Page 829 - Williams Hematology ( PDFDrive )

804 Part VI: The Erythrocyte Chapter 51: Fragmentation Hemolytic Anemia 805

LABORATORY FEATURES additional cryoprecipitate containing fibrinogen, may be useful during
Patients with cancer-associated DIC/MAHA present with moderate-to- bleeding episodes associated with prolonged PT and aPTT, low fibrino-
severe anemia. The blood film reveals schistocytes (accounting for gen levels, and thrombocytopenia. Control of the underlying metastatic
51
approximately 5 to 21 percent of the red cells), burr cells, microsphero- malignancy, if achievable, has been beneficial.
cytes, reticulocytes/polychromasia, and nucleated red cells. Although COURSE AND PROGNOSIS
38
the reticulocyte count can be high, it is an unreliable measure of hemo-
lysis because extensive replacement of the marrow by metastatic tumor MAHA caused by cancer is usually a preterminal event. Life expectancy
(Chap. 45) may prevent the reticulocytosis expected with MAHA. Other following diagnosis is 2 to 150 days, with a mean of 21 days. 37,38
indicators of hemolysis that could be more reliable include increased
levels of serum unconjugated bilirubin and LDH, the presence of plasma HEART VALVE HEMOLYSIS
hemoglobin, and elevated urine urobilinogen and hemoglobinuria (as
αβ dimers). Absent or low levels of haptoglobin may also be found; DEFINITION AND HISTORY
37
however, haptoglobin is an acute-phase reactant that may be increased Anemia arising after cardiac valve replacement was first described in
in malignancy. The direct antiglobulin test is negative. 37,41 1954, soon after corrective valvular surgery became possible. This ane-
38
59
Additional findings in MAHA include thrombocytopenia, with mia was subsequently shown to be caused by erythrocyte shearing and
mean platelet counts of approximately 50 × 10 /L (range: 3 to 225 × fragmentation as the red cells traversed the turbulent flow through or
9
10 /L), caused by a shortened platelet life span without demonstra- around the prosthetic valve. Since then, prevention of irreversible red
9
37
60
ble sequestration of platelets in the liver or spleen. Some patients with cell injury has been a goal when designing new prostheses; as a result,
malignant tumors, however, may have preexisting thrombocytosis, and the incidence of significant valve-associated hemolysis has declined
so superimposed MAHA may reduce the platelet count only toward from 5 to 15 percent in the 1960s and 1970s 61,62 to less than 1 percent
“normal” values. A normal-to-high white cell count with immature with newer-generation prostheses. However, compensated hemo-
38
63
myeloid precursors may also be seen. 37,38,41 Leukoerythroblastosis lysis can occur with any type of valve prosthesis and can be detected
caused by marrow invasion (Chap. 45), along with MAHA, is highly in almost every patient when assayed using appropriate methods. 61,64,65
suggestive of metastatic malignancy. Marrow aspiration and biopsy Additionally, intravascular hemolysis can be seen following mitral valve
38
will demonstrate erythroid hyperplasia, normal-to-high numbers of repair and in unoperated patients with native valvular disease and
61
66
megakaryocytes, and (in 55 percent of patients) cancer cells. 41 hypertrophic obstructive cardiomyopathy. 67
Additional laboratory evidence of DIC has been reported in
approximately 50 percent of patients with MAHA secondary to malig- EPIDEMIOLOGY
nancy. Findings include reduced levels of fibrinogen (mean: 177 g/dL;
range: 8 to 490 mg/dL), increased levels of D-dimers (or fibrin deg- A variety of factors can increase the chance of valvular hemolysis: the
62,68
radation products), and prolonged prothrombin and thrombin presence of central or paravalvular regurgitation, placement of small
62
times. In the early phase of DIC, aPTTs may be shortened (e.g., to valve prostheses with resultant high transvalvular pressure gradients,
37
<23 seconds). 42–45 It is not known if shortened aPTT values reflect the and regurgitation because of bioprosthetic valve failure, seen especially
68
presence of activated coagulation factors in the plasma, consumption of once the valve is more than 10 to 15 years old. Patients with ball-and-
64
69
coagulation inhibitor proteins faster than their production by hepatic cage valves, bileaflet valves versus tilting disk valves, mechanical
70
cells (e.g., protein C, protein S, AT, tissue factor pathway inhibitor), or valve prostheses versus xenograft tissue prostheses, and double-valve
69
the presence in plasma of a cysteine protease capable of directly acti- as compared to single-valve replacement, are more likely to experi-
vating factor X. Cancer-related DIC has been reported to be associ- ence clinically significant hemolysis. Some studies have found no dif-
39
ated with a deficiency of the VWF-cleaving protease, ADAMTS13. ference in the degree of hemolysis when comparing aortic and mitral
46
65,69
Although this was disputed by some investigators, ADAMTS13 levels valve prostheses, whereas others have found that the aortic location
47
71–73
gradually decrease in DIC patients with poor survival rates, perhaps is associated with slightly greater hemolysis than the mitral location.
48
as a result of ADAMTS13 consumption onto the long VWF multimeric ETIOLOGY AND PATHOGENESIS
strings released from cytokine-stimulated endothelial cells. 49
Valve-related hemolysis occurs when red cells are exposed to the shear-
DIFFERENTIAL DIAGNOSIS ing stresses created by turbulent blood flow through and around a valve
prosthesis, impaction against foreign surfaces or cardiac structures such
The most common cause of anemia in malignancy is anemia of chronic as the wall of the atrial appendage, or large pressure fluctuations between
68
disease (Chap. 37). Other diagnostic considerations include blood loss, cardiac chambers. A transvalvular pressure gradient of more than 50 torr
myelophthisis as a result of disease metastatic to the marrow (Chap. 45), can generate shearing forces exceeding 4000 dynes/cm , more than the
2
DIC/MAHA (Chap. 129), and autoimmune hemolytic anemia (Chap. 54). 3000 dynes/cm usually needed to cause red cell fragmentation. In a
2
74
The latter is more often found with lymphoproliferative disease (Chap. study looking at malfunctioning mitral valve prostheses, sophisticated
95) but is occasionally seen with carcinoma of the stomach, colon, breast, computer modeling using transesophageal echocardiography demon-
and cervix. The treatment of cancer can also induce anemia by causing strated a maximal shear value of 6000 dynes/cm when the regurgitant jet
58
2
myelosuppression, oxidative hemolysis (doxorubicin, pentostatin), auto- was divided by a solid structure such as a loose suture or dehisced annu-
immune hemolysis (cisplatin, chlorambucil, cyclophosphamide, melpha- loplasty ring. A maximal shear rate of 4500 dynes/cm was found when
2
lan, teniposide, methotrexate), or thrombotic microangiopathic anemia the regurgitant jet was suddenly decelerated by a solid structure like the
(mitomycin C, cisplatin, gemcitabine, and targeted cancer agents ).
50
left atrial appendage, or when the blood was regurgitated through a small
THERAPY orifice (<2 mm in diameter) such as a leaflet perforation or a paravalvular
leak. Lack of endothelialization of the prosthetic ring may contribute
68
Heparin, glucocorticoids, dipyridamole, indomethacin, and ε-aminocaproic to the severity of hemolysis following valve repair or replacement, but
acid have all been tried without success for malignancy-associated DIC/ it is unclear if this is primary or secondary to the high-velocity jet of
MAHA. Plasma infusion and platelet transfusions, sometimes with blood preventing fibrous incorporation of the prosthetic materials. 68,75
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