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2262 Part XII: Hemostasis and Thrombosis Chapter 132: Thrombotic Microangiopathies 2263

nephrotoxicity, with renal failure occurring in approximately 16 percent 6. Byrnes JJ, Khurana M: Treatment of thrombotic thrombocytopenic purpura with
169
of patients who receive a cumulative dose of at least 50 mg. About half plasma. N Engl J Med 297:1386, 1977.
of the patients with renal toxicity also develop thrombotic microangio- 7. Bell WR, Braine HG, Ness PM, Kickler TS: Improved survival in thrombotic throm-
bocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients.
pathy, usually 4 to 8 weeks after the latest dose. Mitomycin C-induced N Engl J Med 325:398, 1991.
thrombotic microangiopathy does not respond to plasma exchange and 8. Rock GA, Shumak KH, Buskard NA, et al: Comparison of plasma exchange with
has a high mortality rate of approximately 70 percent within 4 months plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian
Apheresis Study Group. N Engl J Med 325:393, 1991.
of onset. 170 9. Moake JL, Rudy CK, Troll JH, et al: Unusually large plasma factor VIII:von Willebrand
Gemcitabine is a nucleoside analogue often used for carcinoma factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl
of the pancreas, bladder, or lung. Thrombotic microangiopathy with J Med 307:1432, 1982.
renal failure occurs with an incidence of approximately 0.3 percent. 10. Furlan M, Robles R, Lämmle B: Partial purification and characterization of a protease
171
from human plasma cleaving von Willebrand factor to fragments produced by in vivo
The median time to develop thrombotic microangiopathy is 7 months proteolysis. Blood 87:4223, 1996.
with a median cumulative dose of 22 g/m , although the range of doses 11. Tsai H-M: Physiologic cleavage of von Willebrand factor by a plasma protease is depen-
2
dent on its conformation and requires calcium ion. Blood 87:4235, 1996.
is broad and very low doses have been associated with thrombotic 12. Furlan M, Robles R, Solenthaler M, et al: Deficient activity of von Willebrand factor-
172
microangiopathy. Death or disability usually results from cancer pro- cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood
gression or renal failure, not from extrarenal manifestations of throm- 89:3097, 1997.
botic microangiopathy. 13. Furlan M, Robles R, Galbusera M, et al: Von Willebrand factor-cleaving protease in
thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl
Drugs that inhibit vascular endothelial growth factor (VEGF) J Med 339:1578, 1998.
signaling like sunitinib and bevacizumab are associated with 14. Tsai HM, Lian EC: Antibodies to von Willebrand factor-cleaving protease in acute
proteinuria, hypertension, and mild thrombotic microangiopathy that thrombotic thrombocytopenic purpura. N Engl J Med 339:1585, 1998.
usually improve when the drug is discontinued. Inhibition of VEGF 15. Fujikawa K, Suzuki H, McMullen B, Chung D: Purification of human von Willebrand
factor-cleaving protease and its identification as a new member of the metalloprotein-
produced within the kidney appears to damage glomerular endothe- ase family. Blood 98:1662, 2001.
lium. In some cases disease has responded to an angiotensin receptor 16. Gerritsen HE, Robles R, Lammle B, Furlan M: Partial amino acid sequence of purified
173
von Willebrand factor-cleaving protease. Blood 98:1654, 2001.
blocker, allowing continued treatment with the VEGF inhibitor. 174 17. Zheng X, Chung D, Takayama TK, et al: Structure of von Willebrand factor-cleaving
protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic
purpura. J Biol Chem 276:41059, 2001.
COBALAMIN METABOLIC DEFECTS 18. Soejima K, Mimura N, Hirashima M, et al: A novel human metalloprotease synthesized
Cobalamin C deficiency is a rare autosomal recessive condition caused in the liver and secreted into the blood: Possibly, the von Willebrand factor-cleaving
protease? J Biochem 130:475, 2001.
by mutations in the MMACHC (methylmalonic aciduria and homo- 19. Levy GG, Nichols WC, Lian EC, et al: Mutations in a member of the ADAMTS gene
cystinuria type C protein) gene. Clinical features may include devel- family cause thrombotic thrombocytopenic purpura. Nature 413:488, 2001.
opmental delay, ataxia, seizures, cognitive impairment, pulmonary 20. Klaus C, Plaimauer B, Studt JD, et al: Epitope mapping of ADAMTS13 autoantibodies
hypertension, thrombotic microangiopathy and renal failure. Symp- in acquired thrombotic thrombocytopenic purpura. Blood 103:4514, 2004.
toms usually appear during infancy but can occur later in childhood or 21. Luken BM, Turenhout EA, Hulstein JJ, et al: The spacer domain of ADAMTS13 con-
tains a major binding site for antibodies in patients with thrombotic thrombocytopenic
rarely in adulthood. Laboratory studies show elevated plasma methyl- purpura. Thromb Haemost 93:267, 2005.
malonic acid and homocysteine, low plasma methionine, and normal or 22. Zheng XL, Wu HM, Shang D, et al: Multiple domains of ADAMTS13 are targeted by
elevated plasma vitamin B . Treatment with high-dose hydroxycobala- autoantibodies against ADAMTS13 in patients with acquired idiopathic thrombotic
thrombocytopenic purpura. Haematologica 95:1555, 2010.
12
min and betaine may reverse or prevent HUS. 175 23. Scheiflinger F, Knobl P, Trattner B, et al: Nonneutralizing IgM and IgG antibodies to
The abnormal red cell and platelet morphology in adults with severe von Willebrand factor-cleaving protease (ADAMTS-13) in a patient with thrombotic
vitamin B deficiency rarely may suggest thrombotic microangiopathy. thrombocytopenic purpura. Blood 102:3241, 2003.
12 24. Miller DP, Kaye JA, Shea K, et al: Incidence of thrombotic thrombocytopenic purpura/
hemolytic uremic syndrome. Epidemiology 15:208, 2004.
25. Terrell DR, Williams LA, Vesely SK, et al: The incidence of thrombotic thrombocy-
MALIGNANT HYPERTENSION topenic purpura-hemolytic uremic syndrome: All patients, idiopathic patients, and
patients with severe ADAMTS-13 deficiency. J Thromb Haemost 3:1432, 2005.
Malignant hypertension is associated with microangiopathic hemo- 26. Zheng XL, Kaufman RM, Goodnough LT, Sadler JE: Effect of plasma exchange on
lytic anemia, thrombocytopenia, neurological symptoms and renal plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in
insufficiency. 176 patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura.
Blood 103:4043, 2004.
27. Kremer Hovinga JA, Vesely SK, Terrell DR, et al: Survival and relapse in patients with
thrombotic thrombocytopenic purpura. Blood 115:1500, 2010.
MECHANICAL HEMOLYSIS 28. Nicol KK, Shelton BJ, Knovich MA, Owen J: Overweight individuals are at increased
risk for thrombotic thrombocytopenic purpura. Am J Hematol 74:170, 2003.
A malfunctioning aortic or mitral valve prosthesis may sufficiently 29. Ridolfi RL, Bell WR: Thrombotic thrombocytopenic purpura. Report of 25 cases and
increase the fluid shear stress experienced by the blood to cause sig- review of the literature. Medicine (Baltimore) 60:413, 1981.
nificant hemolysis, with schistocytes and thrombocytopenia, suggesting 30. McMinn JR, George JN: Evaluation of women with clinically suspected thrombotic
a diagnosis of thrombotic microangiopathy. 41,42 Such patients also are thrombocytopenic purpura-hemolytic uremic syndrome during pregnancy. J Clin
Apher 16:202, 2001.
likely to have acquired von Willebrand syndrome. 31. Coppo P, Busson M, Veyradier A, et al: HLA-DRB1*11: A strong risk factor for acquired
severe ADAMTS13 deficiency-related idiopathic thrombotic thrombocytopenic pur-
pura in Caucasians. J Thromb Haemost 8:856, 2010.
REFERENCES 32. Scully M, Brown J, Patel R, et al: Human leukocyte antigen association in idiopathic
thrombotic thrombocytopenic purpura: Evidence for an immunogenetic link. J Thromb
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2. Singer K, Bornstein FP, Wile SA: Thrombotic thrombocytopenic purpura. Hemorrhagic pura. Int J Hematol 76:471, 2002.
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3. Amorosi EL, Ultmann JE: Thrombotic thrombocytopenic purpura: Report of 16 cases J Clin Apher 24:47, 2009.
and review of the literature. Medicine (Baltimore) 45:139, 1966. 35. Imanirad I, Rajasekhar A, Zumberg M: A case series of atypical presentations of throm-
4. Bukowski RM, Hewlett JS, Harris JW, et al: Exchange transfusions in the treatment of botic thrombocytopenic purpura. J Clin Apher 27:221, 2012.
thrombotic thrombocytopenic purpura. Semin Hematol 13:219, 1976. 36. Htun KT, Davis AK: Neurological symptoms as the sole presentation of relapsed throm-
5. Bukowski RM, King JW, Hewlett JS: Plasmapheresis in the treatment of thrombotic botic thrombocytopenic purpura without microangiopathic haemolytic anaemia.
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