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
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 or indirect bilirubin in serum, or high megakaryocytes 83/jul, erythroblasts 7.1x104 /jli1 (normo. count of reticulocytes in peripheral blood. In addition, before baso. 6.0x103/jli1, normo. poly. 6.2xlO4/jul, normo. ortho. tracheal intubation, her mental status wasstable and alert, 3.4xlO3/jul), proerythrocytes and reticulocytes could not be further supporting the above argument since a lack of mental detected] and there was no evidence of phagocytosis or an instability is commonly observed in patients with thrombotic increase in histiocytes, hence, complication of HPS was ex- microvasculopathy. cluded. Her conditions steadily recovered, and the patient The patient was treated with three consecutive daily could extricate artificial ventilation and continuous daily pulses of one g of methylprednisolone and subsequent 60 hemodialysis about one month after admission. A chest X- mg/day of prednisolone administration (Fig. 3). In addition, ray showed almost full recovery with no residual infiltrative 1,500 mg/day of gabexate mesilate was initiated for DIC. shadows (Fig. 5), and the titer of p-ANCA decreased
852 Internal Medicine Vol. 42, No. 9 (September 2003) DIC Associated with Microscopic Polyangiitis
Feb 5 Feb 25 Mar 17 Apr 6 Apr 26 May 16 Jun 5
| MEPN0.25g | CZOP0.5g | |I/C0.25g| |I/C0.25g| | I/C0.5g | [i/C057]
I å f I t LVFX200 mg PSL 60 mg 50 mg 40 mg 30 mg 25 mg | 20 mg |
Methylprednisolone 1 g
ttt Cyclophosphamide 50 mg
Gabexate mesilate 1,500 mg
Plasma aaa -*exchange \tttftfttfiftfflttffltmt\ \ tt t t
MPO-ANCA 765 195 79 29 14 10> CRP 9.1 4.1 3.2 0.7 2.1 0.4 0.4 0.5 1.5 1.7 9.1 FDP 23.8 122 80.3 29.2 PLT 3.4 5.5 7.0 12.6 9.3 9.7 16.9 15.6 13.8 4.2 1.2
MEPN:meropenem trihydrate, I/C: IPM/CS: imipenem/cilastatin sodium, PSL: prednisolone, CZOP: cefozopran hydrochloride, LVFX: levofloxacin.
Figure 3. The clinical course of the present case.
Figure 5. Chest radiograph of the chest on 60th hospital day re- vealing the complete disappearance of infiltrative shadows.
Figure 4. Axial computed tomographic scan of the brain on 14th hospital day indicating intracerebral hemorrhage shown as two high density areas in the left occipital lobe (arrows).
Internal Medicine Vol. 42, No. 9 (September 2003) 853 Saito et al gradually (Fig. 3). The platelet level was retained at 8.0x case, both thrombocytopenia and coagulation disorder due to lOYjil, indicating the improvement of DIC. However, on the DIC seriously aggravated the systemic hemorrhage origi- 104th hospital day, leukocytopenia (WBC 1,100/pl) and nally induced by MPA.Approximately two weeks after the thrombocytopenia (platelet 10.2x104/jll1), which can be elic- initiation of gabexate mesilate administration, an increase in ited by cyclophosphamide, had abruptly developed. Despite thrombocyte count and recovery of PT was observed. In ad- the administration of granulocyte-colony stimulating factor dition, ventilation was improved and the level of blood urea (150 jug/day) and platelet transfusion, her condition contin- nitrogen decreased, indicating that gastrointestinal bleeding ued to worsen and she finally died of severe infection on the and pulmonary hemorrhage could have been suppressed by 123rd hospital day. the treatment. Furthermore, her consciousness level also re- covered gradually. These findings suggested that ameliora- Discussion tion of DICdramatically resulted in improvement of general conditions. In pathophysiology of ANCA-associated vasculitis in- It is reasonable to suspect that the presence of latent DIC cluding MPA,primed neutrophil activation and endothelial may be overlooked in relatively many cases of ANCA- cell damage is considered as an important initial process (9). associated vasculitis. Systemic vessels could be injured in Activated and primed neutrophils express myeloperoxidase the disease and hemorrhage might occur in any organ includ- (MPO)on the cell surface, and are led to bind p-ANCAthat ing the lung and kidney without complication of DIC. is considered specific for MPO.Moreover, they adhere to en- Moreover, thrombocytopenia due to DIC may often be mis- dothelial cells that express ICAM-1, VCAM-1and E-selectin interpreted as a drug-induced disorder because cyclo- (10). ICAM-1-CD18 interaction provokes neutrophil- phosphamide is usually administrated as an immunosuppres- mediated cytotoxicity via CD18-mediated release of sant in numerous cases of ANCA-associated vasculitis. proteases, such as neutrophil elastase (1 1). Further, there is Therefore, it maynot be easy to detect the presence of latent another pathway in that a highly cationic protein such as DIC. The present case showed thrombocytopenia and coagu- MPO directly causes endothelial damage by a charge- lation disorder in the early stage of MPA,hence we could mediated pathway (12). These phenomena are capable of have diagnosed the presence of DIC. It might be impossible augmenting severe endothelial damage, leading to a subse- to make an adequate diagnosis if these disorders develope quent marked bleeding tendency through consumption of after initial treatment. Importantly, it is known that cytokines multiple coagulant factors. Interestingly, DIC could be in- such as tumor necrosis factor-a (TNF-a) contribute to in- duced through a similar pathway. Microemboli produced by duce endothelial damage in ANCA-associated vasculitis activated neutrophil-induced endothelial damage elicit (18), and gabexate mesilate could potently suppress TNF-a microcirculatory disorder or bleeding tendency, thus leading production (19) and endothelial cell injury (20). In addition, to organ failure (13). In addition, endothelial cell damage- gabexate mesilate has been proven to be safer and moreef- induced coagulation disorder has been shown to activate fective than heparin in the treatment of DIC accompanied by primed neutrophils as well (14). An increase in IL-8 produc- bleeding diathesis (21). Finally, gabexate mesilate has been tion by endothelial cells, mesangial cells and proximal shownto reduce endothelium damageand activation better epithelial cells caused by cytokine stimulation also activates than heparin (22, 23). These findings do not necessarily sug- primed neutrophils and enhances generation of reactive oxy- gest that gabexate mesilate is always the most useful thera- gen species. Thus, these interactions further facilitate endo- peutic agent for DIC. However, it is recommendedat least thelial damage, developing a vicious cycle (2). Although for the treatment of ANCA-associatedvasculitis accompa- these findings strongly suggest that ANCA-associated nied by bleeding tendency. vasculitis often presents with DIC, few reports have de- scribed cases such as the present case (15). Refe rences It is well known that infectious diseases, both from bacte- rial and nonbacterial infection, are often associated with a 1) Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med 337: 1512- coagulation disorder, resulting in DICand multiorgan failure 1523, 1997. (16). However, in the present case, a severe infectious dis- 2) Harper L, Savage CO. Pathogenesis of ANCA-associated systemic vasculitis. J Pathol 190: 349-359, 2000. ease which could have induced DIC was not obviously pre- 3) Falk RJ, Terrell RS, Charles LA, Jennette JC. Anti-neutrophil sent because of the low level of endotoxin, low grade fever cytoplasmic autoantibodies induce neutrophils to degranulate and pro- and no positive cultures in urine, sputum, stool and blood duce oxygen radicals in vitro. Proc Natl Acad Sci USA87: 41 15-41 19, specimen. On the contrary, ANCA-related vasculitis could 1990. 4) Bratt J, Palmblad J. Cytokine-induced neutrophil-mediated injury of easily induce a coagulation disorder (17). Therefore, it was human endothelial cells. J Immunol 159: 912-918, 1997. considered that the main factor in the onset of DICin the 5) Kaplanski G, Fabrigoule M, Boulay V, et al. Thrombin induces endo- present case was ANCA-related vasculitis-induced coagula- thelial type II activation in vitro: IL-1 and TNF-a-independent IL-8 se- tion disorder, but not infectious disease. cretion and E-selectin expression. J Immunol 158: 5435-5441 1997. The patient required repeated blood transfusion of 6) Johnson K, Choi Y, DeGroot E, Samuels I, Creasey A, Aarden L. thrombocytes and fresh frozen plasma incipiently. In this Potential mechanisms for a proinflammatory vascular cytokine
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