Thrombotic thrombocytopenic purpura (TTP) is a life-threatening form of thrombotic microangiopathy, characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and neurological deficits, renal injury, and fever caused by the severe deficiency of plasma ADAMTS13 activity. Although new drugs in recent years show promise in the management of TTP, therapeutic plasma exchange (TPE) remains the frontline treatment for TTP. Replacement fluids of TPE provide exogenous ADAMTS13, which reduces the generation of abnormal high-molecular-weight vWF multimers and prevents the generation of platelet rich-thrombi [
Here, we reviewed the medical records and follow-up data of patients with TTP at our institution. These data provide more information for improving replacement fluid selection in TPE treatments of patients with TTP.
This study was approved by the Ethics Committee of Fujian Medical University Union Hospital. As this study was retrospective and did not affect the patients’ treatments, written informed consent from patients was not sought.
Patients diagnosed with suspected TTP and receiving TPE treatment immediately between January 2013 and March 2018 were included in this study. The Bentley score [
Patients who received the TPE treatment in less than two procedures, those without all five components of the Bentley score, or those with Bentley scores less than 20 points were excluded. Plasma ADAMTS13 activity was detected in some of the enrolled patients.
According to ratio of FFP to CP used per patient, patients were divided into two groups: the CP-dominant group (FFP/CP<1) and FFP-dominant group (FFP/CP
The TPEs were performed by trained apheresis technologists with blood cell separators (COBE Spectra, Terumo BCT; MCS+, Haemonetics). Plasma products acting as replacement fluids were supplied by the Fujian Province Blood Center. The TPE procedures were performed with 1–1.5 volumes of plasma daily until complete therapeutic response was reached. After that, the TPE procedures were performed with 1–1.5 volumes of plasma every other day. The decision to cease TPE was made by clinical physicians.
Steroids (1 mg/kg/day) were used for 3 weeks as a combined treatment to TPE in patients with newly diagnosed TTP. Vincristine (1.4 mg/m2, up to 2.0 mg total dose), cyclophosphamide (0.4 g once a week, up to 2 g total dose), intravenous immunoglobulin (IVIg) (20 g/d, for 3-5 days), or rituximab (600 mg once a week, for 2-4 weeks) was used as an alternative treatment when patients achieved suboptimal response to treatments combining TPE with steroids.
Blood samples were acquired before suspected TTP patients received TPE treatment. Detection of plasma ADAMTS13 activity was performed at Beijing Hightrust Diagnostic Medical Test Laboratory using the surface-enhanced laser-desorption/ionization time-of-flight mass spectrometry.
Complete responses to treatment, remission, exacerbation, and relapse were defined according to the classification, diagnosis, and management of TTP from 2012 American Society for Apheresis (ASFA) consensus conference [
The time to achieve complete response was measured from the date when TPE began to the date the patient achieved the standard of complete response. Overall survival was measured from the date on which the patient was hospitalized to the date of death or last follow-up. All causes of death were included. Survival times were measured until August 22, 2018.
All statistical analyses were performed using the SPSS 19.0 software for Windows. The Chi-square test and independent
A total of 44 patients with suspected TTP were identified from January 2013 to March 2018. A total of 17 patients were excluded: 3 patients without all five components of the Bentley score, 10 patients whose Bentley scores were less than 20 points, and 4 patients who received TPE treatments in less than two procedures. The remaining 27 patients were enrolled in this study (Figure
Demographic and clinicopathological characteristics of the enrolled patients.
Character | CP dominant | FFP dominant | P value |
---|---|---|---|
Number | 11 | 16 | |
FFP/CP ratio |
|
|
0.0015 |
Age(years) |
|
|
0.53 |
Gender | 1.00 | ||
male | 5 | 8 | |
female | 6 | 8 | |
PLASMIC score | 0.39 | ||
5 | 1 | 0 | |
6 | 8 | 11 | |
7 | 2 | 5 | |
Bentley score | 0.43 | ||
20-30 | 8 | 8 | |
>30 | 3 | 8 | |
Platelet count (×109/L) |
|
|
0.95 |
Uncorrected reticulocyte (%) |
|
|
0.49 |
MCV (fL) |
|
|
0.67 |
INR |
|
|
0.04 |
Creatinine ( |
|
|
0.38 |
Indirect bilirubin ( |
|
|
0.58 |
Active cancer | 1(9.09%) | 1(6.25%) | 1.00 |
D-dimer (ug/ml) |
|
|
0.96 |
Procedures to complete response |
|
|
0.04 |
Time to complete response (days) |
|
|
0.04 |
Steroid use (%) | 11(100%) | 16(100%) | 1.00 |
Vincristine use (%) | 1(9.09%) | 0(0%) | 0.41 |
Cyclophosphamide use (%) | 3(27.27%) | 6(37.5%) | 0.69 |
IVIg use (%) | 4(36.36%) | 10(62.5%) | 0.25 |
Rituximab use (%) | 1((9.09%) | 2(12.5%) | 1.00 |
IVIg: intravenous immunoglobulin; MCV: mean corpuscular volume; INR: international normalized ratio.
Components of PLASMIC and Bentley score of the enrolled patients.
Patient Number | FFP/CP |
Platelet count (×109/L) | Indirect bilirubin |
Uncorrected reticulocyte (%) | Active cancer | MCV (fL) | INR | Creatinine |
D-dimer |
PLASMIC |
Bentley |
---|---|---|---|---|---|---|---|---|---|---|---|
1 | 0.61 | 8 | 22.7 | 21.63 | NO | 108.6 | 1.04 | 89 | 2.52 | 6 | 21 |
2 | 0.88 | 20 | 17.5 | 16.59 | NO | 101.1 | 1.05 | 62 | 2.1 | 6 | 21 |
3 |
1.86 | 6 | 65.1 | 22.29 | NO | 108 | 1.02 | 68 | 3.12 | 6 | 41.5 |
4 | 0.73 | 29 | 16.7 | 18.72 | NO | 94.4 | 1.13 | 64.3 | 1.65 | 6 | 21 |
5 | 0.93 | 9 | 23.5 | 14.83 | NO | 86.2 | 1.2 | 84 | 1.18 | 7 | 21 |
6# | 1.48 | 28 | 16.1 | 16.39 | NO | 109.3 | 1.01 | 67 | 2.13 | 6 | 21 |
7 | 0.85 | 6 | 28.1 | 19.74 | NO | 104 | 1.1 | 66 | 2.09 | 6 | 41.5 |
8 |
0.72 | 16 | 12.2 | 10 | NO | 95 | 1.04 | 39 | 0.65 | 6 | 21 |
9 | 1.14 | 12 | 80.4 | 16.73 | NO | 107.3 | 0.73 | 101 | 2.22 | 6 | 41.5 |
10 | 1.11 | 16 | 23.3 | 20.21 | NO | 99 | 0.99 | 62 | 0.8 | 6 | 21 |
11 | 0.94 | 11 | 82.3 | 4.84 | Thyroid | 71.7 | 1.18 | 178 | 6.21 | 5 | 20 |
12 | 1.40 | 18 | 18.6 | 9.76 | NO | 96.5 | 0.81 | 81 | 1.47 | 6 | 21 |
13 |
1.81 | 6 | 73 | 6.55 | NO | 84.1 | 0.98 | 86 | 1.84 | 7 | 41.5 |
14 | 0.56 | 6 | 49.7 | 19.32 | NO | 108.8 | 0.97 | 66.8 | 2.42 | 6 | 41.5 |
15 | 1.21 | 13 | 31.5 | 13.48 | NO | 100.6 | 0.98 | 68.4 | 3.76 | 6 | 41.5 |
16 | 0.73 | 21 | 17.5 | 4.83 | NO | 76.3 | 0.92 | 79 | 1.35 | 7 | 21 |
17 | 3.45 | 11 | 19.5 | 19.47 | NO | 86.4 | 0.72 | 108 | 2.97 | 7 | 21 |
18# | 1.12 | 18 | 17 | 4.22 | esophagus | 88.3 | 0.86 | 67 | 0.99 | 6 | 21 |
19 | 1.08 | 11 | 62 | 4.71 | NO | 87.2 | 1.03 | 92 | 1.08 | 7 | 41.5 |
20 | 1.28 | 10 | 38.4 | 8.94 | NO | 102.2 | 1.11 | 52 | 0.66 | 6 | 41.5 |
21 | 1.25 | 13 | 16.7 | 16.8 | NO | 106 | 1.09 | 74 | 0.89 | 6 | 21 |
22 | 1.17 | 24 | 36.6 | 7.42 | NO | 89.4 | 1.17 | 95 | 3.61 | 7 | 41.5 |
23 |
1.28 | 21 | 12.3 | 11.32 | NO | 92.5 | 1.04 | 104 | 1.07 | 6 | 21 |
24 | 1.17 | 19 | 8.9 | 3.4 | NO | 85.2 | 0.92 | 40 | 0.5 | 7 | 21 |
25 | 0.87 | 11 | 43.3 | 17.22 | NO | 90.4 | 1.07 | 85.8 | 1.68 | 6 | 41.5 |
26 |
1.16 | 8 | 27.2 | 19.43 | NO | 90 | 1.09 | 60 | 8.22 | 6 | 31.5 |
27 | 0.89 | 22 | 8.3 | 9.42 | NO | 97.3 | 1.05 | 142 | 2.01 | 6 | 21 |
MCV: mean corpuscular volume; INR: international normalized ratio;
Patient selection criteria for this study.
All patients enrolled had no previous history of transplantation. None of the patients had low PLASMIC scores (0–4), one patient had intermediate PLASMIC scores (5), and 26 patients had high PLASMIC scores (6–7). Only five patients were assessed for ADAMTS13 activity, which was less than 5% (0-2.5%) for all patients, and their PLASMIC scores were all greater than 6 (Table
Patients No. 3, 6, and 18 received 6, 6, and 4 TPE procedures, respectively, and did not achieve complete response before the clinical physicians ceased TPE for unknown reasons. Except for the three patients previously mentioned, the number of TPE procedures performed in patients of this study ranged from 2 to 23, with a mean of 6.8 TPE procedures per patient. In the CP-dominant group, 11 patients received 47 TPE procedures, with a mean of 4.3 TPE procedures per patient. In the FFP-dominant group, 13 patients received 117 TPE procedures, with a mean of 9 TPE procedures per patient.
Except for the three patients (No. 3, 6, and 18) previously mentioned, the number of TPE procedures performed to achieve complete response in patients of this study ranged from 2 to 23, with a mean of 6.3 TPE procedures per patient. In the CP-dominant group, 11 patients received 44 TPE procedures, with a mean of 4.0 TPE procedures per patient. In the FFP-dominant group, 13 patients received 107 TPE procedures, with a mean of 8.2 TPE procedures per patient. There was a significant difference in the number of TPE procedures to achieve complete response in the patients between CP-dominant group and FFP-dominant group (4.00 ± 0.92 vs 8.23 ± 1.63, P=0.04) (Table
Except for the three patients (No. 3, 6, and 18) previously mentioned, the time to achieve complete response in the patients of this study ranged from 3 to 47 days, with a mean of 10.3 days per patient. There was a significant difference in time to achieve complete response in patients between the CP-dominant group and FFP-dominant group (5.82 ± 1.39 days vs 14.08 ± 3.32 days, P=0.04) (Table
In addition to TPE, other therapeutics, such as steroids, vincristine, cyclophosphamide, IVIg, and rituximab, were used for patients with TTP in our study. There were no significant differences due to the use of other therapeutic methods used for patients with TTP between the CP-dominant group and FFP-dominant group (Table
All 27 patients were enrolled for the overall survival analysis. During the follow-up period, three patients were lost prior to the follow-up, seven patients died, and 17 patients survived. There were no significant differences in the overall survival of patients between the CP-dominant group and FFP-dominant group (13.75 ± 3.25 months vs 21.36 ± 3.84 months, P=0.14) (Figure
Kaplan-Meier curve of overall survival of patients with thrombotic thrombocytopenic purpura treated with therapeutic plasma exchange with fresh frozen plasma (FFP)- or cryosupernatant plasma (CP)-dominant replacement fluids.
TTP is a rare hematologic disorder. The pathogenesis of TTP is based on unrestrained growth of microvascular platelet rich-thrombi due to the deficiency of plasma ADAMTS13 activity, the only biologic marker specific for TTP [
In our study, we used the Bentley score to predict the prognosis of TTP, and the PLASMIC score to predict the severity of ADAMTS13 deficiency. The Bentley score of all patients enrolled in our study was greater than 20 points. The PLASMIC score of all patients enrolled in our study ranged from 5 to 7. These results are different from those of other studies. We believe that screening using the Bentley score excluded patients who have similar symptoms to TTP but with a different diagnosis. In our study, ADAMTS13 activity was measured in only five patients, revealing severe deficiency of ADAMTS13 activity in the plasma. The PLASMIC scores of these patients were high (6–7). This phenomenon validated the PLASMIC score prediction in the severity of ADAMTS13 activity deficiency, though this evidence is not strong. This result was also similar to that reported in studies from other centers [
As the first-line treatment, TPE can replenish ADAMTS13 and block microvascular thrombosis [
First, we analyzed the effects of the CP-dominant and FFP-dominant replacement fluids used on the early response to TPE in patients with TTP. With regard to the number of TPE procedures needed to achieve complete response, a higher number of TPE procedures was required in the FFP-dominant group than in the CP-dominant group. With respect to the time needed to achieve complete response, more time was needed in the FFP-dominant group than in the CP-dominant group. We hypothesized that a lower concentration of vWF in the CP-dominant replacement fluid may contribute to this result, since higher concentrations of vWF accelerate the formation of platelet thrombus in plasma [
Then, we analyzed the effect of the CP-dominant and FFP-dominant replacement fluid on the survival of patients with TTP. However, no significant difference was observed in the overall survival between the two groups.
In conclusion, our data showed that the CP-dominant replacement fluid was superior to the FFP-dominant replacement fluid in early response to TPE in patients with TTP, but did not have an impact on the patients’ long-term survival. However, there are some limitations to our study. Since TTP is a rare disease, the limited sample size may restrict the validity of our results. Although the CP-dominant replacement fluid was a better choice, the difference in the FFP-to-CP ratio in each group makes it impossible to provide a precise ratio for the FFP and CP combination. Therefore, we believe that a prospective, multicenter, large-sample clinical trial is needed for further studies.
Some data of the demographic and clinicopathological characteristics and survival of TTP patients used to support the findings of this study are restricted by the Ethics Committee of Fujian Medical University Union Hospital in order to protect patients’ privacy. Other data used to support the findings of this study are included within the article. Data are available from the corresponding author (Haobo Huang: huanghaobo1981@163.com; Liping Fan: fanliping1982@163.com) for researchers who meet the criteria for access to confidential data.
The authors state that they have no conflicts of interest.
This study was funded by the Startup Fund for Scientific Research of Fujian Medical University (Fuzhou, China; Grant no. 2017XQ1030 and 2016QH035), the Natural Science Foundation of Fujian Province (Fuzhou, China; Grants no. 2018J01311), the Medical Elite Cultivation Program of Fujian Province (Fuzhou, China; Grant no. 2018-ZQN-30), and the Joint Funds for the Innovation of Science and Technology of Fujian Province (Fuzhou, China; Grant no. 2016Y9027).