Extrinsic Nonimmune Hemolytic Anemias

Clinical Manifestations

Patients present with various degrees of hemolytic anemia and compensation, with evidence of RBC fragmentation on smear ( Fig. 48.1 ; see the box on Differential Diagnosis of Extrinsic Nonimmune Hemolytic Anemias ). RBC removal is generally extravascular, with minimal or moderately decreased levels of haptoglobin. If RBC damage is sufficiently severe, signs of intravascular hemolysis may be present. Because of the underlying pathology, some of these syndromes show evidence of platelet removal, leading to thrombocytopenia. Occasionally, the underlying cause produces activation and depletion of procoagulant factors with consequent activation of the fibrinolytic system, consistent with disseminated intravascular coagulation (DIC; see the box on Causes of Red Blood Cell Fragmentation Hemolysis ).

Pathophysiology

Fragmentation hemolysis occurs when mechanical forces disrupt the physical integrity of the RBC membrane. In vitro shear stresses in excess of 3000 dynes/cm ² cause RBC fragmentation. For example, in vivo studies in patients with mitral prosthetic regurgitation and hemolysis show high peak shear stresses of 4500 dynes/cm ² , very rapid acceleration or deceleration, or both. Valvular abnormalities or prosthetic vales can thus cause microangiopathic changes.

Research suggests additional mechanisms of producing microangiopathic hemolysis that involve platelets and small vessel thrombi. The platelet-rich, fibrin-poor microvascular thrombi found in many patients with thrombotic thrombocytopenic purpura (TTP) (see Chapter 134 ) now are thought to be caused by abnormally decreased ADAMTS 13 activity. This metalloprotease is responsible for converting the highly thrombogenic ultra-large multimers of von Willebrand factor made by platelets and endothelial cells into the smaller forms normally found in circulation. Mutations in or antibodies against ADAMTS 13 result in unusually large multimers of von Willebrand factor attached to endothelial cell surfaces, where platelets may excessively aggregate, leading to the formation of microvascular thrombi even in the absence of endothelial damage. In the case of disseminated cancer, the cause of microangiopathy may be microvascular tumor emboli.

Whatever the mechanism of mechanical trauma, the RBC membrane is viscoelastic and has self-sealing properties (see Chapter 45 ) so that little hemoglobin leaks out as the cell is being cut. However, prolonged distortion of the membrane produces a plastic change; therefore, the smaller RBC fragments usually do not become microspheres or microdisks but continue to display evidence of the shearing event or distortion in the form of typical irregular shapes. These irregular shapes and the rigidity that they reflect subsequently interfere with the ability of RBCs to fold, elongate, and deform sufficiently to pass through 3-μm capillaries and even smaller slits in the walls of the sinusoids of the reticuloendothelial system. This sequence leads to their destruction.

Differential Diagnosis

Generally, the differential diagnosis of fragmentation hemolysis can be deduced from the clinical findings. The presence of a prosthetic heart valve or a regurgitant jet that fragments or accelerates (i.e., Waring blender syndrome) can be readily discerned. The clinical picture of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (TTP–HUS) is generally dramatic and acute (see Chapter 134 ). Atrioventricular malformations may be associated with disseminated intravascular coagulation (DIC) and platelet removal; the diagnosis requires a high index of suspicion and imaging studies. The presence of preeclampsia in a pregnant woman with microangiopathic hemolysis usually is obvious, but hemolysis plus elevated liver enzymes plus low platelet count (HELLP) syndrome is a serious complication of pregnancy that can occur without other signs of preeclampsia or hypertension. This syndrome can produce hepatic rupture, visual failure, DIC, seizures, and congestive heart failure and requires treatment by prompt delivery of the fetus. Cancer can be an underlying cause of microangiopathy. Vessels supplying malignant tumors are thought to be structurally abnormal. They exhibit the same sort of fibrin stranding that produces fragmentation hemolysis in DIC and TTP–HUS.

Continued use of invasive diagnostic and therapeutic procedures with insertion of foreign bodies into the circulation has been complicated by microangiopathic hemolysis. A transjugular intrahepatic portosystemic shunt can cause the syndrome in approximately 10% of patients. The hemolysis usually disappears after 12 to 15 weeks. Similarly, the use of coil embolization to seal off a patent ductus arteriosus may also cause significant hemolytic anemia. Vasculitis has also been implicated as a cause.

Multiple drugs are associated with microangiopathic hemolysis, most commonly quinine. A recent review found that in only 22 of 78 drugs reported to produce drug-induced thrombotic microangiopathy was a definite association found. Cyclosporine, tacrolimus, and mitomycin C have been implicated as causing a HUS picture that typically develops within weeks to months of exposure. Total body irradiation and bone marrow transplantation also are associated with microangiopathic hemolysis. Both chemotherapeutic agents and targeted cancer agents, including immunotoxins, monoclonal antibodies, and tyrosine kinase inhibitors, are associated with thrombotic microangiopathy. The thienopyridines ticlodipine and clopidogrel are both capable of producing a significant thrombotic microangiopathy that differs somewhat in presentation. Ticlodipine-associated TTP typically occurs between 2 and 12 weeks after initiation of therapy and presents with severe thrombocytopenia, microangiopathic hemolytic anemia, highly elevated lactate dehydrogenase, and normal renal function and is associated with severe deficiency of plasma ADAMTS13 activity. In contrast, clopidogrel-associated TTP usually presents within 2 weeks of drug initiation and is associated with mild thrombocytopenia, microangiopathic hemolytic anemia, mildly elevated lactate dehydrogenase levels, marked renal insufficiency, and near-normal levels of ADAMTS13 activity. Other reported exposures associated with microangiopathic hemolytic anemia include the use of cocaine and the herb Echinacea. The mechanisms of drug-induced thrombotic microangiopathy are not well understood but include immune-mediated causes (as in the case of quinine) and direct toxicity to the endothelium.

Thrombotic microangiopathic hemolytic anemia can also be the presenting feature of severe, systemic infection, including viral (cytomegalovirus [CMV], HIV), fungal, and bacterial infections. Whether infection “triggers” the development of TTP or instead the presentation remains debatable.

In one large series, 10 of 351 (2.8%) patients diagnosed with TTP were subsequently diagnosed with disseminated malignancy. Symptoms suggesting an underlying malignancy include dyspnea, cough, atypical pain, and poor response to plasma exchange. The diagnosis was made by bone marrow biopsy in six of the 10 patients, and all patients died shortly after the diagnosis of malignancy was made.

A current review highlights four hereditary and four acquired disorders that lead to thrombotic microangiopathy. TTP may be hereditary, due to mutations in ADAMTS13, or acquired, due to autoantibody inhibition of ADAMTS13 activity. In addition, complement mutations causing uncontrolled activation of the alternative pathway, mutations in components of cobalamin metabolism, and mutations in a protein kinase C-associated protein, diacylglycerol kinase, are other hereditary causes of thrombotic microangiopathy. Acquired causes in addition to autoantibodies to ADAMTS13 include shiga toxin (hemolytic uremic syndrome), drug mediated on an immune basis (i.e., quinine), drug mediated on a toxic, dose-related basis (i.e., gemcitabine, cyclosporine), and acquired antibodies to complement factor H.

Therapy

Management is primarily directed toward the underlying disease or event. Compensation of RBC production should be optimized by replacing iron or folic acid if the patient is deficient in these nutrients. Occasionally, removal or repair of a damaged native or prosthetic heart valve is necessary when the hemolysis produces a disabling transfusion requirement. Treatment of TTP with plasma exchange is highly effective in classic TTP with very low ADAMTS13 levels but not indicated in other settings of thrombotic microangiopathy such as cancer where plasma exchange may be ineffective. Where autoantibodies to ADAMTS13 are central to pathogenesis, immunosuppressive treatment with steroids and rituximab is important adjuvant therapy.

Heat Denaturation

Normal RBCs undergo budding and fragmentation when exposed to a temperature of 49°C (120°F) in vitro (see Fig. 48.1B ). In some of the hereditary hemolytic anemias, this process occurs at temperatures as low as 46°C (115°F; see Chapter 45 ). Under some clinical circumstances, temperatures sufficient to cause heat denaturation of RBCs have been generated. Occasionally, cell warmers used with transfusions in cold agglutinin disease have malfunctioned and cooked the RBCs about to be transfused. In one case, a patient’s mother warmed the RBCs with a hot water bottle, reasoning that such cells would cause less vein irritation to her child. Such transfusion was followed by evidence of intravascular and extravascular hemolysis, and the peripheral smear showed RBC budding and fragmentation ( Fig. 48.2 ). Presumably, similar events can lead to hemolysis in patients who have sustained very extensive burns. In patients with heat stroke, the temperature usually is below 42°C (108°F), a temperature at which little RBC denaturation occurs.

Mechanical Trauma

The classic example of RBC damage caused by mechanical trauma is march hemoglobinuria, which occurs in soldiers after a long march, in joggers after running on a hard road, or in karate or conga drumming enthusiasts after practice. Anemia is rare, and reticulocytosis is uncommon. Evidence of typical intravascular RBC destruction is present and is thought to be caused by direct trauma to RBCs in the vessels of the feet or hands. Switching jogging paths or wearing better footwear often relieves the problem. Some cases show evidence of an underlying RBC membrane abnormality. Strenuous exercise may induce oxidant stress, as evidenced by increased levels of malonyldialdehyde, a marker of lipid peroxidation, in marathon runners after a race. Occasionally, malfunction of the cell savers used during abdominal or thoracic surgery mechanically injures RBCs.

Cardiopulmonary Bypass

Postperfusion syndrome occurs in some patients after cardiopulmonary bypass. The syndrome includes acute intravascular hemolysis and leukopenia as part of a febrile, inflammatory clinical picture. Affected patients may develop pulmonary distress and even adult or acute respiratory distress syndrome. Visible hemoglobinemia occurs, with rising plasma hemoglobin levels, and is associated with an increase in lysed RBC ghosts seen in the whole blood and plasma. These ghosts are coated with the complement complex C5bC9 (see Chapter 24 ). Presumably, the complement pathway is activated as the blood passes through the oxygenator. The reason why complement activation results in lytic attack on RBCs (and granulocytes) is unknown. Free hemoglobin released into the plasma secondary to intravascular hemolysis may contribute to acute kidney injury after cardiopulmonary bypass. Treatment involves knowledge of the process and requisite support until the situation corrects itself.

Osmotic Attack

Abrupt changes in osmolality can cause hemolysis. Freshwater drowning may be associated with so much water in the lungs that the RBCs swell as they undergo an in vivo osmotic fragility test in the pulmonary vasculature. Conversely, saltwater drowning can cause profound dehydration of RBCs, producing a situation analogous to xerocytosis (see Chapter 45 ). Rarely, acute hemolysis occurs from the mistaken infusion of or exposure to concentrated hypertonic solutions such as those used in hemodialysis. To manage such an event, the physician must recognize its cause, appreciate the shrunken RBCs on a peripheral smear, and restore isotonicity as quickly as possible. In these cases, the use of a hemodialysis device, if available, may be helpful.