Gold induced thrombocytopenia: 12 cases and a review of the literature

Gold Induced Thrombocytopenia: 12 Cases and a Review of the Literature By Jonathan

D. Adachi,

William

Alfred Cividino, Walter Peter X. Tugwell,

G. Bensen, Yasmin Kassam,

F. Kean, Patrick J. Rooney,

Duncan A. Gordon, Anne Lucarelli, and Dharam

G for the treatment (RA) for many years.

OLD COMPLEXES

have been advocated of rheumatoid arthritis Forestier’ published his favorable results that brought chrysotherapy to the attention of the medical profession in the early 1930s. Numerous well controlled studies have subsequently demonstrated clinical efficacy? Unfortunately, toxicity has been a major limiting factor in its widespread use. Of the toxic reactions, the hematologic ones are the most feared. Recently, much has been written about the efficacy and toxicity of gold therapy and its relationship to a patient’s human leukocyte antiIn this paper, we review the gen (HLA) status.5W’9 literature on gold induced thrombocytopenia2*7,9*‘6~‘8-55 and report our experience, including HLA status, platelet associated immunoglobulin G (PAIgG), and therapy. METHODS From 198 1,12 patients have been diagnosed as having gold induced thrombocytopenia by their attending physician without prior knowledge of their HLA status or the presence of PAIgG at the time of thrombocytopenia. All patients were reviewed by one of us (J.A., Y.K.) and had definite or classical RA as defined by the American Rheumatism Associations6 Gold sodium thiomalate (GSTM) was the gold preparation used at the time of thrombocytopenia, but in one case, 195 mg of aurothioglucose had been used before GSTM. Thrombocytopenia was defined as a platelet count tlO0 X 109/L. In our initial patient, PAIgG was measured using the sheep RBC indicator method of Dixon et aL5’ Subsequently, an immunoradiometric assay method measuring PAIgG on platelets was used.” Lymphocytes were typed for HLA-A, -B, and -C antigens by the microdroplet lymphocytotoxicity test59 with a battery of highly selected typing antisera. HLA-DR typing was performed on a B cell enriched population.s9 DR specificities were defined on the basis of reactivity with sera in the Eighth and Ninth International Histocompatibility Workshops. RESULTS

Twelve patients with gold induced thrombocytopenia were reviewed, nine women and three men. (Table 1). All patients had definite or classic RA, with 11 of 12 being rheumatoid factor positive. All patients were treated with GSTM weekly, with one patient on his second Seminars

in Arthritis

and flheumatism,

Peter J. Powers,

Fernando A. Bianchi,

Gary L. Craig, W. Watson

Buchanan,

P. Singal

course of gold therapy. One other patient was initially commenced on aurothioglucose but was subsequently treated with GSTM. The amount of gold received by each patient before the onset of thrombocytopenia ranged from 115 mg to 1,775 mg, the mean being 585 mg. Thrombocytopenia usually developed early during the course of gold therapy, nine patients becoming thrombocytopenic with 5625 mg of gold. All patients had normal platelet counts before GSTM therapy. In six patients, PAIgG levels were measured before GSTM was commenced, and in each instance levels were normal. Elevated PAIgG levels were measured in all 12 patients during episodes of thrombocytopenia and had returned to normal when measured with resolution of thrombocytopenia.

From the Department of Medicine and Pathology, St Joseph’s Hospital and McMaster University Medical Cenire. McMaster University, Hamilton; and the Department of Medicine, Toronto Western Hospital, University of Toronto. Jonathan D. Adachi, MD, FRCP: Department of Medicine, St Joseph’s Hospital: William G. Bensen, MD, FRCP: Department of Medicine, St Joseph’s Hospital; Yasmin Kassam, MD, FRCP: Department of Medicine, McMaster University Medical Center; Peter J. Powers, MD, FRCP: Department of Pathology. St Joseph’s Hospital; Fernando A. Bianchi, MD, FRCP; Department of Medicine, St Joseph’s Hospital; Alfred Cividino, MD, FRCP: Department of Medicine, St Joseph’s Hospital; Walter F. Kean, MD, FRCP: Department of Medicine, McMaster University Medical Center; Patrick J. Rooney, MD, FRCP: Department of Medicine, McMaster University Medical Center; Gary L. Craig, MD, FRCP: Department of Medicine, St Joseph$ Hospital: W. Watson Buchanan, MD FRCP: Department of Medicine, McMaster University Medical Center; Peter X. Tugwell, MD, FRCP: Department of Medicine, McMaster University Medical Center; Duncan A. Gordon, MD, FRCP: Department of Medicine, Toronto Western Hospital. University of Toronto; Anne Lucarelli, ART: Department of Pathology, St Joseph’s Hospital. McMaster University. Hamilton, Ontario; and Dharam P. Singal, PhD: Department of Pathology, McMaster University Medical Center, McMaster University, Hamilton, Ontario. Address reprint requests to J.D. Adachi, MD, Ste 201-25 Charlton Ave E. Hamilton, Ontario. Canada LBN I Y2. 0 I987 by Grune & Stratton, Inc. 0049-0172/87/l 604-0006%5.00/0

Vol 16, No 4 (May). 1987: pp 287-293

287

ADACHI ET AL

288

Table 1. Clinical Characteristics

Platolet Total Drug

AgdSex

Parent

Dose lmgl

49/F

Plafelef

CO”“t lx

Platelet Antbody

Nadir

10/L)

lx

HLA

10/L]

Befae


505

585

of 12 Patients With Gold Induced Thrombocytopenia

Duing

N/A

35

2.0

62

After

8aneManow

T,eatment

DR3

1.9

+

Pred”lso”e

6.8

+

Predn,sone

51/F

235

260

17

2.8

6.3

2.2

i

Prednisone

50/F

625

265

75

N/A

5.2

1.8

+

Non.2

61/F

1,085

319

17

1.8

10.7

2.0

+

Prednisone

69/F

600

564

N/A

8.2

1.8

+

Prednisone

57/F

350

342

11

N/A

11.9

3.0

+

Predntsone

51/M

135

232

78

2.2

24

4

55/M

<10

115


Outcome

Concom,tant

Tox,aw

None

59/M

1.775

223


2.6

29.1

4.8

+

Predmsana

10

59/F

355

320


2

32.2

N/A

+

PlW”Z3pb,~SlS

11

66/F

445

383


3

9.7

3.6

+

Prednisane

12

66/F

735

243

22

13.8

3.9

Prednirone

N-acetylcyrfeme.

2.8

ATG

Prednsone. gamma globulin. platelet t,a”sf”slo”

Note. MDdif,cat,o” e 3 fg/platelet

I” the technique of measwng

in case8 no 3 through 5. and ~5.5

Abbreviation:

N/A.

PAlgG dunng the period of study resulted in changes in the normal range. The “amal fg/plstelef

I” cases no. 8 through

range was <9 fglplatelet

in cases no. 1 and 2.

12.

test not pwfwmad.

Bone marrow examinations were performed in 11 patients. Ten were normal, however, in one case the marrow was hypoplastic and this patient went on to develop aplastic anemia. All 12 patients were HLA typed (Table 2). HLA-DR3 was present in ten cases and absent in two. Treatment was instituted in ten patients. All treated patients received prednisone, nine with response to therapy. Three patients are currently receiving prednisone, one because of relapse on discontinuation of prednisone and two because of recently diagnosed gold induced thrombocytopenia. One of these latter two cases also received platelet transfusions in a peripheral hospital and high dose gamma globulin in our institution as

Table 2. HLA Type of 12 Patients With Gold induced Thrombocytopenia Case No.

HLAType

1

A2, A3; 88,821;

2

Al, Al 1; 88,827:

CW2: DR3, DR4

3

Al, A30; 88.835;

CW3: DR3, DR5, DRW52

4

A2, A3; B8. 835: DR3

CW4; DR3, DRW52

5

A3, A28: 87.88;

6

Al, A23; 88, BW52; DR3. DRW52; DOW3

DR3, DRW52; DQWl

7

Al, 88: BW50; DR3, DRW52,

8

A2, A26; B 16, B 18; DR4, DR5, DRW52, DRW53;

9

Al, A2; B8.814;

DRW53: DOW3

DOW3 DR3, DR7, DRW52

10

A24; 816,821;

11

Al, A24; BB. B 17; CW6; DR3, DR7, DRW52;

12

Al, A2; 844; DR2

DRl, DR3. DRW52; DOW1

DOW2

part of a trial on immune thrombocytopenia. The one patient who did not respond to prednisone subsequently developed aplastic anemia and despite therapy with N-acetylcysteine, plasmapheresis and anti-thymocyte globulin succumbed to overwhelming septicemia. Two patients did not receive therapy and recovered spontaneously. DISCUSSION

Gold complexes are an established form of therapy in the treatment of RA. Numerous double-blind controlled trials comparing chrysotherapy with placebo in RA have demonstrated clinical efiCaCy~2-4SDS2.6D Unfortunately, their use has been limited by the high incidence of adverse reactions. For the most part, these are minor reactions; however, they may occasionally be life threatening, and in the rare instance, have resulted in death.25.27,28,3’,40Hematologic reactions are probably the most feared of all the toxic reactions and include granulocytopenia, thrombocytopenia, and aplastic anemia. Of these, thrombocytopenia is the most frequent blood dyscrasia associated with gold therapy. The earliest reports of gold induced thrombocytopenia were often referred to as cases of hemorrhagic purpura.20q2’ Weil and Bousser2’ stated that the first case of gold purpura was reported in 1919 by Kate Frankenthall. However, in 1931, Weil was the first to report an actual reduction in platelet count to 5O,OOO/pL after therapy with sodium aurothiosulphate.*’ In this case, the RBC and WBC lines were spared

289

GOLD INDUCED THROMBOCYTOPENIA

and recovery occurred after a transfusion of blood was administered. On reviewing the larger series in the literature, the incidence of gold induced thrombocytopenia ranges from 0% to 5%.2~4~8~‘4~‘6~‘7~25~49~52 Death was frequently observed in earlier reports,25~27~28~3’ but with the advent of corticosteroid and dimercaprol therapy, this appears to have diminished. Thrombocytopenia has been reported with a variety of gold complexes, including gold sodium thiomal2,7,9,'4,'6,25-30,32,33,37-42,44-48,51,53,54 aurothiogluate, sodium aurothiosulphate,2’s25 socase, 25*33*4’-43 dium aurothiopropanol sulphate,22 aurodetoxin3 and auranofin.49x’0 As is evident in our lopion, cases, thrombocytopenia tends to occur in the first 20 weeks of therapy before the administration of 1,000 mg of gold. However, thrombocytopenia has been reported with cumulative doses of GSTM as high as 3.5 g’ or as little as 50 mg.37 Stafford and Crosby reported thrombocytopenia appearing as late as 18 months after gold was last administered.46 Test doses of gold administered on the reinstitution of gold therapy may result in thrombocytopenia. Deren et al reported persistent thrombocytopenia occurring after a 5 mg test dose of aurothioglucose was administered to a patient who had received a total of 185 mg of gold 18 months earlier.4’ MECHANISM

OF THROMBOCYTOPENIA

There are two mechanisms by which thrombocytopenia may occur. The first is in association with bone marrow aplasia, as was seen in one of our patients. The second, more commonly observed mechanism, is associated with adequate megakaryocytes on bone marrow examinaThis suggests that periphtion. “,“,33.35,3’-42,44,46-48 era1 platelet sequestration or destruction accounts for the decrease in platelets. The decrease in platelet survival demonstrated by others36,38*44 would lend credence to this hypothesis. This peripheral platelet destruction is felt to be immune mediated36*38T4’944*47 and is supported by our finding of elevated PAIgG in all our patients and their response to corticosteroid therapy. It is interesting to note that in our patient with bone marrow aplasia, thrombocytopenia was the initial presenting problem and was associated with elevated PAIgG. While marrow aplasia alone can account for the thrombocytopenia, elevated PAIgG levels could also result in peripheral

destruction of platelets. Coblyn et al’ suggested that this immune mediated mechanism is related to the genes (HLA-DR3) of the major histocompatibility complex. The data in this present study supports these earlier findings. Further evidence implicating an immune mediated mechanism include increased thymidine incorporation when gold salts were added to cultures of peripheral blood lymphocytes from gold induced thrombocytopenic patients,44*47*6’ and increased splenic immunoglobulin G (IgG) synthesis in one case, with binding of splenic culture-produced IgG to intact platelets and platelet membrane.” PLATELET ASSOCIATED IGG AND THROMBOCMOPENIA

PAIgG is not specific for gold induced thrombocytopenia. Indeed, Kelton et al reported that there are a number of causes for elevations in PAIgG.62 In their report,62 62 of 68 patients with idiopathic thrombocytopenic purpura, 25 of 36 with thrombocytopenia and neoplasia, 11 of 13 with thrombocytopenia and infective disorders, and four of nine with thrombocytopenia and liver disease had elevated PAIgG levels. However, the actual levels of PAIgG were not reported. In RA, PAIgG may be elevated in patients who are not on gold with normal platelet counts, as evidenced by Walker et a154 and our own experience. A number of hypothesis may be generated to explain these findings. The first would be that PAIgG may only represent non-specific binding of antibody to platelets and would not be of any clinical consequence. Second, it may be postulated that in some instances a reticuloendothelial block may be present. In SLE and Sjogren’s syndrome, it has been suggested that immune complexes might saturate the reticuloendothelial system Fc receptors, leading to competitive inhibition of binding or clearance of more complexes.63-65 In RA, elevated levels of immune complexes and immunoglobulins have been observed. This may lead to Fc receptor blockade with resultant prolongation of platelet survival and normal platelet counts, despite elevations of PAIgG as demonstrated with the administration of high dose intravenous (IV) gamma globulin.66 Finally, we may be dealing with what Karpatkin et a16’ termed the “compensated thrombolytic state.” In this state, platelet counts in patients

ADACHI

290

with antiplatelet antibodies would be dependant on such factors as antibody binding affinity, antibody concentration, phagocytic potency of the reticuloendothelial system, and the plateletproductive capacity of the bone marrow. If a steady state is maintained, the platelet count would remain stable. However, any transient imbalance between increased destruction and production, as may be precipitated by nutritional deficits, infection, toxic agents, or drugs, could disrupt the usual steady state level and lead to thrombocytopenia.67 Despite its lack of specificity, our findings suggest that PAIgG is of pathologic significance in causing thrombocytopenia in gold treated patients. On reviewing this relationship, it is useful to apply criteria established by the McMaster Epidemiology group in establishing causation68 (Table 3). The first criteria requires evidence from true experiments in humans. Our study involved subjects who developed thrombocytopenia in association with gold therapy. However, it was less than ideal in that we did not randomly assign them to receive or not receive gold therapy and then follow them prospectively for the development of thrombocytopenia. This, however, is an impossible study both in terms of ethics and sample size requirements. The second criteria deals with the strength of the association. In our study, all 12 patients had elevated, PAIgG levels during their episode of thrombocytopenia. The third criteria, consistency from study to study, is difficult to evaluate, as most studies that could not demonstrate anti-platelet antibodies were performed at a time when the technology for measuring them was in its infancy. However, in a recent study of chrysotherapy and thrombo-

Table 3.

Causation Criteria

1, Is there evidence from true experiments in humans? 2. Is the association strong? 3. Is the association consistent from study to study? 4.

Is the temporal relationship correct?

5. Is there a dose-response gradient? 6. Does the association make epidemiology sense? 7. Does the association make biologic sense? 8. Is the association specific? 9. Is the association analogous to a previously proven causal association?

ET AL

cytopenia, Madhok demonstrated platelet antibodies using an enzyme linked immunosorbent assay in five of six patients with abrupt onset of thrombocytopenia.‘5 The fourth criteria, temporal relationship, provides the strongest evidence of causation in our study. In all of our cases, PAIgG levels were elevated during episodes of thrombocytopenia and were normal before therapy and with resolution of thrombocytopenia. The fifth criteria addresses the question of a dose response gradient. In our study, the degree of thrombocytopenia was not addressed directly. However, in those patients who had serial platelet counts and PAIgG levels, there appeared to be an inverse relationship. In an analagous situation, idiopathic thrombocytopenic purpura (ITP), Kelton points out that most investigators have reported that PAIgG is inversely related to the platelet count, but that platelet life span also correlates with the platelet count. Therefore, the apparent causal relationship between PAIgG and platelet count could be erroneous, as each may be related to a third factor.69 The sixth criteria, epidemiologic sense, is not useful in this situation, as we would have to provide evidence that thrombocytopenia in general is more frequent since gold therapy has become more widely used. Biologic sense, the seventh criteria, is apparent. Thrombocytopenia is either a problem of inadequate platelet production or increased peripheral platelet destruction. The demonstration of adequate megakaryocytes on bone marrow examination would argue against the former, while the presence of PAIgG would support the latter. The eighth criteria asks if the association is specific. As was pointed out earlier, the association between PAIgG and gold induced thrombocytopenia is not specific. However, in his paper concerning drug induced thrombocytopenia, Kelton et al reported two cases of gold induced thrombocytopenia in which in vitro testing resulted in serum platelet bindable IgG with gold and not with other test drugs. These findings imply that gold was the specific drug responsible for thrombocytopenia.” The ninth criteria, an analagous association between PAIgG and thrombocytopenia, may be seen in ITP.

GOLD INDUCED THROMBOCYTOPENIA

291

HLA STATUS

Recently, attention has been focused on the efficacy and toxicity of gold therapy in RA as it relates to the genes of the major histocompatibility complex. ‘-I’ In general, the frequency of HLA-DR3 in patients with RA is approximately ~O’%J.~~‘~ Controversy exists, with some groups reporting increased toxicity with HLA-DR3,5‘ ‘J~-‘*J~ while others have not.8,9*‘3Toxic reactions to gold and penicillamine have included thrombocytopenia, skin rash, and proteinuria. The frequency with which these reactions occur in HLA-DR3 patients ranged from 21 .9%16 to 68.4%.14 Thrombocytopenia is reported in the literature; however, only four reports7*‘4,54 have given the HLA types of those patients with gold induced thrombocytopenia. In a retrospective study, Coblyn et al were the first to report the presence of HLA-DR3 in 12 of 15 patients with gold induced thrombocytopenia.’ Walker et al had three patients with gold thrombocytopenia, two of whom were HLA-DR3 positive.54 Madhok et al reported that all ten patients with a precipitous decrease in platelet count associated with gold therapy were HLA-DR3 positive.s5 We previously reported three cases of gold induced thrombocytopenia14”’ (included in this report), all of whom were HLA-DR3 positive. By including our additional thrombocytopenic patients receiving gold therapy, we now have a total of ten patients who are HLA-DR3 positive with gold induced thrombocytopenia. By pooling the data from these reports of gold induced thrombocytopenia in those patients with known HLA status, 34 of 40 (85%) are HLA-DR3 positive. This strongly supports the concept that gold induced thrombocytopenia is related to HLA-DR3. THERAPY

Therapy for gold induced thrombocytopenia has included corticosteroids,32*34~37-44*46-4a*54 ACTH,32.34,35,4’di merca prol,29,3*~34~3’~42.44.46~48~54 N_

acetylcysteine,48 penicillamine,47 vincristine,47 6thioguanine,42 testosterone,37 splenectomy,30”3-” splenic irradiation3’ and high dose IV gamma globulin.‘* In many instances, no therapy or transfusion alone has resulted in a resolution of thrombocytopenia. In our experience, corticosteroids are usually all that is required for patients with thrombocytopenia and adequate marrow production. The only patient from our series who did not respond had complete marrow aplasia. Dimercaprol, an agent that chelates gold, may be a useful adjunct to corticosteroid therapy. However, dimercaprol must be administered intramuscularly, with the risk of hematomas and sterile abscess formation. It has been suggested that large total doses of dimercaprol are required in relation to the total gold dosage to ensure treatment success.37*39 N-acetylcysteine has recently been proposed as an alternative and safer gold chelator.48 Penicillamine, while said not to chelate gold,73 may still be an effective agent in therapy.47 Vincristine and splenectomy, modes of therapy in the treatment of ITP, have also been used successfully in gold induced thrombocytopenia.30*33S44*47 High dose IV gamma globulin,66 a novel approach to the treatment of ITP, may also prove useful in the treatment of gold induced thrombocytopenia. SUMMARY

Gold induced thrombocytopenia is immune mediated, with the production of platelet associated IgG leading to peripheral platelet destruction. An association with HLA-DR3 has been demonstrated. Corticosteroid therapy is effective in treatment, although other modes of therapy may be as efficacious. ACKNOWLEDGMENT To the Canadian Arthritis and Rheumatism the assistantship granted to Dr J.D. Adachi.

Society

for

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292

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does not chelate