rank correlation coefficient was used to assess the correlation of two parameters, and the Mann-Whitney U test was used to compare two groups, with p values of ＜0.05 were considered statistically significant. The thrombosis-free survival was assessed with the Kaplan-Meier method.
Results
Characteristics of the patients
The characteristics of the 47 patients at presentation are shown in Table 1. The median age was 73 (range 19-89) years old, and there were 25 men and 22 women. Thirty-seven patients were diagnosed with WIAHA, and 10 were diagnosed with Evans syndrome. ITP preceded the diagnosis of WHAIA in 2 patients with Evans syndrome, and both were on corticosteroids, with platelet counts of 168 and 273×109/L when Evans syndrome was diagnosed. Twenty-one WAIHA patients (57%) had primary disease, and 16 had underlying conditions and were thus diagnosed with secondary WAIHA. The underlying conditions included autoimmune diseases in six, lymphoproliferative disorders in eight, small-cell lung cancer in one, and allogeneic stem cell transplantation in one. Eight patients (80%) with Evans syndrome were diagnosed with primary disease; the remaining 2 had a lymphoproliferative disorder and colon cancer and were considered to have secondary disease. Twenty-nine patients had at least one risk factor for thrombosis, such as high blood pressure (HBP), diabetes mellitus, dyslipidemia, or a history of thrombosis, and another had an aortic stent due to aortic dissection. These 30 patients were considered to have thrombotic risk. Ten patients were taking prophylaxis for thrombosis with anticoagulation and/or anti-platelet drugs.
Table 1.
Patients' Characteristics at Presentation.
| All patients (n=47) | WAIHA (n=37) | Evans syndrome (n=10) | |
|---|---|---|---|
| Age (years), median (range) | 73 (19-89) | 71 (19-89) | 74.5 (61-89) |
| Male/female | 25/22 | 21/16 | 4/6 |
| Primary/secondary | 29/18 | 21/16 | 8/2 |
| Thrombotic risk factor present, (n) | 30 | 22 | 8 |
| Anti-thrombotic therapy, (n) | 10 | 6 | 4 |
| Hemoglobin (g/dL) | 7.5 (3.7-12.9) | 7.2 (3.7-12.9) | 9.15 (4.1-11.9) |
| MCV (fL), median (range) | 102.7 (82.9-145) | 106.2 (82.9-145) | 95.5 (83.4-140) |
| Reticulocytes (×106/L), median (range) | 11.92 (0.053-42.09) | 12.11 (0.053-42.09) | 11.08 (0.17-26.07) |
| WBC (×106/L), median (range) | 6.4 (0.9-35.6) | 6.7 (1.2-35.6) | 5.2 (0.9-12.2) |
| Platelets (×109/L), median (range) | 203 (6-520) | 216 (24-520) | 33.5 (6-273) |
| LDH (U/L), median (range) | 343 (188-2,329) | 533 (188-2,329) | 296.5 (229-442) |
| Total bilirubin (mg/dL) | 1.96 (0.35-9.22) | 2.7 (0.35-9.22) | 1.415 (0.61-3.16) |
| Direct antiglobulin test pattern (n) | |||
| IgG only | 36 | 28 | 8 |
| IgG+C3d | 9 | 8 | 1 |
| Polyspecific only | 2 | 1 | 1 |
WAIHA: warm autoimmune hemolytic anemia, MCV: mean corpuscular volume, WBC: white blood cells, LDH: lactate dehydrogenase
Laboratory findings at presentation
The median Hb value at presentation was 7.5 (range, 3.7-12.9) g/dL, and the median mean corpuscular volume (MCV) was 102.7 (range, 82.9-145) fL (Table 1). The reticulocyte response was highly heterogeneous, as shown by the wide range of the reticulocyte count. All patients had positive polyspecific DAT results. Two patients were not subjected to monospecific DAT, while monospecific DAT data were obtained in 45 patients. Of these 45 patients, 36 were positive for IgG only, and 9 were positive for IgG and C3d, suggesting the activation of complements on the RBC surface.
D-dimer levels were studied only in 18 patients whose C-reactive protein levels were below 1.0 mg/dL in order to exclude the possible effects of inflammation on the vascular endothelium, and the data are shown in Fig. 1A. The D-dimer level was frequently elevated in patients with WAIHA (reference range, 0-1.0) with a median value of 2.57 (range, 0.55-9.4) μg/mL, suggesting that the coagulation was activated to some extent in a considerable number of patients with WAIHA. Elevation of the D-dimer level appeared to be less frequent in patients with Evans syndrome with a median of 1.1 (range, 0.71-2.49) μg/mL than those with WAIHA; however, the difference was not significant (p=0.21). There was no correlation between the D-dimer and LDH levels.
Figure 1.
(A) D-dimer levels of patients with warm autoimmune hemolytic anemia (WAIHA) (n=13) and Evans syndrome (n=5). (B) The percentage of the immature platelet fraction (IPF%) among patients with primary WAIHA (n=11) and Evans syndrome (n=8).
The IPF% was studied in 19 patients with primary WAIHA (n=11) and Evans syndrome (n=8) (Fig. 1B). Secondary cases were excluded, as the underlying diseases, especially lymphoproliferative disorders, might affect the thrombopoiesis and kinetics of platelets. The median IPF% of WAIHA patients was 1.8% (range, 0.4-11.1%), and that of Evans syndrome was 5.4% (range, 1.2-15.8%). The IPF% was significantly higher in patients with Evans syndrome than in those with WAIHA (p＜0.05). All but 1 patient with WAIHA had an IFP% within the reference range (reference range, 0.1-5.0%). The platelet count in that WAIHA patient with an increased IPF% was 131×109/L, which exceeded the value in the diagnostic criteria of ITP.
Thrombotic events and outcomes
Two patients were transferred to other hospitals shortly after the diagnosis of WAIHA, so the follow-up periods for all patients ranged from 0.5 to 105.2 months (median, 15 months). (Table 2, Fig. 2). No patients had thrombosis at presentation. During the observation periods, three patients had ischemic cerebral vascular accidents (Table 3). One patient had a transient ischemic attack (TIA) at 16.2 months, and 2 had a stroke at 85.1 and 47.6 months, respectively, after the presentation (Fig. 2). The patient who had TIA (Patient 1) was 75 years old at the presentation of primary Evans syndrome and had HBP but was not taking thrombotic prophylaxis. One of the two patients who had a stroke (Patient 2) was diagnosed with secondary WAIHA associated with autoimmune hepatitis. She was 73 years old at the presentation and had HBP but was not taking antithrombotic prophylaxis. Another patient (Patient 3) was 61 years old at the presentation of primary Evans syndrome and had active hemolysis which was compensated without treatment. He was hypertensive and taking edoxaban following catheter ablation for atrial fibrillation, but he unfortunately suffered a stroke. Both of the patients with Evans syndrome had positive anti-β2-glycoprotein I complex antibodies. No venous thromboembolism occurred in any patients either at presentation or during the follow-up period.
Table 2.
Outcomes of Patients with Autoimmune Hemolytic Anemia.
| All patients (n=47) | WAIHA (n=37) | Evans syndrome (n=10) | |
|---|---|---|---|
| Follow-up duration (months), median (range) | 15 (0.5-105.2) | 17.3 (0.5-105.2) | 14.9 (1-92.4) |
| Outcome | |||
| Alive | 22 | 18 | 4 |
| Transferred or lost to follow | 17 | 13 | 4 |
| Dead | 8 | 6 | 2 |
| Cause of deaths | |||
| Infection | 3 | 3 | |
| Malignancy | 4 | 3 | 1 |
| Heart failure | 1 | 1 | |
| Thrombotic complications | 3 | 1 | 2 |
WAIHA: warm autoimmune hemolytic anemia
Figure 2.
The thrombosis-free survival of patients with warm autoimmune hemolytic anemia (n=47).
Table 3.
Three Patients Who Had Thrombosis.
| Patient 1 | Patient 2 | Patient 3 | |
|---|---|---|---|
| Thrombotic event | TIA | Stroke | Stroke |
| Age at the presentation, sex | 75, male | 73, female | 61, male |
| Diagnosis | Evans syndrome | WAIHA | Evans syndrome |
| Time of thrombosis (months since presentation) | 16.2 | 85.1 | 47.6 |
| Thrombotic risk factors | High blood pressure | High blood pressure | High blood pressure |
| Prophylaxis for thrombosis | No | No | Edoxaban |
| WHAIHA status at thrombosis | In remission | Controlled | Compensated |
| Treatment | No | PSL (5mg) | No |
| Hb (g/dL) | 11.6 | 13.9 | 8.5 |
| LDH (U/L) | 223 | 241 | 459 |
TIA: transient ischemic attack, WAIHA: warm autoimmune hemolytic anemia, PSL: prednisolone, Hb: hemoglobin, LDH: lactate dehydrogenase
The outcomes of the patients are presented in Table 2. There were eight deaths. Two of the three patients who had an ischemic cerebral vascular accident were alive, and the other was transferred to another hospital nine months after the stroke; no deaths were attributable to thrombosis. Three patients with primary WAIHA died of infection, and one with primary Evans syndrome died of heart failure. All four deaths in the secondary cases were due to the underlying malignancies.
Discussion
Patients with both WAIHA and cold-type AIHA are considered to be at a greater thrombotic risk than general population (3-10). Hemolysis itself is a risk factor for thrombosis directed by various mechanisms, including free heme released from damaged RBCs, exposure of phosphatidylserine on the RBC surface, circulating RBC-derived microparticles, endothelial impairment, stimulated macrophages with increased procoagulant activity, and release of neutrophil extracellular traps (22-25). In addition, other prothrombotic mechanisms contribute to thrombosis in AIHA patients, such as autoantibody-induced RBC membrane alteration, presence of autoantibodies including the antiphospholipid antibodies (APAs), activation of the complement system, and splenectomy (8,12,23).
Most thrombotic events in AIHA patients are VTE, which is complicated mostly during active hemolysis and is an important cause of mortality (2-4,6,8,9,11-15). Therefore, British guidelines and major reviews from the United States recommend prophylaxis for VTE during acute exacerbation of hemolysis for AIHA patients (2,11,13). In addition, the recommendation from the International Consensus Meeting suggests the consideration of disease-specific risk factors, such as acute hemolysis, in addition to general risk factors, to determine the indication of VTE prophylaxis (1). However, these observations and recommendations are from Europe and the United States, and it is unclear if they are similarly applicable and should be considered in Asian patients. Furthermore, whether or not Asian AIHA patients are similarly at an increased thrombotic risk is also unclear, as, to our knowledge, there have been no reports from Asia that specifically address this issue, and the description of thrombotic complications in this population is also limited. A study from Korea that included 32 AIHA patients, of whom 31 had WAIHA, reported that 5 patients had thrombosis at the diagnosis, and 3 developed thrombosis with a median follow-up of 14 months; however, the details concerning the thromboses were not described (16). Another study from Thailand simply reported that 1 out of 20 deaths among WAIHA patients was due to acute coronary syndrome (17). Thus, the frequency and risk of thrombotic complications in Asian AIHA patients are unknown, and the need for prophylaxis for thrombosis has not been explored.
The present study involving 47 patients with WAIHA demonstrated that 3 patients were complicated with arterial thrombotic events (i.e. ischemic cerebral vascular accidents); however, no venous thrombosis occurred either at presentation or during a median follow-up period of 15 months. All three thrombotic events occurred in patients with other thrombotic risks more than one year after the presentation. In addition, no deaths were attributable to thrombosis. These findings are in contrast to the description in the British guideline noting that VTE is an important cause of mortality in AIHA patients but are similar to the reports from Korea and Thailand (2,16,17), suggesting that the thrombotic risk of Japanese WAIHA patients is not increased unless other thrombotic risk factors are also present. Thus, prophylaxis for thrombosis may not be recommended for all patients but should instead be considered on an individual basis depending on the presence of other risk factors (4,13). Although we did not include patients with cold-type AIHA in our study as we found only four patients with cold-type AIHA during the study period, a retrospective cohort study of hospital-based claims reported that Japanese CAD patients had an increased thromboembolic risk, with the risk of arterial thromboembolism particularly increased (26). This observation and our results imply that Japanese patients with AIHA are more susceptible to arterial than venous thrombosis, regardless of the type of autoantibodies, although the occurrence is infrequent in WAIHA patients. However, as the majority of arterial thromboembolism in CAD patients were myocardial infarction, and the risk of cerebral thromboembolism was not increased, this assumption needs to be explored in future studies.
While our results indicated that the risk of overt thrombosis was not increased in Japanese WAIHA patients, it might be possible that they had prothrombotic features and their coagulation system was activated to the level below the threshold to cause overt thrombosis. We studied the D-dimer levels of patients without apparent systemic inflammation at presentation to see if there was subclinical activation of the coagulation system and found that coagulation was indeed activated in a considerable number of patients, but not to such a level as to be associated with clinically overt thrombosis.
ITP patients are reported to be at an increased risk of both venous and arterial thrombotic complications, contrary to the assumption that they are unlikely to be complicated with thrombosis (27). The IPF% is measured automatically with automated hematology analyzers and reflects the percentage of young, reticulated platelets, which are more active than older ones (20,28,29). It is elevated in patients with ITP, reflecting the increased destruction of platelets. We suspected that patients diagnosed with WAIHA might be complicated with compensated ITP and have more active circulating platelets, so the IPF% value was studied (28-30). One patient diagnosed with WAIHA whose platelet count was 131×109/L had an elevated IPF%, suggesting that this patient had Evans syndrome with compensated thrombocytopenia. The IPF% of the other WAIHA patients was not elevated. As expected, the IPF% was significantly higher among patients with Evans syndrome than those with WAIHA. However, IPF% values in the three patients who had ischemic cerebral vascular accidents were not elevated (1.3% for the WAIHA patient, and 5.7% and 3.0% for the Evans syndrome patients). These results indicated that platelets were not activated in WAIHA patients as assessed with the IPF% unless they had Evans syndrome, and platelet activation did not appear to be associated with thrombosis.
Activation of complements was indicated to play a role in thrombosis in AIHA patients; however, we were unable to explore this point due to the small number of patients with complement activation and thrombosis (5,23). Studies on the associations between the presence of APA and thrombosis have reported variable results (8,9,31). Both patients with Evans syndrome complicated with ischemic cerebral vascular accidents were APA-positive, suggesting a possible association between APA and thrombosis; however, this should be confirmed in larger studies (32).
The major limitations of this study are the relatively small number of patients, the retrospective nature of the study, and lack of the tests that directly evaluate the activity of the platelets. Nonetheless, our results indicate that Japanese patients with WAIHA are not at a particularly increased risk of thrombosis because of their disease, although coagulation is often activated. Mortality due to thrombosis is rare, and the indication of prophylaxis for thrombosis should be determined individually after considering other risks.
The authors state that they have no Conflict of Interest (COI).
References
- 1.Jäger U, Barcellini W, Broome CM, et al. Diagnosis and treatment of autoimmune hemolytic anemia in adults: recommendations from the First International Consensus Meeting. Blood Rev 41: 100648, 2020. [DOI] [PubMed] [Google Scholar]
- 2.Hill QA, Stamps R, Massey E, et al. The diagnosis and management of primary autoimmune haemolytic anaemia. Br J Haematol 176: 395-411, 2017. [DOI] [PubMed] [Google Scholar]
- 3.Barcellini W, Fattizzo B, Zaninoni A, et al. Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients. Blood 124: 2930-2936, 2014. [DOI] [PubMed] [Google Scholar]
- 4.Roumier M, Loustau V, Guillaud C, et al. Characteristics and outcome of warm autoimmune hemolytic anemia in adults: new insights based on a single-center experience with 60 patients. Am J Hematol 89: E150-E155, 2014. [DOI] [PubMed] [Google Scholar]
- 5.Barcellini W, Zaninoni A, Fattizzo B, et al. Predictors of refractoriness to therapy and healthcare resource utilization in 378 patients with primary autoimmune hemolytic anemia from eight Italian reference centers. Am J Hematol 93: E243-E246, 2018. [DOI] [PubMed] [Google Scholar]
- 6.Lecouffe-Desprets M, Néel A, Graveleau J, et al. Venous thromboembolism related to warm autoimmune hemolytic anemia: a case-control study. Autoimmun Rev 14: 1023-1028, 2015. [DOI] [PubMed] [Google Scholar]
- 7.Hendrick AM. Auto-immune haemolytic anaemia - a high-risk disorder for thromboembolism? Hematology 8: 53-56, 2003. [DOI] [PubMed] [Google Scholar]
- 8.Pullarkat V, Ngo M, Iqbal S, Espina B, Liebman HA. Detection of lupus anticoagulant identifies patients with autoimmune haemolytic anaemia at increased risk for venous thromboembolism. Br J Haematol 118: 1166-1169, 2002. [DOI] [PubMed] [Google Scholar]
- 9.Audia S, Bach B, Samson M, et al. Venous thromboembolic events during warm autoimmune hemolytic anemia. PLoS One 13: e0207218, 2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Schär DT, Daskalakis M, Mansouri B, Mansouri B, Rovo A, Zeerleder S. Thromboembolic complications in autoimmune hemolytic anemia: retrospective study. Eur J Haematol 108: 45-51, 2022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Hill A, Hill QA. Autoimmune hemolytic anemia. Hematol Am Soc Hematol Educ Program 2018: 382-389, 2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Shah S, Padrnos L. Complications of autoimmune hemolytic anemia. Hematol Oncol Clin North Am 36: 353-363, 2022. [DOI] [PubMed] [Google Scholar]
- 13.Berentsen S, Barcellini W. Autoimmune hemolytic anemias. N Engl J Med 385: 1407-1419, 2021. [DOI] [PubMed] [Google Scholar]
- 14.Ungprasert P, Tanratana P, Srivali N. Autoimmune hemolytic anemia and venous thromboembolism: a systematic review and meta-analysis. Thromb Res 136: 1013-1017, 2015. [DOI] [PubMed] [Google Scholar]
- 15.Solari D, Alberio L, Ribi C, Grandoni F, Stalder G. Autoimmune hemolytic anemia and pulmonary embolism: an association to consider. TH Open 5: e8-e13, 2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Baek S, Lee M, Ryu H, et al. Clinical features and outcomes of autoimmune hemolytic anemia: a retrospective analysis of 32 cases. Korean J Hematol 46: 111-117, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Rattarittamrong E, Eiamprapai P, Tantiworawit A, et al. Clinical characteristics and long-term outcomes of warm-type autoimmune hemolytic anemia. Hematology 21: 368-374, 2016. [DOI] [PubMed] [Google Scholar]
- 18.Ota S, Matsuda A, Ogihara Y, et al. Incidence, characteristics and management of venous thromboembolism in Japan during 2011. Circ J 82: 555-560, 2018. [DOI] [PubMed] [Google Scholar]
- 19.Nishimura J, Kanakura Y, Ware RE, et al. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore) 83: 193-207, 2004. [DOI] [PubMed] [Google Scholar]
- 20.Buttarello M, Mezzapelle G, Freguglia F, Plebani M. Reticulated platelets and immature platelet fraction: clinical applications and method limitations. Int J Lab Hematol 42: 363-370, 2020. [DOI] [PubMed] [Google Scholar]
- 21.Hill QA, Stamps R, Massey E, et al. Guidelines on the management of drug-induced immune and secondary autoimmune, haemolytic anaemia. Br J Haematol 177: 208-220, 2017. [DOI] [PubMed] [Google Scholar]
- 22.L'Acqua C, Hod E. New perspectives on the thrombotic complications of haemolysis. Br J Haematol 168: 175-185, 2015. [DOI] [PubMed] [Google Scholar]
- 23.Capecchi M, Ciavarella A, Artoni A, Abbattista M, Martinelli I. Thrombotic complications in patients with immune-mediated hemolysis. J Clin Med 10: 1764, 2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Chapin J, Terry HS, Kleinert D, Laurence J. The role of complement activation in thrombosis and hemolytic anemias. Transfus Apher Sci 54: 191-198, 2016. [DOI] [PubMed] [Google Scholar]
- 25.Thachil J. Autoimmune haemolytic anaemia - an under-recognized risk factor for venous thromboembolism. Transfus Med 18: 377-378, 2008. [DOI] [PubMed] [Google Scholar]
- 26.Kamesaki T, Nishimura J, Wada H, et al. Demographic characteristics, thromboembolism risk, and treatment patterns for patients with cold agglutinin disease in Japan. Int J Hematol 112: 307-315, 2020. [DOI] [PubMed] [Google Scholar]
- 27.Swan D, Newland A, Rodeghiero F, Thachil J. Thrombosis in immune thrombocytopenia - current status and future perspectives. Br J Haematol 194: 822-834, 2021. [DOI] [PubMed] [Google Scholar]
- 28.Schmoeller D, Picarelli MM, Paz Munhoz T, Poli de Figueiredo CE, Staub HL. Mean platelet volume and immature platelet fraction in autoimmune disorders. Front Med (Lausanne) 4: 146, 2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Hamad MA, Schanze N, Schommer N, Nührenberg T, Duerschmid D. Reticulated platelets - which functions have been established by in vivo and in vitro data? Cells 10: 1172, 2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Sakuragi M, Hayashi S, Maruyama M, et al. Clinical significance of IPF% or RP% measurement in distinguishing primary immune thrombocytopenia from aplastic thrombocytopenic disorders. Int J Hematol 101: 369-375, 2015. [DOI] [PubMed] [Google Scholar]
- 31.Bongarzoni V, Annino L, Roveda A, Amendolea MA, Tirindelli MC, Avvisati G. Risk of thromboembolism in patients with idiopathic autoimmune hemolytic disease and antiphospholipid antibodies: results from a prospective, case-control study. Haematologica 90: 711-713, 2005. [PubMed] [Google Scholar]
- 32.Fattizzo B, Michel M, Giannotta JA, et al. Evans syndrome in adults: an observational multicenter study. Blood Adv 5: 5468-5478, 2021. [DOI] [PMC free article] [PubMed] [Google Scholar]