Thrombopoietic cytokines in relation to platelet recovery after bone marrow transplantation

In order to evaluate the importance of different thrombopoietic stimulatory cytokines in accelerating platelet recovery after bone marrow transplantation (BMT), we assayed serial plasma concentrations of three cytokines, thrombopoietin (TPO), interleukin-6 (IL-6), and IL-11 through the course of platelet nadir and recovery after BMT. Both mean TPO and IL-6 levels showed a marked rise and later fall preceding or coincident with the platelet nadir and recovery, suggesting their potential role as circulating regulators or stimulators of thrombopoiesis. In contrast, IL-11 levels remained remarkably constant through the whole course suggesting that this cytokine, though capable of stimulating thrombopoiesis, does not serve as a circulating regulator of platelet production. Additionally, we assayed the levels of these three cytokines following initial platelet transfusion to assess the capacity of transfused platelets to adsorb these thrombopoietic cytokines from the plasma and reduce their circulating levels, thus potentially modifying their availability for stimulating megakaryocyte proliferation. No consistent falls in TPO, IL-6 or IL-11 levels were observed following the initial two platelet transfusions. These data support the importance of circulating TPO and IL-6 as hormones capable of stimulating platelet production. Their physiologic relevance as in vivo regulators of thrombopoiesis and clinical utility for therapy of thrombocytopenia need further investigation.     

Thrombopoietic cytokines in patients with hepatitis C virus-associated immune thrombocytopenia

Objectives: Complex and multiple mechanisms are involved in the etiology of Hepatitis C virus-associated immune thrombocytopenia (HCV-ITP). Many hematopoietic growth factors affect the thrombopoiesis. The aim of this study was to clarify the interaction of the thrombopoietic factors in patients with HCV-ITP.

Methods: We selected 33 patients with HCV-ITP and 17 normal individuals. We compare serum interleukin (IL)-3, IL-6, IL-11, thrombopoietin (Tpo), stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor-α (TNFα), and spleen size between these two groups.

Results: Our study shows that Tpo, IL-6, and TNFα significantly increased in patients with HCV-ITP compared to the normal population (Tpo:122.577 vs. 40.602; IL-6: 2.175 vs. 0.943; TNFα: 2.460 vs. 1.322). IL-11 was significantly lower in the HCV-ITP group (10.829 vs. 15.042). HCV-ITP patients had a higher spleen index (21.121 vs 13.498, P?=?0.003). According to regression analysis and multiple linear regression analysis, only IL-11 had a significantly positive correlation with platelet count, while TNFα showed a negative correlation.

Discussions: Tpo and IL-6 increased in patients with HCV-ITP, suggesting a positive feedback of low platelet count. TNFα-associated immune response is suspected to have an impact on low platelet count. IL-11 is assumed to directly affect thrombopoiesis.

Conclusions: This study is the most comprehensive study to evaluate the interaction between platelet count and the important thrombopoetic factors in patients with HCV-ITP. The thrombopoietic factors clearly play an important role in HCV-ITP.     

Thrombopoietic growth factors and cytokines

Chemotherapy-induced thrombocytopenia is largely managed with platelet transfusions and reductions of chemotherapy doses. In the last decade, several thrombopoietic cytokines have been investigated without much success. Thrombopoietin (TPO), a key physiologic regulator of platelet production, is found to be the most potent thrombopoietic cytokine studied so far. Unfortunately, the clinical development of recombinant human thrombopietin has met challenges related to the biology of TPO with a delayed peak platelet response and the findings of neutralizing antibodies to the pegylated molecule. Recent clinical studies showed the importance of TPO schedule in relation to chemotherapy. Also, recombinant TPO facilitated collection of platelets in normal donors and patients for transfusions. The initial trials in leukemia or transplant settings did not impact the need for platelet transfusions. Future developments of TPO and mimetics will require carefully designed clinical trials with the consideration of unique biology of TPO and the time lag for a peak platelet response.     

Immune thrombocytopenia in dogs after fetal liver hematopoietic cell transplantation

Immune thrombocytopenia occurred in 6 of 33 engrafted dogs (18%) after fetal liver hematopoietic cell transplantation. Concurrent granulocytopenia occurred in three of six dogs and anemia in one. All dogs were receiving cyclosporin to prevent graft rejection and graft-versus-host disease (GVHD). None of the dogs had signs of GVHD. Bone marrow obtained at the time of platelet nadir was hypercellular with megakaryocyte hyperplasia. All dogs exhibited anti-megakaryocyte antibodies detected by direct immunofluorescence of bone marrow smears. Treatment with oral prednisolone resulted in normalization of platelet counts in five of six dogs and granulocyte and erythrocyte counts in dogs exhibiting concurrent leukopenia or anemia. Two long-term survivors (greater than 2.5 years) have not developed further hematologic abnormalities since initial diagnosis and treatment.     

Successful laparoscopic splenectomy after living-donor liver transplantation for thrombocytopenia caused by antiviral therapy

Although interferon （IFN） based therapy for recurrent hepatitis C virus （HCV） infection after liver transplantation has been widely accepted, it induces various adverse effects such as thrombocytopenia, resulting in its interruption. Recently, concomitant splenectomy at the time of living donor liver transplantation （LDLT） has been tried to overcome this problem, but this procedure leads to several complications such as excessive intraoperative bleeding and serious infection. A 60-year-old female received LDLT using a left lobe graft from her second son for liver failure caused by hepatitis C-related cirrhosis. Six months after LDLT, she was diagnosed as recurrent HCV infection by liver biopsy. IFN monotherapy was started from 7 mo after LDLT and her platelet count decreased to less than 50000/μL, which thus made it necessary to discontinue the treatment. We decided to attempt laparoscopic splenectomy （LS） under general anesthesia. Since intra-abdominal findings did not show any adhesion formations around the spleen, LS could be successfully performed. After LS, since her platelet count immediately increased to 225000/μL 14 d after operation, IFN therapy was restarted and we could convert the combination therapy of IFN and ribavirin, resulting in no detectable viral marker. In conclusion, LS can be performed safely even after LDLT, and LS after LDLT is a feasible and less invasive modality for thrombocytopenia caused by antiviral therapy.     

Thrombopoietin induces rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production

Thrombopoietin (TPO) deficiency has been proposed as an important etiologic factor for thrombocytopenia in advanced-stage liver disease. To clarify the contributions of platelet production, platelet consumption, coagulation activation, and splenic sequestration to thrombocytopenia in liver disease, we studied TPO serum levels and markers of platelet production, platelet activation, and coagulation activation before and 14 days after orthotopic liver transplantation (OLT) in 18 patients with advanced liver cirrhosis. Thrombocytopenia before transplantation occurred with low-normal serum levels of TPO, normal levels of platelet and coagulation activation markers, and no increase in bone marrow production of platelets. TPO serum levels increased significantly on the first day after OLT, preceding the increase of reticulated platelets by 3 days and peripheral platelets by 5 days. Normalization of the peripheral platelet count occurred in most patients within 14 days of OLT, irrespective of the change in spleen size assessed by computed tomography volumetry. Normalization of platelet counts was not hampered by a certain degree of platelet activation observed during the steepest increase in the peripheral platelet count. Bone marrow production of platelets increased significantly within 2 weeks of transplantation. Low TPO serum levels with low platelet counts and without platelet consumption suggests low TPO production in end-stage liver disease. The rapid increase in TPO serum levels after transplantation induces an increase in the bone marrow production of platelets. Decreased TPO production in the cirrhotic liver is an important etiologic factor for thrombocytopenia in liver disease that is rapidly reversed by transplantation.     

Acute bleeding and thrombocytopenia after bone marrow transplantation

The relationship between hemorrhage and low platelet count was first established in patients with acute leukemia, and has been widely applied to thrombocytopenic patients, including BMT patients. Yet, the role of thrombocytopenia in bleeding post BMT has not been systematically studied. We evaluated the risk of bleeding and outcome associated with thrombocytopenia in BMT patients who had prophylactic platelet transfusions at a trigger of 20 x 10(9)/l. Thrombocytopenia was investigated in 321 patients with moderate or severe bleeding (BLD), and in a matched comparison group of 287 patients who did not bleed (NBLD). Profound thrombocytopenia (< or = 10 x 10(9)/l) was found in 8.6% of the BLD patients during the week before the bleeding onset, significantly more frequent than in NBLD patients (2.1% to 4%, P < 0.02), during weeks 2 to 6 post BMT (the period when 75% of the bleeding initiated). On the first day of bleeding, platelet counts < or = 10 x 10(9)/l were found in 13.5%, 11-20 x 10(9)/l in 20.4%, and > 20 x 10(9)/l in 66.1% of all episodes. Overall survival in BLD patients was not associated with the severity of thrombocytopenia before bleeding onset. Severity of thrombocytopenia was significantly associated with reduced survival in NBLD patients. We concluded that bleeding post BMT was significantly associated with thrombocytopenia, but the attributable risk of bleeding from profound thrombocytopenia was not large. Thrombocytopenia may be an important clinical sign in NBLD patients, and should be further explored in relation to acute toxicities other than bleeding.     

Prolonged thrombocytopenia after autologous bone marrow transplantation

Thirty two patients with hematologic malignancies and solid tumors were treated with intensive therapy and autologous bone marrow transplantation. In nine out of 32 patients, it took more than 50 days to achieve a sustained platelet count of 50,000/microliter or greater. Significant associations with poor platelet recovery were found for patient age, diseases, period of cryopreservation, the kinds of eradicative therapy and in vitro purging. But most of these factors overlapped each other in the same patients. No correlation was found between platelet recovery and number of cells or CFU-GM infused.     

Hypertrophic osteoarthropathy related to end stage cholestatic cirrhosis: reversal after liver transplantation.

A case is reported of hypertrophic osteoarthropathy with recovery after a liver graft in a young man with end stage cholestatic cirrhosis related to non-Wilsonian copper overload. To our knowledge this is the first case in the literature illustrating the curative role of liver grafting on hypertrophic osteoarthropathy associated with chronic cholestatic liver disease.     

Thrombopoietin concentrations are low in patients with cirrhosis and thrombocytopenia and are restored after orthotopic liver transplantation

BACKGROUND: Thrombocytopenia in cirrhotic patients may be due to deficient production of thrombopoietin. AIMS: To determine the relation between thrombopoietin and thrombocytopenia in cirrhotic patients before and after orthotopic liver transplantation. METHODS: Thrombopoietin concentrations and platelet counts were measured in 43 cirrhotic patients and 21 normal controls and serially for 14 days after transplantation in 23/43 patients. RESULTS: 27 of the 43 patients had thrombocytopenia (platelet count less than 120 x 10(9)/l; group 1) whereas 16 patients had normal platelet count (group 2). Thrombopoietin concentrations were lower in group 1 than in group 2 (92.5 (20.3-286.3) v 226.6 (30.1-848.3) pg/ml, p=0.003) and normal controls (92.5 (20.3-286.3) v 158.3 (22.5-232.9) pg/ml, p=0.028). Post-transplantation thrombopoietin concentrations increased with a peak at day 5. The rise was significant in patients with low pretransplantation platelet count (89.1 (21.29-247.6) to 545.1 (66.2-2569) pg/ml; n=16, p=0.001) but not in those with normal platelet count (262.8 (30.1-848.3) to 315.1 (114-954.6) pg/ml; n=7, p=0.47). No correlation was found pretransplantation between spleen volume and platelet count (r=-0.11, p=0.6) or thrombopoietin concentrations (r=-0.04, p=0.8). However, pretransplantation thrombopoietin concentrations correlated with platelet count (r=0.47, p=0.0015), whereas an inverse correlation was found between peak thrombopoietin concentrations and nadir platelet count (r=-0.41 p=0. 049) post-transplantation. CONCLUSIONS: Inadequate thrombopoietin production may contribute to cirrhotic thrombocytopenia. Thrombopoietin production is restored after liver transplantation leading to the resolution of thrombocytopenia.     

Acquired autoimmune thrombocytopenia after allogeneic bone marrow transplantation

A 29-year-old man in remission from acute myeloblastic leukaemia was treated by chemoradiotherapy and transplantation of bone marrow (BMT) collected from his HLA identical brother. Engraftment was documented on D12. Transient acute GVHD (grade II) appeared from D34. No infection complicated the BMT. Nevertheless severe thrombocytopenia persisted and was unresponsive to marrow donor platelet transfusion. The platelet immunofluorescence test demonstrated the autoimmune basis of the thrombocytopenia. This study suggests that the transient immune imbalance observed in the early post graft period could facilitate the appearance of autoimmune cytopenias.     

Immune thrombocytopenia after renal transplantation for IgA nephropathy

Immune thrombocytopenic purpura associated with renal disease is usually therapy-related, occurring after administration of intravenous immunoglobulin therapy or anti-D. Secondary cases occurring after renal transplantation are extremely rare. We present the second reported case of immune thrombocytopenic purpura occurring after renal transplantation for IgA nephropathy. Primary IgA nephropathy is the most common form of primary glomerulonephritis and although the pathogenesis of the disease remains incompletely understood, recent evidence suggests that the basic abnormality lies within the IgA immune system rather than in the kidney. We postulate a novel mechanism for thrombocytopenia occurring in such cases.     

Pregnancy after liver transplantation

Although the transplant community has begun to gather experience in pregnancy after liver transplant, much remains to be learned about the effects of pregnancy on mother and child. Most women with end stage liver disease have amenorrhea or are unable to conceive due to medical complications. Liver transplantation offers such patients the opportunity to have children. Since libido and fertility can return fairly rapidly, it is important to discuss birth control in the early post transplant period. It is recommended that pregnancy be delayed for 1 and preferably 2 years post-transplant as pregnancies within the first year are associated with higher rates of premature birth and cellular rejection. The current evidence suggests that pregnancy is safe after transplant, however it requires close follow-up by a team of experienced physicians.     

Employment after liver transplantation

The objective of this study was to study the factors affecting employment after liver transplantation. The employment status and health status of 203 adult liver transplant recipients was assessed retrospectively in a survey comprising an employment questionnaire, the Sickness Impact Profile (SID), and the Medical Outcomes Survey (MOS). The patient population consisted of all surviving adult patients who had undergone liver transplantation between 1982 and 1992 at our institution and who had survived a minimum of 9 months. Fifty-seven percent of the recipients were employed and 43% of the recipients were unemployed. Eighteen percent of the recipients considered themselves not well enough to work. Other reasons cited for not working in the unemployed patients were early retirement (8%), return to school (3%), family reasons (3%), no work available (3%), and chose not to work (3%). Patient age, duration of disability before transplantation, and type of job before transplantation significantly affected posttransplantation employment status. Health status measurements predicting employment were ambulation, home management, physical functioning, and pain. Older recipients and those who were continuously out of the workforce for several years before transplantation were the least likely to return to gainful employment after liver transplantation. These findings have implications for assessing the success of liver transplantation and the implementation of strategies to fully rehabilitate patients after liver grafting.     

Analgesia after liver transplantation

This article addresses postoperative analgesia in patients with end-stage liver disease who have undergone liver transplantation(LT). Postoperative analgesia determines how patients perceive LT. Although important, this topic is underrepresented in the current literature. With an increased frequency of fast tracking in LT, efficient intraand postoperative analgesia are undergoing changes. We herein review the current literature, compare the benefits and disadvantages of the therapeutic options, and make recommendations based on the current literature and clinical experience.     

Severe thrombocytopenia before liver transplantation is associated with delayed recovery of thrombocytopenia regardless of donor type

AIM： To compare the recovery of thrombocytopenia and splenomegaly during long-term follow-up after liver transplantation in patients receiving a living donor transplant or a cadaveric donor transplant.
METHODS： This was a retrospective cohort study of 216 consecutive liver transplant patients who survived for 〉 6 mo after transplantation; 169 received a liver transplant from a living donor and 47 from a cadaveric donor. The platelet counts or spleen volumes were examined before transplant, i, 6, and 12 mo after transplant, and then annually until 5 years after transplant.
RESULTS： The mean follow-up period was 49 mo （range, 21-66）. Platelet counts increased continuously for 5 years after orthotopic liver transplant. The restoration of platelet counts after transplant was significantly slower in patients with severe pretransplant thrombocytopenia （〈 50000/μL） until 4 years after transplant （P = 0.005）. Donor type did not significantlyaffect the recovery of platelet count and spleen volume in either patient group. In multivariate analysis, pretransplant severe thrombocytopenia （〈 50000/μL） was an independent factor associated with sustained thrombocytopenia （P 〈 0.001, odds ratio 6.314; confidence interval, 2.828-14.095）. Thrombocytopenia reappeared after transplant in seven patients with portal flow disturbance near the anastomosis site.
CONCLUSION： Our study suggests that severe thrombocytopenia before transplant is closely associated with delayed recovery of platelet count after transplant and donor type did not affect the recovery of thrombocytopenia. The reappearance of thrombocytopenia after transplant should be considered a possible indicator of flow disturbance in the portal vein.