Thrombocytopenia is a common complication in critically ill patients. Clinically, about 70% of patients with cirrhosis are associated with thrombocytopenia. The practice of European and American countries usually defines the platelet count <150×109/L as the absolute decrease in platelets. Because the normal range of platelets in the Chinese population is lower than that in the European and American populations, platelet count <100×109/L is usually defined as thrombocytopenia in China, and platelet count <50× 109/L was defined as severe thrombocytopenia. Thrombocytopenia is often regarded as one of the hallmarks of advanced liver disease, and some studies have shown that moderate to severe thrombocytopenia is an independent predictor of mortality in patients with liver disease.
Spontaneous bleeding is unlikely to occur in the setting of mild to moderate thrombocytopenia and is usually not clinically relevant. However, moderate to severe thrombocytopenia can prevent patients from receiving important interventions, such as being unable to take certain medications and receiving invasive treatments; delaying treatment while also correcting the patient’s platelet abnormalities ultimately prolongs hospitalization and overall Medical costs have greatly increased.
Pathophysiology of chronic liver disease complicated by thrombocytopenia
Previously, thrombocytopenia in patients with liver cirrhosis was thought to be mainly due to portal hypertension-induced congestive splenomegaly, which further resulted in hypersplenism and abnormal platelet distribution. However, several other mechanisms of platelet production and destruction in cirrhotic patients have been discovered (Figure 1).
Figure 1 Common mechanism of thrombocytopenia in liver cirrhosis
Thrombopoietin (TPO) level decreased: The production of platelets is mainly related to TPO. TPO is mainly synthesized by the liver, and can also be produced in small amounts by tissues such as kidney and bone marrow. TPO binds to the c-mpl receptor on megakaryocytes, which in turn promotes the differentiation of immature megakaryocytes and promotes platelet production. Progression of liver fibrosis has been shown to lead to a decrease in circulating TPO levels, which leads to thrombocytopenia.
Myelosuppression: Another cause of decreased platelet production includes myelosuppression, which may be caused by a number of causative factors, the most common of which are Alcoholism and hepatitis virus infection.
Platelet destruction due to autoimmune disorders and sepsis: Increased destruction of platelets may also lead to thrombocytopenia in patients with cirrhosis. Autoimmune disorders play an important role in platelet destruction, especially in patients with autoimmune liver disease and chronic HCV infection, both of which have been shown to be associated with autoimmune thrombocytopenia (ITP). Sepsis is also an important factor in platelet destruction. Compared with the general population, patients with cirrhosis have an increased risk of developing sepsis. In addition, the release of tumor necrosis factor alpha during inflammatory states can also lead to the destruction of platelets.
Pseudo-Thrombocytopenia: Abnormalities and laboratory errors in test specimens can lead to pseudo-thrombocytopenia. Anticoagulants such as ethylenediaminetetraacetic acid (EDTA) in test tubes can induce platelet aggregation. It is important to rule out pseudothrombocytopenia, which can be identified by microscopic counting on a viable blood smear.
Pulmonary hypertension and pulmonary embolism are also associated with increased platelet consumption, often in patients with cirrhosis.
Treatment of thrombocytopenia in cirrhosis
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Treatment of thrombocytopenia in cirrhosis includes platelet transfusion, splenectomy, partial splenic artery embolization, and transjugular intrahepatic portosystemic shunt (TIPS). and platelet-promoting drugs.
1. Platelet transfusion
Thrombocytopenia caused by Platelet transfusions may be given when there is an increased risk of bleeding or when bleeding has occurred. But in addition to the failure to correct platelet function, platelet transfusion also has some related problems: (1) There is no clear safe transfusion threshold to guide platelet transfusion. (2) Platelet transfusion increases the risk of infection in patients with cirrhosis and increases the risk of graft-versus-host disease (GVHD) in transplant patients. (3) Multiple platelet transfusions will lead to platelet refractoriness (PTR), that is, the required platelet count cannot be achieved after transfusion.
2. Treatment of hypersplenism
treatment of spleen The means of hyperfunction include splenectomy, partial splenic artery embolization and TIPS.
Laparoscopic splenectomy and partial splenic artery embolization have been shown to be effective in improving thrombocytopenia. However, both were associated with significantly increased rates of patient complications.
TIPS is effective in some patients, especially those with severe thrombocytopenia; however, it is not an effective intervention. There are few studies on the effectiveness of TIPS, and the mechanism by which it corrects thrombocytopenia is not fully understood.
3. Thrombopoietic drugs
TPO is affected by Body agonists are a new class of drugs that can stimulate platelet production. These drugs act on the human TPO receptor (c-mpl), thereby promoting megakaryocyte proliferation and increased platelet count.
The first approved TPO receptor agonist, Eltrombopag, was approved by the FDA in 2008 for the treatment of idiopathic thrombocytopenic purpura (ITP). In a study by Afdhal et al, eltrombopag reduced the need for platelet transfusions in patients with chronic liver disease who were planning to undergo invasive treatment, but also increased the risk of portal vein thrombosis in patients. Therefore, Eltrombopag is not recommended for patients with chronic liver disease who are planning to undergo surgery.
In 2018, the FDA approved two new drugs, avatrombopag and lusutrombopag, for thrombocytopenia in adults with chronic liver disease who are planning to receive invasive treatment. Both drugs have been shown to reduce platelet transfusions before surgery and reduce bleeding risk after surgery.
Yimaitong compiled and compiled from: Andrew H. Moore, Thrombocytopenia in Cirrhosis: A Review of Pathophysiology and Management Options [J]. 20 December 2019. https: //doi.org/10.1002/cld.860