Drug-induced nonautoimmune hemolytic anemia

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Drug-induced nonautoimmune hemolytic anemia
Specialty Hematology

Drug-induced nonautoimmune hemolytic anemia is a uncommon cause of hemolytic anemia. In drug-induced nonautoimmune hemolytic anemia, red blood cells (RBC) are destroyed from various non-immune mechanisms such as direct oxidative stress from certain drugs. [1] This is in contrast to drug-induced autoimmune hemolytic anemia where certain drugs result in the formation of antibodies against RBCs, resulting in hemolysis.

Contents

Since drug-induced nonautoimmune hemolytic anemia often occurs due to oxidative mechanisms, it is commonly seen in those with antioxidant enzyme deficiencies such as in Glucose-6-phosphate dehydrogenase deficiency or Hemoglobin H disease, often in response to drugs such as primaquine or dapsone. [2] Drug-induced nonautoimmune hemolytic anemia can also occur due to other various mechanisms that damage RBCs such as in drug induced thrombotic microangiopathy. [3]

Individuals with drug-induced nonautoimmune hemolytic anemia often have symptoms of fatigue, pallor, shortness of breath, and abdominal pain. Treatment involves stopping of the suspected drug and supportive measures such as hydration and possible transfusions. [4]

Signs and symptoms

The initial signs and symptoms of drug-induced nonautoimmune hemolytic anemia can initially present suddenly after exposure to a drug or can begin to present days to weeks after exposure. Signs and symptoms can range from mild to severe. Drug-induced nonautoimmune hemolytic anemia can present with symptoms of anemia such as pallor, fatigue, dizziness, shortness of breath, increased heart rate, or fainting. It can also present with signs and symptoms of hemolysis including abdominal pain, back pain, jaundice, or dark or red urine. [4] [5] More severe complications include shock, disseminated intravascular coagulation, acute renal failure, or death. [4] [6] [7]

Causes

Many drugs have been implicated in causing oxidative damage to RBCs, which may cause a hemolytic anemia especially if these drugs are used in individuals with compromised antioxidant mechanisms such as G6PD deficiency or Hemoglobin H disease.

Drugs commonly implicated in causing hemolytic anemia in these individuals include [1] :

Methemoglobinemia may also uncommonly cause hemolytic anemia and commonly implicated drugs include topical anesthetics such as benzocaine or lidocaine, dapsone, inhaled nitric oxide, rasburicase, chloroquine, sulfasalazine and primaquine. Notably, methylene blue is used as the main treatment for methemoglobinemia, however in G6PD individuals, methylene blue may cause further oxidative stress and that may induce or worsen hemolysis in those with methemoglobinemia. [1]

Hemolytic anemia may also occur secondarily due to thrombotic microangiopathy after exposure to certain drugs. Drug-induced thrombotic microangiopathy can occur due to autoimmune and nonautoimmune mechanisms and commonly implicated causes of nonautoimmune thrombotic microangiopathy various chemotherapeutic drugs, immunosuppressive drugs such as cyclosporine A and tacrolimus, cocaine, or polyethylene oxide (an inert ingredient included with opioids). [8] [9] [10]

Mechanism

Drug-induced nonautoimmune hemolytic anemia can occur due to multiple different mechanisms. A common mechanism is RBC destruction through oxidative injury. Many drugs cause oxidative injury by causing the formation of intracellular oxidizing radicals such as hydrogen peroxide which can interact with hemoglobin and the RBC membrane. These oxidizing radicals can directly damage and crosslink the membrane and intracellular structures of RBCs, cause lipid peroxidation, and promote the formation of Heinz bodies that further impede RBC function. [11]

Those with a deficiency in antioxidant mechanisms such as those with G6PD deficiency or Hemoglobin H disease are particularly susceptible to oxidative injury from drugs. In G6PD deficiency, there is a deficiency of the glucose-6-phosphate dehydrogenase enzyme, which plays a crucial role in the generation of the key antioxidant [[Nicotinamide adenine dinucleotide phosphate|NADPH]. [2] In Hemoglobin H disease, individuals have a loss of three alpha hemoglobin chain genes, leading to the formation of abnormal hemoglobin and also increasing the generation of oxidizing radicals. [12]

Methemoglobinemia is also an uncommon cause of drug-induced nonautoimmune hemolytic anemia. In methemoglobinemia, drug-induced oxidative stress causes the oxidation of the Fe2+ ion within the heme molecule in hemoglobin to Fe3+, forming excessive amounts of methemoglobin. Methemoglobin is unable to bind to oxygen causing the individual to be unable to oxygenate their tissues. [13] Continued oxidation and eventual precipitation of methemoglobin can cause the formation of Heinz bodies, which attach to the RBC membrane. These Heinz bodies are then removed by macrophages in the spleen, causing hemolysis and forming bite cells. [14]

Hemolytic anemia can also occur in drug-induced thrombotic microangiopathies (DITMA) where drugs cause platelets to collect together to form platelet collections against the walls of the small vessels of the body. These collections of platelets are referred to as thrombi and shear passing RBCs, causing hemolysis. DITMA can occur due to autoimmune or non-immune mechanisms. In the autoimmune mechanisms, drugs will bind to naturally occurring antibodies that then proceed to bind to platelets, neutrophils, and the walls of the small vessels. Non-immune DITMAs occur generally due to direct tissue injury to the small vessels of the body causing cellular damage and increased accumulation of platelets. This injury may occur after a single dose of a drug or may occur due to a cumulative effect over long term exposure to the drug. [3]

Diagnosis

Drug-induced nonautoimmune hemolytic anemia can occur often suddenly and severely after exposure to a drug and initial work up typically includes a complete blood count and a blood smear. Initial laboratory results will show likely show a decrease in hemoglobin and hematocrit as the initial production of new RBCs in the bone marrow is not quick enough to compensate for the ongoing hemolysis. Reticulocytes may be increased as the bone marrow attempts to increase the production of new RBCs as the hemolytic anemia progresses. Laboratory results may also show signs of hemolysis such as an increase in lactate dehydrogenase and unconjugated bilirubin with a decrease in haptoglobin. [15] A urine dipstick may also be positive for heme and the a urine study may also be positive for hemosiderin. A peripheral blood smear may show abnormally shaped RBCs such as blister or "bite" cells, particularly in those with G6PD deficiency. [15]

Direct antiglobulin testing can be used to differentiate between an autoimmune hemolytic anemia and a nonautoimmune hemolytic anemia. Direct antiglobulin testing helps determine whether the RBCs of the patient are bound by IgG or complement. Since nonautoimmune hemolytic anemia occurs due to mechanisms that do not involve the creation of IgG or complement, direct antiglobulin testing will often be negative. [16]

Treatment

When drug-induced nonautoimmune hemolytic anemia is suspected, stabilizing or life saving treatments should be taken aggressively prior to diagnosis. These include aggressive hydration with IV fluids or transfusion. [4] Treatment with corticosteroids can also be considered. [17] Once diagnosis is established, the suspected drug must be stopped and most patients can be expected to recover over the next few days to weeks. [4]

If drug-induced nonautoimmune hemolytic anemia occurs secondarily to drug induced methemoglobinemia, methylene blue can be used as a first-line therapy. However methylene blue should be avoided in those with a concomitant G6PD deficiency as methylene blue may cause further oxidative hemolysis. In these individuals, Vitamin C is the preferred treatment. [18]

See also

Related Research Articles

<span class="mw-page-title-main">Hemolysis</span> Rupturing of red blood cells and release of their contents

Hemolysis or haemolysis, also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid. Hemolysis may occur in vivo or in vitro.

<span class="mw-page-title-main">Anemia</span> Reduced ability of blood to carry oxygen

Anemia or anaemia is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin available for oxygen transport, or abnormalities in hemoglobin that impair its function.

<span class="mw-page-title-main">Glucose-6-phosphate dehydrogenase deficiency</span> Medical condition

Glucose-6-phosphate dehydrogenase deficiency (G6PDD), also known as favism, is the most common enzyme deficiency anemia worldwide. It is an inborn error of metabolism that predisposes to red blood cell breakdown. Most of the time, those who are affected have no symptoms. Following a specific trigger, symptoms such as yellowish skin, dark urine, shortness of breath, and feeling tired may develop. Complications can include anemia and newborn jaundice. Some people never have symptoms.

<span class="mw-page-title-main">Thrombotic thrombocytopenic purpura</span> Medical condition

Thrombotic thrombocytopenic purpura (TTP) is a blood disorder that results in blood clots forming in small blood vessels throughout the body. This results in a low platelet count, low red blood cells due to their breakdown, and often kidney, heart, and brain dysfunction. Symptoms may include large bruises, fever, weakness, shortness of breath, confusion, and headache. Repeated episodes may occur.

<span class="mw-page-title-main">Hemolytic anemia</span> Reduced oxygen-carrying ability of the blood due to breakdown of red blood cells

Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels or elsewhere in the human body (extravascular). This most commonly occurs within the spleen, but also can occur in the reticuloendothelial system or mechanically. Hemolytic anemia accounts for 5% of all existing anemias. It has numerous possible consequences, ranging from general symptoms to life-threatening systemic effects. The general classification of hemolytic anemia is either intrinsic or extrinsic. Treatment depends on the type and cause of the hemolytic anemia.

<span class="mw-page-title-main">Megaloblastic anemia</span> Medical condition

Megaloblastic anemia is a type of macrocytic anemia. An anemia is a red blood cell defect that can lead to an undersupply of oxygen. Megaloblastic anemia results from inhibition of DNA synthesis during red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis (M) stage. This leads to continuing cell growth without division, which presents as macrocytosis. Megaloblastic anemia has a rather slow onset, especially when compared to that of other anemias. The defect in red cell DNA synthesis is most often due to hypovitaminosis, specifically vitamin B12 deficiency or folate deficiency. Loss of micronutrients may also be a cause.

<span class="mw-page-title-main">Reticulocytosis</span> Medical condition

Reticulocytosis is a laboratory finding in which the number of reticulocytes in the bloodstream is elevated. Reticulocytes account for approximately 0.5% to 2.5% of the total red blood cells in healthy adults and 2% to 6% in infants, but in reticulocytosis, this percentage rises. Reticulocytes are produced in the bone marrow and then released into the bloodstream, where they mature into fully developed red blood cells between 1-2 days. Reticulocytosis often reflects the body’s response to conditions rather than an independent disease process and can arise from a variety of causes such as blood loss or anemia.

Autoimmune hemolytic anemia (AIHA) is an autoimmune disorder which occurs when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to an insufficient number of oxygen-carrying red blood cells in circulation (anemia). The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases. The intracellular components of the RBCs are released into the circulating blood and into tissues, leading to some of the characteristic symptoms of this condition. The antibodies are usually directed against high-incidence antigens, therefore they also commonly act on allogenic RBCs. AIHA is a relatively rare condition, with an incidence of 5–10 cases per 1 million persons per year in the warm-antibody type and 0.45 to 1.9 cases per 1 million persons per year in the cold-antibody type. Autoimmune hemolysis might be a precursor of later onset systemic lupus erythematosus.

<span class="mw-page-title-main">Thrombotic microangiopathy</span> Medical condition

Thrombotic microangiopathy (TMA) is a pathology that results in thrombosis in capillaries and arterioles, due to an endothelial injury. It may be seen in association with thrombocytopenia, anemia, purpura and kidney failure.

Paroxysmal cold hemoglobinuria (PCH) or Donath–Landsteiner hemolytic anemia (DLHA) is an autoimmune hemolytic anemia featured by complement-mediated intravascular hemolysis after cold exposure. It can present as an acute non-recurrent postinfectious event in children, or chronic relapsing episodes in adults with hematological malignancies or tertiary syphilis. Described by Julius Donath (1870–1950) and Karl Landsteiner (1868–1943) in 1904, PCH is one of the first clinical entities recognized as an autoimmune disorder.

Hematologic diseases are disorders which primarily affect the blood and blood-forming organs. Hematologic diseases include rare genetic disorders, anemia, HIV, sickle cell disease and complications from chemotherapy or transfusions.

Normocytic anemia is a type of anemia and is a common issue that occurs for men and women typically over 85 years old. Its prevalence increases with age, reaching 44 percent in men older than 85 years. The most common type of normocytic anemia is anemia of chronic disease.

<span class="mw-page-title-main">6-phosphogluconate dehydrogenase deficiency</span> Medical condition

6-Phosphogluconate dehydrogenase deficiency, or partial deficiency, is an autosomal hereditary disease characterized by abnormally low levels of 6-phosphogluconate dehydrogenase (6PGD), a metabolic enzyme involved in the Pentose phosphate pathway. It is very important in the metabolism of red blood cells (erythrocytes). 6PDG deficiency affects less than 1% of the population, and studies suggest that there may be race variant involved in many of the reported cases. Although it is similar, 6PDG deficiency is not linked to glucose-6-phosphate dehydrogenase (G6PD) deficiency, as they are located on different chromosomes. However, a few people have had both of these metabolic diseases.

Congenital hemolytic anemia (CHA) is a diverse group of rare hereditary conditions marked by decreased life expectancy and premature removal of erythrocytes from blood flow. Defects in erythrocyte membrane proteins and red cell enzyme metabolism, as well as changes at the level of erythrocyte precursors, lead to impaired bone marrow erythropoiesis. CHA is distinguished by variable anemia, chronic extravascular hemolysis, decreased erythrocyte life span, splenomegaly, jaundice, biliary lithiasis, and iron overload. Immune-mediated mechanisms may play a role in the pathogenesis of these uncommon diseases, despite the paucity of data regarding the immune system's involvement in CHAs.

<span class="mw-page-title-main">Drug-induced autoimmune hemolytic anemia</span> Medical condition

Drug-induced autoimmune hemolytic anemia also known as Drug-induced immune hemolytic anemia (DIIHA) is a rare cause of hemolytic anemia. It is difficult to differentiate from other forms of anemia which can lead to delays in diagnosis and treatment. Many different types of antibiotics can cause DIIHA and discontinuing the offending medication is the first line of treatment. DIIHA has is estimated to affect one to two people per million worldwide.

<span class="mw-page-title-main">Degmacyte</span> Abnormally shaped mature red blood cell

A degmacyte or bite cell is an abnormally shaped mature red blood cell with one or more semicircular portions removed from the cell margin, known as "bites". These "bites" result from the mechanical removal of denatured hemoglobin during splenic filtration as red cells attempt to migrate through endothelial slits from splenic cords into the splenic sinuses. Bite cells are known to be a result from processes of oxidative hemolysis, such as Glucose-6-phosphate dehydrogenase deficiency, in which uncontrolled oxidative stress causes hemoglobin to denature and form Heinz bodies. Bite cells can contain more than one "bite." The "bites" in degmacytes are smaller than the missing red blood cell fragments seen in schistocytes.

<span class="mw-page-title-main">Upshaw–Schulman syndrome</span> Medical condition

Upshaw–Schulman syndrome (USS) is the recessively inherited form of thrombotic thrombocytopenic purpura (TTP), a rare and complex blood coagulation disease. USS is caused by the absence of the ADAMTS13 protease resulting in the persistence of ultra large von Willebrand factor multimers (ULvWF), causing episodes of acute thrombotic microangiopathy with disseminated multiple small vessel obstructions. These obstructions deprive downstream tissues from blood and oxygen, which can result in tissue damage and death. The presentation of an acute USS episode is variable but usually associated with thrombocytopenia, microangiopathic hemolytic anemia (MAHA) with schistocytes on the peripheral blood smear, fever and signs of ischemic organ damage in the brain, kidney and heart.

Intravascular hemolysis describes hemolysis that happens mainly inside the vasculature. As a result, the contents of the red blood cell are released into the general circulation, leading to hemoglobinemia and increasing the risk of ensuing hyperbilirubinemia.

Hemolytic jaundice, also known as prehepatic jaundice, is a type of jaundice arising from hemolysis or excessive destruction of red blood cells, when the byproduct bilirubin is not excreted by the hepatic cells quickly enough. Unless the patient is concurrently affected by hepatic dysfunctions or is experiencing hepatocellular damage, the liver does not contribute to this type of jaundice.

References

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