Thrombocytopenia is likely the most common hematological abnormality in patients with chronic hepatitis C virus (HCV). In these patients, the presence of thrombocytopenia may be a limiting factor when considering antiviral therapy and may be associated with decreased sustained virological response rates. Thrombocytopenia may interfere with diagnostic procedures such as liver biopsy, because of risk of bleeding. Pathogenetic mechanisms include hypersplenism secondary to portal hypertension, bone marrow suppression resulting from either HCV itself or interferon treatment, and aberrations of the immune system resulting in the formation of anti-platelet antibodies and/or immune-complexes that bind to platelets and facilitate their premature clearance. The ability to increase platelet levels could significantly reduce the need for platelet transfusions and facilitate the use of interferon-based antiviral therapy and other medically indicated treatments in patients with liver disease. Therapeutic options include pharmacologic and non- pharmacologic therapies. This review summarizes the available data on these therapeutic options.
Definition and prevalence:
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Thrombocytopenia was defined as a platelet count < 150,000 cells/ÂµL. In a recent systemic review, the definitions of thrombocytopenia varied between studies and were based either on platelet counts, with threshold levels ranging between â‰¤ 100 Ã- 10(9) and â‰¤ 180 Ã- 10(9) /L, or on criteria set in hematological guidelines.(1)
The prevalence of thrombocytopenia related to chronic liver disease has been reported as 15% to 70% in patients with advanced fibrosis and portal hypertension, depending on disease stage and the platelet level used to define thrombocytopenia.(2-4) Patients with more advanced end-stage disease tend to have a higher degree of thrombocytopenia than patients with compensated liver disease (5). Approximately 25% to 50% of cirrhotic patients have counts of < 100,000 cells/ÂµL.(2,6) Platelet counts of < 50,000 cells/ÂµL occur in approximately 1% of patients with chronic HCV infection.(2)
In patients with chronic hepatitis C, the prevalence of Thrombocytopenia ranged from 0.16% to 45.4% and more than half of the studies reported a prevalence of 24% or more (1)
Etiology of Thrombocytopenia in patients with Chronic HCV
The pathophysiology of thrombocytopenia in patients with HCV-related chronic liver disease is complex and involves the interaction of multiple factors. In general, these factors may be grouped into disease-related factors and treatment-related factors. Factors related to the disease include hepatic fibrosis or cirrhosis, hypersplenism, bone marrow suppression, immune dysfunction, and decreased thrombopoietin levels or activity.
The prevalence and severity of thrombocytopenia is associated with the severity of hepatocellular damage, as shown by an increased degree of fibrosis. The inverse correlation between platelet count and the severity of hepatic fibrosis was demonstrated in treatment-naive patients with chronic hepatitis C (7)
Several studies have demonstrated an inverse correlation between spleen size and platelet count in patients with chronic hepatitis C.(8-10) Redistribution of blood to the spleen due to portal hypertension results in pooling of platelets in the spleen and increased clearance of platelets from the circulation.(11) Splenomegaly and platelet sequestration, or hypersplenism, is seen in 11% to 55% of patients with cirrhosis and portal hypertension.(3,12) and, therefore, does not explain all cases of thrombocytopenia in chronic hepatitis C.(13,14)
Bone Marrow Suppression
Bone marrow suppression caused by HCV infection has been proposed as a contributing factor in the development of thrombocytopenia.(15) The reduction of HCV RNA levels following interferon treatment correlated with significant increases in platelet counts in the absence of hypersplenism or serologic evidence of platelet autoantibodies in some patients.(13) Excessive consumption of alcohol, may have additional direct toxic effects on megakaryocytes resulting in decreased platelet production and ineffective thrombopoiesis.(16)
In patients with chronic hepatitis C, autoantibodies directed against platelet surface antigens can promote platelet sequestration and destruction by fixed macrophages in the spleen and liver.(8, 17,18) It has been suggested that the binding of HCV to platelets may induce the development of neoantigens on the platelet surface or alter the conformation of platelet membrane glycoproteins (GPs), thereby contributing to autoantibody formation against target platelet GPs.(19) Immune complex-associated platelet clearance and reticuloendothelial destruction have been proposed to contribute to thrombocytopenia in patients with chronic hepatitis C.(18) High titers of platelet-associated immunoglobulin G (PAIgG), which could represent immune complex-coated platelets, have been found in up to 88% of patients with chronic hepatitis C.( 8,20,21) The PAIgG levels have been shown to correlate directly with liver disease severity,(21) suggesting that prolonged HCV infection causes marked immune system abnormalities.
Decreased Thrombopoietin Levels or Activity
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Thrombopoietin, also known as c-Mpl ligand is the prime cytokine implicated in megakaryocyte maturation and platelet formation. It is produced mainly by hepatocytes and usually released at a constant rate into the circulation.(22) Thrombopoietin binds to c-Mpl receptors on hematopoietic stem cells and on megakaryocytes and promotes all stages of platelet production, from megakaryocyte proliferation to maturation and platelet formation. At various stages of platelet production, circulating thrombopoietin acts in conjunction with other hematopoietic cytokines, including interleukin (IL)-11, steel factor, erythropoietin, and stromal cell-derived factor-1.(23,24) Thrombopoietin also binds to platelets and enhances platelet activation and function.(23 )Platelets not only bind thrombopoietin but also internalize and degrade it.(22) As a result, serum levels of thrombopoietin are normally regulated by the total platelet mass, including platelets sequestered in the spleen, rather than by its production rate.(23) Under normal conditions, if platelet production decreases, the circulating platelet count falls, less thrombopoietin is bound to platelets, and as a result, the plasma thrombopoietin concentration increases. Consequently, megakaryocytopoiesis increases to restore platelet homeostasis, resulting in more production and release of platelets. When the platelet count increases, excess thrombopoietin is bound by circulating platelets, and thrombopoietin levels decrease to normal levels.
It is important to understand that serum thrombopoietin levels in patients with chronic liver disease do not reflect thrombopoietin production alone but also the complex interactions between thrombopoietin production, thrombopoietin degradation, platelet turnover, and thrombocytopenia. In patients with chronic liver disease, serum thrombopoietin levels have been reported to be low, normal, or elevated in the presence of thrombocytopenia. (10,12)
Thrombocytopenia is a well-known adverse effect of peginterferon, which, together with ribavirin, is the current treatment of choice for chronic hepatitis C. Interferon (IFN) therapy is known to cause a 10-50% fall in the platelet count. It is more severe with pegylated interferon/ribavirin (PEG-IFN/RBV) combination therapy as compared to non-pegylated IFN/RBV therapy. It is worst with PEG-IFN monotherapy, (26) suggesting that some reactive thrombocytosis may be occurring secondary to RBV-induced anemia. Since successful treatment of HCV infection has clearly shown to improve the platelet counts.(27,28)
Bone marrow suppression, including inhibition of megakaryocytopoiesis, is considered to be the major mechanism of interferon-induced thrombocytopenia.(29) There is also evidence that interferon treatment may suppress the secretion of thrombopoietin.(30)
The most important clinical consequence of thrombocytopenia during interferon-based therapy is that it can result in total doses of interferon being reduced, resulting in suboptimal therapy and lowered opportunity for the patient to achieve sustained virologic response.
Impact of Thrombocytopenia on the Management of Hepatitis C
The greatest challenge in the care of chronic hepatitis C patients with thrombocytopenia is the difficulty in starting or maintaining anti-HCV therapy. In general, initiation of antiviral therapy is contraindicated when platelet counts are below 75,000-100,000 cells/ÂµL. The American Gastroenterological Association suggests that patients with severe thrombocytopenia should not receive interferon-based antiviral therapy.(31) Postponement of treatment due to thrombocytopenia can result in diminished sustained virologic response because of the potential for further progression of liver disease in the absence of treatment; it may also heighten the need for additional therapies.(32)
The product labels for both formulations of peginterferon recommend dose reductions for patients with platelet counts between 50,000 and 80,000 cells/ÂµL and discontinuation of therapy if platelet counts fall below 25,000-50,000 cells/ÂµL.(31) Treatment with peginterferon has been shown to reduce platelet counts by up to 33%.(33) Therefore, even in patients with adequate platelet counts before therapy, decreases in platelet counts may occur during therapy, which could require a dose modification that may ultimately lower the chances of attaining sustained virologic response.
An important clinical concern with thrombocytopenia is the inability to initiate or maintain therapeutic or diagnostic interventions, which arises from the likelihood that low platelet counts may lead to increased morbidity or mortality. Thrombocytopenia can complicate or delay certain aspects of routine care due to the increased risk of bleeding from invasive procedures. These procedures include liver biopsies by any route,(34-36) variceal banding, paracentesis(37-39) and thoracentesis for ascites, liver transplantation,(39) central line insertion, endoscopy, prostate biopsy, and elective surgeries. Some physicians avoid or postpone these procedures, as well as dental extractions, because of concerns about hemorrhage.(2,34) This trepidation can cause postponement of necessary procedures and therapy, hinder planned medical care, and significantly add to healthcare costs in these patients.
Strategies for Management of Thrombocytopenia in patients with chronic Hepatitis C
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The most practical strategy in treating HCV-related thrombocytopenia is based on the principle that eradication of HCV infection should result in remission of thrombocytopenia. Thus the usual protocol to treat HCV-related thrombocytopenia is to continue with IFN therapy but reduce its dose if platelet count falls to < 30 Ã- 109/L or discontinue if it falls to < 20 Ã- 109/L.(40,41) The minimum effective dose of PEG-IFN appears to be 1 Âµg/kg/week. If platelet counts of < 30 Ã- 109/L persist even after reducing PEG-IFN dose to the minimum effective level, initiating some adjunct therapy like Eltrombopag may be considered.(42)
1- Pharmacological treatment
The use of steroid therapy in the management of HCV-related thrombocytopenia has never gained popularity because despite conflicting reports of variable increases in platelet counts, steroid therapy has shown to cause a rise in transaminase levels and HCV viral load, and worsening of liver damage. Steroids have even shown to cause an elevation in serum bilirubin levels and development of overt jaundice.(43)
Platelet transfusion does not always ensure maintenance of adequate platelet levels, and patients are at risk for serious transfusion-related complications including viral or bacterial infection, alloimmunization, and febrile nonhemolytic reactions following repeated transfusions.(44,45) Platelet transfusion complications occur in up to 30% of patients. The most common adverse event is the development of "refractoriness," occurring in approximately 50% of all patients undergoing multiple platelet transfusions.(45) Refractoriness typically arises from human leukocyte antigen alloimmunization and nonimmune platelet consumption associated with splenomegaly, disseminated intravascular coagulation, and septicemia.(45)
The use of prophylactic platelet transfusions is controversial in many patients. Additionally, for uncomplicated patients without liver disease and platelet counts > 20,000 cells/ÂµL, platelet transfusion is generally not necessary.(45) For patients with platelet counts < 20,000 cells/ÂµL, platelet transfusions are given or the planned medical procedure is postponed.(46) Patient populations at higher risk for bleeding complications, including surgical patients and those with infection or splenomegaly, may warrant higher cutoff values of 50,000-100,000 cells/ÂµL.(47) Platelet transfusions are not indicated prior to anti-HCV therapy or during therapy unless patients have active bleeding with platelet counts lower than 50,000 cells/ÂµL.
Targeting General Thrombopoiesis: Cytokines and Growth Factors
Thrombopoietin is a potent megakaryocyte colony-stimulating and maturation factor, shown to induce colony formation from as many as two thirds of all megakaryocyte progenitors. Although thrombopoietin has profound effects on the proliferation and maturation of megakaryocytes,(48) its effects on the release of platelets from the mature megakaryocyte are less significant.
High levels of thrombopoietin activate megakaryocyte production, increasing the number of platelets, thereby normalizing thrombopoietin levels through feedback regulation. When liver function is impaired (eg, due to cirrhosis), thrombopoietin secretion decreases, which results in a reduction in platelet counts.( 23, 48)
Two forms of recombinant thrombopoietin have been evaluated in clinical trials. Although both produced a dose-dependent increase in platelet counts in healthy volunteers and cancer patients, clinical development of them was halted because of adverse effects as thrombocytopenia and pancytopenia from the generation of neutralizing antibodies to thrombopoietin. (49,50) However, clinical development of these compounds did provide important clinical proof-of-principle for the use of thrombopoietin agonists in the treatment of various types of thrombocytopenia.
IL-1, IL-3, IL-6, and GM-CSF
IL-1, IL-3, IL-6 and GM-CSF have been shown to play a role in the generation of megakaryocytes in animals and have demonstrated thrombopoietic activity in clinical studies. However, these compounds resulted in unacceptable toxicity profiles or did not produce significant increases in platelet counts. These findings led to the discontinuation of research on possible therapeutic uses of these cytokines for the treatment of thrombocytopenia.(51)
Promegapoietin, a thrombopoietin/IL-3 chimeric molecule, was engineered based on the synergy of IL-3 and thrombopoietin on megakaryocyte proliferation and maturation. When administered in a primate model of severe radiation-induced myelosuppression, platelet regeneration was restored, virtually eliminating the need for whole blood transfusions.(52) However, in a phase I clinical study, antibody formation resulted in severe thrombocytopenia, terminating further development of promegapoietin.(53)
In vitro, IL-11 works synergistically with other cytokines to promote multiple stages of megakaryocyte development. Megakaryocytes and megakaryocyte precursors express IL-11 receptors. IL-11 promotes megakaryocyte maturation, stimulates platelet production, and can enhance hematopoietic recovery following myelosuppression. Clinically, recombinant human IL-11 (rhIL-11; oprelvekin) has been successful in some specific patient groups. In a phase I study in advanced breast cancer patients treated with myelosuppressive chemotherapy, treatment with rhIL-11 produced dose-dependent increases in bone marrow progenitor cells, megakaryocytes, and platelets.(54) In a randomized, placebo-controlled trial in patients with solid tumors who were severely thrombocytopenic because of myelosuppressive chemotherapy and had previously received platelet transfusions, treatment with oprelvekin provided positive results to support approval for the indication of chemotherapy-induced thrombocytopenia. Adverse events associated with IL-11 include edema, fluid retention, and less frequently, cardiac arrhythmia and syncope. The adverse event profile and the modest improvement of platelet counts have limited the use of this agent for its approved indication. One case study has demonstrated that oprelvekin can correct HCV-associated thrombocytopenia, raising the possibility that the compound could allow some HCV patients with low platelet counts to complete antiviral therapy. (54) However, oprelvekin is not currently approved for chronic liver disease-related thrombocytopenia.