Chapter 19: Fragmentation Hemolytic Anemia

• Acquired erythrocyte fragmentation occurs when red cells are forced at high shear stress through partial vascular occlusions or over abnormal vascular surfaces.

• In circumstances in which fragmentation of red cells occurs in the microcirculation, it is often referred to as microangiopathic hemolytic anemia.

• In three primary disorders—thrombotic thrombocytopenic purpura (TTP) (Chap. 90), hemolytic uremic syndrome (HUS) (Chap. 90), and disseminated intravascular coagulation (DIC) (Chap. 85)—microangiopathic (fragmentation) hemolytic anemia is an essential diagnostic feature. These disorders are discussed in other chapters.

• In addition to signs of hemolysis such as anemia, reticulocytosis, decreased haptoglobin, elevated indirect bilirubin, and sometimes elevated serum lactic dehydrogenase, fragmented red cells (schistocytes) are evident in the blood film (Figure 19–1). Their prevalence may vary.

• Fragmentation hemolytic anemia syndromes discussed in this chapter include (1) hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, (2) disseminated malignancy, (3) heart valve hemolysis, (4) march hemoglobinuria, and (5) the Kasabach-Merritt phenomenon.

• HELLP syndrome, a life-threatening condition of pregnancy, causes hemolysis, elevated liver function tests, and low platelets.

Etiology and Pathogenesis

• Abnormal development of the placental vasculature causes increased vascular tone, hypertension, proteinuria, enhanced platelet activation and aggregation, and decreased levels of the vasodilators prostaglandin I₂ and nitrous oxide.

• Concurrent activation of the coagulation cascade results in platelet-fibrin deposition in the capillaries, multiorgan microvascular injury, microangiopathic (fragmentation) hemolytic anemia, elevated liver enzymes because of hepatic necrosis, and thrombocytopenia because of peripheral consumption.

• Risk factors for HELLP syndrome include European ancestry, multiparity, advanced maternal age (> 34 years), and a personal or familial history of the disorder.

• Homozygosity for the 677C → T polymorphism of the methylenetetrahydrofolate reductase gene is a modest risk factor for the development of preeclampsia but is not associated with the development of HELLP syndrome. Whether or not the factor V Leiden or prothrombin 20210 gene mutations are risk factors for HELLP syndrome remains controversial.

Clinical Features

• Two thirds of patients are diagnosed antepartum, usually between 27 and 37 weeks. The remaining one third are diagnosed postpartum, from a few to 48 hours following delivery (occasionally as long as 6 days).

• Ninety percent of patients will present with malaise and right upper quadrant or epigastric pain.

• About 50% of patients will have nausea, vomiting, edema, or headache.

• Although hypertension is found in 85% of affected patients, 15% will not develop either hypertension or proteinuria.

• In patients with severe liver involvement, hepatic ultrasonography shows areas of increased echogenicity. As the disease progresses, large areas of necrosis can coalesce and dissect into the liver capsule. This produces a subcapsular hematoma and the risk of hepatic rupture.

• Maternal death occurs in 3% to 5% of those with HELLP syndrome and can be due to cerebral hemorrhage, cardiopulmonary arrest, DIC, adult respiratory distress syndrome, hypoxic ischemic encephalopathy, infection, placenta abruptio, postpartum hemorrhage, intra-abdominal bleeding, and subcapsular liver hematomas with resultant rupture.

• Renal complications include acute renal failure, hyponatremia, and nephrogenic diabetes insipidus.

• Pulmonary complications consist of pleural effusions, pulmonary edema, and adult respiratory distress syndrome.

• Neurologic sequelae not mentioned above are retinal detachment, postictal cortical blindness, and hypoglycemic coma.

• Fetal morbidity and mortality occurs in 9% to 24% of cases due to prematurity, placental abruption, intrauterine asphyxia, and intraventricular hemorrhage.

Laboratory Features

• In approximately two thirds of patients, the blood film has schistocytes, helmet cells, and burr cells consistent with microangiopathic hemolytic anemia.

• Reticulocytosis can be present.

• Low haptoglobin levels are both sensitive and specific haptoglobin level is sensitive for confirming hemolysis and return to normal 24 to 30 hours postpartum.

• Lactate dehydrogenase (LDH) level is increased, due most likely to liver damage rather than hemolysis.

• Serum levels of aspartic acid transaminase (AST) and alanine transaminase (ALT) can be more than 100 times normal, whereas alkaline phosphatase values are typically only about twice normal and total bilirubin ranges between 1.2 and 5 mg/dL. Liver enzymes usually return to baseline within 3 to 5 days postpartum.

• The more severe the thrombocytopenia, the greater the risk of bleeding, perinatal and maternal morbidity and mortality, and disease recurrence with subsequent pregnancies.

• The prothrombin time (PT) and activated partial thromboplastin time (aPTT) are usually within normal limits.

• Low fibrinogen levels are found inconsistently.

• Values of von Willebrand factor (VWF) antigen increase in proportion to the severity of the disease, reflecting the extent of endothelial damage; however, no unusually large VWF multimers are present in plasma. ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin domains-13) levels are within a broad normal range (ADAMTS13 normally declines moderately during pregnancy).

Differential Diagnosis

• Other complications of pregnancy that can be confused with HELLP include TTP, HUS, sepsis, DIC, connective tissue disease, antiphospholipid antibody syndrome, and acute fatty liver of pregnancy.

• Acute fatty liver of pregnancy is seen in the last trimester or postpartum and presents with thrombocytopenia and right upper quadrant pain, but the levels of AST and ALT are usually only 1 to 5 times above normal and the PT and PTT are both prolonged.

• Because it causes right upper quadrant pain and nausea, HELLP has been provisionally misdiagnosed as viral hepatitis, biliary colic, esophageal reflux, cholecystitis, and gastric cancer.

Treatment

• Supportive care includes intravenous administration of magnesium sulfate to control hypertension and prevent eclamptic seizures, stimulation of fetal lung maturation with beclomethasone, and delivery of the fetus as soon as possible.

• Postpartum uterine curettage can lower the mean arterial pressure and increase the urine output and platelet count.

• Transfusion therapy with packed red cells, platelets, or fresh-frozen plasma is indicated in cases complicated by severe anemia or bleeding because of coagulopathy.

• Dexamethasone is no longer used because large randomized trials found that it did not reduce the duration of hospitalization, amount of blood products transfused, maternal complications, or time to normalization of laboratory abnormalities.

• Plasma exchange cannot arrest or reverse HELLP syndrome when used antepartum, but it may minimize hemorrhage and morbidity peripartum. It can also be tried postpartum in the 5% of patients who fail to improve within 72 to 96 hours of delivery.

• Liver transplantation may be necessary in occasional patients with large hepatic hematomas or total hepatic necrosis.

Etiology and Pathogenesis

• Cancer-associated microangiopathic hemolytic anemia (MAHA) has been described in a wide variety of malignancies and is more likely to occur with metastatic mucinous adenocarcinomas than with localized cancers or benign tumors.

• MAHA by either intravascular tumor emboli or DIC with intravascular occlusions of small vessels by platelet-fibrin thrombi.

• Table 19–1 lists the metastatic cancers most frequently associated with red cell fragmentation.

Clinical Features

• MAHA caused by cancer is usually a preterminal event. Life expectancy following diagnosis is 2 to 150 days, with a mean of 21 days.

Laboratory Features

• Patients present with moderate to severe anemia.

• The blood film reveals schistocytes, burr cells, microspherocytes, reticulocytes, polychromasia, and nucleated red cells.

• Although the reticulocyte count can be high, it is an unreliable measure of hemolysis because extensive replacement of the marrow by metastatic tumor and cancer caused anemia of chronic disease (Chap. 5) may prevent the reticulocytosis expected.

• Absent or low levels of haptoglobin may be seen; however, it is also unreliable because haptoglobin is an acute phase reactant that can increase in malignancy.

• The mean platelet count among affected patients is approximately 50 × 10⁹/L (range: 3–225 × 10⁹/L). Some patients with malignant tumors may have preexisting thrombocytosis, and so superimposed MAHA may reduce the platelet count only toward “normal” values.

• Leukoerythroblastosis caused by marrow invasion, along with MAHA, is highly suggestive of metastatic malignancy.

• Laboratory evidence of DIC has been reported in approximately 50% of patients with MAHA secondary to malignancy.

Differential Diagnosis

• The most common cause of anemia in malignancy is anemia of chronic disease-inflammation (Chap. 5).

• Also consider blood loss, myelophthisis as a result of disease metastatic to the marrow (Chap. 12), and autoimmune hemolytic anemia (Chap. 22). The latter is more often found with lymphoproliferative disease but is occasionally seen with carcinoma of the stomach, colon, breast, and cervix.

• Drug treatment of cancer can also induce anemia by causing myelosuppression, oxidative hemolysis (doxorubicin, pentostatin), autoimmune hemolysis, or thrombotic microangiopathic anemia (mitomycin C, cisplatin, gemcitabine, and targeted cancer agents).

Treatment

• Heparin, glucocorticoids, dipyridamole, indomethacin, and ε-aminocaproic acid have all been tried without proven success.

• Transfusion of plasma, platelets, and cryoprecipitate may be useful during bleeding episodes associated with prolonged PT and PTT times, low fibrinogen levels, and thrombocytopenia.

• Control of the underlying malignancy can be beneficial.

Etiology and Pathogenesis

• Anemia arising after cardiac valve replacement is caused by erythrocyte shearing and fragmentation as the red cells traversed the turbulent flow through or around the prosthetic valve.

• The incidence of significant valve-associated hemolysis is currently less than 1% with newer-generation prostheses.

• Hemolysis can be seen following mitral valve repair and in unoperated patients with native valvular disease and hypertrophic obstructive cardiomyopathy.

• Risk factors for valvular hemolysis include central or paravalvular regurgitation, placement of small valve prostheses with resultant high transvalvular pressure gradients, regurgitation because of bioprosthetic valve failure, ball-and-cage valves, bileaflet valves versus tilting disk valves, mechanical valve prostheses versus xenograft tissue prostheses, double-valve versus single-valve replacement, and aortic versus mitral valve prostheses.

Clinical Features

• Patients with valve-induced hemolysis can present with symptoms caused by anemia or congestive heart failure, pallor, icterus, and dark urine (described variously as red, brown, or black).

• Urine excreted during periods of physical activity may be darker than that excreted at rest.

• Hemolysis can be exacerbated by supraventricular tachycardia or other tachyarrhythmias and regress once normal sinus rhythm is restored.

Laboratory Features

• The red cells on the blood film will reveal moderate poikilocytosis, schistocytosis (fragmentation), and polychromasia.

• The red cells are usually normochromic but can occasionally be hypochromic and microcytic as a result of long-standing urinary iron loss.

• Table 19–2 lists the principal findings by severity of hemolysis in patients with prosthetic heart valves. The reticulocyte count, urine hemosiderin, plasma hemoglobin, and serum levels of total and indirect bilirubin, and LDH may be elevated, whereas the serum haptoglobin is decreased.

• Both the number of schistocytes in the blood and the elevation of LDH correlate with the severity of hemolysis.

• Hemoglobinuria is usually only seen in those with particularly severe hemolysis and high LDH levels.

Differential Diagnosis

• Factors that can promote valve-associated hemolysis or worsen the resultant anemia include iron deficiency, because (1) anemia increases cardiac output and shear stress and (2) hypochromic red cells are more fragile than normal.

• Folate deficiency can result from the increased erythropoiesis associated with hemolysis limiting the erythropoietic compensatory response (see Chap. 8).

• Infectious endocarditis causes anemia of chronic disease.

• Anticoagulation to minimize thrombosis around mechanical heart valves can cause gastrointestinal blood loss and subsequent iron-deficiency anemia.

Treatment

• Iron and folate replacement, if deficient, may be effective.

• Surgical repair or replacement of the malfunctioning prosthesis should take place, if possible. Poor surgical candidates with perivalvular leaks may benefit from percutaneous closure with an Amplatzer occluder device.

• Adjunctive measures to be tried include β-adrenergic blockade to slow the velocity of the circulation, erythropoietin therapy to stimulate erythropoiesis, and pentoxifylline therapy (400 mg orally 3 times daily) to increase the deformability of red cells.

• Ursodeoxycholic acid, 600 mg orally once daily beginning 1 week before valve replacement surgery, significantly decreases the incidence of pigmented gallstone formation.

• The presenting complaint is passage of dark urine immediately following physical exertion in the upright position, occasionally accompanied by nausea, abdominal cramps, aching in the back or legs, or a burning feeling in the soles of the feet.

• Hepatosplenomegaly and transient jaundice have been rarely reported.

• This condition is caused by red cell trauma within the vessels of the soles of the feet, the severity is influenced by the hardness of the running surface, the distance run, the heaviness of the athlete’s stride, and the quality of one’s footwear.

• Anemia is uncommon and if present is usually mild, but repeated episodes can cause iron deficiency and resultant anemia.

• Morphologic evidence of red cell damage on the blood film is usually not seen.

• Renal damage is also not commonly seen, but cases of acute tubular necrosis and resultant acute renal insufficiency have been described.

• This condition usually develops in early childhood and is characterized by thrombocytopenia, microangiopathic hemolytic anemia, consumptive coagulopathy, and hypofibrinogenemia caused by an enlarging kaposiform hemangioendothelioma or tufted angiomas.

• Kaposiform hemangioendotheliomas are highly aggressive, vascular tumors that occur equally in males and females and show little tendency to resolve spontaneously. However, they have never been reported to metastasize.

• It is postulated that endothelial cell abnormalities and vascular stasis lead to activation of platelets and the coagulation cascade within the tumor’s vessels, with subsequent depletion of both platelets and clotting factors.

• Microangiopathic hemolytic anemia results from mechanical trauma sustained by the erythrocytes traversing the tumor’s abnormal, partially thrombosed vascular channels.

• The mortality can be as high as 30%.

• Surgical resection is always followed by normalization of hematologic parameters, but many lesions are too large to be resected without severe disfigurement.

• Other treatments include glucocorticoids, interferon-α, antifibrinolytic agents, antiplatelet agents, low-molecular-weight heparin, embolization, radiation, laser therapy, and various forms of chemotherapy.

These include malignant systemic hypertension; pulmonary hypertension; giant cavernous hemangiomas of the liver; and vasculitides, including Wegener granulomatosis and giant cell arteritis.