1 Introduction
Sjögren’s syndrome (SS) is a common autoimmune disease (AID) characterized by exocrine gland damage, and mainly affects the salivary glands and lacrimal gland. Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening condition with significant mortality and is associated with many diseases. The association of SS with TTP is rare, but it carries a high death rate and can be easily misdiagnosed (Kremer Hovinga et al., 2010). We report herein a case of SS complicated with TTP. Furthermore, we review 14 similar cases reported in the literature and briefly discuss the manifestations of this special condition. 

2 Case Presentation
A 72-year-old woman with fatigue for 5 days and purpura on her limbs for 2 days came to our clinic. She also had gingival bleeding, bloody sputum, and bloody urine for 2 days. When she came to us on November 1, 2011, her blood tests showed: white blood cell (WBC) count 4.91×10⁹/L, hemoglobin (Hb) 80 g/L, platelet (PLT) count 4.4×10⁹/L; fasting blood glucose 4.7 g/L; urine tests showed occult blood (3+). She was admitted to our hematology department on November 3, 2011. She had no relevant medical, family or drug history. Physical examination revealed ochrodermia and purpura on her limbs. Her nervous system examination was normal. Her WBC count had decreased to 2.81×10⁹/L, Hb decreased to 82 g/L, and PLT count reduced to 3×10⁹/L. Her purpura had gotten worse and she was given a platelet transfusion on the first day after hospitalization. Her laboratory tests were: AST 54 IU/L, ALT 37 IU/L, LDH 862 IU/L, TB 23.4 mol/L, DB 7.2 mol/L, CRP 1.9 mg/dL, BUN 56.7 mg/dL, IgG 15.7 g/L, IgA 4.97 g/L, IgM 0.61 g/L, IgE 449 g/L, antinuclear antibody 1: 3 200 (granular pattern) positive, anti-SSA antibody positive, anti-SSB antibody positive. Renal function test, anti-dsDNA antibody and anti-phospholipid antibody were all negative, and serum levels of C3, C4 were in the normal range. The patient was ANCA negative and chest X-ray was normal. Bone marrow smear was unremarkable. The patient had had mild dry mouth and dry eyes for 10 years. A diagnosis of connective tissue disease (CTD) was made and the patient was transferred to our rheumatology and immunology department. On the first night in the in-patient ward, the patient presented with sudden speech disorder and allolalia. She also had a fever (peaking at 38.1?) with no symptoms or signs of infection. The nervous system examination was unremarkable. A cranial computed tomography revealed mild white matter demyelination. She was treated with oxiracetam, but her speech and allolalia got worse, and, in addition, she was restless and became comatose. A repeated brain nuclear magnetic resonance showed a new ischemic focus on the right parietal lobe and on both sides of the frontal lobe. Her PLT count and Hb level were 60×10⁹/L and 6.6 g/L, respectively. Bone marrow biopsy disclosed a hypoproliferative marrow with normal maturation of granulocytic series. Coombs’ test was negative. D-dimer, prothrombin time (PT), and activated partial thromboplastin time (APTT) were all within normal limits. Twenty-four hour urine protein secretion was 676 mg. She was diagnosed with TTP. She was immediately given a plasma exchange once daily for 6 days (2 000 mL on each occasion), then the frequency was changed to every other day (2 000 mL on each occasion), and, at the same time, high-dose methylprednisolone was infused (120 mg for 3 days, then 80 mg for 5 days, after which this was changed to prednisone 60 mg each day). Two days after the plasma exchange, her PLT count increased to 68.4×10⁹/L. Furthermore, her LDH level decreased from 875 to 219 U/L. After her PLT count rose to 60×10⁹/L, Schirmer’s test was bilaterally positive, associated with positive Rose Bengal corneal staining. Radionuclide imaging of the glands showed abnormalities. Ophthalmologic evaluation was consistent with keratoconjunctivitis sicca. Salivary gland biopsy revealed inflammatory infiltrations of lymphocytes in the periductal and periacinar areas. A diagnosis of primary SS (pSS) was made. Immunoglobulin injection was given for 5 days and mycophenolate mofetil was added at the same time. After this treatment, the patient’s condition improved remarkably. She remains stable and continues to be followed-up at our out-patient clinic. She now takes prednisone 10 mg qd and mycophenolate mofetil 1.0 bid. Eight months later, her laboratory studies were: WBC count 9.76×10⁹/L, Hb 147 g/L, PLT count 214×10⁹/L, serum AST 27 IU/L, ALT 22 IU/L, LDH 126 IU/L, IgG 10.7 g/L, IgA 3.42 g/L, IgM 1.01 g/L, IgE 71 g/L. 

3 Discussion
SS is a common AID characterized by an exocrine gland disorder in which the salivary and lacrimal glands are most commonly involved. Hematological manifestations of pSS usually consist of mild anemia and thrombocytopenia, and moderate neutropenia and lymphopenia. Hematological changes include purpura haemorrhagica, anemia, immune-induced hemolytic anemia, eosinophilia, leukemia, aplastic anemia, and lymphoma. Laboratory examination may show multiclonal hyperglobulinemia, high titer rheumatoid factor, and an evident increase in the erythrocyte sedimentation rate. Individual cases of TTP preceding the diagnosis of SS, systemic lupus erythematosus (SLE) or scleroderma have been reported. A close relationship between SLE and TTP was first described in 1939. TTP is frequently associated with CTD, with a frequency of 1%~6% in the patient population (Sato et al., 2006); however, TTP associated with SS is rare. TTP is a pathological condition characterized by generalized microvascular occlusion by platelet thrombi, thrombocytopenia, and microangiopathic hemolytic anemia. It is a syndrome consisting of hemolytic anemia, thrombocytopenic purpura, neurologic disease, fever, and renal disease. It was ?rst described by Moschcowitz in 1925. In contrast to idiopathic TTP, the causes associated with TTP include drugs (especially chemotherapeutic agents), malignancy, CTDs, hematopoietic stem cell transplantation, Escherichia coli O157 H7, pregnancy, and many other causes (Yoshihiro and Masanori, 2010). Endothelial cell injury is the postulated mechanism of TTP. Endothelial dysfunction, including release of nitric oxide and von Willebrand factor, and increased levels of tissue plasminogen activator, thrombomodulin, plasminogen activator inhibitor, are described as promoting the development of TTP (Yoshihiro and Masanori, 2010). ADAMTS13 is synthesized in endothelial cells and megakaryocytes from identical 250 kD subunits into disul?de-linked multimers ranging in size from about 500 to 20 000 kD (Gerritsen et al., 2001). It was initially identified within the liver, and then more specifically in hepatic stellate cells (Uemura et al., 2005). ADAMTS13 is also present in platelets (Suzuki et al., 2004), vascular endothelial cells (Manea et al., 2007), and kidney podocytes (Manea et al., 2007). Severe deficiency of ADAM TS-13 activity (ADAMTS13:AC) has been thought to be a unique feature of TTP, and can be caused by genetic mutations or by acquired autoantibody (ADAMTS13:INH) to this enzyme (Furlan et al., 1998; Tsai and Lian, 1998). ADAMTS13 is assumed to efficiently cleave unusually large VWF multimers (UL-VWFMs) released from vascular endothelial cells as a solid phase enzyme by binding to the cell surface, after secretion into the circulation (Coppo and Veyradier, 2009). Although TTP is a highly heterogeneous pathological condition, one-third of TTP patients have severe deficiency of ADAMTS13:AC. Platelet transfusions in such patients are contraindicated.

Plasma exchange is now the most common first-line therapy for TTP. In addition to corticosteroids, immunosuppressive agents and immunoglobulin are needed for CTD-associated TTP. The possible mechanism of plasma exchange is removal of the noxious substance in the patient’s circulation blood, such as autoantibody, and it can also supply certain agents, such as blood coagulation factor. High-dose corticosteroids and immunosuppressive agents can inhibit immune inflammatory reaction and the activity of T/B cells in order to decrease cytokinemia and autoantibody, and are considered to be beneficial in maintaining a good long-term prognosis in immuneinduced TTP. The effect of large-dose immunoglobu-
lin and immunosuppressive agents has not been confirmed yet, but in our case, large-dose immunoglobulin and immunosuppressive agents did prove to be effective. 

A review of the literature revealed 14 other such cases (Table 1): 14 out of 15 patients were female, 3 patients died after plasma exchange and glucocorticosteroid treatment, and 2 patients died quickly after diagnosis but before treatment. Relapsing and chronic forms of TTP are unusual. In one case, ADAMTS13 activity was negative. Plasma exchange, plasma infusion, and glucocorticosteroid were used as therapy. In one case, rituximab (375 mg/m²) was used as the disease-modifying antirheumatic drug (DMARD). For our patient, the DMARD used was mycophenolate. After treatment, the patient’s condition stabilized, and to date, the patient continues to be healthy with no disease recurrence.
 

Table 1 Comparison of reported patients with SS complicated with TTP

Since SS complicated with TTP is a rare but life-threatening condition with a high death rate, and misdiagnosis is high, more attention should be paid to it in clinical practice.

References
Campbell G.N., and Gallo J.H., 1998, Relapsing thrombotic thrombocytopenic purpura (TTP) in Sjogren syndrome, Australian and New Zealand Journal of Medicine, 28(2): 214 http://dx.doi.org/10.1111/j.1445-5994.1998.tb02974.x

Coppo P., and Veyradier A., 2009, Thrombotic microangiopathies: Towards a pathophysiology-based classification, Cardiovasc. Hematol. Disord. Drug Targets, 9: 36-50  http://dx.doi.org/10.2174/187152909787581318 

Furlan M., Robles R., Galbusera M., Remuzzi G., Kyrle P.A., Brenner B., Krause M., Scharrer I., Aumann V., Mittler U., Solenthaler M., and Lämmle B., 1998, von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome, N. Engl. J. Med., 339(22): 1578-1584 http://dx.doi.org/10.1056/NEJM199811263392202 PMid: 9828245  

Garcia H., Fagot T., and Foissaud V., 2008, Thrombotic thrombocytopenic purpura: A case report, Ann. Biol. Clin., 66(3): 327-331 

Gerritsen H.E., Robles R., Lammle B., and Furlan M., 2001, Partial amino acid sequence of purified von Willebrand factor-cleaving protease, Blood, 98(6): 1654-1661 http://dx.doi.org/10.1182/blood.V98.6.1654

Haruo A., Norioki T., and Sonosuke Y., 2004, Thrombotic thrombocytopenic purpura complicating Sjögren syndrome with crescentia glomerulonephritis and membranous nephritis, Mod. Rheumatol., 14: 174-178 

Koga T., Yamasaki S., and Nakamura H., 2013, Renal thrombotic microangiopathies/thrombotic thrombocyto-penic purpura in a patient with primary Sjögren‘s syndrome complicated with IgM monoclonal gammopathy of undetermined significance, Rheumatol. Int., 23(1): 227-230 http://dx.doi.org/10.1007/s00296-010-1569-0 PMid: 20652270 

Manea M., Kristoffersson A., Schneppenheim R., Saleem M.A., Mathieson P.W., Mörgelin M., Björk P., Holmberg L., and Karpman D., 2007, Podocytes express ADAMTS13 in normal renal cortex and in patients with thrombotic thrombocytopenic purpura, Br. J. Haematol., 138(5): 651-662 http://dx.doi.org/10.1111/j.1365-2141.2007.06694.x PMid: 17627784 

Sato T., Hanaoka R., Ohshima M., Miwa Y., Okazaki Y., Yajima N., Ishizashi H., Matsumoto M., Fujimura Y., and Inokuma S., 2006, Analyses of ADAMTS13 activity and its inhibitor in patients with thrombotic thrombocytopenic purpura secondary to connective tissue diseases: Observations in a single hospital, Clin. Exp. Rheumatol., 24(4): 454-455 PMid: 16956441 

Schattner A., Friedman J., and Klepsh A., 2002, Thrombotic thrombocytopenic purpura as an initial presentation of primary Sjögren syndrome, Clin. Rheumatol., 21: 57-59  http://dx.doi.org/10.1007/s100670200013

Steinberg A.D., Green W.T., and Talal N., 1971, Thrombotic thrombocytopenic purpura complicating Sjögren syndrome, JAMA, 215: 757-761 http://dx.doi.org/10.1001/jama.215.5.757 http://dx.doi.org/10.1001/jama.1971.03180180033007

Suzuki M., Murata M., Matsubara Y., Uchida T., Ishihara H., Shibano T., Ashida S., Soejima K., Okada Y., and Ikeda Y., 2004, Detection of von Willebrand factor-cleaving protease (ADAMTS-13) in human platelets, Biochem. Biophys. Res. Commun., 313(1): 212-216 http://dx.doi.org/10.1016/j.bbrc.2003.11.111

Tsai H.M., and Lian E.C., 1998, Antibodies to von Willebrand factor cleaving protease in acute thrombotic thrombocytopenic purpura, N. Engl. J. Med., 339(22): 1585-1594 http://dx.doi.org/10.1056/NEJM199811263392203 PMid: 9828246 PMCid: PMC3159001

Uemura M., Tatsumi K., Matsumoto M., Fujimoto M., Matsuyama T., Ishikawa M., Iwamoto T.A., Mori T., Wanaka A., Fukui H., and Fujimura Y., 2005, Localization of ADAMTS13 to the stellate cells of human liver, Blood, 106(3): 922-924 http://dx.doi.org/10.1182/blood-2005-01-0152 PMid: 15855280  

Wen C., 1999, Thrombotic thrombocytopenic purpura complicating Sjögren‘s syndrome: A case report, Chin. J. Hematol., 20: 497 

Yoshihiro F., and Masanori M., 2010, Registry of 919 Patients with thrombotic microangiopathic across Japan: Database of Nara Medical University during 1998-2008, Intern. Med., 49(1): 7-15 http://dx.doi.org/10.2169/internalmedicine.49.2706

Zhang R., Dong J.L., and Xie Q.B., 2007, Thromobotic thrombocytopenic purpura as initial presentation of primary Sjögren syndrome and literatures review, West China Med. J., 22(1): 51-56