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The Oncologist, Vol. 1, No. 6, 371–380, December 1996
© 1996 AlphaMed Press

The Problem of Thrombocytopenia after Hematopoietic Stem Cell Transplantation

Richard A. Nasha,b, Ted Gooleya, Chris Davisa, Frederick R. Appelbauma,b

a Fred Hutchinson Cancer Research Center and the b University of Washington School of Medicine, Seattle, Washington, USA

Correspondence: Richard A. Nash, M.D., Fred Hutchinson Cancer Research Center, 1124 Columbia Street, M318, Seattle, Washington 98104-2092, USA. Telephone: 206-667-4978; Fax: 206-667-6124.


   ABSTRACT
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Thrombocytopenia after hematopoietic stem cell transplantation (HSCT) is associated with an increased risk of bleeding and utilization of significant resources. This review presents an analysis of risk factors associated with delayed platelet engraftment. The retrospective analysis included 1,468 recipients of autologous or allogeneic transplants treated between January 1, 1990 and July 1, 1995. Risk factors associated with delayed platelet engraftment after autologous HSCT included use of marrow rather than peripheral blood as the source of stem cells, being transplanted for acute myeloid leukemia rather than other diseases, positive patient serology for cytomegalovirus and the presence of infection post-transplant before engraftment. Risk factors associated with delayed platelet engraftment after allogeneic marrow transplantation included unrelated as opposed to related donor transplants, being transplanted for diseases other than chronic myelogenous leukemia, increased age, onset of acute graft-versus-host disease (GVHD), male gender, the administration of methotrexate for GVHD prophylaxis and the presence of infection before engraftment. Delayed platelet recovery is associated with decreased survival after both autologous and allogeneic transplants. Management of delayed platelet recovery by transfusion of blood products requires significant medical resources and is of some risk to the patients. Further development of new strategies may safely reduce the need for blood products. These include peripheral blood stem cell transplants (allogeneic and autologous), new algorithms for administering routine platelet transfusions and investigative biological agents for stimulating megakaryocytopoiesis. Further studies may elucidate the cause of increased platelet consumption associated with infection and GVHD.

Key Words. Platelets • Thrombocytopenia • Transplantation • Hematopoiesis • Allogeneic • Autologous • Leukemia


   INTRODUCTION
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Myeloablative chemotherapy and radiotherapy followed by hematopoietic stem cell transplantation (HSCT) is a successful treatment strategy for a variety of hematologic malignancies and aplastic anemia, as well as congenital immunodeficiencies and inborn errors of metabolism [1]. Depending on the diagnosis being treated and the availability of donors, the source of stem cells can be autologous or allogeneic and derive from the marrow or mobilized peripheral blood. Mobilized stem cells are usually harvested from the peripheral blood after four days of G-CSF treatment or during the recovery of counts after chemotherapy [2, 3]. Thrombocytopenia is one of the critical problems that must be managed after myeloablative treatment and HSCT. With routine platelet transfusions, serious bleeding is now unusual in the absence of significant post-transplant complications like infection, graft-versus-host disease (GVHD) or veno-occlusive disease (VOD) of the liver. Alloimmunization to random donor platelets may occur but is effectively managed in most cases by administering HLA-matched platelets. This review will attempt to analyze some of the characteristics of thrombocytopenia after transplantation, including trying to identify risk factors associated with delayed platelet recovery. Transplant complications associated with delayed platelet engraftment or secondary failure in platelet counts will also be discussed. The identification of risk factors for delayed platelet engraftment and secondary failure should be useful for the design and conduct of future studies of biological agents that stimulate megakaryocytopoiesis, including interleukin 11 (IL-11) and Mpl-ligand.

For the purpose of this article and for many previous analyses of clinical studies at the Fred Hutchinson Cancer Research Center (FHCRC), the day of platelet engraftment was defined as the first of seven consecutive days with a platelet count >20,000/µl without platelet transfusion support. The rationale for the use of 20,000 platelets/µl as the threshold for engraftment was the perceived risk of bleeding at counts below this level based on earlier studies. More recently, the studies on which this practice was based have been re-evaluated.

The practice of administering prophylactic platelet transfusions at a 20,000/µl threshold was established in the 1960s when platelet transfusion support of leukemia patients after chemotherapy was being developed [4, 5] as recently reviewed by Ernest Beutler [6]. In 1978, Slichter and Harker, using fecal blood loss as an indicator of bleeding [7], noted a threshold of 5,000 platelets/µl at which fecal blood loss increased markedly. The issue of the threshold platelet count at which platelet transfusions should be routinely administered has also been readdressed by other investigators. Gmür et al. reported in a 1991 study on the successful use of an algorithm for platelet transfusions in which platelets were transfused at a level of <=5,000 if patients were stable without fever or hemorrhagic complications [8]. If fever or minor hemorrhagic complications occurred, then routine platelet transfusions were administered at a platelet count of <=10,000/µl. The platelet transfusion practice at this center prior to 1993 was to maintain platelet counts above 20,000/µl. Subsequently, after 1993, stable patients being followed in the outpatient department were transfused at platelet counts <10,000/µl, and inpatients who were less stable or were early after transplantation were routinely transfused at platelet counts <20,000/µl. For interventions required after transplantation, it was the general practice to maintain platelet counts >20,000/µl for one day for bronchoscopy, >=50,000/µl for one day for central line placement or lumbar punctures, >=50,000/µl for three days for endoscopy of the gastrointestinal tract with biopsy, and >50,000-70,000/µl for five days for major surgery. An understanding of the current practices for routine platelet transfusions is important for any discussion of delayed platelet engraftment after marrow transplantation, since it has been a very effective practice in preventing most significant bleeding complications without pre-existing significant lesions. However, administration of platelets, as with any blood product, is not without risk and is a costly practice.


   METHODS
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
A retrospective analysis of 1,468 patients transplanted at the FHCRC between January 1, 1990 and July 1, 1995 was performed. Patients were categorized according to the source of stem cells and the disease for which they were transplanted (Table 1Go), and eight groups were defined. The day to platelet recovery was determined for all patients as previously defined. Patients were followed to day 60 or discharge after autologous marrow or stem cell transplantation, and to day 100 or discharge after allogeneic marrow transplants. After autologous transplants, the database beyond day 60 was less complete since patients were discharged from the transplant service earlier than those patients who had received allogeneic marrow transplantation. Of the 523 autologous patients, the source of stem cells was "mobilized" peripheral blood in 247 patients and marrow in 276 patients. Of 945 patients who received allogeneic marrow transplantation, 475 were from HLA-matched siblings and 470 were from matched unrelated volunteers. Also analyzed was secondary failure of platelet counts. This was defined as a recovery of platelet counts to >50,000/µl without platelet transfusions for seven days with a subsequent drop to below 20,000/µl.


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  		Table 1. Selected patient characteristics
 
In order to identify risk factors associated with the probability of engraftment, multivariable Cox proportional hazards regression models were fit with the outcome of engraftment. Potential explanatory variables included diagnosis and type of transplant, age at transplant, occurrence of acute GVHD (for allogeneic patients), patient gender, patient/donor cytomegalovirus (CMV) serostatus (patient serostatus for autologous patients), use of methotrexate (MTX) for GVHD prophylaxis (for allogeneic patients) and presence of any infection prior to engraftment. Occurrence of acute GVHD and presence of infection were used as time-dependent covariables in the models. Allogeneic and autologous patients were analyzed separately, as associations between the probability of engraftment and various explanatory variables did not appear similar across these groups. No adjustments were made for multiple comparisons in calculating reported p values. All p values are two-sided and are derived from the Wald test. The log-rank test was used to compare the hazard of all-cause mortality between patients who had engrafted and those who had not engrafted, by day 60 (for autologous patients) or day 100 (for allogeneic patients) or discharge home.


   RESULTS
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Engraftment after Autologous Transplantation
There were 523 autologous HSCT patients eligible for analysis in this study. The source of hematopoietic stem cells (marrow versus peripheral blood stem cell [PBSC]) and diagnosis at transplant (acute myeloid leukemia [AML] versus diseases other than AML) were important risk factors for platelet recovery (Fig. 1Go). For patients with diseases other than AML, platelet engraftment was significantly shorter after PBSC transplants (median = 10; range 6-67 days) compared to marrow (median = 24; range 3-95 days). The conditional probability of platelet engraftment (probability of platelet recovery given that patient is alive and relapse free) on day 35 was 0.56 and 0.85, and on day 60 was 0.76 and 0.90 for marrow and PBSC transplants, respectively. The diagnosis of AML was a statistically significant predictor for poor platelet engraftment after both autologous marrow (p < 0.001) and PBSC (± marrow) transplantation (p = 0.058) when compared to transplants for "other diseases" with PBSC. In most cases of autologous marrow transplantation for AML, the marrow was purged but the delay in engraftment in this disease was present even after nonpurged PBSC transplants (± marrow) relative to PBSC transplants for "other diseases." The median day-to-platelet engraftment for patients with AML was 38 (range 12-87) days after marrow transplant and 14 (range 6-35) days after PBSC transplant. Only 23 AML patients have received nonpurged PBSC transplants (± marrow), so these observations will need confirmation. Other factors associated with delayed platelet recovery after autologous transplantation were a positive serology for CMV and the presence of infection post-transplant before engraftment (Table 2Go). Age at transplant and patient gender were not statistically significant risk factors for delayed platelet recovery.



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  		Figure 1. Conditional probability of platelet recovery after autologous HSCT for AML or diseases other than AML. Source of stem cells is from PBSCs or marrow.

 

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  		Table 2. Autologous patients
 
Recovery after Allogeneic Transplantation
There were 945 patients eligible for analysis in this period after allogeneic HSCT. The source of marrow (HLA-matched unrelated donor [URD] versus HLA-matched related donor [RD]) and diagnosis at transplant (chronic myelogenous leukemia [CML] in chronic phase versus diseases other than CML) were important predictors for platelet recovery. Among the four primary groups of allogeneic marrow transplant patients analyzed (CML-RD, CML-URD, other than CML-RD and other than CML-URD), patients transplanted for CML from RDs were significantly more likely to achieve platelet engraftment compared to the other three groups. Median day to engraftment for this group was day 20 (range 7-75) compared to day 22 (range 10-98) for CML patients transplanted from URDs (Fig. 2Go). The conditional probability of platelet engraftment on day 35 was 0.89 and 0.78, and on day 100 was 0.96 and 0.91 for CML-RD and CML-URD transplants, respectively. In this analysis, the effect of a "diagnosis other than CML" was observed on delay in platelet recovery after both HLA-matched RD and URD transplants. Diseases other than CML were predictors for a delay in platelet recovery in a multivariable analysis when compared to CML groups of the same stem cell source (Table 3Go). Other factors in a multivariable analysis associated with delay in platelet engraftment were increased age as a continuous variable, the onset of grades II-IV acute GVHD before engraftment, male gender, the administration of MTX for GVHD prophylaxis and the presence of infection before engraftment. The development of VOD of the liver was not considered for this analysis since this information was not readily available.



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  		Figure 2. Conditional probability of platelet recovery after allogeneic HSCT for CML or diseases other than CML. Source of stem cells is marrow from HLA-matched related or unrelated donors.

 

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  		Table 3. Allogeneic patients
 
Secondary Failure
A decrease in platelet counts may occur after patients have achieved engraftment. Patients were considered secondary failures if, after recovery to platelet counts of 50,000/µl for seven days, there was a subsequent decrease in platelet counts below 20,000/µl. A platelet count of 50,000/µl was selected since this was a minimum required for minor procedures, and helped to avoid small variations in the platelet count triggering the secondary failure endpoint. Of 146 patients who received autologous PBSC transplant for a disease other than AML and had platelet engraftment to 50,000/µl, 16 patients (11%) had secondary failure of platelet counts. This was similar to the experience in autologous marrow transplants for diseases other than AML, where among 108 patients who achieved platelet engraftment to 50,000/µl by day 60, five (5%) developed secondary failure. Of 15 patients who recovered to 50,000/µl after autologous marrow transplant for AML, one patient (7%) developed secondary failure. Five of nine patients (56%) developed secondary failure after autologous PBSC transplants for AML. Secondary failure occurred frequently after allogeneic marrow transplantation. Twenty of 160 patients (13%) went on to secondary failure in the group of patients who received matched related transplants for CML in chronic phase. However, the probability of secondary failure was higher after RD transplants for diseases other than CML and URD transplants for CML or other diagnoses than CML (22%, 28% and 24%, respectively). Further analysis is required to identify other factors associated with secondary failure.

Platelet Transfusions
Mean platelet transfusions per week are shown in Figure 3Go for autologous and allogeneic patients. This figure illustrates that platelet utilization for support of patients after autologous HSCT has been greatly diminished with the use of peripheral blood rather than marrow. However, there also was a change in the practice of routine platelet transfusions during the period of time we were increasing the number of PBSC transplants at our center. The increased utilization of platelets after URDs compared to related transplants is also illustrated. Also demonstrated in Figure 3Go is the persisting requirement of platelet transfusions in a group of patients up to 15 weeks after transplant.



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  		Figure 3. Mean weekly platelet transfusion events after autologous HSCT for diseases other than AML and allogeneic HSCT for CML. Each event represents a transfusion of single donor apheresed platelets or random donor platelet units.

 
Association of Platelet Recovery and Survival
Recovery of platelet counts by day 60 for autologous stem cell transplants and by day 100 for allogeneic marrow transplants is an important predictor of survival for both these groups. Among the autologous patients, 427 of 523 (82%) survived relapse-free to day 60. Of these 427, 322 (75%) had platelet recovery by day 60 and 105 (25%) failed to recover platelets. The incidence of subsequent mortality at any time from transplant-related complications or relapse was 0.39 in patients who had platelet recovery and 0.56 in patients who had failed to recover platelets (p = 0.0003 by log-rank test). This difference persisted even after adjusting for disease, type of cell used for transplant, patient age, patient gender and CMV serostatus. Among the allogeneic patients, 670 of 945 (71%) survived relapse-free to day 100. Of these 670, 616 (92%) recovered platelets by day 100 and 54 (8%) failed to recover. The incidence of mortality at any time from transplant-related complications or relapse was 0.30 in patients who had platelet recovery and 0.57 in patients who failed to recover (p < 0.0001 by log-rank test). Patients who fail to recover platelet counts after either autologous or allogeneic stem cell transplantation are a high-risk group, and this must be considered in any studies of interventions to reverse states of persistent thrombocytopenia.

In a separate analysis, a review of autopsies performed on FHCRC patients in 1994 and 1995 was completed to determine the incidence of significant bleeding complications contributing to the cause of death (n = 150) (unpublished). Of 150 patients, 40 (26.6%) patients were considered to have had significant bleeding complications which contributed to their death. These events occurred in the gastrointestinal tract (18), lungs (12) and cranium (8). Thirty-four patients (85%) had significant disease (severe GVHD, infections or adult respiratory distress syndrome [ARDS]) associated with the hemorrhagic event, suggesting that control of hemorrhage was unlikely to affect eventual outcome. Six patients (15%) had no pathology identified on autopsy to explain the severe hemorrhagic event associated with significant thrombocytopenia. During these two years, more than 800 transplants were performed at this center. Survival is unlikely to be an endpoint for studies of interventions affecting platelet recovery since the frequency of spontaneous hemorrhagic events contributing to death is very low, and it is improbable that significant differences between treatment groups could be measured.


   DISCUSSION
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The causes of persisting thrombocytopenia after marrow or PBSC transplantation are varied and complex. An understanding of already-defined mechanisms for the development of thrombocytopenia in a nontransplant setting is helpful in the consideration of this issue. Delayed platelet engraftment might result from a failure of production in a marrow that is recovering and then undergoes a second insult. It might also arise from a decrease in the survival of platelets in the circulation. There are several possible mechanisms with which platelet survival may be reduced. In many circumstances, a combination of a recovering marrow, still limited in its capacity to produce platelets, and an event that shortens platelet survival which might otherwise have been well-tolerated, results in persisting thrombocytopenia or secondary failure. GVHD, VOD of the liver and infections are common complications after transplantation and are all associated with a decreased survival of platelets in the circulation. In the current analysis, both the development of GVHD and infections contributed to delayed platelet engraftment.

Decreased Production
Decreased platelet production after transplantation has been associated with A) insufficient number of transplanted cells; B) relapse or persistence of hematologic disorders for which the patient was transplanted; C) persistent marrow fibrosis; D) graft-versus-stroma effect, or E) drug-induced inhibition of marrow. A poorly functioning stem cell graft is likely the most frequent reason for inadequate platelet production relative to the demand for platelets, and may relate to transplantation of inadequate numbers of stem cells/progenitor cells or accessory cells. It is now clear that improved platelet recovery is seen after both autologous and allogeneic transplantation when the number of transplanted cells is increased. After G-CSF-mobilized autologous PBSC transplants, a correlation between platelet engraftment (a platelet count >20,000/mm3 and transfusion independent for seven days) and the number of CD34 cells in the graft was observed. In an analysis of 243 patients, three groups of patients were defined based on the number of autologous CD34+ cells in the graft: A) >5 x 106/kg; B) 2.5 x 106/kg, and C) <2.5 x 106/kg. As cell dose decreased, there were progressively longer intervals to achieve platelet engraftment [9]. This has been confirmed recently in a larger study of platelet engraftment after transplantation with G-CSF-mobilized PBSCs [10]. An effect of cell dose is also observed after allogeneic stem cell transplantation even though transplant-related complications like GVHD and infection which affect platelet recovery are frequent. Nucleated cell dose and CD34+ cell dose are substantially higher in "mobilized" PBSC grafts than in marrow grafts. In a cohort of 37 patients with advanced hematologic malignancies who received G-CSF-mobilized PBSCs (median 12.3 x 106 CD34+ cells/kg [range 3.84 - 21.64]) from HLA-matched siblings for advanced hematologic malignancy, the median day to platelet engraftment was day 11 compared to day 15 in a concurrent control group of 37 patients who received a marrow graft and were matched for diagnosis, disease stage, age and GVHD prophylaxis [11]. The PBSC group required a median of 24 units of platelets compared to 118 units of platelets for marrow recipients. The improved engraftment may not necessarily be a cell-dose effect only but a result of the stem cell source. These results need to be confirmed in a phase III study. Further support for the importance of cell dose in enhancing platelet recovery came from a study of patients transplanted from URDs. After marrow transplantation from HLA-matched URDs for acute leukemia, those patients who received greater than the median marrow cell dose (3.7 x 108/kg) for the whole group had a marked increase in the rate and incidence of recovery of platelets at 100 days compared to those patients who received <=3.7 x 108/kg (J. Sierra et al., unpublished). The beneficial effects of an increased number of cells in the graft is an important observation in view of the otherwise high incidence of delayed platelet recovery after transplantation for patients from HLA-matched URDs. Improvements in platelet recovery after both autologous and allogeneic HSCT have resulted with marrow or peripheral blood cell grafts which contain a higher number of CD34+ cells or total nucleated cells.

Other considerations for explaining poor platelet production after HSCT are the persistence or relapse of leukemia or lymphoma. Also, patients with severe marrow fibrosis before transplantation have been noted to have slower platelet recovery [12]. The delayed platelet recovery in patients with severe marrow fibrosis might also result in part from hypersplenism which may be present. After allogeneic transplant, a graft-versus-stroma effect might contribute to poor marrow function resulting in delayed platelet recovery [13, 14]. Commonly used drugs, after allogeneic HSCT associated with delayed platelet engraftment or secondary failure, include among others, MTX, ganciclovir and trimethoprim-sulfamethoxazole [15-19]. The administration of MTX in combination with cyclosporine and prednisone after marrow transplantation to prevent acute GVHD has been associated with delayed platelet engraftment when compared to only cyclosporine and prednisone [15]. However, in an earlier study comparing the combination of cyclosporine and MTX to cyclosporine alone, there were no differences between the groups in the median days to discontinuation of platelet transfusions [16]. Ganciclovir, used prophylactically at engraftment to prevent CMV infection after marrow transplantation, was associated with a delay in the median days to achieve platelet counts of 100,000 x 106/l but not to 50,000 x 106/l [17]. No significant effects of ganciclovir were noted on platelet counts in the other prophylaxis study of ganciclovir [18]. Although both these agents affect the recovery of neutrophil counts after marrow transplantation, the impact on recovery of platelet counts may be mitigated by their effectiveness in preventing complications which are themselves associated with delayed platelet recovery.

Platelet Destruction
Since it is likely that the potential for production of platelets in the normal recovering marrow after transplantation will in many cases be limited, events or complications associated with decreased survival of circulating platelets which increase the demand on the marrow may also cause delayed recovery or secondary failure (Table 2Go). Three common complications after HSCT which are associated with a decreased survival of platelets in the circulation are GVHD, VOD of the liver and infections. The incidence of moderate-to-severe acute GVHD is 30%-70% depending on the degree of HLA match and the relation of the donor to the patient. GVHD involves the skin, gastrointestinal tract and the liver. The association of persistent thrombocytopenia with GVHD has been previously reported [19, 20]. Thrombocytopenia was reported as a marker for a group of patients with severe chronic GVHD that had an increased incidence of transplant-related complications and a higher mortality rate. In the analysis discussed in this article, delayed platelet recovery was associated with the presence of GVHD. Although decreased production of platelets might be present because of a graft-versus-stroma effect, the numbers of megakaryocytes in the marrow have been reported as relatively normal in most patients with the chronic thrombocytopenia syndrome associated with chronic GVHD [19, 21]. Platelet survival studies demonstrate that platelets persist in the circulation for a shorter period of time in patients with GVHD [21]. An immune mechanism was implicated in the premature removal of platelets from the circulation in some cases, but platelet-specific alloantibodies or autoantibodies were not identified. Platelet increments after transfusions in patients with GVHD have also been reported as less than in controls without GVHD [22]. These observations support the conclusion that GVHD influences platelet recovery primarily by decreasing their survival in the peripheral blood rather than through an effect on production. However, production of platelets was also limited even in those patients who were identified with reduced platelet survival [21].

VOD of the liver is a common complication of cytoreductive therapy. The most prominent site of liver damage is at the terminal hepatic venule. Necrosis of hepatocytes, perivenular fibrosis and engorgement of sinusoids with hepatocytes and red blood cells are observed [23]. VOD of the liver may occur in up to 54% of patients [24]. Severe VOD may result in liver failure. VOD has been associated with persistent thrombocytopenia and refractoriness to platelet transfusions [22, 25]. Refractoriness to platelet transfusions may occur prior to the classical manifestations of VOD. Systemic infections are also known to result in decreased platelet survival and, as observed in this analysis, delayed platelet engraftment. Delay in platelet recovery after autologous transplantation in patients with a positive serology for CMV has been previously observed [26]. Infections are frequent events in this immunosuppressed population, but in most cases the effects that these have on platelets should be successfully managed with appropriate preventive or early antibiotic or antiviral therapy.

Other events that may affect primary recovery of platelet counts or result in secondary failure after HSCT are much less frequent. The syndrome of hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) has been reported to occur in 13% and 9% of patients after allogeneic transplantation, and in 10% of patients after autologous transplantation [27, 28]. This is most commonly seen as the combination of an intravascular hemolytic anemia and a decrease in platelet counts. Renal abnormalities are common and neurologic complications may occur. The cause of the syndrome has been attributed to cyclosporine, acute GVHD and radiation nephritis. FK506 has also been associated with the development of HUS/TTP after allogeneic HSCT [29]. In some patients, attenuation of the cyclosporine or FK506 dose may be sufficient to reverse these manifestations. Plasmapheresis has been described as a potentially effective therapeutic option. HUS/TTP after marrow transplantation and its treatment have recently been reviewed [30]. Disseminated intravascular coagulation may be associated with infections or severe VOD associated with liver failure, but again is an unusual cause for delayed platelet recovery or secondary failure. The development of platelet-specific auto- (or allo-) antibodies has been reported and may be delayed in onset [31-33].

In a study including splenectomized patients, it was noted that the presence of the spleen was an important factor in delaying recovery of platelet counts [34]. However, among unsplenectomized patients, the study was not able to demonstrate that splenic size affected the speed of platelet recovery or platelet transfusion requirements. In a subsequent study there was a trend for splenectomized patients to have a faster recovery of platelet counts compared to nonsplenectomized controls [35].

In two common complications after HSCT (GVHD and infection) which cause a decreased platelet survival in the peripheral circulation, our analysis demonstrated that there was an association with delayed platelet recovery. The mechanism(s) responsible for the premature removal of platelets in these post-transplant complications have not been described. It is of interest, however, that in both of these complications, serum cytokine levels including G-CSF, M-CSF, interleukin 1{alpha} (IL-1{alpha}), IL-1ß and IL-6 were significantly increased (unpublished). A similar serum cytokine profile was observed in patients with VOD of the liver. All of these cytokines may contribute to the activation of monocytes and macrophages. The monocyte/macrophage system is a critical component of the elimination pathway of platelets. Administration of both GM-CSF and M-CSF in pharmacologic doses may result in dose-dependent reduction in platelet counts or delay in platelet recovery after chemotherapy [36-40]. In dogs, GM-CSF and M-CSF induced a local process in the liver and spleen resulting in platelet destruction. No abnormalities of platelets were detected ([41] and unpublished). The mechanisms which might be implicated in other diseases associated with consumptive thrombocytopenia are not apparent during GM-CSF- or M-CSF-induced thrombocytopenia (e.g., hemolytic anemia). Further in vivo studies in animal models of cytokine-induced thrombocytopenia are required to identify the potentially unique, nonautoimmune mechanism causing platelet destruction. The association of increased serum cytokine levels and an activated monocyte/macrophage system with delayed platelet recovery or secondary failure in patients with GVHD, infection and VOD deserves further study in this context.

Delayed platelet engraftment or secondary failure is a problem after HSCT, requiring significant resources to manage effectively. In autologous transplants, PBSCs have significantly reduced the time required for achieving platelet engraftment compared to marrow-derived sources. The use of allogeneic PBSCs from RDs is currently being investigated. Newer cytokines which stimulate megakaryocytopoiesis (IL-11 and Mpl-ligand) may make additional contributions, if used, to further stimulate production of platelets while the marrow is recovering or in the "mobilization" of stem cell grafts. Patients who have received marrow transplants from matched URDs, a group at high risk for delayed platelet engraftment, would be suitable for studies of these cytokines since studies of allogeneic PBSCs in this group are not likely to occur until more experience has accrued in the setting of HLA-matched RD transplants.


   ACKNOWLEDGMENT
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 Discussion
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We thank all the nurses and physicians on the transplant wards and in the outpatient department for their contributions. We would also like to thank Bonnie Larson and Harriet Childs for typing the manuscript.

This work was supported in part by grants CA18029, CA18221, CA47748, and HL36444 awarded by the National Institutes of Health, DHHS, Bethesda, Maryland.


   FOOTNOTES
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From THROMBOPOIETIN AND CYTOKINE REGULATION OF PLATELET PRODUCTION. STEM CELLS 1996;14(suppl 1):261-273.


   REFERENCES
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 Abstract
 Introduction
 Methods
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 Discussion
 References
 

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