CASE REPORT Microscopic Polyangiitis Associated with Marked Systemic Bleeding Tendency Caused by Disseminated Intravascular Coagulation Takatoshi SAITO, Masahito TSUCHIYA, Chihiro SHIKATA, Hiroshi YAMAGUCHI, Shu-ichi MlYATA, Sei-ichiro MATSUO,Sho Ishizawa and Kunihiko YOSHIMURA Abstract Introduction A 57-year-old womanwas admitted to our hospital be- It has been well documented that anti-neutrophil cyto- cause of severe dyspnea due to pulmonaryhemorrhage plasmic antibody (ANCA)-associated vasculitis, such as and rapidly progressive renal failure. The patient was Wegener's granulomatosis and microscopic polyangiitis positive for perinuclear pattern anti-neutrophil cyto- (MPA), elicits a severe bleeding tendency as a clinical mani- plasmic antibody (p-ANCA) and was manifested with festation (1, 2). Activation of primed neutrophils induced by gastrointestinal bleeding and brain hemorrhage. Thus, ANCAand subsequent endothelial damage due to cytokine she was diagnosed as having microscopic polyangiitis release are regarded as an important initial process of (MPA). Laboratory examination demonstrated severe vasculitis, leading to hemorrhage in multiple organs and tis- thrombocytopenia, increased prothrombin time and a sues (3, 4). In addition, an increase in thrombin production high concentration of fibrin degradation products. In ad- responding to coagulation activation augments IL-8 produc- dition, the elevated plasma levels of D-dimer, thrombin- tion, which in turn activates TNF-primedneutrophils and antithrombin complex and plasmin-plasmin inhibitor further causes deterioration of systemic vasculitis (5, 6). complex led us to make a diagnosis of disseminated In contrast to MPA,disseminated intravascular coagula- intravascular coagulation (DIC). Complication of DIC tion (DIC) is also known to cause systemic bleeding ten- was considered to have caused further deterioration in dency. Similar to ANCA-associated vasculitis, impairment bleeding tendency due to MPAin the present case. The of endothelial cells causes subsequent augmentation of co- patient was treated with plasma exchange, hemodialysis, agulation and fibrinolysis through the release of proinflam- administration of corticosteroid including pulse therapy matory cytokines (7). Thus, similarity exists between the two and cyclophosphamide. Continuous infusion of gabexate diseases in pathophysiology, although it is very rare that mesilate proved effective for improvement of systemic ANCA-associated vasculitis is accompanied by DIC. bleeding tendency. However, she finally died of severe in- Here, we describe a case of MPAassociated with DIC fectious diseases. In conclusion, it is suggested that whoshowed a marked systemic bleeding tendency. Wealso ANCA-associated vasculitis could be accompanied by present evidence that gabaxate mesilate is a very effective DICand gabexate mesilate maybe a useful therapeutic therapeutic agent for DIC. agent for these disorders. (Internal Medicine 42: 850-855, 2003) Case Report Key words: anti-neutrophil cytoplasmic antibody, pulmo- A 57-year-old womanvisited our hospital complaining of nary hemorrhage, rapidly progressive pulmo- sore throat, productive cough, sputum, general fatigue and nary failure, gabexate mesilate slight fever on December ll, 2000. Her initial laboratory data showed renal insufficiency (serum creatinine and blood urea nitrogen were 1.9 mg/dl, and 24 mg/dl, respectively). Prior to onset, she had been well with no significant medical From the Division of Respiratory and Infectious Diseases, the Department of Internal Medicine, Aoto Hospital, Jikei University School of Medicine, Tokyo Received for publication June 22, 2001; Accepted for publication March 17, 2003 Reprint requests should be addressed to Dr. Takatoshi Saito, the Division of Diabetes and Endocrinology, the Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461 850 Internal Medicine Vol. 42, No. 9 (September 2003) DIC Associated with Microscopic Polyangiitis or familial history, and she was a life-long non-smoker. antibody were negative. Hepatitis B and C serology were Despite the initial daily medication including fluticasone negative. A clotting screening test was consistent with DIC propionate (400 jug), ambroxol hydrochloride (45 mg), epra- as shown in Table 2. Urinalysis showed moderate hematuria zinone hydrochloride (60 mg) and levofloxacin (300 mg), and proteinuria. Melena was also observed. Blood gas analy- her symptomswere only slightly improved. sis under 5 //min oxygen inhalation showed severe She was admitted to our hospital due to massive hemopty- hypoxemia and hypocapnea along with metabolic acidosis sis on February 5, 2001. Her blood pressure was 122/84 (pH 7.44, PaCO2 25 torr, PaO2 50.1 torr, HCO3" 16.2 mEq/Z, mmHgrecumbent, pulse rate was 76/min regular, body base excess - 4.7 mEq/Z, SaO2 87.8%). A chest X-ray temparature was 37. 1 °C. Her conjunctiva was pale. Chest ex- showed a normal size heart, air space consolidation with air amination showed systolic heart murmurand coarse crackles bronchogram in the right lung (Fig. 1). A computerized on the right lung. Slight pitting edema and subcutaneous tomogram (CT) of the chest also demonstrated infiltrative bleeding in bilateral pretibial regions were detectable. There opacities and bilateral pleural effusion (Fig. 2). The pleural was no abnormal pigmentation, cyanosis, peripheral lymph effusion was found to be biochemically consistent with a node swelling or clubbed fingers. Neurological findings transudate, and cytological examination revealed no malig- showed no abnormalities. nant cells. Bronchoscopic examination further confirmed As shown in Table 1, hematological test revealed severe hemorrhage from the right lung (data not shown). anemia, marked thrombocytopenia and leukocytosis. Blood With the presence of rapidly progressive renal failure with chemistries showeddeteriorated renal function, electrolytes hematuria and proteinuria, pulmonary and gastrointestinal abnormalities, hypoproteinemia and elevation of C-reactive hemorrhage, subcutaneous bleeding in the bilateral pretibial protein. Immunological tests showed a high titer of P- areas, elevated CRPlevel and p-ANCAtiter in serum, as ANCA, but antinuclear antibody, cytoplasmic ANCA(C- well as chest X-ray and CTfindings, we diagnosed her as ANCA), cryoglobulin, anti-GBM antibody or anti-platelet MPAbased on diagnostic criteria made by the Vasculitis Table 1. Laboratory Data on Admission WBC (/ill) 1 3,300 Haptoglobin (mg/dl) 329 RBC (lOVfil) 144 Coombs test direct (+) Hb (g/dl) 4.7 indirect (-) Ht (%) 13.9 RF (IU/ml) 3.0> PLT (lOVjul) 3.4 ANA (+) Reticulocyte (%0) 17.3 lgG (mg/dl) 1 ,560 GOT (IU//) 17 lgA (mg/dl) 213 GPT (IU//) 7 lgM (mg/dl) 5 1 LDH (IU//) 354 PA lgG (ng/107cell) 171.9 ChE (IU//) 982 Endotoxin (pg/ml) 5> yGTP (IU//) 7 (3-D glucan (mg/dl) 8.3 ALP (IU//) 208 C3 (mg/dl) 56.0 TBi (mg/dl) 0.5 C4 (mg/dl) 14.0 IP (g/dl) 5.1 CH50 (U/ml) 19.9 Alb (g/dl) 2.0 Free T3 (pg/ml) 0.74 BUN (mg/dl) 50 Free T4 (ng/ml) 1.36 Cr (mg/dl) 4.5 TSH (jaU/ml) 1.74 Na (mEq//) 1 26 MPO-ANCA (EU) 765 K (mEq//) 5. 1 PR3-ANCA (EU) 10> Cl (mEq//) 98 Cryoglobulin (-) Ca (mg/dl) 6.5 Immuno complex (Clq: juU/ml) 5.2 P (mg/dl) 5.5 CRP (mg/dl) 9. 1 <Urinalysis> Anti legionella Ab (-) Prot (++) Anti GBMAb (-) Sugar (+) Anti platelet Ab (-) Occult (+++) LE test (-) RBC Many Anti RNP Ab (-) WBC 5-9 Anti Sm Ab (-) CCr (ml/min) 8.8 GBM: glomerular basement membrane, PA lgG: platelet-associated lgG, RNP: ribonuc- leoprotein, TSH: thyroid stimulating hormone, RF: rheumatoid factor, PR3-ANCA: proteinase 3 ANCA. Internal Medicine Vol. 42, No. 9 (September 2003) 851 Saito et al Table 2. Data for Coagulation and Fibrinolysis on Admission Values Reference intervals Prothrombin time (%) 58 70-100 Activated partial thromboplastin time (sec) 29.8 24.2-36.3 Fibrinogen (mg/dl) 303 250-400 Fibrin degradation product (jug/ml) 23.8 <10 Thrombin-antithrombin complex (ng/ml) 52. 1 <3.0 Plasmin-plasmin inhibitor complex (|ug/ml) 1.3 <0.8 Anti-thrombin III (%) 58 79-121 Plasminogen (%) 3 1 75-125 D-dimer (ng/ml) 5.3 <1.0 Figure 2. Axial computedtomographic scan of the chest show- ing severe pulmonary hemorrhage in both lungs and moderate pleural effusion. Controlled ventilation was started on the third hospital day Figure 1. Chest radiograph on admission showing bilateral via tracheal intubation. Four days later, in order to suppress progression of MPA,plasma exchange using fresh frozen massive air space consolidation due to pulmonary hemorrhage. plasma was performed three times and hemodialysis was also introduced to treat renal failure. However, FDPconcen- tration increased up to 1 12 jug/ml on 7th hospital day, indi- Study Group of the Japanese Ministry of Health and Welfare cating progression of DIC. Eventually, she developed in 1998. Furthermore, based on laboratory examination and delayed unconsciousness, and the brain CT showed small clinical features, a diagnosis of DICcould have also been high density areas indicating brain hemorrhage (Fig. 4). To made. Thrombotic microvasculopathy such as hemolytic elucidate whether anemia and thrombocytopenia were in- uremic syndrome or thrombotic thrombocytopenic purpura duced by hemophagocytic syndrome (HPS) or not (8), we were ruled out because of the absence of hemolytic anemia evaluated bone marrow. Cell counts including megakaryo- documented by several laboratory data including a low level cytes were within the normal range [cell counts 17.0x104/jul, of LDH,haptoglobin