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C H A P T E R 47

EXTRINSIC NONIMMUNE HEMOLYTIC ANEMIAS

William C. Mentzer and Stanley L. Schrier

By definition, extrinsic causes of hemolysis are abnormalities in the evidence of platelet removal, leading to thrombocytopenia. Occa-
environment in which the red blood cells (RBCs), usually normal sionally, the underlying cause produces activation and depletion of
themselves, circulate. These abnormalities can be acute or chronic in procoagulant factors with consequent activation of the fibrinolytic
nature. They can arise from congenital lesions but usually result from system, consistent with disseminated intravascular coagulation (DIC;
acquired lesions. Inherited anomalies of glucose-6-phosphate dehy- see box on Causes of Red Blood Cell Fragmentation Hemolysis).
drogenase (G6PD) deficiency, which reduces the RBCs ability to deal
with oxidative insults, can leave RBCs more vulnerable to environ-
mental insults. Determination of hemolysis with various levels of Pathophysiology
compensation as the cause of an anemia is accomplished using the
approaches described in Chapter 34. Signs of extrinsic hemolysis with Fragmentation hemolysis occurs when mechanical forces disrupt the
minimal or no anemia can be valuable clues to diseases of other organ physical integrity of the RBC membrane. In vitro shear stresses in
2
systems. Among the most important forms of extrinsic hemolytic excess of 3000 dynes/cm cause RBC fragmentation. In vivo studies
anemia are those caused by immune mechanisms; these are discussed in patients with mitral prosthetic regurgitation and hemolysis show
2
in Chapter 46. high peak shear stresses of 4500 dynes/cm , very rapid acceleration
Clinical and morphologic findings suggest the many misfortunes or deceleration, or both.
that can befall RBCs in their travels. They can be trapped in an Research suggests alternative mechanisms of producing microan-
abnormal bone marrow stroma network, sheared by jets in an abnor- giopathic hemolysis that involve platelets and small vessel thrombi.
mal heart, cut and fragmented by fibrin strands stretched across The platelet-rich, fibrin-poor microvascular thrombi found in many
damaged areas in the microvasculature, or attacked by parasites. They patients with TTP now are thought to be caused by abnormally
1,2
can undergo stasis and perhaps metabolic depletion in giant heman- decreased ADAMTS-13 activity. This metalloprotease is responsible
giomas or in an enlarged spleen. An abnormally functioning liver or for converting the highly thrombogenic ultra large multimers of von
kidney can cause a buildup of substances in plasma that alter RBC Willebrand factor made by platelets and endothelial cells into the
shape and metabolism. Drugs can cause oxidation or other metabolic smaller forms normally found in circulation. Mutations in or anti-
damage. Oxidant injury provokes degradation of hemoglobin with bodies against ADAMTS-13 result in unusually large multimers of
the formation of hemichromes (see Drug-Induced Oxidative Hemo- von Willebrand factor attached to endothelial cell surfaces, where
lysis later). Degraded hemoglobin and hemichromes bind avidly to platelets may excessively aggregate, leading to formation of microvas-
the cytoplasmic tail of the major transmembrane protein band 3 (see cular thrombi even in the absence of endothelial damage. In the case
Chapter 45) and cause clustering of band 3 oligomers. Immuno- of disseminated cancer, the cause of microangiopathy may be micro-
globulins (Igs) and complement then bind to the external membrane vascular tumor emboli.
face over clusters of band 3, promoting immune destruction. Other Whatever the mechanism of mechanical trauma, the RBC mem-
membrane proteins may be subject to oxidative attack. Toxins, brane is viscoelastic and has self-sealing properties (see Chapter 45),
venoms, heat, and mechanical trauma can directly destroy the mem- so that little hemoglobin leaks out as the cell is being cut. However,
brane. These agents may cause an alteration in the asymmetry of the prolonged distortion of the membrane produces a plastic change;
phospholipid bilayer, causing phosphatidylserine to move from the therefore, the smaller RBC fragments usually do not become micro-
inner leaflet of the membrane bilayer to the outer leaflet, where it spheres or microdisks but continue to display evidence of the shearing
can be recognized by macrophages. event or distortion in the form of typical irregular shapes. These
In general, only the most devastating damage leads to direct irregular shapes and the rigidity that they reflect subsequently inter-
intravascular destruction. Usually, the initial insult leads to an even- fere with the ability of RBCs to fold, elongate, and deform sufficiently
tual change in the external portion of the RBC membrane, which to pass through 3-µm capillaries and even smaller slits in the walls of
causes macrophages to retard, hold, remove, or otherwise modify the sinusoids of the reticuloendothelial system. This sequence leads
RBCs. Infection or inflammation can activate these macrophages. to their destruction.
Some RBC changes are accompanied by a decrease in RBC deform-
ability, which retards flow and thereby facilitates the action of mac-
rophages on the affected RBC. All of these changes lead to Differential Diagnosis
extravascular hemolysis.
Generally, the differential diagnosis of fragmentation hemolysis can
be deduced from the clinical findings. The presence of a prosthetic
FRAGMENTATION HEMOLYSIS: MICROANGIOPATHY heart valve or a regurgitant jet that fragments or accelerates (i.e.,
Waring blender syndrome) can be readily discerned. The clinical
Clinical Manifestations picture of TTP–HUS is generally dramatic and acute (see Chapter
134). Atrioventricular malformations may be associated with DIC
Patients present with various degrees of hemolytic anemia and com- and platelet removal; the diagnosis requires a high index of suspicion
pensation, with evidence of RBC fragmentation on smear (Fig. 47.1; and imaging studies. The presence of preeclampsia in a pregnant
see box on Differential Diagnosis of Extrinsic Nonimmune Hemo- woman with microangiopathic hemolysis usually is obvious, but
lytic Anemias). RBC removal is generally extravascular, with minimal HELLP syndrome is a serious complication of pregnancy that can
or moderately decreased levels of haptoglobin. If RBC damage is occur without other signs of preeclampsia or hypertension. This
sufficiently severe, signs of intravascular hemolysis may be present. syndrome can produce hepatic rupture, visual failure, DIC, seizures,
Because of the underlying pathology, some of these syndromes show and congestive heart failure, and requires treatment by prompt

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