CHAPTER 51 MICROANGIOPATHIC HEMOLYTIC ANEMIA
CHAPTER 51 MICROANGIOPATHIC HEMOLYTIC ANEMIA
Etiology and Pathogenesis
Localized Vascular Abnormalities
Therapy, Course, and Prognosis
The term microangiopathic hemolytic anemia refers to a group of clinical disorders characterized by the fragmentation of red cells as they pass through the platelet-fibrin mesh present in microthrombi which are deposited in capillaries and arterioles. Since platelet-fibrin clot deposition in the small vessels is the main pathogenic mechanism, this disorder has also been referred to as thrombotic microangiopathy. The formation of arteriolar microthrombi can be caused by a variety of mechanisms, including activation of the coagulation system as occurs in disseminated intravascular coagulation, or by the formation of platelet aggregates induced by the release of very large von Willebrand factor multimers as in thrombotic thrombocytopenic purpura (TTP). In addition, antineoplastic and immunosuppressive agents as well as radiation therapy and bacterial toxins may induce endothelial cell injury leading to the formation of microthrombi in the affected vessels. Identification of the microangiopathic process and its specific etiology can help the clinician to institute prompt and appropriate treatment that frequently improves the hemolytic process and reverses end-organ failure.
Microangiopathic hemolytic anemia, first described in 1962,1 refers to a group of clinical disorders that are characterized by fragmentation of the red cells within the circulatory system, leading to intravascular hemolysis. The common pathogenic mechanism is extracorpuscular and involves red cell fragmentation as a result of passage of the red cell through abnormal arterioles. Since deposition of platelets and fibrin is the most frequent cause of the microvascular lesion, this type of anemia has also been named thrombotic microangiopathic hemolytic anemia2 or simply thrombotic microangiopathy.2,3
ETIOLOGY AND PATHOGENESIS
Thrombus formation inside blood vessels can play a major role in the disruption of red cells, as it can be directly observed when the red cells are forced through a loose fibrin clot formed inside a slide chamber.4 The cells, after attaching to the fibrin, fold around the strands and are either released or fragmented by the force of the flowing blood. Some of the cell fragments reseal their membranes and acquire different shapes that are dependent upon the position and plane in which the red cell attaches and upon the distribution of membrane and hemoglobin within each fragment (Fig. 51-1). Fragmentation of the red cells induced by shear stress from interaction with platelet-fibrin deposits in the vascular bed may not be the only explanation. It is also possible that young erythrocytes may attach to endothelial cells via the association of red cell integrins with endothelial cells expressing adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1).5 Other mechanisms for the attachment of red cells to the endothelium may include the interaction of large von Willebrand factor multimers as bridges between integrins present in the membrane of both young red cells and endothelial cells.6 The attached red cells are then fragmented by the high shear stress present in microvessels. In vivo studies have also demonstrated the role of fibrin in the pathogenesis of microangiopathic hemolytic anemia. For example, snake venoms injected into rabbits induce a rapid defibrination syndrome that is associated with morphological alterations of the red cell, hemoglobinemia, and thrombus formation in several organs. The degree of hemoglobinemia correlates with the intensity of defibrination, and the hemolytic process is aggravated by treating the rabbits with fibrinolytic inhibitors.7 Injection of endotoxin or thrombin into rabbits can also lead to intravascular coagulation with thrombosis of the renal vascular bed, resulting in the fragmentation of the red cells and intravascular hemolysis.8 This experimental model resembles the microangiopathic hemolytic anemia and vascular occlusion found in some patients with sepsis, mainly induced by gram-negative bacteria,9 or purpura fulminans.10 Gastrointestinal infections with Shigella dysenteria or with Escherichia coli, mainly the serotype E. coli O157:H7, can induce a syndrome which is similar to either the uremic hemolytic syndrome or thrombotic thrombocytopenic purpura. Both Shigella and E. coli produce exotoxins that cause endothelial cell injury and platelet-fibrin microthrombi formation.11,12 Microangiopathic hemolysis due to thrombotic thrombocytopenic purpura and uremic hemolytic syndrome is also associated with HIV infection, and the clinical and hematological manifestations of this group of patients respond as well to plasma exchange as non-HIV infected individuals.13,14
FIGURE 51-1 Hanged red cell. Dense fibrin band in background was formed from accumulations of finer strands, some of which are still evident. It is only these denser, more amorphous structures that typically persist postmortem. ×5200 in vitro model, scanning electron microscope. [From BS Bull, Kuhn IN: The production of schistocytes by fibrin strands (a scanning electron microscope study). Blood 35:104, 1970, with permission.]
Patients with invasive carcinoma may have a microangiopathic hemolytic anemia as described in one of the first reports of this syndrome.1 It occurs in approximately 5 percent of cases, and its presence in patients with cancer suggests the presence of disseminated disease.15,16 and 17 Thrombocytopenia, leukocytosis, with a shift to the left, and nucleated red blood cells in the blood film may also be present in this group of patients. The hemolytic process is most likely caused by fibrin deposition inside the blood vessels, but vascular disruption by malignant cells and secretion of cytokines that cause endothelial cell injury may also play a role.15,16 and 17 In some instances, the diagnosis of intravascular coagulation can be made by finding a decrease in the concentration of specific clotting factors and detection of fibrin degradation products (see Chap. 126).16 Mucin-producing tumors are more frequently associated with intravascular coagulation,16 possibly due to the release of tissue factor and of a cysteine protease that is capable of activating factor X directly.18
Intravascular hemolysis can accompany certain complications of pregnancy, most notably preeclampsia, eclampsia, and abruptio placentae.19,20 Intravascular coagulation is thought to play a role in the pathogenesis of the hemolytic process present in preeclampsia and eclampsia. This is supported by the presence of a small number of schistocytes, thrombocytopenia, high levels of fibrinopeptide A, and the deposition of fibrin in the kidney and liver.19,20 and 21 These manifestations are most prominent in a subset of patients with severe preeclampsia, known as the HELLP syndrome, which is characterized by hemolysis, elevated liver enzymes, and low platelets.19,22 However, hemolysis due to red cell fragmentation is also associated with malignant hypertension,1 and it is possible that the severe hypertension which occurs in most of these patients contributes to the disruption of the red cell. The cause of the hemolysis is obscure, but narrowing and hardening of the arterioles along with endothelial cell swelling probably contributes to the mechanical destruction of the erythrocyte. Moreover, hemolysis may subside following normalization of the blood pressure.23
TTP AND UREMIC HEMOLYTIC SYNDROME
Two related clinical entities, thrombotic thrombocytopenic purpura and uremic hemolytic syndrome, are prototypical of microangiopathic hemolysis, which is accompanied by thrombocytopenia and by thrombosis of the small blood vessels of several organs, mainly the central nervous system and/or the kidneys24 (see Chap. 117). Moreover, these microthrombi are mainly formed by platelet aggregates containing small amounts of fibrin(ogen).25 In TTP the platelet thrombi appear to be formed by the binding of large multimers of von Willebrand factor to platelets under high shear stress.26,27
Certain drugs, especially antineoplastic agents, can cause clinical disorders that resemble uremic hemolytic syndrome or, less frequently, thrombotic thrombocytopenic purpura17,28 (see Chap. 117). Mitomycin, given alone or in combination with other agents, is the drug most frequently associated with this disorder. However, bleomycin, daunorubicin in combination with cytosine arabinoside, and regimens containing cisplatin also have been implicated.17,28 The clinical manifestations of uremic hemolytic syndrome following mitomycin therapy frequently do not become apparent until several weeks or months after discontinuation of the drug.17,28 Although the pathogenesis of the hemolytic uremic syndrome is unclear, in some patients the disease is stable while in others the malignant process is in remission at the time of diagnosis, suggesting that mitomycin is, at least in part, responsible for the hematological abnormalities and for the lesions seen in the kidneys.17,28 It is unclear whether mitomycin directly induces endothelial damage of the renal vascular bed or the lesions are induced by the deposition of immune complexes.17 The pathological lesions consist of arteriolar microthrombi similar to those described in idiopathic uremic hemolytic syndrome, and these patients frequently die from renal failure.17,28 The recognition of this entity is important, since these patients can develop severe complications following the transfusion of blood products, whereas they may improve following extracorporeal immunoadsorption of their plasma on columns of staphyloccocal protein A.28,29 Paradoxically, ticlopidine, a drug that inhibits platelet function, can cause severe thrombotic thrombocytopenic purpura leading to the demise of about one-third of the affected individuals.30,31 The mechanism by which ticlopidine, or one of its metabolites, induces the thrombotic disorder is unknown, but the early recognition of this disorder is important, since plasma exchange reduces the mortality substantially.31
Patients who have undergone kidney or liver transplantation occasionally develop microangiopathic hemolysis, thrombocytopenia, and impaired kidney function.32 Multiple pathogenic mechanisms may be involved in this group of patients, including vascular damage induced by tissue rejection, the formation of immune complexes, and immunosuppressive therapy. These factors may lead to the formation of microthrombi in the small vessels of the kidney.32,33 Among the immunosuppressive agents, cyclosporine is the drug most frequently associated with the hemolytic syndrome in this group of patients, and reduction of the dose or discontinuation of the drug followed by plasma exchange can reverse this pathologic process.34,35 Hemolytic uremic syndrome can also occur after allogeneic and autologous marrow transplants, and it seems that total body irradiation, rather than chemotherapy, given to ablate the bone marrow is the responsible agent for the appearance of the uremic hemolytic syndrome.32,33
Patients with generalized vasculitis associated with immunological disorders (e.g., systemic lupus erythematosus, polyarteritis nodosa, Wegener’s granulomatosis, and scleroderma) may also develop intravascular hemolysis due to microangiopathic hemolytic anemia.36 The deposition of immune complexes in the arterioles may lead to local activation of the coagulation factors and fibrin formation. Damaged endothelium together with fibrin deposition are responsible for the fragmentation of the red cells.36
LOCALIZED VASCULAR ABNORMALITIES
Although the majority of cases of microangiopathic hemolytic anemia are due to disorders involving the vascular bed of several organs, occasionally fragmentation of the red cells occurs due to localized vascular abnormalities. Patients with cutaneous cavernous hemangiomas and with hemangioendotheliomas of the liver can sometimes develop microangiopathic hemolytic anemia associated with intravascular coagulation induced by the vascular malformation.37,38
The clinical manifestations of microangiopathic hemolytic anemia are the consequence of the primary process and may also reflect the organ affected by the intravascular deposition of platelets and fibrin (e.g., neurological manifestations of thrombotic thrombocytopenic purpura). Severe anemia and kidney failure may contribute to the constitutional symptoms in these patients. The physical findings can also reflect those expressed by the clinical entity causing the microangiopathic hemolytic anemia.
The most prominent laboratory findings in microangiopathic hemolytic anemia are the alteration in the shape of the red blood cell, such as helmet cells, and formation of fragments termed schistocytes. Increases in the number of schistocytes to more than 3 per 5000 red cells should be considered abnormal, and a cause for this abnormality should be sought.39 The typical schistocyte can be recognized by the presence of one to three sharp spicules (see Chap. 22). Microspherocytosis is also commonly seen. The alteration in the morphology of the red cell is similar to that seen in traumatic cardiac hemolytic anemia (see Chap. 50 and Fig. 50-1). The reticulocyte count is usually elevated, while the degree of thrombocytopenia is variable depending on the intensity of the consumption of platelets and on the capacity of the bone marrow to compensate for this process.
Another pertinent laboratory finding is a decrease in the concentration of haptoglobin, and some patients with marked hemolysis also have increased levels of plasma hemoglobin and hemoglobinuria. High levels of lactic dehydrogenase is almost a constant finding in microangiopathic hemolysis, and the level of this enzyme correlates with the activity of the disease. Coagulation abnormalities due to consumption coagulopathy can be seen in this group of patients. In patients with overt disseminated intravascular coagulation, factors V, VIII, antithrombin III, and fibrinogen are usually depleted. In addition, the levels of fibrinogen and fibrin degradation products are elevated, reflecting increased fibrinolytic activity. In other patients, the coagulation abnormalities are rather subtle, and immunological assays of fibrinopeptide A or of fibrin D dimer are useful in establishing the diagnosis. In several of the clinical entities associated with microangiopathic hemolysis like TTP, the formation of microthrombi is mainly due to platelet aggregates rather than fibrin deposition secondary to the activation of the coagulation system, and these cases show minimal or no evidence of intravascular coagulation.24,25
Microangiopathic hemolytic anemia should be differentiated from other types of intravascular hemolysis, for example, certain forms of autoimmune hemolytic anemia or paroxysmal nocturnal hemoglobinuria. However, the presence of schistocytes in the blood film, thrombocytopenia, negative Coombs’ test combined with the detection of intravascular coagulation, and identification of the primary process are characteristic of microangiopathic hemolytic anemia. The causes of the anemia can be multifactorial; iron and/or folate deficiency, hemorrhage, and marrow involvement due to infiltrative processes can contribute to the anemia. The most common causes of microangiopathic hemolytic anemia are listed in Table 51-1.
TABLE 51-1 CLASSIFICATION OF MICROANGIOPATHIC HEMOLYTIC ANEMIA
THERAPY, COURSE, AND PROGNOSIS
The treatment of this disorder should be directed toward the management of the underlying process that is responsible for the microangiopathic hemolysis. Frequently, patients require red cell transfusions to maintain an adequate level of hemoglobin. In cases presenting bleeding manifestations and thrombocytopenia, platelet transfusions can help to arrest the bleeding. The clinical management of thrombotic thrombocytopenic purpura and uremic hemolytic syndrome is discussed in detail in Chap. 117.
Although intravascular coagulation is commonly a pathogenic mechanism in microangiopathic hemolytic anemia, the use of anticoagulants is controversial. In a few selected cases, heparin therapy seems to improve this process,40 but the use of anticoagulants does not seem to be efficacious in the majority of patients40 (Chap. 126). In the particular case of uremic hemolytic syndrome associated with mitomycin C, immunoadsorption of patient plasma by staphylococcal protein A can normalize the platelet count and stabilize the serum creatinine.29
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn