Thrombotic Thrombocytopenic Purpura with Severe Hypertension in a Patient with Systemic Sclerosis Sine Scleroderma and Polymyositis

□ CASE REPORT □

Masao Iwagami, Kanae Kubo, Ryoichi Tanaka, Kimito Kawahata, Akiko Okamoto, Noboru Hagino and Kazuhiko Yamamoto

Abstract

We present the first documented case of thrombotic thrombocytopenic purpura (TTP) with severe hypertension complicated by polymyositis and systemic sclerosis sine scleroderma. TTP developed in the progressive phase of visceral fibrosis in the absence of skin thickening. ADAMTS13 activity was not useful for the diagnosis of TTP. Although TTP and scleroderma renal crisis (SRC) share similar findings of thrombotic microangiopathy, severe thrombocytopenia with multiple organ injuries and hemorrhagic manifestations suggested TTP rather than SRC. The patient’s condition improved dramatically with plasmapheresis.

Key words: Polymyositis, Systemic sclerosis sine scleroderma, Thrombotic microangiopathy, Thrombotic thrombocytopenic purpura

(Intern Med 50: 2413-2416, 2011) (DOI: 10.2169/internalmedicine.50.5653)

ferential diagnosis between TTP and SRC. Introduction Case Report Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopathic hemolytic anemia (MAHA), A 70-year-old Japanese woman was admitted to our hos- thrombocytopenia and functional impairment of multiple or- pital in August 2008 with headache and epigastric pain. She gans, especially the brain and kidneys. Thrombocytopenia had a 6-year history of polymyositis with anti-aminoacyl- and MAHA are shared by many disorders, including hemo- tRNA synthetase antibody and anti-signal recognition parti- lytic uremic syndrome (HUS), malignant hypertension, dis- cle antibody, which was under control with tapering of pred- seminated intravascular coagulation, drug-induced disorders, nisolone from the initial dose of 60 mg. She also had a his- antiphospholipid syndrome and scleroderma renal crisis tory of insulin-controlled diabetes with HbA1c of 6-7% and (SRC). TTP and HUS are often described as TTP-HUS syn- hypertension treated with candesartan for at least 6 years. In drome because of the similar clinical features and the diffi- addition, she had been diagnosed as having scleroderma culty in distinguishing between the two conditions. The spectrum disorder, considered as ssSSc (1), with Raynaud’s pathological findings are endothelial cell injury, and mi- phenomenon, contraction of lingual frenulum, bleeding of crovascular aggregation of platelets leading to ischemia, nailfold, telangiectasia, reflux esophagitis and interstitial called thrombotic microangiopathy (TMA). pneumonia, in the absence of anti-centromere antibody, anti- TTP is a rare complication of systemic sclerosis (SSc) topoisomerase I antibody and anti-U1-RNP antibody. No ob- and polymyositis, and has not been reported in association vious skin thickening was observed on physical examination with SSc sine scleroderma (ssSSc). We present a case of except for temporarily suspected sclerodactyly of one finger. TTP with severe hypertension, ssSSc and polymyositis, and Three months before admission, she presented with chest discuss the clinical features of the present case and the dif- pain and pericardial effusion on echocardiography sugges-

Department of Allergy and Rheumatology, The University of Tokyo Hospital, Japan Received for publication April 14, 2011; Accepted for publication July 6, 2011 Correspondence to Dr. Kanae Kubo, [email protected]

2413 Intern Med 50: 2413-2416, 2011 DOI: 10.2169/internalmedicine.50.5653

Figure 1. Clinical course: laboratory data and treatment. LDH: lactate dehydrogenase, ACE: angiotensin-converting enzyme, ARB: angiotensin II receptor blocker, FFP: fresh frozen plasma tive of pericarditis associated with polymyositis and ssSSc, tivity was high after diuretics use (47.5 ng/mL/h; reference which persisted during her hospital stay. Candesartan was range 0.2-2.7 ng/mL/h). Urinary findings included protein- once discontinued because of a drop in blood pressure to uria of 1 g/day without hematuria, granular and red blood around 90/60 mmHg. Her blood pressure then became ele- cell casts. vated to 144/98 mmHg one month before admission. Ileus Upon a provisional diagnosis of TTP, plasmapheresis was without mechanical obstruction, which was diagnosed as in- initiated on hospital day 1 along with prednisolone 40 mg/ testinal pseudo-obstruction associated with ssSSc, occurred day and intravenous nicardipin for hypertension in the state in the following month. of disturbed consciousness, which did not permit oral ad- Physical examination revealed a normal temperature, an ministration of antihypertensive drugs. After plasmapheresis elevated blood pressure of 204/122 mmHg, fluctuating levels for two consecutive days, her consciousness level and of drowsiness and disorientation, and ecchymosis on her ex- thrombocytopenia were dramatically improved. Captopril, tremities, but no skin sclerosis over her extremities. A com- valsartan and nifedipine were added for uncontrolled hyper- puted tomography (CT) showed wall thickening of jejunum tension. Abdominal pain was resolved within a week. Renal and ascending colon. Platelet count was significantly de- function was gradually improved (Fig. 1). Thrombocy- creased from a pre-admission level of around 18×104/μL to topenia and hemolytic anemia repeatedly relapsed during 3.2×104/μL. A decrease in hemoglobin from 11.8 g/dL one plasmapheresis tapering but they responded well to daily month before to 8.5 g/dL, a reticulocyte count of 7.2%, in- plasmapheresis. Infusion of fresh frozen plasma was not ef- creased levels of bilirubin (2.7 mg/dL) and lactate dehydro- fective. Renal function remained stable. She underwent plas- genase (1,099 IU/L; reference range 125-237 IU/L) with mapheresis for two and a half months to sustain a remission. normal ranges of aspartate aminotransferase (47 IU/L) and Follow-up CT showed improvement of intestinal wall thick- alanine aminotransferase (26 IU/L), undetectable haptoglo- ening after withdrawal of plasmapheresis. Activity of bin, and fragmented erythrocytes indicated microangiopathic ADAMTS13 (a disintegrin and metalloprotease domain, hemolytic anemia. Coombs’ test was negative. Serum cre- with thrombospondin type 1 motif 13) on admission was atinine was elevated from 0.64 mg/dL one month before to within the normal range (86%), and anti-ADAMTS13 inacti- 1.62 mg/dL. Normal ranges of prothrombin time (10.5 s), vating antibodies were negative. She was readmitted for activated partial thromboplastin time (30.7 s), and fibrinogen pseudo-obstruction and malnutrition associated with (368 mg/dL) with small elevation of D-dimer (3.4 μg/mL; scleroderma and died of miliary tuberculosis 8 months later. reference range 0-0.9 μg/mL), thrombin antithrombin com- Autopsy revealed fibrotic changes in the gastrointestinal plex (4.4 ng/mL; reference range 0-2.9 ng/mL), and no an- tract, myocardium and skeletal muscles, and diabetic neph- tiphospholipid antibodies ruled out coagulation disorders ropathy with nodular lesions of the glomerular extracellular such as disseminated intravascular coagulation and antiphos- matrix, glomerulosclerosis, interstitial fibrosis and mild re- pholipid syndrome. Serum complement levels were C3 59 duplication of the internal elastic lamina in small arteries of mg/dL, C4 8 mg/dL, and CH50 33.9 IU/mL. Plasma renin ac- the kidney. There was no evidence of persistent TMA.

2414 Intern Med 50: 2413-2416, 2011 DOI: 10.2169/internalmedicine.50.5653

oles, organization and recanalization of luminal thrombi, in- Discussion terstitial fibrosis, and glomerulosclerosis as a result of chronic ischemic damages. Marked intimal thickening leads ssSSc is characterized by visceral involvement typical of to severe luminal narrowing in renal arteries after SRC (9). SSc including esophageal hypomotility, small bowel hypo- However, it is difficult to determine the cause of intimal fi- motility, pulmonary interstitial fibrosis, pulmonary arterial brosis without severe luminal narrowing, interstitial fibrosis hypertension and scleroderma renal crisis, and peripheral and glomerulosclerosis, as in the present case, because this vascular involvement such as Raynaud’s phenomenon, digi- pattern of chronic changes may be seen in the chronic stage tal pitting scars, digital-tip ulcers and abnormal nailfold cap- of TTP, longstanding essential hypertension, and SSc with- illaries, without skin sclerosis. It is thought to be in the out SRC (9). spectrum of SSc (1). Cases of SRC sine scleroderma were Patients with idiopathic TTP do not typically have severe reported previously and have been shown to have poor renal hypertension, though SSc-associated TTP is often accompa- prognosis even with the use of angiotensin-converting en- nied by mild to severe hypertension (7). In the present case, zyme inhibitors (2). TMA with acute renal dysfunction and antihypertensive drug withdrawal before admission may hypertension may be primarily regarded as hypertensive have resulted in exacerbation of essential hypertension. It is SRC in the course of scleroderma, as well as in ssSSc (3). It difficult, however, to associate the high plasma renin activity is often difficult to distinguish TTP from SRC because of during hospitalization with SRC on the grounds of the clini- similar clinical and pathological features of TMA. However, cal response to plasmapheresis and histological findings the differentiation of TTP from SRC is indispensable, since from autopsy. High plasma renin activity may suggest renal these are life-threatening diseases that require different man- hypoperfusion. Apart from the use of diuretics, thrombi in agement strategies. renal arteries and arterioles may activate the renin- In the present case, purpura, severe thrombocytopenia, angiotensin system. There was no evidence of renovascular fluctuating levels of consciousness, multiple organ injury, hypertension. and dramatic improvement in thrombocytopenia and con- Deficient activity of von Willebrand factor (VWF) cleav- sciousness after the initial course of plasmapheresis strongly ing protease, also known as ADAMTS13, has been shown to suggest TTP rather than SRC. TTP may have caused injuries provide useful diagnostic information and serve as a marker to multiple organs including the kidneys, brain and intestine of treatment responsiveness in congenital and acquired idi- in the present case, although TMA was pathologically un- opathic TTP. The therapeutic outcomes of patients with nor- proven. In previous reports, abdominal pain was noted as a mal ADAMTS13 activity tended to be worse than patients presenting complaint in 11-14% of patients with TTP (4) with severe deficiency (10). A previous report described a and intestinal involvement was reported in TTP (5). Severe case of scleroderma-associated TTP with severe deficiency thrombocytopenia was the initial finding that made us sus- of ADAMTS13 activity (7). However, ADAMTS13 activity pect TTP in this case since thrombocytopenia is generally did not facilitate the decision in making the diagnosis of not severe in SRC. A higher incidence of profound thrombo- TTP in the present case. cytopenia and a significantly reduced survival were reported Underlying mechanisms of TTP-HUS syndrome are het- previously in patients with “normotensive SRC” (6). How- erogeneous. Matsuyama found severe deficiency of ever, TTP may not have been accurately distinguished from ADAMTS13 activity only in 17% of patients with connec- SRC due to a significantly high rate of marked anemia with tive tissue disease (CTD) -TMA, which was associated with microangiopathy and hemorrhagic manifestations. inhibitory autoantibodies against ADAMTS13 (10). Other The trigger for TTP was unknown in the present case. autoantibodies may be involved in the pathogenesis of TTP. However, the development of TTP may be relevant to the Autoantibodies against CD36, a transmembrane protein on progressive phase of visceral fibrosis in gastrointestinal tract endothelial cells of microvasculature and platelets, may in- and pericarditis in the absence of skin thickening. Eight of terfere with binding of CD36 to ADAMTS13 and impair the 10 cases previously reported as scleroderma-associated TTP enzymatic function of ADAMTS13 cleaving unusually-large had limited scleroderma (5, 7). It has been suggested that VWF multimers (11, 12). On the other hand, elucidating ab- TTP tends to occur in patients without extensive skin sclero- normalities of the complement system with gene mutations sis, while SRC occurs predominantly in patients with diffuse of complement regulators and activators including factor H, and progressive skin sclerosis (8). factor I and membrane co-factor protein, and autoantibodies TTP and SRC have similar renal histological features. En- against factor H contributed to the understanding of different dothelial cell injuries represented by mucoid intimal hyper- etiologies of atypical HUS other than Shiga-like toxin (13). plasia with luminal narrowing in arteries and arterioles and Another possible pathogenetic mechanism of TTP, inferred endothelial swelling and subendothelial widening in from a high plasma VWF level and a slight decrease in glomerular capillaries, and luminal thrombi are characteristic ADAMTS13 activity in CTD, is disequilibrium between the findings during the acute stage. Chronic changes include re- enzyme, ADAMTS13, and the substrate, unusually-large duplication of the glomerular basement membranes, intimal VWF multimers (10, 14). fibrosis with severe luminal narrowing in arteries and arteri- No specific diagnostic marker has been established in

2415 Intern Med 50: 2413-2416, 2011 DOI: 10.2169/internalmedicine.50.5653

Table 1. Findings Suggestive of TTP Rather Than SRC in Scleroderma

Severe thrombocytopenia (especially < 50,000/ȝ/ with MAHA Hemorrhagic manifestations including purpura Fever Normal blood pressure Treatment failure of ACE inhibitors Severe deficiency of ADAMTS-13 activity with anti-ADAMTS13 antibody TTP: Thrombotic thrombocytopenic purpura, MAHA: microangiopathic hemolytic anemia, SRC: scleroderma renal crisis, ACE: angiotensin converting enzyme

TTP. Its diagnosis is still based on routine blood tests and pura in a patient with systemic sclerosis. J Clin Rheumatol 7: 106- clinical findings. Table 1 shows the findings that led us to 111, 2001. suspect TTP rather than SRC. Severe thrombocytopenia with 6. Helfrich DJ, Banner B, Steen VD, Medsger TA. Normotensive re- MAHA and purpura were found in this case. Plasmapheresis nal failure in systemic sclerosis. Arthritis Rheum 32: 1128-1134, 1989. should be considered when at least one of these findings, es- 7. Manadan AM, Harris C, Block JA. Thrombotic thrombocytopenic pecially severe thrombocytopenia with MAHA, is present, purpura in the setting of systemic sclerosis. Semin Arthritis because TTP is a potentially life-threatening disease. Rheum 34: 683-688, 2005. In conclusion, this is the first documented case of TTP 8. Penn H, Howie AJ, Kingdon EJ, et al. Scleroderma renal crisis: with hypertension in a patient with ssSSc and polymyositis patient characteristics and long-term outcomes. QJM 100: 485- 494, 2007. who exhibited normal ADAMTS13 activity. Her condition 9. Trostle DC, Bedetti CD, Steen VD, Al-Sabbagh MR, Zee B, was successfully managed with urgent plasmapheresis, de- Medsger TA Jr. Renal vascular histology and morphometry in sys- spite difficulty differentiating TTP from SRC because of se- temic sclerosis. A case-control autopsy study. Arthritis Rheum 31: vere hypertension. 393-400, 1988. 10. Matsuyama T, Kuwana M, Matsumoto M, Isonishi A, Inokuma S, Fujimura Y. Heterogeneous pathogenic processes of thrombotic The authors state that they have no Conflict of Interest (COI). microangiopathies in patients with connective tissue diseases. Thromb Haemost 102: 371-378, 2009. 11. Tandon NN, Rock G, Jamieson GA. Anti-CD36 antibodies in References thrombotic thrombocytopenic purpura. Br J Haematol 88: 816- 825, 1994. 1. Poormoghim H, Lucas M, Fertig N, Medsger TA Jr. Systemic 12. Davis AK, Makar RA, Stowell CP, Kuter DJ, Dzik WH. sclerosis sine scleroderma: demographic, clinical, and serologic ADAMTS13 binds to CD36: a potential mechanism for platelet features and survival in forty-eight patients. Arthritis Rheum 43: and endothelial localization of ADAMTS13. Transfusion 48: 206- 444-451, 2000. 213, 2009. 2. Canet JJ, Castane J, Alvarez M, Nava JM, Llibre J. Scleroderma 13. Dragon-Durey MA, Loirat C, Cloarec S, et al. Anti-factor H renal crisis sine scleroderma. Nephron 90: 119-120, 2002. autoantibodies associated with atypical hemolytic uremic syn- 3. Teixeira L, Mouthon L, Mahr A, et al. Mortality and risk factors drome. J Am Soc Nephrol 16: 555-563, 2005. of scleroderma renal crisis: a French retrospective study of 50 pa- 14. Mannucci PM, Vanoli M, Forza I, Canciani MT, Scorza R. Von tients. Ann Rheum Dis 67: 110-116, 2008. Willebrand factor cleaving protease (ADAMTS-13) in 123 patients 4. Ridolfi RL, Bell WR. Thrombotic thrombocytopenic purpura. Re- with connective tissue diseases (systemic lupus erythematosus and port of 25 cases and review of the leterature. Medicine 60: 413- systemic sclerosis). Haematologica 88: 914-918, 2003. 428, 1981. 5. Yusin J, Lewin P, Clements P. Thrombotic thrombocytopenia pur-

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