Hematologic Manifestations of End-Organ Failure

Morphologic Abnormalities

In liver disease, the size and shape of the RBC membrane is affected by abnormal lipid metabolism. Excess cholesterol in the outer RBC membrane bilayer causes macrocytosis and target cells ( Fig. 150.1 ). These morphologic changes usually do not lead to significant anemia by themselves, but they are sometimes encountered in the setting of anemia due to other impairments of red cell homeostasis in liver disease (e.g., hypersplenism, GI bleeding). Excess membrane cholesterol also decreases RBC membrane fluidity due to impaired migration of integral membrane proteins and inability to repair peroxidized membrane lipids. When these less deformable RBCs traverse the splenic microcirculation, cytoskeletal damage and permanent deformation can occur, resulting in the formation of acanthocytes (spur cells) and increased clearance in the reticuloendothelial system.

Spur cell anemia is a hemolytic anemia associated with severe cirrhosis. It is rare and associated with a poor prognosis. Treatments for spur cell anemia associated with liver disease are limited. The most effective therapy is liver transplantation. Clinical improvement using flunarizine, pentoxifylline, and cholestyramine has been reported.

Anemia

Anemia in patients with liver disease occurs through hemodilution, sequestration, reduced production, and blood loss. The anemia may be related to the liver disease or the underlying cause of the liver disease itself. Fluid retention increases whole blood volume in patients with cirrhosis which can result in normal red cell mass but a subnormal hematocrit from hemodilution. Portal hypertension related to liver disease can result in hypersplenism with subsequent sequestration of erythrocytes. Erythropoiesis is reduced by nutritional deficiencies in folate or vitamin B ₁₂ resulting from poor intake or malabsorption. Bone marrow suppression can occur from alcohol consumption, viral hepatitis, hepatitis-associated aplastic anemia, and anemia of chronic disease. Patients with chronic liver disease or cirrhosis can also experience nonimmune hemolysis because of acquired alterations in the RBC membrane (e.g., spur cell anemia), Zieve syndrome (hemolytic anemia, hypertriglyceridemia, and jaundice), or treatment-related marrow suppression (e.g., ribavirin).

The therapeutic approach to anemia in liver disease includes transfusion support for symptomatic disease, identification and treatment of GI bleeding, nutrient supplementation for deficiencies, discontinuation of bone marrow suppressive medications, alcohol cessation, and treatment for the primary cause of liver disease.

Leukopenia

Leukopenia, particularly neutropenia, has also been noted in patients with cirrhosis. Causes of leukopenia include splenic sequestration, medications, or bone marrow suppression mediated by primary infections or toxins (e.g., hepatitis B or C, alcohol). Patients with cirrhosis may also be at higher risk for severe infections due to impairment in neutrophil recruitment and phagocytic function. Granulocyte colony-stimulating factor (G-CSF) is thought to improve neutrophil transendothelial migration in patients with cirrhosis. The use of G-CSF in patients with decompensated cirrhosis was shown to improve survival in a randomized trial ; however, the role of G-CSF in the treatment of patients with cirrhosis and the exact mechanisms through which it may ameliorate liver disease are still uncertain and warrant further research.

Thrombocytopenia

Thrombocytopenia is the most common cytopenia associated with liver disease, occurring in up to 77% of patients with cirrhosis. Severe thrombocytopenia (<30 × 10 ⁹ /L) and spontaneous bleeding are uncommon.

Many factors contribute to thrombocytopenia in liver disease. Decreased platelet counts may result from hypersplenism, impaired thrombopoiesis related to nutritional deficiencies (folate or vitamin B ₁₂ ), direct toxicity of alcohol, viral hepatitis, or reduced hepatic synthesis of thrombopoietin. Autoantibodies to platelet antigens have been demonstrated in patients with cirrhosis, suggesting that accelerated destruction of platelets may occur via immune-mediated mechanisms. Hepatitis C is a secondary cause of immune thrombocytopenia. Thrombocytopenia in patients with cirrhosis, especially in combination with leukopenia, is associated with increased morbidity and mortality.

Platelet Dysfunction

Intrinsic platelet defects leading to abnormal platelet aggregation or adhesion include impaired transmembrane signaling and thromboxane A2 synthesis, storage pool deficiency, or defects in platelet glycoprotein Ib or α _IIb β ₃ receptors. Extrinsic defects resulting in platelet dysfunction include circulating fibrinogen degradation products, bile salts, abnormal high-density lipoproteins, and excess production of nitric oxide.

The clinical significance of platelet dysfunction demonstrated in vitro is unclear. This discordance between laboratory findings and clinical bleeding may be explained by two observations. First, platelets studied under physiologic flow conditions show normal adhesion to fibrinogen and collagen even in cirrhosis. Second, elevated levels of von Willebrand factor (vWF) are commonly found in patients with cirrhosis and may compensate for thrombocytopenia or platelet dysfunction.

Platelet transfusions can be considered in thrombocytopenia associated with liver disease; however, they are generally not indicated unless the patient has severe thrombocytopenia (<10 × 10 ⁹ /L) or platelets less than 50 × 10 ⁹ /L with bleeding. Platelet counts greater than 50 × 10 ⁹ /L are usually considered adequate for invasive procedures. Thrombopoietin (TPO) mimetic agents (e.g., eltrombopag, romiplostim) may offer potential treatment for these patients. Avatrombopag, a second generation TPO agonist, has been examined in patients with chronic liver disease in a pre-procedural setting. Compared to placebo, avatrombopag reduced the frequency of platelet transfusion or rescue therapy. The 2020 American College of Gastroenterology guidelines suggest that TPO agonists can be considered for patients with cirrhosis and a platelet count < 50 × 10 ⁹ /L in anticipation of an elective procedure (conditional recommendation, very low level of evidence).