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Thrombocytopenia is likely the most common haematological abnormalcy in patients with chronic hepatitis C virus ( HCV ) . In these patients, the presence of thrombopenia may be a confining factor when sing antiviral therapy and may be associated with reduced sustained virological response rates. Thrombocytopenia may interfere with diagnostic processs such as liver biopsy, because of hazard of shed blooding. Pathogenetic mechanisms include hypersplenism secondary to portal high blood pressure, bone marrow suppression ensuing from either HCV itself or interferon intervention, and aberrances of the immune system ensuing in the formation of anti-platelet antibodies and/or immune-complexes that bind to thrombocytes and ease their premature clearance. The ability to increase thrombocyte degrees could significantly cut down the demand for thrombocyte transfusions and ease the usage of interferon-based antiviral therapy and other medically indicated interventions in patients with liver disease. Curative options include pharmacologic and non- pharmacologic therapies. This reappraisal summarizes the available informations on these curative options.

Definition and prevalence:

Thrombocytopenia was defined as a thrombocyte count & lt ; 150,000 cells/AµL. In a recent systemic reappraisal, the definitions of thrombopenia varied between surveies and were based either on thrombocyte counts, with threshold degrees runing between a‰¤ 100 A- 10 ( 9 ) and a‰¤ 180 A- 10 ( 9 ) /L, or on standards set in haematological guidelines. ( 1 )

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The prevalence of thrombopenia related to chronic liver disease has been reported as 15 % to 70 % in patients with advanced fibrosis and portal high blood pressure, depending on disease phase and the thrombocyte degree used to specify thrombopenia. ( 2-4 ) Patients with more advanced end-stage disease tend to hold a higher grade of thrombopenia than patients with remunerated liver disease ( 5 ) . Approximately 25 % to 50 % of cirrhotic patients have counts of & lt ; 100,000 cells/AµL. ( 2,6 ) Platelet counts of & lt ; 50,000 cells/AµL occur in about 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 surveies reported a prevalence of 24 % or more ( 1 )

Etiology of Thrombocytopenia in patients with Chronic HCV

The pathophysiology of thrombopenia 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 disfunction, and decreased thrombopoietin degrees or activity.

Hepatic Fibrosis

The prevalence and badness of thrombopenia is associated with the badness of hepatocellular harm, as shown by an increased grade of fibrosis. The reverse correlativity between thrombocyte count and the badness of hepatic fibrosis was demonstrated in treatment-naive patients with chronic hepatitis C ( 7 )


Several surveies have demonstrated an reverse correlativity between spleen size and thrombocyte count in patients with chronic hepatitis C. ( 8-10 ) Redistribution of blood to the lien due to portal high blood pressure consequences in pooling of thrombocytes in the spleen and increased clearance of thrombocytes from the circulation. ( 11 ) Splenomegaly and thrombocyte segregation, or hypersplenism, is seen in 11 % to 55 % of patients with cirrhosis and portal high blood pressure. ( 3,12 ) and, hence, does non explicate all instances of thrombopenia in chronic hepatitis C. ( 13,14 )

Bone Marrow Suppression

Bone marrow suppression caused by HCV infection has been proposed as a lending factor in the development of thrombopenia. ( 15 ) The decrease of HCV RNA degrees following interferon intervention correlated with important additions in thrombocyte counts in the absence of hypersplenism or serologic grounds of thrombocyte autoantibodies in some patients. ( 13 ) Excessive ingestion of intoxicant, may hold extra direct toxic effects on megakaryocytes ensuing in reduced thrombocyte production and uneffective thrombopoiesis. ( 16 )

Immune Dysfunction

In patients with chronic hepatitis C, autoantibodies directed against thrombocyte surface antigens can advance thrombocyte segregation and devastation by fixed macrophages in the lien and liver. ( 8, 17,18 ) It has been suggested that the binding of HCV to thrombocytes may bring on the development of neoantigens on the thrombocyte surface or change the conformation of thrombocyte membrane glycoproteins ( GPs ) , thereby lending to autoantibody formation against mark thrombocyte GPs. ( 19 ) Immune complex-associated thrombocyte clearance and reticuloendothelial devastation have been proposed to lend to thrombocytopenia in patients with chronic hepatitis C. ( 18 ) High titres of platelet-associated Ig G ( PAIgG ) , which could stand for immune complex-coated thrombocytes, have been found in up to 88 % of patients with chronic hepatitis C. ( 8,20,21 ) The PAIgG degrees have been shown to correlate straight with liver disease badness, ( 21 ) proposing that prolonged HCV infection causes marked immune system abnormalcies.

Decreased Thrombopoietin Levels or Activity

Thrombopoietin, besides known as c-Mpl ligand is the premier cytokine implicated in megakaryocyte ripening and thrombocyte formation. It is produced chiefly by hepatocytes and normally released at a changeless rate into the circulation. ( 22 ) Thrombopoietin binds to c-Mpl receptors on haematopoietic root cells and on megakaryocytes and promotes all phases of thrombocyte production, from megakaryocyte proliferation to ripening and thrombocyte formation. At assorted phases of thrombocyte production, go arounding thrombopoietin Acts of the Apostless in concurrence with other haematopoietic cytokines, including interleukin ( IL ) -11, steel factor, erythropoietin, and stromal cell-derived factor-1. ( 23,24 ) Thrombopoietin besides binds to thrombocytes and enhances platelet activation and map. ( 23 ) Platelets non merely adhere thrombopoietin but besides internalise and degrade it. ( 22 ) As a consequence, serum degrees of thrombopoietin are usually regulated by the entire thrombocyte mass, including thrombocytes sequestered in the lien, instead than by its production rate. ( 23 ) Under normal conditions, if platelet production lessenings, the go arounding thrombocyte count falls, less thrombopoietin is bound to thrombocytes, and as a consequence, the plasma thrombopoietin concentration additions. Consequently, megakaryocytopoiesis additions to reconstruct thrombocyte homeostasis, ensuing in more production and release of thrombocytes. When the thrombocyte count additions, extra thrombopoietin is bound by go arounding thrombocytes, and thrombopoietin degrees decrease to normal degrees.

It is of import to understand that serum thrombopoietin degrees in patients with chronic liver disease make non reflect thrombopoietin production entirely but besides the complex interactions between thrombopoietin production, thrombopoietin debasement, thrombocyte turnover, and thrombopenia. In patients with chronic liver disease, serum thrombopoietin degrees have been reported to be low, normal, or elevated in the presence of thrombopenia. ( 10,12 )

Treatment-Related Thrombocytopenia

Thrombocytopenia is a well-known inauspicious consequence of peginterferon, which, together with Virazole, is the current intervention of pick for chronic hepatitis C. Interferon ( IFN ) therapy is known to do a 10-50 % autumn in the thrombocyte count. It is more terrible 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 happening secondary to RBV-induced anaemia. Since successful intervention of HCV infection has clearly shown to better the thrombocyte counts. ( 27,28 )

Bone marrow suppression, including suppression of megakaryocytopoiesis, is considered to be the major mechanism of interferon-induced thrombopenia. ( 29 ) There is besides grounds that interferon intervention may stamp down the secernment of thrombopoietin. ( 30 )

The most of import clinical effect of thrombopenia during interferon-based therapy is that it can ensue in entire doses of interferon being reduced, ensuing in suboptimal therapy and lowered chance for the patient to accomplish sustained virologic response.

Impact of Thrombocytopenia on the Management of Hepatitis C

The greatest challenge in the attention of chronic hepatitis C patients with thrombopenia is the trouble in get downing or keeping anti-HCV therapy. In general, induction of antiviral therapy is contraindicated when thrombocyte counts are below 75,000-100,000 cells/AµL. The American Gastroenterological Association suggests that patients with terrible thrombopenia should non have interferon-based antiviral therapy. ( 31 ) Delay of intervention due to thrombocytopenia can ensue in lessened sustained virologic response because of the potency for farther patterned advance of liver disease in the absence of intervention ; it may besides rise the demand for extra therapies. ( 32 )

The merchandise labels for both preparations of peginterferon recommend dose decreases for patients with thrombocyte counts between 50,000 and 80,000 cells/AµL and discontinuance of therapy if thrombocyte counts fall below 25,000-50,000 cells/AµL. ( 31 ) Treatment with peginterferon has been shown to cut down thrombocyte counts by up to 33 % . ( 33 ) Therefore, even in patients with equal thrombocyte counts before therapy, decreases in thrombocyte counts may happen during therapy, which could necessitate a dose alteration that may finally take down the opportunities of achieving sustained virologic response.

An of import clinical concern with thrombopenia is the inability to originate or keep curative or diagnostic intercessions, which arises from the likeliness that low thrombocyte counts may take to increased morbidity or mortality. Thrombocytopenia can perplex or detain certain facets of everyday attention due to the increased hazard of shed blooding from invasive processs. These processs include liver biopsies by any path, ( 34-36 ) variceal stria, abdominocentesis ( 37-39 ) and thoracocentesis for ascites, liver organ transplant, ( 39 ) cardinal line interpolation, endoscopy, prostate biopsy, and elected surgeries. Some doctors avoid or postpone these processs, every bit good as dental extractions, because of concerns about bleeding. ( 2,34 ) This trepidation can do delay of necessary processs and therapy, hinder planned medical attention, and significantly add to healthcare costs in these patients.

Schemes for Management of Thrombocytopenia in patients with chronic Hepatitis C

The most practical scheme in handling HCV-related thrombopenia is based on the rule that obliteration of HCV infection should ensue in remittal of thrombopenia. Thus the usual protocol to handle HCV-related thrombopenia is to go on with IFN therapy but cut down its dosage if thrombocyte count falls to & lt ; 30 A- 109/L or stop if it falls to & lt ; 20 A- 109/L. ( 40,41 ) The minimal effectual dosage of PEG-IFN appears to be 1 Aµg/kg/week. If platelet counts of & lt ; 30 A- 109/L persist even after cut downing PEG-IFN dosage to the minimal effectual degree, originating some accessory therapy like Eltrombopag may be considered. ( 42 )

1- Pharmacological intervention


The usage of steroid therapy in the direction of HCV-related thrombopenia has ne’er gained popularity because despite conflicting studies of variable additions in thrombocyte counts, steroid therapy has shown to do a rise in aminotransferase degrees and HCV viral burden, and deterioration of liver harm. Steroids have even shown to do an lift in serum hematoidin degrees and development of open icterus. ( 43 )

Platelet Transfusions

Platelet transfusion does non ever guarantee care of equal thrombocyte degrees, and patients are at hazard for serious transfusion-related complications including viral or bacterial infection, alloimmunization, and feverish nonhemolytic reactions following perennial transfusions. ( 44,45 ) Platelet transfusion complications occur in up to 30 % of patients. The most common inauspicious event is the development of “ unmanageableness, ” happening in about 50 % of all patients undergoing multiple thrombocyte transfusions. ( 45 ) Refractoriness typically arises from human leucocyte antigen alloimmunization and liable thrombocyte ingestion associated with splenomegaly, disseminated intravascular curdling, and blood poisoning. ( 45 )

The usage of contraceptive thrombocyte transfusions is controversial in many patients. Additionally, for unsophisticated patients without liver disease and thrombocyte counts & gt ; 20,000 cells/AµL, thrombocyte transfusion is by and large non necessary. ( 45 ) For patients with thrombocyte counts & lt ; 20,000 cells/AµL, thrombocyte transfusions are given or the planned medical process is postponed. ( 46 ) Patient populations at higher hazard for shed blooding complications, including surgical patients and those with infection or splenomegaly, may justify higher cutoff values of 50,000-100,000 cells/AµL. ( 47 ) Platelet transfusions are non indicated prior to anti-HCV therapy or during therapy unless patients have active hemorrhage with thrombocyte counts lower than 50,000 cells/AµL.

Targeting General Thrombopoiesis: Cytokines and Growth Factors


Thrombopoietin is a powerful megakaryocyte colony-stimulating and ripening factor, shown to bring on settlement formation from every bit many as two tierces of all megakaryocyte primogenitors. Although thrombopoietin has profound effects on the proliferation and ripening of megakaryocytes, ( 48 ) its effects on the release of thrombocytes from the mature megakaryocyte are less important.

High degrees of thrombopoietin activate megakaryocyte production, increasing the figure of thrombocytes, thereby normalising thrombopoietin degrees through feedback ordinance. When liver map is impaired ( eg, due to cirrhosis ) , thrombopoietin secernment lessenings, which consequences in a decrease in thrombocyte counts. ( 23, 48 )

Two signifiers of recombinant thrombopoietin have been evaluated in clinical tests. Although both produced a dose-dependent addition in thrombocyte counts in healthy voluntaries and malignant neoplastic disease patients, clinical development of them was halted because of inauspicious effects as thrombopenia and pancytopenia from the coevals of neutralizing antibodies to thrombopoietin. ( 49,50 ) However, clinical development of these compounds did supply of import clinical proof-of-principle for the usage of thrombopoietin agonists in the intervention of assorted types of thrombopenia.

IL-1, IL-3, IL-6, and GM-CSF

IL-1, IL-3, IL-6 and GM-CSF have been shown to play a function in the coevals of megakaryocytes in animate beings and have demonstrated thrombopoietic activity in clinical surveies. However, these compounds resulted in unacceptable toxicity profiles or did non bring forth important additions in thrombocyte counts. These findings led to the discontinuance of research on possible curative utilizations of these cytokines for the intervention of thrombopenia. ( 51 )


Promegapoietin, a thrombopoietin/IL-3 chimeric molecule, was engineered based on the synergism of IL-3 and thrombopoietin on megakaryocyte proliferation and ripening. When administered in a primate theoretical account of terrible radiation-induced myelosuppression, thrombocyte regeneration was restored, virtually extinguishing the demand for whole blood transfusions. ( 52 ) However, in a stage I clinical survey, antibody formation resulted in terrible thrombopenia, ending further development of promegapoietin. ( 53 )


In vitro, IL-11 works synergistically with other cytokines to advance multiple phases of megakaryocyte development. Megakaryocytes and megakaryocyte precursors express IL-11 receptors. IL-11 promotes megakaryocyte ripening, stimulates platelet production, and can heighten haematopoietic recovery following myelosuppression. Clinically, recombinant human IL-11 ( rhIL-11 ; oprelvekin ) has been successful in some specific patient groups. In a stage I study in advanced chest malignant neoplastic disease patients treated with myelosuppressive chemotherapy, intervention with rhIL-11 produced dose-dependent additions in bone marrow primogenitor cells, megakaryocytes, and thrombocytes. ( 54 ) In a randomised, placebo-controlled test in patients with solid tumours who were badly thrombocytopenic because of myelosuppressive chemotherapy and had antecedently received thrombocyte transfusions, intervention with oprelvekin provided positive consequences to back up blessing for the indicant of chemotherapy-induced thrombopenia. Adverse events associated with IL-11 include hydrops, fluid keeping, and less often, cardiac arrhythmia and faint. The inauspicious event profile and the modest betterment of thrombocyte counts have limited the usage of this agent for its sanctioned indicant. One instance survey has demonstrated that oprelvekin can rectify HCV-associated thrombopenia, raising the possibility that the compound could let some HCV patients with low thrombocyte counts to finish antiviral therapy. ( 54 ) However, oprelvekin is non presently approved for chronic liver disease-related thrombopenia.

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