Microangiopathic hemolytic anemia in Wegener's granulomatosis

CASE REPORTS

Microangiopathic Hemolytic Anemia in Wegen&s Granulomatosis

CHARLES

S. CRUMMY,

ELLIOTT PERLIN,

M.D.*

M.D.

ROSS B. MOQUIN,

M.D.

Bethesda, Maryland

From the Hematology Branch, Department of internal Medicine, Naval Hospital, National Naval Medical Center, Bethesda, Maryland 20014. The opinions or assertions contained herein are the private ones of the’authors and are not to be construed as official or reflecting the views of the Navy Department or the naval service at large. Requests for reprints should be addressed to Dr. Charles S. Crummy. Manuscript received June 1, 1970. *Present address: 19 E. Main Street, Mendham, New Jersey 07945.

544

Microangiopathic hemolytic anemia (MHA) is a prominent feature of many forms of generalized vasculitis, especially those associated with rapidly progressive renat failure. A patient with Wegener’s granulomatosis and MHA is described. Treatment with heparin, prednisone and azathioprine was associated with a complete remission. It is suggested that MHA should be considered a serious but potentially reversible complication in advanced Wegener’s granulomatosis. Microangiopathic hemolytic anemia (MHA) with characteristic burr, helmet and triangular red blood cells is a prominent feature of many forms of angiitis, especially those associated with rapidly progressive renal failure. It has been reported in association with thrombotic thrombocytopenic purpura, “small vessel hemolytic uremic syndrome, renal cortical nepolyarteritis,” crosis, malignant hypertension, acute necrotizing glomerulonephritis and systemic lupus erythematosus [1,2]. When these disorders are associated with MHA many of the clinical and pathologic features are strikingly similar to those of advanced Wegener’s granulomatosis. The triad of necrotizing lesions of the upper or lower respiratory tract (or both), generalized vasculitis and focal glomerulitis defines Wegener’s granulomatosis [3,4]. The presenting symptoms of the disease are usually respiratory: sinusitis, “asthma,” hemoptysis. The initial phase may last from days to years; the second phase is usually abrupt in onset and is characterized by rapidly progressive generalized vasculitis, glomerulitis and death in’weeks or months secondary to renal failure or to sepsis [3,5]. The patient to be described had Wegener’s granulomatosis and MHA. We have found no previous reports of the association of these two entities. CASE REPORT A fifty-five

year old Caucasian man had leg pain for three days and was admitted to the hospital on June 2, 1969. Pain and swelling of

The American

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1971

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both calves had not been relieved by rest and leg elevation. At the time of referral the diagnosis was deep and superficial thrombophlebitis of both legs. Two weeks before admission intermittent epistaxis developed and persisted. At times the bleeding had been profuse. During the week preceding admission he lost 5 pounds in weight. During the fourteen years before admission he had had many attacks of paroxysmal dyspnea and wheezing, increasing in frequency and severity during the several months just before admission. Five weeks before admission the wheezing and dyspnea became persistent, and he responded only partially to the administration of aminophylline and epinephrine. All pulmonary symptoms abruptly cleared two weeks before admission, coincident with the onset of epistaxis. Physical examination was of a well developed moderately ill man. The blood pressure was 100/60 mm Hg, the pulse loo/minute and the oral temperature was 100°F. Both legs distal to the knees were swollen, the right more than the left. There were unequivocal signs of bilateral deep thrombophlebitis.

Both saphenous veins were palpable and tender throughout the entire course. No other leg lesions were noted, and the phlebitis was limited to the lower extremities. All arterial pulses were present and normal. The nasal mucous membranes were hyperemic. No specific lesions were noted, and the nasopharyngeal airway was patent bilaterally. The remainder of the examination was unremarkable. On admission the hematocrit was 38 per cent, the hemoglobin 12.6 gm/ 100 ml and the white blood cell count 11,6OO/cu mm. The white cell differential was 76 per cent segmented neutrophils, 1 per cent juvenile forms, 3 per cent eosinophils, 19 per cent lymphocytes and 1 per cent monocytes. The red blood cell morphology was normal. The platelet count was 1,235,0OO/cu mm. The uncorrected erythrocyte sedimentation rate was 52 mm/hour. The urine was straw colored and clear, specific gravity was 1.019 and pH 6. There was a trace of ketones; glucose and protein tests were negative. The urine sediment contained 5 to 10 red blood cells and 3 to 8 white blood cells/hpf. A rare granular

Figure 2. A, nasal biopsy specimen. Necrotizing arteritis, interstitial hemorrhage and a few intact mucous glands. 8, same nasal biopsy specimen. Necrotizing arteritis with chronic and acute inflammatory reaction. C, section from amputated leg. Necrotizing arteritis and diffuse necrosis in muscle and fat. D, section from skin of amputated leg. Sobendothelial plaque in capillary with associated inflammatory reaction. Hematoxylin and eosin stain, original magnification x 41 (A), x 109 (B), x 61 (C) and x 343 (D).

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TABLE

I

Selected

lmmunohematologic

Day

FSP’

Total Serum Proteins &m/100 ml)

~40,000

.

. .

8.0 . .

140,000 120,000 565,000 360,000

+ +

45 140

8.8

..

5.6 5.6

1,;35.000

1

6 10 11 25 58

--

. -

* FSP = fibrin split products. t ELT = euglobulin lysis time (normal $ IgG = immunoglobulin G antibodies

150

120-300 (normal

min). 600-1,200

October

1971

CRUMMY

ET

bL.

Gamma Globulin

(%)

(%)

36

27

...

. .

Wf (mg/lOO ml)

. ...

31

33

2,150

...

.

...

37 54

30 14

1,400 600

C’:,§ (mg/lOO ml)

ilbrmogen (mg:lOO ml) 600

.. 245 240 245

350 260 440 565

mg/lOO

ml). system (normal 145 Z!Z22 mg/lOO ml).

cast was noted. The blood urea nitrogen was 18 mg and the glucose 100 mg/lOO ml. The serum sodium was 138 mEq, potassium 4.5 mEq, chloride 100 mEq and carbon dioxide content 26.4 mM/L. The total protein was 7.8 gm and the albumin 3.0 gm/lOO ml. The partial thromboplastin time was 25.4 seconds (normal twenty-five to thirty-five seconds), and the prothrombin time was 12.4 seconds with a normal control of ten seconds. Posteroanterior and left lateral chest films were negative. A lung scan was consistent with decreased perfusion at the base of the right lung. During the first six weeks of hospitalization all stools were negative for occult blood. A profile of the hospital course is shown in Figure 1. Administration of heparin was begun on the day of admission, and it was given subcutaneously at six hour intervals. Blood samples for partial thromboplastin time determinations were drawn five hours after the previous heparin dosage. Superficial thrombophlebitis was noted in the upper extremities within twenty-four hours of admission, but by the fourth day all signs of thrombophlebitis had abated. Epistaxis, right periorbital swelling, purulent sinusitis and bilateral nasopharyngeal airway obstruction developed between the fourth and sixth days. The hematocrit was 38 per cent and the platelet count 54O,OOO/cu mm. The urine sediment contained 50 to 60 red blood cells and 20 to 30 white blood cells/hpf. Many mixed cellular and red blood cell casts were noted. The endogenous creatinine clearance was 102 ml/minute. There were no signs of recurrent thrombophlebitis, the epistaxis persisted, so the heparin dose was reduced. A nasal mucosal biopsy specimen obtained on the ninth day was consistent with Wegener’s granulomatosis (Figure 2). Recurrent thrombophlebitis of all extremities associated with isolated and confluent petechial lesions on both legs was noted on the morning of the tenth day. Presacral and bilateral flank edema was prominent. The blood urea nitrogen was 48 mg/lOO ml and the endogenous creatinine clearance 52 ml/minute. The hematocrit was 29 per cent and the platelet count

51,

Albumin

..

§ C’r = symbol was formerly: B’C globulin of complement

Volume

ANEMIA----

Data

ELTi(min)

Platelets (per cu mm)

Hospital

HEMOLYTIC

14O,OOO/cu mm. Many burr, helmet and triangular red blood cells were noted on peripheral smear. The serum fibrinogen was 350 mg/lOO ml and fibrin split products were found. The euglobulin lysis time was forty-five minutes (normal 120 to 300 minutes) and the IgG 2,150 mg/lOO ml (normal 600 to 1,200 mg/lOO ml). The urine sediment was telescoped. Nine blood cultures were sterile. The heparin dose was increased, and treatment with prednisone was begun. On the eleventh day fibrin split products were still present, and the euglobulin lysis time was 140 minutes. Selected immunohematologic data are presented in Table I. By the fourteenth day further deterioration was manifested by progressive gangrene of the right leg, more numerous and extensive petechial lesions of both legs, persistent sinusitis and progressive renal failure. Administration of azathioprine and allopurinol was begun. The heparin dose was increased. On the sixteenth day the route of heparin administration was changed to continuous intravenous infusion with a variable speed syringe pump (Harvard model 975). After the sixteenth day sustained gradual improvement was noted in the patient’s general condition, in his sinusitis and in renal function. The vasculitis in both arms and in the left leg diminished. The distal right leg was gangrenous. In anticipation of the operation, the intravenous heparin dose was reduced from the twenty-first to the twenty-fourth day and was discontinued three hours preoperatively. On the twentyfourth day an above the knee amputation of the right leg was performed. The procedure was uncomplicated. Pathologic examination of the amputated leg confirmed the clinical impression of vasculitis (Figure 2). Six hours postoperatively the left leg was again swollen and tender; new petechial and ecchymotic lesions were noted. Heparin infusion was reinstituted, and within two days the swelling and the cutaneous lesions had resolved. Healing of the operative wound was delayed but uncomplicated. Further improvement in renal function was noted, and the sinusitis cleared completely. Four days after the institution of warfarin therapy the

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dosage of heparin was gradually reduced, the administration of allopurinol was discontinued, and reduction in prednisone dosage was begun. On the ninety-fourth hospital day the patient was discharged. Medications were warfarin, prednisone 30 mg every other day, and azathioprine 100 mg and isoniazid 300 mg, daily. The subsequent course has been uncomplicated; there have been no respiratory or other symptoms. The dosages of warfarin and prednisone were reduced during the next three and five months, respectively, and then discontinued. At this writing, six months after discharge, the endogenous creatinine clearance is 96 ml/minute. Treatment with azathioprine and isoniazid continues. (Treatment with azathioprine was discontinued in October 1970. Twenty-one months after discharge.the

patient

is entirely

asymptomatic.)

COMMENTS Microangiopathic hemolytic anemia (MHA) progresses in a vicious cycle: vascular damage, intravascular coagulation, red blood cell fragmentation and further coagulation, and tissue damage [8]. The manifestations of intravascular coagulation in MHA are variable. Thrombocytopenia (of less than 1OO,OOO/cu~ mm) and hemorrhage secondary to consumption coagulopathy are common but may be absent [2,8,9]. Serum fibrinogen is often normal, but fibrinogen catabolism is accelerated. Nonclottable fibrin split products are associated with rapid fibrinogen catabolism and reflect the presence of significant intravascular coagulation with secondary fibrinolysis [1,8]. This patient’s progessive anemia, evidence of intravascular coagulation (positive fibrin split products, generalized vasculitis and azotemia) and characteristic bizarre poikilocytosis are consistent with MHA [2].

The clinical course and evidence of respiratory, renal and generalized vasculitis fulfill the diagnostic criteria of Wegener’s granulomatosis [3,6]. The ultimate remission in this case is consistent with previous reports of the efficacy of prednisone and azathioprine [lo] and other immunosuppressive therapy in this disorder [11,12]. The response to heparin is consistent with the results of Brain and colleagues in the treatment of MHA [l]. In this case the presence, progression and regression of MHA correlated well with the amount and route of heparin therapy. Reduction of the heparin dose from the sixth to tenth day, and brief discontinuation on the twenty-fourth day, were associated with signs of recurrent, progressive vasculitis. The constant intravenous infusion of heparin appears to have been more efficacious than the subcutaneous administration of heparin. The patient’s condition improved more rapidly after the constant intravenous infusion of heparin was started. Significantly smaller amounts were required for a given degree of anticoagulation, and more positive control was obtained. This case suggests that control of intravascular coagulation with heparin may effectively inhibit the progression of Wegener’s granulomatosis and may facilitate control of the disease with other agents. We believe that MHA should be considered a serious but potentially reversible complication in advanced Wegener’s granulomatosis. ACKNOWLEDGMENT We wish to acknowledge the aid of Dr. Boyd L. Harris in interpreting pathological material, the technical assistance of Miss Grace K. Henner and the editorial consultation of Miss Frances H. Atkinson.

REFERENCES 1.

2.

3. 4.

5.

6. 7.

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Brian MC, Baker LRI, McBride JA, Rudenberg ML, Dacie JV: Treatment of patients with microangiopathic haemolytic anaemia with heparin. Brit J Haemat 15: 603,1968. Brain MC, Dacie JV, Hourihane DO: Microangiopathic haemolytic anaemia: the possible role of vascular lesions tin Npathogenesis. BritJlHaemat8:358,1962. Fahey JL, Leonard E, Churg J, Godman G: Wegener’s granulomatosis. Amer J Med 17: 168, 1954. Bouroncle BA, Smith EJ, Cuppage FE: Treatment of Wegener’s granulomatosis with Imuran. Amer J Med 42: 314, 1967. Walton EW: Giant-cell granuloma of the respiratory tract (Wegener’s granulomatosis). Brit Med J 2: 265, 1958. Godman GC, Churg J: Wegener’s granulomatosis. Arch Path (Chicago) 58: 533, 1954. Brain MC, Hourihane DO: Microangiopathic haemo-

8.

9. 10.

11.

12.

lytic anaemia. The occurrence of haemolysis in experimentally produced vascular disease. Brit J Haemat 13: 135, 1967. Baker LRI, Rubenberg ML, Dacie JV, Brain MC: Fibrinogen catabolism in microangiopathic haemolytic anaemia. Brit J Haemat 14: 617, 1968. Harker LA: Platelet production. New Eng J Med 282: 492, 1970. Norton WL, Suki W, Strunk S: Combined corticosteroid and azathioprine therapy. Arch Intern Med (Chicago) 121: 554, 1968. Hollander D, Manning RT: The use of alkylating agents in the treatment of Wegener’s granulomatosis. Ann Intern Med 67: 393, 1967. Kaplan SR, Hayslett JP, Calabresi P: Treatment of advanced Wegener’s granulomatosis with azathioprine and duazomycin A. New Eng J Med 278: 239, 1968.

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