However, the entire picture often does not emerge in a single patient. Waiting for the entire pentad to develop before diagnosing TTP can have grave clinical consequences, and the presence of thrombocytopenia and unexplained microangiopathic hemolytic anemia are considered clinically sufficient to suspect TTP.
Laboratory evidence typically includes hemolytic anemia and thrombocytopenia. This procedure is the mainstay of therapy and brings 70 to 90 percent of patients with idiopathic TTP to remission. Corticosteroids are used in combination with daily therapeutic plasma exchange, although evidence from controlled trials of their efficacy in this setting is lacking.
However, if there is a strong clinical suspicion of TTP, plasma exchange should be initiated immediately without waiting for test results. Monitoring ADAMTS13 activity or inhibitor during initial plasma exchange therapy has had conflicting results in several studies and is generally not recommended for patients with acquired TTP. About 20 to 50 percent of patients with idiopathic TTP experience a relapse. Most relapses occur within the first two years after the initial episode, with an estimated risk of 43 percent for relapse at 7.
During clinical remission, persistence of autoantibodies also indicates increased risk. Patients who have a relapse and whose disease is refractory to therapeutic plasma exchange 10 to 20 percent of cases have been treated with corticosteroids, splenectomy or immunosuppressive agents cyclosporine, azathioprine or cyclophosphamide with varying rates of success.
Rituximab has recently been used as second-line therapy in refractory or relapsing immune-mediated TTP or idiopathic TTP with neurologic or cardiac symptoms associated with a poor prognosis. The disease is thought to have a relatively benign course, despite the frequent occurrence of very low platelet counts. This prevailing conception often guides therapeutic decisions. Design Age-adjusted bleeding risk was derived from a pooled analysis of ITP clinical series based on a systematic literature search.
The risk estimate was incorporated into a Markov model to determine its impact on prognosis. Results Seventeen case series complied with inclusion criteria, including patients with ITP. There were 49 cases of fatal hemorrhage over an estimated to patient-years at risk.
The rate of fatal hemorrhage before age adjustment was estimated at between 0. Age-adjusted rates were 0. Predicted 5-year mortality rates ranged from 2. A year-old woman remaining thrombocytopenic due to ITP was predicted to lose At age 70, predicted loss was 9. Conclusions Idiopathic thrombocytopenic purpura with persistent low platelet counts carries a grave prognosis. Therefore, an active therapeutic approach in the clinical management of affected patients should be considered.
In view of the significant potential implications of the model results, we call for initiating a well-designed prospective inception cohort study of patients with ITP. Nonetheless, the natural history of this condition is unknown. However, this estimate is an average risk obtained in a heterogeneous group of patients. It included both patients who had favorable responses to therapy, and those who remained refractory. In addition, it does not account for the large variations in bleeding risk at different ages.
Such dilemmas arise in patients refractory to first-line therapy or those at high risk for adverse effects. Hence, the consequences of withholding treatment must be weighed against immediate and long-term risks associated with this treatment.
Knowledge of the natural history of ITP in terms of bleeding risk and decline in life expectancy LE and quality of life QOL could greatly contribute to the decision process. We assumed no difference in bleeding rates between the sexes.
We used the results of the extensive systematic literature search performed by the ASH panel for establishing practice guidelines for ITP. The bleeding rate was calculated as the ratio between the pooled number of bleeding events and the pooled patient time at risk for major bleeding in the studies included in the analysis.
The rates of fatal bleeding events and major nonfatal bleeding events were calculated separately. The calculation of the latter was based on the subset of articles that followed up and reported major, nonfatal bleeding events. Patient time at risk for major bleeding events included the period prior to response to therapy in all patients and the follow-up period among refractory patients or patients who had experienced relapse. Time until response was estimated according to the treatment modality used: 2, 3, and 4 weeks for splenectomy, corticosteroid treatment, and cytotoxic therapy, respectively.
Estimation of the follow-up period for patients who did not respond to therapy or those who experienced a relapse was either 1 the exact period of follow-up, when reported, or 2 when the exact period was not stated, we estimated a plausible range between a high boundary maximum follow-up period in the study and a low boundary the median follow-up period.
We selected this low boundary based on the assumption that patients who remained thrombopenic tended to continue with medical attention for longer rather than shorter periods.
For patients who experienced relapse, time until relapse was subtracted from the follow-up period. Age adjustment of bleeding risk was based on the findings of Cortelazzo et al, 4 who reported the age-associated risk for major bleeding in chronic ITP.
They reported an odds ratio OR of 2. Considering the low absolute annual fatal bleeding risk, these ORs were used as estimates of the relative risks. We performed a subanalysis of the articles that reported the age distribution of their populations. Assuming linear relations, a set of equations was derived based on the age distribution of the pooled cohort, the relative risks in different age groups, estimated patient time in each age group, and the total number of bleeding events.
From these equations, the age-adjusted risks within each of the above age groups were determined Appendix. The incidence of disabling stroke was not specified in any of the studies included in our analysis.
Since this complication has major long-term effects on QOL, we used an indirect approach to estimate its frequency, based on the outcomes of hemorrhagic stroke from all causes ie, not necessarily related to ITP : 1 The proportion of strokes among patients with ITP and fatal bleeding events was calculated based on the studies in our analysis that reported the site of bleeding ie, central nervous system, gastrointestinal tract, etc.
At each cycle of the simulation lasting 1 year , any cohort member may suffer a major hemorrhage that may be fatal, disabling, or transient.
Accordingly, at the end of the cycle, members are transferred to dead or disabled states or remain in the well state. Major transient hemorrhagic events are assumed to exert a negative effect on ITP health states for 1 week. The probabilities of these events are determined according to the patient's age, based on the results of our pooled analysis. Patients also stand a chance of achieving a spontaneous remission, transferring into a remission state, or they may die from causes unrelated to ITP.
The simulation continues until the entire hypothetical cohort has died. The QALE is calculated by summing up the number of patients in each state multiplied by the utility of that state, and dividing the sum by the cohort size. The average LE for cohort members is calculated similarly using a utility value of 0 for death and 1 year for all other health states.
The model was constructed using DATA 3. Model probabilities were based on the estimates from our pooled analysis 4 , 9 - 24 Figure 2. Probabilities derived for age groups younger than 40, 40 to 60, and older than 60 years were affiliated with ages 30, 50, and 70 years, respectively.
Linear interpolation was used to estimate bleeding probabilities for ages between these points. The model considered death from any reason other than ITP, according to age and sex. Probabilities were based on the report of the National Center for Health Statistics. Utility coefficients introduced QOL weightings for the various health states into the model. Patients in remission were considered equivalent to the general population, based on a survey using the Quality of Well-Being Index QWB.
The QWB was previously used to estimate utility values for the general population, adjusted to age and sex. The QWB scale derives its values from an assessment of patient answers to questions directed toward current symptoms and health-related reductions in mobility and physical and social activity.
Scale scores range from 0 death to 1. For these patients, we used a utility value of 0. Sensitivity analysis was performed on all model estimates within plausible ranges within the DATA model. In addition, we used structural sensitivity analysis of assumptions regarding age adjustments.
The model was modified to examine the effect of no age adjustment and different levels of relative risks among age groups. In addition, we examined the effect of using an analytic exponential equation based on the risk at 3 ages 30, 50, and 75 years for calculation of age-adjusted risk. To validate the model's predictions of survival unrelated to ITP, the probability of remission was set to 1.
These studies included a total of patients with ITP. There were 49 cases of fatal hemorrhage. The total patient time at risk for fatal bleeding events was estimated between and patient-years low and high patient time estimates ; accordingly, the annual fatal bleeding rate without age adjustment was estimated to be between 0. Twelve of the 17 studies reported the anatomic site of bleeding.
Nine of the 17 included studies that reported the age distribution of their cohorts 4 , 9 , 10 , 12 - 14 , 17 , 19 , 24 : these studies included 34 of the 49 fatalities. Subanalysis of these 9 studies yielded risk for fatal bleeding event ranges between 0. Estimation of the risk for major, nonfatal hemorrhage was based on 2 studies with relatively elderly cohorts 4 , 12 ; 29 events were reported within an observation time ranging from 77 to patient-years.
Figure 4 , top, shows the cumulative probability for fatal bleeding for periods between 6 months and 5 years for each of the age groups analyzed. Predicted 5-year fatality ranges from 2. Seventy-six percent of the patients older than 60 years who remain with persistent low platelet counts will undergo at least 1 major nonfatal bleeding event during 2 years of follow-up Figure 4 , bottom.
A year-old woman with low platelet counts stands a A year-old woman is predicted to lose 5 quality-adjusted life years QALY 9. Table 2 gives results of the sensitivity analyses on all model estimates.
Implementation of low and high bleeding risk estimates yielded predicted QALEs of The complex, initially devised assays for ADAMTS activity and the possible limitations of static in vitro assays are described. A new, simple assay using a recombinant amino acid VWF peptide as substrate will hopefully be useful.
Recognition of this condition by clinicians is of utmost importance, because it can be easily treated and--if untreated--frequently results in death. The pathogenesis of cases without severe deficiency of the VWF-cleaving protease remains unknown, affected patients cannot be distinguished clinically from those with severely decreased ADAMTS activity.
0コメント