Platelet turnover and kinetics in immune thrombocytopenic purpura: results with autologous 111In-labeled platelets and homologous 51Cr- labeled platelets differ

Mean platelet survival and turnover were simultaneously determined with autologous 111In-labeled platelets (111In-AP) and homologous 51Cr- labeled platelets (51Cr-HP) in ten patients with chronic immune thrombocytopenic purpura (ITP). In vivo redistribution of the 111In-AP was quantitated with a scintillation camera and computer-assisted image analysis. The patients were divided into two groups: those with splenic platelet sequestration (spleen-liver 111In activity ratio greater than 1.4), and those with diffuse sequestration in the reticuloendothelial system. The latter patients had more severe ITP reflected by pronounced thrombocytopenia, decreased platelet turnover, and prominent early hepatic platelet sequestration. Mean platelet life span estimated with 51Cr-HP was consistently shorter than that of 111In-AP. Platelet turnover determined with 51Cr-HP was thus over-estimated. The difference in results with the two isotope labels was apparently due to greater in vivo elution of 51Cr. Although the limitations of the techniques should be taken into account, these findings indicate that platelet turnover is not always normal or increased in ITP, but is low in severe disease. We suggest that this may be ascribed to damage to megakaryocytes by antiplatelet antibody. The physical characteristics in 111In clearly make this radionuclide superior to 51Cr for the study of platelet kinetics in ITP.     

Platelet kinetics with indium-111 platelets: comparison with chromium-51 platelets

The application of 111In-oxine to platelet labeling has contributed to the understanding of platelet kinetics along three lines: 1. It allows the measurement of new parameters of splenic function, such as the intrasplenic platelet transit time, which has shed new light on the physiology of splenic blood cell handling. 2. It facilitates the measurement of platelet life span in conditions, such as ITP, in which 51Cr may undergo undesirable elution from the platelet as a result of platelet-antibody interaction. 3. It allows the determination of the fate of platelets, that is, the site of platelet destruction in conditions in which reduced platelet life span is associated with abnormal platelet consumption, as a result of either premature destruction of "abnormal" platelets by the RE system, or the consumption (or destruction) of normal platelets after their interaction with an abnormal vasculature. Future research using 111In platelets may yield further valuable information on the control as well as the significance of intrasplenic platelet pooling, on the role of platelets in the development of chronic vascular lesions, and on the sites of platelet destruction in ITP. With regard to the latter, methods will have to be developed for harvesting sufficient platelets representative of the total circulating platelet population from severely thrombocytopenic patients for autologous platelet labeling. This would avoid the use of homologous platelets, which is likely to be responsible for some of the contradictory data relating to the use of radiolabeled platelet studies for the prediction of the response of patients with ITP to splenectomy.     

The Effect of Antiplatelet Autoantibodies on Megakaryocytopoiesis

Immune thrombocytopenic purpura (ITP) is a disorder manifested by isolated thrombocytopenia. In vivo infusion studies in the 1950s and 1960s provided evidence that the thrombocytopenia was due to autoantibody-induced platelet destruction. However, there is mounting evidence that platelet production in this disorder may also be suppressed by antibodies. Early morphologic studies showed megakaryocytic damage in ITP, and these results have been confirmed by ultrastructural studies. Autologous platelet turnover studies in the 1980s showed that most ITP patients have either normal or reduced platelet turnover rather than increased turnover, as would be expected if platelet destruction were the only pathogenetic mechanism. More recently, in vitro culture studies of both adult and pediatric ITP have shown that some ITP plasmas suppress both megakaryocytopoiesis and thrombopoiesis. In view of these findings, both platelet destruction and suppression of platelet production seem likely to be involved in the pathogenesis of ITP.     

The use of electron microscopy in the investigation of the ultrastructural morphology of immune thrombocytopenic purpura platelets

Ultrastructural studies have proven useful for the accurate identification and classification of certain lymphoid and hematopoietic disorders; however, the value of electron microscopy in the diagnosis and clinical management of platelet pathology is less well defined. Electron microscopy has been used to evaluate inherited platelet disorders. In these disorders, certain platelet structural defects can be characteristic. Recently, we investigated the ultrastructural morphology and immunogold localization of IgG in platelets from patients with idiopathic thrombocytopenic purpura (ITP). The accelerated platelet destruction of ITP is mediated by antiplatelet autoantibodies directed against platelet surface glycoproteins and by the functional capacity of the reticuloendothelial system. The basic dysregulation that occurs in these patients remains unexplained. Traditionally, laboratory investigation of ITP has focused on the development of serologic assays to measure the autoantibodies. As an alternative investigative approach, determination of the immunomorphologic characteristics of platelet-associated IgG (PAIgG) in ITP platelets may prove useful in the diagnosis or clinical management of patients with ITP. Our results showed that the ultrastructural morphology of ITP platelets is similar to that observed for normal platelets. No structural abnormalities are observed in ITP platelets. Immunogold labeling of IgG within alpha-granules of ITP platelets is significantly higher than that of normal platelets. Additionally, in some ITP platelets, immunogold labeling is also observed on the platelet surface and within channels of the open-cannalicular system. In comparison, immunogold labeling of these structures in normal platelets, is rare, or absent. In conclusion, electron microscopic studies should contribute to furthering our understanding of this common autoimmune disorder, and may provide possible biological explanations for the increased levels of PAIgG in platelets from patients with ITP.     

Different patterns of platelet turnover in chronic idiopathic thrombocytopenic purpura

Platelet turnover, platelet production, platelet mean life span (MLS), platelet count, mean platelet volume (MPV) and platelet-associated antibodies have been examined in 26 patients with chronic idiopathic thrombocytopenic purpura (ITP) and in 1 patient with hypomegakaryocytic thrombocytopenia (HT). 15 ITP patients had normal or increased platelet turnover and platelet production, while 11 had subnormal values despite shortened MLS, while the patient with HT had normal MLS. The differences between the two groups with high and low platelet turnover were statistically significant. No correlation was found between kinetics parameters and bone marrow pattern in a total of 19 patients examined. These data suggest that in some cases of chronic ITP, the pathogenesis of thrombocytopenia can be due not only to the peripheral destruction of platelets, but also to a deficient platelet production by megakaryocytes. Since the number of megakaryocytes in bone marrow slides is not decreased in the low turnover compared with the high turnover group, it is possible that an impaired pattern of megakaryocyte maturation be the cause of the low platelet production in these patients, unlike in the HT patient where megakaryocytes are almost absent.     

The interpretation of platelet kinetic studies for the identification of sites of abnormal platelet destruction

The kinetics of platelets labelled with 111In have been studied in a series of 175 subjects including 18 normal volunteers, and 12 patients with idiopathic thrombocytopenic purpura (ITP), but excluding patients in whom there was scintigraphic evidence of intravascular platelet consumption. From analysis of the kinetics, the following parameters were calculated: splenic blood flow (SBF), intrasplenic platelet transit time (t-), splenic platelet pool capacity (expressed as a percentage of the total circulating platelet population), the fraction of the dose of labelled platelets ultimately destroyed in the spleen and the mean platelet life span (MPLS). SBF increased with increasing spleen size up to values of 25% total blood volume (TBV) per min. Some patients with immune complex related diseases were identified with elevated SBF (up to 24% TBV min-1) but without significant splenomegaly. Patients with cardiac decompensation had reduced SBF relative to spleen size. t- showed no relationship with spleen size. It tended to fall in patients who had high SBF relative to spleen size and to rise in those with low SBF relative to spleen size; i.e. it was inversely related to splenic perfusion (flow per unit tissue volume). The splenic platelet pool capacity is dependent on platelet input (SBF) and splenic platelet clearance (reciprocal of t-), and showed a close relationship with spleen size. When all subjects except those with ITP were considered, splenic platelet destruction showed a good correlation (r = 0.70, n = 42, P less than 0.001) with the splenic platelet pooling capacity. The ratio of the fraction of platelets destroyed in the spleen to the fraction pooling there, the D/P ratio, was approximately unity and did not appear to vary with MPLS, spleen size or the patient's condition, except in ITP where it varied between about 0.5 and 2. This variation in ITP was thought to be the result of an immune mediated re-direction of reticulo-endothelial platelet destruction. It is suggested that the D/P ratio, rather than the absolute quantity of 111In labelled platelets destroyed in the spleen, may be a more useful predictor of response to splenectomy since it takes into account the observed, appropriate, tendency for the spleen to destroy platelets in proportion to its platelet pooling capacity.     

Kinetics and in vivo distribution of 111-In-labelled autologous platelets in chronic hepatic disease: mechanisms of thrombocytopenia

The kinetics and distribution in vivo of autologous 111-In-labelled platelets were studied in 20 patients with chronic hepatic disease. The patients, 16 of whom were thrombocytopenic, exhibited a shortened platelet mean life time, a reduced platelet recovery and a normal platelet turnover, the latter 2 of which were positively correlated to the platelet count. Platelet in vivo recovery was negatively correlated to the spleen volume. In accordance with this, scintigraphic studies revealed that the spleen was the major organ of platelet sequestration and destruction, the role of the liver being almost negligible. Signs of platelet destruction in the bone marrow were also found. Our results indicate that splenic platelet pooling and accelerated platelet destruction, accompanied by inability of the bone marrow to compensate for the thrombocytopenia are the main causes of the thrombocytopenia accompanying chronic hepatic disease.     

Pathogenesis of chronic immune thrombocytopenia: increased platelet destruction and/or decreased platelet production

Chronic immune thrombocytopenia (ITP) is a haematological disorder in which patients predominantly develop skin and mucosal bleeding. Early studies suggested ITP was primarily due to immune-mediated peripheral platelet destruction. However, increasing evidence indicates that an additional component of this disorder is immune-mediated decreased platelet production that cannot keep pace with platelet destruction. Evidence for increased platelet destruction is thrombocytopenia following ITP plasma infusions in normal subjects, in vitro platelet phagocytosis, and decreased platelet survivals in ITP patients that respond to therapies that prevent in vivo platelet phagocytosis; e.g., intravenous immunoglobulin G, anti-D, corticosteroids, and splenectomy. The cause of platelet destruction in most ITP patients appears to be autoantibody-mediated. However, cytotoxic T lymphocyte-mediated platelet (and possibly megakaryocyte) lysis, may also be important. Studies supporting suppressed platelet production include: reduced platelet turnover in over 80% of ITP patients, morphological evidence of megakaryocyte damage, autoantibody-induced suppression of in vitro megakaryocytopoiesis, and increased platelet counts in most ITP patients following treatment with thrombopoietin receptor agonists. This review summarizes data that indicates that the pathogenesis of chronic ITP may be due to both immune-mediated platelet destruction and/or suppressed platelet production. The relative importance of these two mechanisms undoubtedly varies among patients.     

Pathophysiology and thrombokinetics in autoimmune thrombocytopenia

Studies that have measured platelet survival by autologous platelet labeling with (111)In and (51)Cr have differed in their results. Although all studies have revealed a significant decrease in platelet life span, the rates of platelets entering the circulation, a calculated and inferred determination, have been found to be moderately decreased to as much as five times normal. Several mechanisms have been proposed to explain an apparent decrease in platelet production, including a true decrease due to damage to the megakaryocytes by autoantibody, versus a decrease only in 'effective' production due to intramedullary destruction by the reticuloendothelial system. Recently, the identification of the cytokine, thrombopoietin, has allowed the evaluation of another aspect of the pathophysiology of thrombocytopenic states. Megakaryocyte growth factor levels are increased 10 to 20 times in patients who are thrombocytopenic due to chemotherapy or aplastic anemia, but may be decreased, normal, or only modestly raised in patients with immune platelet destruction. Autologous platelet survival measurements, prior to and while on therapy with a stable platelet count, reveal that removal of part of the reticuloendothelial system with splenectomy leads to increased platelet survival and platelet number. Similar studies reveal that corticosteroid treatment for immune thrombocytopenic purpura (ITP) effectively increases the rate of platelet production but does not change platelet survival. It may be that other therapies are effective by a combination of these mechanisms. Stimulation of thrombopoietin production or administering exogenous cytokine may have a role to play in future management of patients with ITP.     

Platelet survival and turnover: important factors in predicting response to splenectomy in immune thrombocytopenic purpura

Autologous indium-111 platelet sequestration and survival studies were performed on 59 immune thrombocytopenic purpura (ITP) patients, 21 of whom underwent splenectomy shortly thereafter. Sequestration patterns were primarily splenic in 46 patients, primarily hepatic in 6 patients, and both splenic and hepatic in 8 patients. The mean platelet survival ranged from 15 to 211 hr (normal, 180-220 hr), and mean platelet turnover (a measure of platelet production rate) varied from 99 platelets/microliters/hr to 7,585 platelets/microliters/hr (normal 1,200-1,600 platelets/microliters/hr). Among splenectomy patients, 13 had an excellent response, and 8 had a fair or poor response. Neither the pattern of platelet sequestration nor the quantity of platelet-associated IgG was useful in predicting response to splenectomy. There was, however, a striking correlation between platelet studies showing short survival/high turnover and subsequent excellent response to splenectomy. Conversely, patients with only moderately decreased survival and low turnover had an unpredictable response to splenectomy. This investigation demonstrates that ITP patients are a heterogeneous population and include a significant subset whose thrombocytopenia results primarily from decreased turnover. Platelet kinetic studies appear useful in predicting beneficial response to splenectomy.     

Comparative Studies of the in Vivo Kinetics of Simultaneously Injected 111In- and 51Cr-Labelled Human Platelets

The kinetics of simultaneously injected ¹¹¹In- and ⁵¹Cr-labelled platelets have been assessed in 40 subjects, 13 of them thrombocytopenic. 4 platelet survival models were applied. The mean life-time (MLT) of ⁵¹Cr-platelets from non-thrombocytopenic individuals was found to be slightly, but significantly, longer than that of ¹¹¹In-platelets by applying linear and exponential models for data fitting. The in vivo recovery (IVR) of ¹¹¹In-platelets was significantly higher than that of ⁵¹Cr-platelets in this patient group when using all 4 models. In the group of thrombocytopenic patients no statistically significant differences in MLT or IVR were found between ¹¹¹In- and ⁵¹Cr-platelets. However, for each of the 11 ⁵¹Cr-labelled platelet suspensions with the shortest MLT, a longer MLT was observed in the corresponding ¹¹¹In-platelets, a finding probably related to antibody-induced elution of ⁵¹Cr-activity. The same mechanism might be responsible for an increasing ¹¹¹In-/⁵¹Cr-recovery ratio in the early post-injection period. The efficiency of platelet isolation from blood prior to labelling seemed to influence the IVR, inasmuch as the difference in IVR between ¹¹¹In- and ⁵¹Cr-platelets was eliminated in the group where the yield of ¹¹¹In-platelets surpassed that of the ⁵¹Cr-platelets by more than 15 %.     

Kinetics of 111In-labelled platelets in healthy subjects

25 healthy subjects underwent platelet kinetic and scintigraphic studies following injection of 111In-labelled platelets. Using the multiple hit model, platelet mean lifetime averaged 185.3 hours (range 141.2-225.6), and platelet in vivo recovery averaged 56% (range 42-89). The platelet disappearance pattern was almost linear. However, in comparison with simultaneously injected 51Cr-labelled platelets (7 subjects studied), the 111In-platelet survival curves were slightly more curved. Our results indicate that this may be ascribed to a slight degree of elution of 111In from the circulating platelets. The plateau or even slight increase in circulating activity following the initial steep decline in activity appears mainly to reflect reversible sequestration of platelets in the spleen and maybe in the liver. Using a semiquantitative scintigraphic approach, we estimated 45%, 25% and 30% platelet destruction to occur in the spleen, liver and bone marrow, respectively. Our results indicate that the discrepancy between the course of circulating platelet-bound activity and of chest wall activity reflects platelet destruction in the bone marrow.     

Study of platelet-associated immunoglobulins of IgG,IgM, IgA,and IgE classes and platelet kinetics in 33 patients with idiopathic thrombocytopenic purpura

Summary The role of platelet-associated immunoglobulins (PAIg) of four different immunoglobulin classes -IgM, IgG, IgA, and IgE- and their relation to platelet count and platelet kinetics was studied in 33 patients with idiopathic thrombocytopenic purpura (ITP). During the course of 1 year, repeated determinations of PAIg were made. The results indicate that PAIgG, PAIgM, and PAIgA are present in all ITP patients, and that autoantibodies of all three Ig classes show highly significant correlations to the platelet counts (p< 0.0001). Double logarithmic negative correlations have been found between PAIgG and platelet count (r=–0.71), PAIgM and platelet count (r=–0.84), and PAIgA and platelet count (r=–0.79). Statistical analyses using partial correlation and multiple regression methods showed that PAIgM is predominantly related to the platelet count, whereas PAIgG and PAIgA are only of secondary importance. Accordingly, a relation of PAIgM (and PAIgA) to increased liver destruction of platelets was found in kinetic studies using¹¹¹indium-labeled platelets. Taken together, these results suggest a predominant role of PAIgM in the pathogenesis of ITP.     

The Exchangeable Splenic Platelet Pool Studied with Epinephrine Infusion in Idiopathic Thrombocytopenic Purpura and in Patients with. Splenomegaly

S ummary . The exchangeable splenic platelet pool (ESPP) was studied with epinephrine infusion and platelet labelling with ⁵¹Cr in five healthy students, 10 patients with idiopathic thrombocytopenic purpura (ITP) and 10 patients with splenomegaly. Five of the ITP-patients were studied after splenectomy. Platelet recovery of infused labelled platelets was calculated in all subjects and also in nine healthy volunteers who had been splenectomized for traumatic rupture of the spleen. Spleen size was determined by gamma camera scintigraphy. It was shown that the spleen is the only site of an exchangeable platelet pool in ITP and that this pool was of the same size in ITP-patients as in the normal controls, viz ∼30% of the total body platelet mass.
In patients with splenomegaly the ESPP was larger than that in controls and ITP-patients. A highly significant correlation was found between the ESPP and the spleen volume. In splenectomized and in non-splenectomized ITP-patients platelet recovery was significantly less than in their respective control groups, indicating that a proportion of the labelled platelets was immediately removed from the circulation after infusion into an ITP recipient and that the recovery of labelled platelets cannot be used as a measure of the ESPP in ITP.
It is suggested that the early destruction of platelets may be due to slight damage to the platelets during the labelling procedure. These damaged platelets can survive in a normal recipient, but are destroyed when infused into the'milieu' of an ITP-patient.     

Immunopathology of childhood idiopathic thrombocytopenic purpura

Modern laboratory techniques have begun to elucidate the pathophysiology of chronic childhood ITP. Quantitative assays of PAIgG, complement, immune complexes, and platelet kinetic studies have all provided important information. Chronic ITP of childhood appears to be similar to adult ITP, with production of an antibody directed against platelets and megakaryocytes. Most of the antibody is produced in the spleen, but other parts of the RES can also produce antibody. Complement, immune complexes, and cell-mediated immunity may play a role in the pathogenesis. Sensitized platelets are cleared by the RES, particularly in the spleen. Platelet kinetic studies show that platelet turnover is usually rapid with compensatory increased thrombopoiesis, but there are some patients who have decreased thrombopoiesis. Acute ITP of childhood is a brief illness, characterized by abrupt onset of hemorrhagic symptoms and complete recovery. It often follows a viral illness, suggesting that immune complexes as well as antibodies are important in the pathogenesis. Both the spleen and liver may be important organs of immune clearance.     

The Platelet Destruction Site in Thrombocytopenic Purpuras

The site of sequestration of ⁵¹Cr-labelled platelets has been studied in 465 subjects, of whom 317 suffered from idiopathic thrombocytopenic purpura. The validity of the method was demonstrated in several ways: a given subject usually showed the same site of platelet sequestration when investigated more than once even after a long interval; there were characteristic and very different platelet sequestration curves in the thrombocytopenias due to bone marrow hypoplasia, hypersplenism or ITP; and there was a correlation between the preoperative in vivo results and the radioactivity found in the spleen after splenectomy.
In ITP the destruction of labelled platelets was more often splenic in children and in patients whose thrombocytopenia responded to steroid therapy. There was a perfect correlation between the site of platelet destruction and the platelet rise immediately after splenectomy. There was a good correlation between the site of platelet destruction and the long-term effectiveness of splenectomy.     

The kinetics of short-lived indium-111 radiolabelled platelets

We have studied the kinetics of autologous 111In-labelled platelets in patients with reduced platelet life span (less than 4.5 d), most of whom were thrombocytopenic, and of homologous 111In-labelled platelets in patients with severe thrombocytopenia. Intrasplenic platelet transit time (t) was calculated by compartmental and deconvolution analysis. In patients with a mean platelet life span of less than a few h, compartmental analysis may not be valid and so only deconvolution analysis was applied. There was a close correlation between values of t given by the two approaches (r = 0.88, n = 18, P less than 0.001). In some patients with severely reduced mean platelet life span (MPLS), the deconvolved splenic platelet clearance curves appeared to approach an asymptote, the relative magnitude of which was indicative of the irreversible extraction fraction by the spleen of incoming platelets. In other patients with severely reduced MPLS resulting from abnormal intra-hepatic platelet destruction, the deconvolved splenic curves resembled the normal. The intrasplenic platelet transit time showed no clear relationship with other parameters. It was concluded that platelet pooling within the spleen is normal in patients with reduced platelet life span, including idiopathic thrombocytopenic purpura, even when the predominant site of destruction is the spleen, and that platelets are not delayed in transit through the spleen in preparation for their removal from the circulation and ultimate destruction.     

Platelet Survival and Platelet Production in Idiopathic Thrombocytopenic Purpura (ITP)

S ummary . Platelet mean life span (MLS) and platelet production were measured in 3–5 patients with idiopathic thrombocytopenic purpura (ITP) and in 21 healthy subjects.
The mean platelet production in ITP was 2.3 times normal: the highest values were 3–5 times normal. There was a highly significant negative correlation between platelet production and peripheral platelet count. With platelet counts above 50000μl, platelet turnover was within the upper part of the normal range, but with lower platelet counts, turnover progressively increased. It is concluded that the bone marrow in ITP increases platelet production in response to a low platelet count and that this response does not differ from that hitherto known to occur in man and animals rendered thrombocytopenic by thrombopheresis.
The disappearance curve of ⁵¹Cr labelled platelets in ITP consists of two components, a rapid initial one covering the first 15 min after infusion and then a slower one. The pattern was the same whether autologous or homologous platelets were used for labelling. It is suggested that the initial part of the curve does not represent in vivo survival but is due to slight damage to the platelets during the labelling procedure. These slightly damaged cells can resume normal viability when infused into a normal recipient but are rendered less viable when further damaged by platelet antibodies in patients with ITP. This explains the low recovery of infused labelled platelets in ITP recipients, despite the fact that the size of their splenic platelet pool is normal.     

Kinetics of indium-111-labelled platelets in HIV-infected patients with and without associated thrombocytopaenia.

Seven to 12% of HIV-infected patients have thrombocytopaenia. The pathophysiology of the thrombocytopaenia is not clear. It has been variously suggested that it may be caused by an increased peripheral platelet destruction, a defect in platelet production, or by a combination of these. The aim of the study was to elucidate the pathogenesis of HIV-associated thrombocytopaenia. We determined the mean platelet life span (MPLS) and calculated the turnover of autologous indium-111-labelled platelets in 17 HIV-positive patients, seven with thrombocytopaenia. The sites of sequestration of labelled platelets were quantified. The thrombocytopaenic patients had a very short MPLS (3.0+/-3.8 h) and a marked increase in platelet production (18.2+/-12.6x10(9)/l/h). The majority of these patients (5 of 7) had excessive sequestration of platelets in the spleen. Five of the patients with a normal blood platelet count had a shortened MPLS (109+/-23 h) and increased platelet turnover (3.8+/-1.2x10(9)/l/h), i.e. the increased peripheral platelet destruction was compensated for by increased platelet production. The other five patients with a normal platelet count had normal MPLS (195+/-11 h) and slightly increased platelet production (2.5+/-0.6x10(9)/l/h). We conclude that patients with HIV-associated thrombocytopaenia have increased peripheral platelet destruction. Platelet production is elevated but is insufficient to maintain a normal peripheral platelet count. In these patients platelets are predominantly sequestrated in the spleen. Patients with HIV infection and a normal blood platelet count may also have increased platelet production. This may be an early subclinical phase in the development of full-blown HIV-associated thrombocytopaenia.     

Platelet kinetic studies in patients with idiopathic thrombocytopenic purpura

PURPOSE: To determine the value in diagnosis and treatment of mean platelet life, platelet production, and major sites of platelet destruction in patients with idiopathic thrombocytopenic purpura (ITP). PATIENTS AND METHODS: Sternal or posterior superior iliac spine bone marrow aspiration was performed in 141 patients. Platelet kinetic studies with Indium-111 tropolonate labeled autologous platelets were utilized to determine platelet production. RESULTS: Two subgroups of patients could be defined. The first group (n = 81, 58%) had normal or increased platelet production and increased peripheral platelet destruction. These patients fulfilled the conventional criteria for ITP, including reduced platelet survival time (mean +/- SD, 1.6 +/- 1.4 days). Forty-eight (59%) of these patients had increased splenic sequestration and 30 (88%) of the 34 patients who underwent splenectomy had a complete or partial remission. The second group (n = 60, 42%) had decreased platelet production, with significantly greater platelet survival times (3.6 +/- 2 days, P <0.0001). In this group, the proportion of patients with complete or partial response to splenectomy (62%) was somewhat lower (P = 0.09). These patients mainly had ineffective platelet production in the bone marrow. CONCLUSIONS: Platelet kinetic studies suggest that ITP is a heterogeneous disease that comprises two subgroups. Further studies are needed to validate these findings and to determine their effect on the choice and outcome of therapy.