Thrombocytopenia associated with platelet-associated immunoglobulin G in alcoholic hepatitis

Abstract A 45 year old Japanese man with alcoholic hepatitis developed thrombocytopenia together with an increase in the level of platelet-associated immunoglobulin G (PAIgG). Bone marrow aspiration revealed a normal nucleated cell count and a slight increase of megakaryocytes. After abstinence from alcohol, laboratory and symptomatic improvement occurred in association with a prompt increase in the platelet count and a corresponding decrease of PAIgG. These findings suggest that PAIgG may have been involved in the development of thrombocytopenia in this patient.     

免疫抑制治疗无效的特发性血小板减少性紫癜患者血小板相关免疫球蛋白的亚型分析

目的分析糖皮质激素、环孢菌素A治疗无效的特发性血小板减少性紫癜(ITP)患者血小板相关免疫球蛋白(PAIg)的亚型。方法采用酶联免疫法(ELISA)对19992004年绵阳市中心医院收治的17例激素治疗无效、4例激素 环孢菌素A治疗无效以及30例激素治疗有效ITP患者的PAIg亚型进行检测。结果17例激素治疗无效的患者PAIg各亚型抗体较之激素治疗有效ITP患者差异有显著性(P<0·01),激素治疗无效组PAIg各亚型水平均明显增高;激素 环孢菌素A治疗无效组PAIgM较之激素治疗有效ITP患者有所增高(P<0·05)。结论激素治疗无效的ITP患者PAIg各亚型均显著增高,提示PAIg在介导ITP患者异常免疫反应过程中起重要作用,PAIg各亚型水平的增高可能有助于预测ITP患者对激素治疗的敏感性。     

Neonatal autoimmune thrombocytopenia: role of high-dose intravenous immunoglobulin G therapy

Summary High-dose intravenous immunoglobulin G (IVIgG) therapy results in a rapid reversal of thrombocytopenia in over 80% of children with acute immune thrombocytopenic purpura (ITP). Comparable results were observed in eleven infants with an analogous condition, neonatal autoimmune thrombocytopenia (NATP), who received IVIgG (2 g/kg body weight) administered alone (n=6) or in combination with steroids (n=5). The median platelet count pre-IVIgG therapy was 25×10⁹/l (range 5 to 74×10⁹/l). The overall response rate to IVIgG therapy, administered alone or in combination with steroids was 75% (12 of 16 treatment episodes). A good response to therapy was defined as an increase in the platelet count to 50×10⁹/l and at least twice the pre-treatment value at 48 h after completion of the IVIgG infusion. The rapid and generally excellent response to IVIgG therapy in infants with NATP suggests that this treatment approach should be considered as first-line therapy for severely thrombocytopenic infants with this self-limiting but potentially serious disorder.Presented at the International Workshop on ITP, August 26 and 27, 1988, Lucerne, Switzerland     

Pattern of platelet-associated immunoglobulin (classes and IgG subclasses) in childhood immune thrombocytopenic purpura

Platelet-associated Ig classes and IgG subclasses were studied by a semiquantitative platelet ELISA test in 17 children with immune thrombocytopenic purpura (ITP). An elevation of PAIg was found in 94% of the children. In nearly all cases increased amounts of PAIgG of subclass G1 was seen, and in half of the cases increased amounts of PAIgM were also seen. No statistical difference in the composition of PAIg classes and PAIgG subclasses in acute and in chronic ITP was found. However, a correlation of increased amount of PAIgG3 and very low platelet count (20 x 10(9)/l) was observed.     

Splenomegaly, hypersplenism and coagulation abnormalities in liver disease

Splenomegaly is a frequent finding in patients with liver disease. It is usually asymptomatic but may cause hypersplenism. Thrombocytopenia is the most frequent manifestation of hypersplenism and may contribute to portal hypertension related bleeding. A number of therapies are available for treating thrombocytopenia due to hypersplenism including splenectomy, partial splenectomy, partial splenic embolization, TIPS etc. None is entirely satisfactory. Hypersplenism usually improves following liver transplantation. Therapy with cytokines such as thrombopoietin may offer hope for the future. Patients with liver disease also have abnormalities in coagulation. This is not surprising as all coagulation proteins (except for von willebrand factor vWF) and most inhibitors of coagulation are synthesized in the liver. Genetic or acquired abnormalities of coagulation may predispose to thrombosis of the hepatic or portal veins with significant clinical sequelae. An understanding of the mechanisms involved in coagulation and thrombosis is valuable in choosing from the increasing treatment options available. These include clotting factors, haemeostatic drugs and newer therapies such as recombinant factor VIIa. Splenic artery aneurysms are the most common visceral artery aneurysms in man. Rupture is frequently catastrophic. These aneurysms are being increasingly recognized in liver transplant patients and require treatment before or during transplant surgery.     

Reversal of immune thrombocytopenia in mice by cross-linking human immunoglobulin G with a high-affinity monoclonal antibody

Intravenous immunoglobulins (IVIgs) are used to treat an increasing number of autoimmune diseases, but their exact mechanism of action remains unknown. This study showed that cross-linking of human IgG present in IVIg preparations using a mouse monoclonal anti-human IgG generated complexes that prevented or reversed thrombocytopenia in mice more efficiently than IVIg. Furthermore, biologically active complexes were obtained simply by adding the monoclonal antibody to human serum. These results suggest the possible development of an IVIg-free substitute through the ex vivo, and possibly in vivo, formation of immune complexes containing autologous IgG of immune thrombocytopenic purpura patients.     

Improvement of thrombocytopenia with disappearance of HCV RNA in patients treated by interferon-alpha therapy: possible etiology of HCV-associated immune thrombocytopenia

We evaluated the relationship between the severity of thrombocytopenia and the serum hepatitis C virus (HCV) RNA level to investigate the mechanism of thrombocytopenia in patients with HCV infection. Patients who had chronic hepatitis without splenomegaly were divided into two groups according to the platelet count, which were 18 patients with a platelet count < or =150 x 10(9)/L and 22 patients with a platelet count >150 x 10(9)/L. HCV RNA, platelet-associated immunoglobulin G (PAIgG), rheumatoid factor (RF), and other immunological parameters were measured and correlations were investigated. Patients in the low platelet group had higher levels of PAIgG, Th1 cells, thrombopoietin (TPO), and RF than those in the normal platelet group (textitP < 0.05). Twenty-two patients completed 6 months of IFN therapy and were followed for more than 1 yr afterwards. Twelve patients who responded to IFN therapy with clearance of HCV showed an increase of the platelet count, whereas the 10 patients who did not respond to IFN showed a decrease of the platelet count. The improvement of thrombocytopenia after interferon therapy suggests a contribution of HCV infection to this condition.     

Thrombocytopenia in chronic liver disease

Thrombocytopenia is a common haematological disorder in patients with chronic liver disease. It is multifactorial and severity of liver disease is the most influential factor. As a result of the increased risk of bleeding, thrombocytopenia may impact upon medical procedures, such as surgery or liver biopsy. The pathophysiology of thrombocytopenia in chronic liver disease has long been associated with the hypothesis of hypersplenism, where portal hypertension causes pooling and sequestration of all corpuscular elements of the blood, predominantly thrombocytes, in the enlarged and congested spleen. Other mechanisms of importance include bone marrow suppression by toxic substances, such as alcohol or viral infection, and immunological removal of platelets from the circulation. However, insufficient platelet recovery after relief of portal hypertension by shunt procedures or minor and transient recovery after splenic artery embolization have caused many to question the importance and relative contribution of this mechanism to thrombocytopenia. The discovery of the cytokine thrombopoietin has led to the elucidation of a central mechanism. Thrombopoietin is predominantly produced by the liver and is reduced when liver cell mass is severely damaged. This leads to reduced thrombopoiesis in the bone marrow and consequently to thrombocytopenia in the peripheral blood of patients with advanced‐stage liver disease. Restoration of adequate thrombopoietin production post‐liver transplantation leads to prompt restoration of platelet production. A number of new treatments that substitute thrombopoietin activity are available or in development.     

Hepatic fibrosis plays a central role in the pathogenesis of thrombocytopenia in patients with chronic viral hepatitis

The pathogenesis of thrombocytopenia in chronic hepatitis is not well known. This study evaluated the relationship between liver injury, serum thrombopoietin, splenomegaly and thrombocytopenia in chronic viral hepatitis. Two hundred and nine patients were enrolled, 85 with splenomegaly and 124 without. Thrombocytopenia was present in 71% and 23% of patients with or without splenomegaly respectively. In subjects with low platelet count, those with splenomegaly showed significantly lower platelet numbers than those without splenomegaly. The spleen size correlated with portal hypertension. An inverse correlation between spleen size and platelet count was observed (r = -0.54; P < 0.0001). In patients without splenomegaly, thrombocytopenia was associated with the grade of fibrosis; platelet counts were the highest in patients with fibrosis 0-2, lower in those with grade 3 (P < 0.008) and lowest in those with grade 4 (P < 0.05). These findings were independent of demographic and biochemical characteristics, hepatic necroinflammatory activity, portal hypertension and splenomegaly. Patients with normal platelet counts showed higher thrombopoietin levels than those with low platelet counts (P < 0.0001). An inverse correlation between thrombopoietin levels and fibrosis grade was observed (r = - 0.50; P < 0.0001). Median thrombopoietin levels were 58 and 27 pg/ml for fibrosis grade 0-1 and grade 4 respectively (P < 0.001). These data indicate that advanced hepatic fibrosis, causing an altered production of thrombopoietin and portal hypertension, plays the central role in the pathogenesis of thrombocytopenia in chronic viral hepatitis.     

Reduced expression of thrombopoietin is involved in thrombocytopenia in human and rat liver cirrhosis

It is widely accepted that thrombocytopenia associated with liver cirrhosis is caused by increased platelet destruction in the enlarged spleen, but this issue has not yet been analysed sufficiently in terms of platelet production. Thrombopoietin is produced mainly in the liver and strongly promotes platelet production. We studied serum thrombopoietin and the levels of its mRNA in liver tissue of cirrhotic patients and also in a rat model of liver cirrhosis. Furthermore, to clarify the influence of the spleen, we investigated thrombopoietin mRNA in splenectomized rats. The serum thrombopoietin level in humans with liver cirrhosis was not significantly reduced instead of thrombocytopenia. The expression of thrombopoietin mRNA in liver tissue decreased with the progression of liver cirrhosis in both patients and the rat model and no compensatory expression was observed in other organs or nonparenchymal cells. The level of thrombopoietin mRNA did not differ significantly in splenectomized cirrhotic rats before or after administration of dimethylnitrosamine, but was lower than that in splenectomized rats without cirrhosis. We conclude that thrombocytopenia in liver cirrhosis is caused not only by platelet destruction but also by decreased platelet production, perhaps due to reduction of thrombopoietin mRNA in the liver.     

肝硬化患者血清血小板生成素水平的测定及临床意义

探讨肝硬化患者血清血小板生成素(TOP)浓度与血小板减少的关系。用酶联免疫吸附法(ELISA)测定肝硬化肝功能代偿期、失代偿期以及正常人血清TPO浓度。血清TOP浓度正常人、肝硬化肝功能代偿期、失代偿期分别为(136.24±68.56)pg.m l-1、(124.34±41.31)pg.m l-1和(59.05±52.77)pg.m l-1。肝硬化肝功能失代偿期的血清TPO浓度较正常人明显降低(t=4.04,P<0.001);正常人的血清TPO浓度受外周血小板计数的调节,而肝硬化患者的血清TPO浓度与外周血小板计数之间无明显相关而与血清白蛋白浓度呈正相关(r=0.86,P<0.001)、血清总胆红素浓度呈负相关(r=0.49,P<0.05)。肝细胞产生TPO不足可能是肝硬化发生血小板减少的主要原因。血清TPO浓度可能是评价肝硬化患者肝功能的有用指标。     

Thrombopoietin and its receptor expression in pediatric patients with chronic immune thrombocytopenia

Objectives: Chronic immune thrombocytopenia (cITP) is common in children. However, the pathogenesis has not been fully elucidated. This study aimed to determine whether thrombopoietin (TPO) and its receptor c-mannosylation of the TPO receptor (c-Mpl) have an impact on childhood cITP.

Methods: Sixty-four patients with newly diagnosed ITP (nITP), 64 patients with persistent ITP, 80 patients with cITP, and 64 healthy children (control) were enrolled in this study. Plasma TPO was measured with an ELISA, and c-Mpl was determined by flow cytometry.

Results: Plasma TPO levels showed differences among the four groups (p?=?0.001). TPO levels in the cITP group were significantly decreased compared to those in the nITP group (p?p?=?0.0275). c-Mpl MFI was lower in the cITP group than in the nITP group(p?p?p?=?0.023). The control group, compared with the other groups, had lower levels of c-Mpl mRNA.

Conclusions: The expression of TPO and c-Mpl was significantly decreased in the cITP group compared to the nITP group, suggesting that TPO and its receptor may play important roles in childhood cITP pathogenesis.     

血小板生成素在慢性乙型肝炎血小板减少症中的作用

目的：探讨血小板生成素在慢性乙型肝炎血小板减少症患者中的作用。方法：对76例慢性乙型肝炎血小板减少症患者进行血清血小板生成素水平、凝血酶原活动度、骨髓巨核细胞计数检查。结果：血小板生成素水平与凝血酶原活动度、骨髓巨核细胞计数、外周血小板计数相关（r分别为0．423、0.396、0．297，P〈0．05）；76例患者标本中有22例骨髓巨核细胞计数〈7（个／4．5cm^2），占20％；巨核细胞成熟障碍29例，占38％。结论：血小板生成素在慢性乙型肝炎血小板减少症的发病机制中起一定作用。     

Role of platelets in chronic liver disease and acute liver injury

Platelets contain not only hemostatic factors but also many growth factors that play important roles in wound healing and tissue repair. Platelets have already been used for the promotion of tissue regeneration in the clinical setting, such as dental implantation and plastic surgery. Thrombocytopenia, which is frequently found in patients with chronic liver disease and cirrhosis, is due to various causes such as decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism. However, the relationship between thrombocytopenia and hepatic pathogenesis and the role of platelets in chronic liver disease are poorly understood. In acute liver injury, it is reported that platelets are recruited to the liver and contribute to liver damage by promoting the induction of chemotactic factors and the accumulation of leukocytes in the liver, whereas platelets or mediators released by platelets can have a protective effect against liver injury. In this review, we highlight the recent accumulated knowledge concerning the role of platelets in chronic liver disease and acute liver injury.     

Close correlation between chronic sclerosing sialadenitis and immunoglobulin G4

In four patients with chronic sclerosing sialadenitis, serum immunoglobulin G4 concentration was markedly increased and abundant infiltration of immunoglobulin G4-positive plasma cells was observed in the salivary glands. Autoimmune pancreatitis occurred in the two patients during follow up. Chronic sclerosing sialadenitis and autoimmune pancreatitis would appear to show essentially the same pathophysiological mechanism. Measurement of serum immunoglobulin G4 concentration is useful in differentiating chronic sclerosing sialadenitis from neoplasia.     

Usefulness of a low-dose intravenous immunoglobulin regimen for the treatment of thrombocytopenia associated with AIDS

Infection with the human immunodeficiency virus (HIV) frequently is complicated with thrombocytopenia (HIV-Thr) during all stages of the infection. The treatments for autoimmune thrombocytopenic purpura (ITP) are used in HIV-Thr; however, their effects upon the immune status of patients with acquired immunodeficiency syndrome (AIDS) are unknown. Intravenous immunoglobulin (IVIg) is used in patients with ITP and HIV-Thr; however, its usefulness in thrombocytopenic AIDS patients has not been directly addressed. We used a low-dose IVIg regimen (0.04 g/kg per week during five weeks) for the treatment of HIV-Thr complicating AIDS. Thirteen patients received IVIg. We observed a response to IVIg in 13 patients by the end of week one and in 10 patients by the end of week five. Long-term response, evaluated three months after stopping IVIg, was present in four cases. IVIg was well tolerated and no opportunistic infections were observed during the study period. Compared with previous reports, we used 10% of the previously proposed dosage with an important decrease in the cost of treatment. Our results suggest that this low-dose IVIg regimen is a highly effective, nonexpensive alternative in treating HIV-Thr in AIDS. If sustained responses can be obtained with a similar low-dose maintenance regimen, IVIg may be the first choice for the treatment of HIV-Thr in AIDS patients. Am. J. Hematol. 59:127–132, 1998. © 1998 Wiley-Liss, Inc.     

Treatment algorithm for thrombocytopenia in patients with chronic liver disease undergoing planned invasive procedures

Thrombocytopenia is highly prevalent in patients with chronic liver disease (CLD) and these patients often require invasive procedures that carry a risk of bleeding. To prevent bleeding, guidelines recommend increasing platelet counts in patients with CLD who have thrombocytopenia and are planned to undergo invasive procedures. There are currently two options to increase platelet counts in patients in this setting: platelet transfusion or thrombopoietin receptor agonists (TPORAs). Several treatment algorithms have been developed in the US to help physicians choose the best course of treatment for each patient; however, to date, no such algorithm has been proposed in other countries, where the choice of treatment has been based on each physician's judgment and experience. Here, we discuss the pathogenesis and treatment of thrombocytopenia in patients with CLD, we review and present current evidence of the efficacy of TPORAs for the treatment of thrombocytopenia in patients with CLD, and we present our expert opinion on a Japanese treatment algorithm for thrombocytopenia in patients with CLD who are planned to undergo invasive procedures. This algorithm aims to provide guidance for optimal decision making in the selection of TPORA therapy or platelet transfusion based on the latest evidence and according to actual clinical practice.