Patients with malignant hypertension sometimes exhibit microangiopathic hemolytic anemia/thrombocytopenia known as thrombotic microangiopathy (TMA). On the other hand, severe hypertension is sometimes associated with hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura (TTP). Because the clinical features of the two entities overlap significantly, it is sometimes difficult to distinguish one from the other. However, such differentiation is indispensable, since early performance of plasmapheresis is critical in HUS/TTP. It has been suggested that severe thrombocytopenia is one of the most useful differential points in diagnosing HUS/TTP from malignant hypertension caused by other etiologies. Early performance of plasmapheresis can be justified in the presence of both TMA and thrombocytopenia. However, thrombocytopenia can be seen in the cases with malignant hypertension from etiologies other than HUS/TTP, and in these particular cases, plasmapheresis is useless and can be harmful. Recently, the plasma level of ADAMTS13 (a disintegrin and metalloprotease domain, with thrombospondin type 1 motif 13), which is a von Willebrand Factor cleaving protease, has been shown to be very low in familial or some of the sporadic cases of TTP, and a low level of ADAMTS13 is very specific to TTP. Some reports have shown that patients with a very low plasma level of ADAMTS13 respond very well to plasmapheresis. We recently experienced two cases with TMA. Although both of our patients had severe hypertension with TMA, different therapeutic strategies ameliorated their illness: symptomatic treatment was effective in case 1, which showed normal ADAMTS13 activity, whereas plasma infusion was necessary to save case 2, which showed low ADAMTS13 activity. Thus, patients with a low level of ADAMTS13 activity might respond well to plasmapheresis or plasma infusion. When presented with patients with severe hypertension and thrombotic microangiopathy, ADAMTS13 activity may prove to be a promising adjunctive tool in differentiating TTP from TMA due to other etiologies, but in the meantime, we should make the choice of whether or not to perform plasmapheresis based on the degree of thrombocytopenia.
Vaughan CJ, Delanty N : Hypertensive emergencies. Lancet 2000; 356: 411– 417.
Khanna A, McCullough PA : Malignant hypertension presenting as hemolysis, thrombocytopenia, and renal failure. Rev Cardiovasc Med 2003; 4: 255– 259.
Moake JL : Thrombotic microangiopathies. N Engl J Med 2002; 347: 589– 600.
Ruggenenti P, Noris M, Remuzzi G : Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int 2001; 60: 831– 846.
Elliott MA, Nichols WL : Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Mayo Clin Proc 2001; 76: 1154– 1162.
Furlan M, Robles R, Galbusera M, et al : von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 1998; 339: 1578– 1584.
Tsai HM, Lian EC : Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339: 1585– 1594.
Vuylsteke P, Knockaert DC, Blockmans D, Arnout J, Vanderschueren S : Abdominal pain, hypertension, and thrombocytopenia. Lancet 2003; 362: 1720.
Brain MC, Dacie JV, Hourihane DO : Microangiopathic haemolytic anaemia: the possible role of vascular lesions in pathogenesis. Br J Haematol 1962; 8: 358– 374.
Espinosa G, Bucciarelli S, Cervera R, et al : Thrombotic microangiopathic haemolytic anaemia and antiphospholipid antibodies. Ann Rheum Dis 2004; 63: 730– 736.
Shibota M, Nagaoka A, Shino A, Fujita T : Renin-angiotensin system in stroke-prone spontaneously hypertensive rats. Am J Physiol 1979; 236: H409– H416.
Stier CT Jr, Chander P, Gutstein WH, Levine S, Itskovitz HD : Therapeutic benefit of captopril in salt-loaded stroke-prone spontaneously hypertensive rats is independent of hypotensive effect. Am J Hypertens 1991; 4: 680– 687.
Camargo MJ, von Lutterotti N, Campbell WG Jr, et al : Control of blood pressure and end-organ damage in maturing salt-loaded stroke-prone spontaneously hypertensive rats by oral angiotensin II receptor blockade. J Hypertens 1993; 11: 31– 40.
Rocha R, Chander PN, Khanna K, Zuckerman A, Stier CT Jr : Mineralocorticoid blockade reduces vascular injury in stroke-prone hypertensive rats. Hypertension 1998; 31: 451– 458.
Chander PN, Rocha R, Ranaudo J, Singh G, Zuckerman A, Stier CT Jr : Aldosterone plays a pivotal role in the pathogenesis of thrombotic microangiopathy in SHRSP. J Am Soc Nephrol 2003; 14: 1990– 1997.
Brain MC : Microangiopathic hemolytic anemia. N Engl J Med 1969; 281: 833– 835.
Tsai HM : Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol 2003; 14: 1072– 1081.
Upshaw JD Jr : Congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia. N Engl J Med 1978; 298: 1350– 1352.
Levy GG, Nichols WC, Lian EC, et al : Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413: 488– 494.
Kokame K, Matsumoto M, Soejima K, et al : Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci USA 2002; 99: 11902– 11907.
Matsumoto M, Kokame K, Soejima K, et al : Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. Blood 2004; 103: 1305– 1310.
Remuzzi G : Is ADAMTS-13 deficiency specific for thrombotic thrombocytopenic purpura? No. J Thromb Haemost 2003; 1: 632– 634.
Tsai HM : Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes. J Thromb Haemost 2003; 1: 625– 631.
Tsai HM, Rice L, Sarode R, Chow TW, Moake JL : Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidine-associated thrombotic thrombocytopenic purpura. Ann Intern Med 2000; 132: 794– 799.
King AJ : Acute inflammation in the pathogenesis of hemolytic-uremic syndrome. Kidney Int 2002; 61: 1553– 1564.
Tsai HM, Chandler WL, Sarode R, et al : von Willebrand factor and von Willebrand factor-cleaving metalloprotease activity in Escherichia coli O157:H7-associated hemolytic uremic syndrome. Pediatr Res 2001; 49: 653– 659.
Pichette V, Querin S, Schurch W, Brun G, Lehner-Netsch G, Delage JM : Familial hemolytic-uremic syndrome and homozygous factor H deficiency. Am J Kidney Dis 1994; 24: 936– 941.
Noris M, Ruggenenti P, Perna A, et al : Hypocomplementemia discloses genetic predisposition to hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: role of factor H abnormalities. Italian Registry of Familial and Recurrent Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura. J Am Soc Nephrol 1999; 10: 281– 293.
Dragon-Durey MA, Fremeaux-Bacchi V, Loirat C, et al : Heterozygous and homozygous factor h deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases. J Am Soc Nephrol 2004; 15: 787– 795.
George JN : How I treat patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Blood 2000; 96: 1223– 1229.
Matsumoto M, Yagi H, Ishizashi H, Wada H, Fujimura Y : The Japanese experience with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Semin Hematol 2004; 41: 68– 74.
Zheng XL, Kaufman RM, Goodnough LT, Sadler JE : Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood 2004; 103: 4043– 4049.
Moore JC, Hayward CP, Warkentin TE, Kelton JG : Decreased von Willebrand factor protease activity associated with thrombocytopenic disorders. Blood 2001; 98: 1842– 1846.
Dundas S, Murphy J, Soutar RL, Jones GA, Hutchinson SJ, Todd WT : Effectiveness of therapeutic plasma exchange in the 1996 Lanarkshire Escherichia coli O157:H7 outbreak. Lancet 1999; 354: 1327– 1330.
Amorosi E, Ultmann J : Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine 1966; 45: 139– 159.
Rock G, Kelton JG, Shumak KH, Buskard NA, Sutton DM, Benny WB : Laboratory abnormalities in thrombotic thrombocytopenic purpura. Canadian Apheresis Group. Br J Haematol 1998; 103: 1031– 1036.
Gavras H, Brown WC, Brown JJ, et al : Microangipathic hemolytic anemia and the development of the malignant phase of hypertension. Circ Res 1971; 28 ( Suppl 2): 127– 142.
Beutler JJ, Koomans HA : Malignant hypertension: still a challenge. Nephrol Dial Transplant 1997; 12: 2019– 2023.
About this article
Cite this article
Shibagaki, Y., Fujita, T. Thrombotic Microangiopathy in Malignant Hypertension and Hemolytic Uremic Syndrome (HUS)/Thrombotic Thrombocytopenic Purpura (TTP): Can We Differentiate One from the Other?. Hypertens Res 28, 89–95 (2005). https://doi.org/10.1291/hypres.28.89
- malignant hypertension
- thrombotic thrombocytopenic purpura/hemolytic uremic syndrome
- thrombotic microangiopathy
- ADAMTS13 (a disintegrin and metalloprotease domain, with thrombospondin type 1 motif 13)
BMC Nephrology (2013)
Modern Pathology (2009)
Pediatric Nephrology (2009)
Nature Clinical Practice Rheumatology (2007)
Pediatric Nephrology (2007)