Viral hepatitis is quite common in China, with 20 million and 5.6 million people infected with hepatitis B virus (HBV) and hepatitis C virus (HCV), respectively. The incidence of thrombocytopenia in patients with hepatitis is 10.6-17.7%, and HCV is more prone to thrombocytopenia than HBV (incidence of 17.7% vs. 13.1%, respectively). Large-scale statistics from the United States showed that the incidence of immune thrombocytopenia in patients with HCV was 30.2/100,000 compared to 18.5/100,000 in those without viral hepatitis.
On the other hand, the prevalence of hepatitis virus infection is also higher in immune thrombocytopenic patients than in other populations, with 20% of immune thrombocytopenic patients being accompanied by HCV infection. One of our scholars reported that the HBsAg positivity rate in immune thrombocytopenic patients was 14.7%, compared with 9.5% in healthy controls.
Given the close association between hepatitis virus infection and thrombocytopenia, the American Society of Hematology guidelines for the diagnosis and management of primary immune thrombocytopenia (ITP) and the international ITP consensus consistently recommend routine testing for hepatitis virus in older patients with thrombocytopenia. Viral hepatitis thrombocytopenia and immune thrombocytopenia have both similarities and significant differences in pathogenesis and treatment.
This issue has not received sufficient attention. Clinicians often treat patients with viral hepatitis thrombocytopenia simply by referring to immune thrombocytopenia protocols. Some important advances have been made in recent years in the study of the mechanism and treatment of viral hepatitis thrombocytopenia, which are reviewed below.
I. Pathogenesis of viral hepatitis thrombocytopenia
The mechanism of viral hepatitis thrombocytopenia is complex and is associated with a variety of factors in addition to concomitant immune thrombocytopenia.
1. Immune platelet destruction: Hepatitis virus (especially HCV) infection can cause disorders of the body’s immune system, producing autoantibodies and inducing autoimmune diseases such as mixed cryoglobulinemia, dry syndrome, arthritis and autoimmune thrombocytopenia.
Panzer et al. detected anti-platelet membrane glycoprotein (GP) antibodies in 48 patients with HCV by direct monoclonal antibody capture platelet antigen technique (MAIPA), and the positive rate was 66% (predominantly anti-GPIIIa), and the antibodies decreased or disappeared after antiviral treatment. This suggests that HCV is directly associated with the production of antiplatelet membrane GP antibodies.
It has been further investigated the molecular mechanism that HCV can specifically bind to platelet membrane CD81 receptors to form new antigens, and the anti-HCV-, CD81 complex antibodies produced by the organism lead to platelet destruction. In addition, Zhang et al. found by phage display peptide library scanning technique that the coreenvelope of HCV
1, structure is highly homologous to the amino acid sequence 49-66 of platelet GPIIIa, and sera from HCV thrombocytopenic patients bind with high affinity to core envelope 1.
They confirmed in animal experiments that NZB/WFI mice produced the corresponding antibodies after injection of recombinant core envelope 1 protein, while thrombocytopenia occurred. This suggests that HCV’s 1 causes thrombocytopenia by producing anti-platelet cross-antibodies through a similar structure to platelet GPllla49-66.
2, inhibition of bone marrow by hepatitis virus: E1Barbary et al. found that megakaryocyte colony-forming units (CFU-meg) were inhibited in short-term in vitro megakaryocyte cultures of chronically HCV-infected patients, and the degree of inhibition was positively correlated with platelet counts as well as serum TPO levels Almeida et al. showed that 60% of HCV-infected patients had thrombocytopenia Almeida et al. showed that 60% of HCV-infected patients had thrombocytopenia, while only 35% of negative patients had thrombocytopenia, indicating that HCV is directly related to thrombocytopenia.
3, hypersplenism: Patients with chronic hepatitis often have varying degrees of splenomegaly, which is more pronounced in the presence of cirrhosis. Splenic stasis due to portal hypertension is the main cause of splenomegaly. A large number of platelets are stagnated in the spleen, while hypersplenism is accompanied by an active proliferation of mononuclear macrophages with an increased ability to phagocytose platelets. The size of the spleen in patients with hepatitis is often negatively correlated with the peripheral platelet count.
It has long been believed that hypersplenism is the main cause of thrombocytopenia in patients with viral hepatitis, but some patients do not have obvious splenomegaly, while about 1/3 of patients with splenomegaly have basically normal platelet counts, and some patients fail to restore normal platelet counts even after splenectomy, so splenomegaly is not the only cause of thrombocytopenia in patients with hepatitis.
TPO synthesis is reduced: TPO is mainly synthesized by hepatocytes. TPO promotes the growth and maturation of megakaryocytes and platelet production by binding to the TPO receptor (c-Mp1) of the bone marrow megakaryocyte lineage. Reduced TPO synthesis by hepatocytes leads to a decrease in peripheral blood platelets. TPO levels and platelet counts were significantly lower than normal in the presence of liver destruction or impaired hepatocyte function and correlated with the degree of liver damage.
Olariu et al. performed a comprehensive analysis of patients with HCV with thrombocytopenia and found that platelet immune destruction was predominant in mild thrombocytopenia, whereas severe thrombocytopenia was often due to a combination of platelet immune destruction and bone marrow megakaryocyte suppression, and the degree of thrombocytopenia was closely related to liver enzyme levels, viral load, and liver fibrosis.
Clinical features of thrombocytopenia in viral hepatitis
Viral hepatitis with thrombocytopenia is quite common and occurs mainly in middle-aged and elderly patients. The degree of thrombocytopenia is directly related to the severity of liver damage and fibrosis. The clinical manifestations of thrombocytopenia in viral hepatitis are the same as those of immune thrombocytopenia, with skin petechiae, rhinorrhea and gingival bleeding predominating. It is generally accepted that patients with HCV complicated by ITP are less likely to bleed than those without HCV, but the proportion of patients who develop severe bleeding (25%) is higher than the latter ( 10%). Our data showed no difference between these two groups of patients in terms of platelet count and degree of bleeding.
Treatment of thrombocytopenia in viral hepatitis
The treatment of ITP is relatively homogeneous and has been standardized. Because viral hepatitis thrombocytopenia involves both hepatitis and thrombocytopenia, treatment of one may aggravate the other, and clinicians are often in a dilemma, increasing the difficulty of treatment.
1, glucocorticoids: glucocorticoids are the main first-line drugs for ITP, but the effect on patients with viral hepatitis with ITP is relatively poor, with an efficiency of about 50%. Long-term use of glucocorticoids can make hepatitis virus replication tend to be active and aggravate liver damage.
Rajan et al. treated HCV-positive thrombocytopenic patients with prednisone, and six of seven patients had increased HCV viral counts with elevated liver enzymes, and two had increased serum bilirubin. Therefore, clinicians should carefully consider the use of glucocorticoid therapy for patients with thrombocytopenia in viral hepatitis, and try to avoid the application of glucocorticoids in patients with platelet counts ≥ 30×109/L and less severe bleeding tendency.
2, intravenous gammaglobulin (IVIG): IVIG inhibits the role of mononuclear macrophages to remove the encapsulated antibody platelets; according to the conventional dose of ITP 1.0g.kg-1.d-1, continuous use for 2d, can make 2/3 of viral hepatitis with ITP patients platelet count rise, but only maintain 1-2 weeks, so it is mainly suitable for patients with severe disease.
3, immunosuppressants: immunosuppressants used for the treatment of chronic ITP (such as cyclophosphamide, azathioprine, CsA, mycophenolate, rituximab) are toxic to the liver and may contribute to hepatitis virus replication.
These drugs are not recommended as routine treatment for patients with viral hepatitis with ITP and are only used in recalcitrant cases with significant bleeding. Splenectomy is effective in some patients with intractable viral hepatitis with ITP, but should be considered in conjunction with liver function, cirrhosis and portal hypertension before determining the need for surgery.
4, anti-hepatitis virus treatment: interferon alpha inhibits hepatitis virus replication by increasing the number and function of NK cells in the body, which has anti-viral, immunomodulatory and anti-fibrotic effects, and is currently one of the drugs of choice for the treatment of chronic viral hepatitis. Interferon alpha contributes to the recovery of platelet production mainly by enhancing the inactivation of hepatitis virus and reducing the inflammatory response of the liver. However, interferon itself has a direct inhibitory effect on bone marrow and can cause thrombocytopenia.
Therefore, interferon is a double-edged sword for viral hepatitis with ITP. Some patients with active hepatitis are not suitable for antiviral therapy due to low platelet levels or have to reduce or discontinue the drug due to thrombocytopenia during the course of antiviral therapy.
RNA levels decreased, liver function improved, and platelet counts increased in 12 of these patients; the other 10 patients who did not see antiviral effects had increased thrombocytopenia.
This suggests that interferon alpha can only increase platelet counts while exerting an antiviral effect. It has also been suggested that the effect of longer (24 weeks) interferon treatment to elevate platelets is more pronounced and the duration of efficacy is longer than with shorter (4-16 weeks) dosing. Notably, interferon may cause severe thrombocytopenia and bleeding in individual patients, which may return to normal after discontinuation of the drug.
In addition, ribavirin is also a widely used antiviral drug. The combination of interferon and ribavirin has a synergistic effect and has become a standard treatment regimen for viral hepatitis, effectively clearing the virus in most patients. Comprehensive analysis of the data showed that the sustained virological response rate (SVR) of patients with chronic HCV was 14% for plain interferon alone, 31% for pegylated interferon alone, and 55% for the combination of interferon and ribavirin.
5. TPO analogues: Platelet white body antibodies not only cause excessive platelet destruction, but also lead to impaired proliferation and maturation of bone marrow megakaryocytes, resulting in reduced platelet production. TPO increases peripheral platelet count by stimulating megakaryocyte maturation and proliferation and platelet production. There are two main TPO analogues, a recombinant peptide regulator, romiplostim, and a small molecule non-peptide analogue, eltrombopag.
TPO analogs are also effective in thrombocytopenia in viral hepatitis, allowing treatment of patients who cannot be treated with antiviral drugs because of thrombocytopenia.
McHutchison et al. treated HCV thrombocytopenia with three doses (30, 50, and 75 mg) of eltrombopta, and after 4 weeks, 75%, 79%, and 95% of patients had significantly increased platelet counts, respectively, and 36%, 53%, and 65% of patients completed interferon-ribavirin combination antiviral therapy, respectively; only 6% of patients in the no-eltrombopta control group completed Antiviral therapy.
In a recent multicenter, randomized, controlled, double-blind phase III clinical study, patients with HCV combined with thrombocytopenia were given either eltrombopta or placebo along with pegylated interferon a2a and ribavirin (ENABLE 1 regimen) or pegylated interferon alpha 2b and ribavirin (ENABLE 2 regimen), resulting in ENABLE
PLT increased to 50×l09/L in 6g% of patients in the treatment group compared to 15% in the control group without eltrombopta; platelet count was consistently higher in 81% of patients in the ENABLE 2 treatment group compared to 23% in the control group. In addition, 23% and 1g% of patients in each of the ENABLE 1 and ENABLE 2 treatment groups were controlled for HCV, compared to 14% and 13% of the control group, respectively. This result clearly demonstrates that the platelet-raising effect of eltrombopta allows patients who would otherwise be unsuitable for antiviral therapy to receive interferon therapy, increasing the effectiveness of anti-HCV, but forcing individual patients to discontinue the drug due to elevated liver enzymes. The US FDA has recently approved Eltrombopta for chronic HCV thrombocytopenia.
IV. Conclusion
Viral hepatitis is prone to complicate thrombocytopenia, and a significant proportion of ITP patients have an onset related to viral hepatitis; therefore, all adult ITP patients should be tested for hepatitis virus. The pathogenesis of viral hepatitis thrombocytopenia is more complex than ITP, which also increases the difficulty of treatment and requires consideration of both antiviral and treatment of thrombocytopenia, which are often contradictory to each other.
The clinician should pay attention to the difference in treatment between viral hepatitis thrombocytopenia and ITP, and individualize the treatment according to various factors such as the degree of liver damage, viral load, platelet level, severity of bleeding and adverse drug reactions of the patient. the combination of TPO analogues and antiviral drugs has a better effect and will become the main method of treatment for viral hepatitis thrombocytopenia.