Chronic autoimmune thrombocytopenic purpura

oral medicine Editor: JAMES W. LITTLE, D.M.D., M.S.D.

School of Dentistry University of Minnesota 515 S.E. Delaware St. Minneapolis, Minn. 55455

Chronic autoimmune thrombocytopenic purpura A 3-year case study Pete G. Fotos, D.D.S., M.S.,* William L. Graham, D.D.S.,** Dale C. Bowers, D.D.S..*** and Stephen P. Perfetto, MT(ASCP), M.S.,**** Morgantown, W. Va. WEST VIRGINIA

UNIVERSITY

MEDICAL

CENTER

Idiopathic (autoimmune) thrombocytopenic purpura (ATP) is accepted to be a disorder resulting from accelerated platelet destruction attributed to an autoimmune process. The patient whose case is presented in this article was first seen by a dentist. The oral Rndings have been documented as the case was followed for 3 years through acute exacerbations, pregnancy, and delivery of an infant with thrombocytopenia. The patient was managed with intermittent steroid therapy and splenectomy.

T hrombocytopenia is defined as a decreasein the number of circulating platelets which is either primary (idiopathic) or secondary (symptomatic) in nature (Fig 1). The term idiopathic is applied in those cases in which no apparent exogenous etiologic factor or underlying diseaseprocessis evident, suggesting that the deficiency results from an autoimmune process. Among adults, autoimmune thrombocytopenia (ATP) developsin personswho have a genetic as well as sex (female) predisposition generally following an environmental event.’ In the following case an unsuspecting patient presented for routine dental care. Various oral findings have been documented, and the etiology, pathogenesis,and sequela of the thrombocytopenic patient are addressed. Assistant Professor and Research Associate, Departments of Oral Diagnosis and Microbiology. **Professor, Chairman, and Assistant Dean, Department of Oral Diagnosis and Radiology. ***Associate Professor, Department of Oral Diagnosis and Radiology. ****Supervisor, Tissue Typing Laboratory, Department of Pathology. 564

CASE REPORT

A 23-year-old white woman came to the dental clinic for a routine dental check-up and prophylaxis, The patient claimed good general health except for a persistent “head cold” of 5 weeks’ duration, for which ampicillin had been prescribed by her family physician. During the prophylaxis, an excessive amount of gingival hemorrhage was encountered (Fig. 2). Closer questioning and grossappraisal revealed multiple 2 to 4 cm, bruises of the legs and right arm. The patient could recall no previous trauma and could not offer any other explanation for the bruises. In addition, petechiae, randomly distributed on the back and neck, were barely evident. Other than severe gingival bleeding, no other intraoral lesions were noted. The patient was immediately referred to a clinical laboratory for a complete blood count and coagulation profile. The results included the following: hemoglobin 12.4; hematocrit, 37; white blood cells 10,000 (segmented cells, 59; stab cells, 3; lymphocytes, 36); and platelets, 13,000,with normal prothrombin and partial thromboplastin test values. The patient was advised of her precarious condition and referred for a hematologic evaluation. On the following day the patient was admitted to the hospital and the case was followed.

ATP case study

Volume 55 Number 6 Secondary

Primary

1. Autoimmune (idiopathic) 2. Hereditary 3. Congenital Characteristics

Peak age incidence Sex predilection Hemorrhagic onset Antecedent infection Oral hematomas Platelet count Duration Spontaneous remissions

565

1. Infection 2. Exogenous agents 3. Organic disease

of autoimmune Acute

thrombocytopenia Chronic

Children (2-6 yr.) None Abrupt Common In severecases 20,000 cm.3 2 to 6 weeks Frequent

Adults (20-40 yr.) Females (3 : 1) Insidious Occasional Infrequent 20,000 to 40,000 cm.3 Months-lifelong Uncommon, fluctuating course

Fig. 1. Classification of thrombocytopenias. (Derived from Bithell, T. C.: Thrombocytopenia. In Wintrobe, M. M. (editor): Clinical Hematology, eighth edition, Philadelphia, 1981, Lea & Febiger.)

Physical examination findings were unremarkable except for the purpura and slight splenomegaly. No signs of inflammation, fever, or elevation in erythrocyte sedimentation, etc. were evident. A bone marrow aspiration failed to show infiltrates or proliferation of any cell line, resulting in the diagnosis of ATP by exclusion of other diseasesknown to produce secondary thrombocytopenia. Treatment with prednisone, beginning at 60 mg. per day, was instituted on an outpatient basis and resulted in a gradual disappearance of the symptoms. However, failure of the platelet count to rise above 33,000 led to the decision to perform a splenectomy. The procedure was accomplished uneventfully, with frozen platelets administered immediately prior to surgery. The platelet count increased dramatically to a high of 740,000 over the next several days, decreasing to a relatively constant level of 250,000 to 275,000 with tapering doses of prednisone. Prednisone therapy was terminated 2 months after onset of the initial symptoms. At this point, the patient was judged to be in clinical remission, although high titers of platelet specific serum antibody remained. The next 3 years were without incident except that the patient delivered a full-term infant of normal development. The child was thrombocytopenic at birth (platelet count, 8,000) with generalized petechiae, and soon developed a large ecchymosis covering the hard palate, which was attributed to nursing trauma. Treatment of the infant was deferred, and nursing continued. At 18 weeks the child’s platelet count began to increase gradually with a corresponding decreasein size of the palatal lesion and petechiae, until normal platelet levels were seen at 5 months. The adult patient again became aware of bruising and oral bleeding on brushing, with a platelet count of 22,000. As before, this recurrence corresponded to a viral type of illness of 2 weeks’ duration, for which no medications were taken. A solitary painless submucosal hemorrhage was noted on the dorsal-lateral tongue surface (Fig. 3). Predni-

sone therapy was restarted at 40 mg. per day on an outpatient basis and resulted in a rapid increase in the platelet count to 488,000 by the end of the first week, after which the prednisone was tapered by 10 mg. per week. At the end of this therapy, the platelet count was stable in the 150,000 range and the patient again was judged to be in clinical remission. DISCUSSION

Thrombocytopenia is essentially a symptom. In this case, it was the major reason for excessive bleeding following minor dental treatment. The clinical onset of ATP may be sudden, or there may be a vague history of easy bruising.2 Acute and chronic forms exist, with the latter found most often in adults and generally persisting indefinitely. Spontaneous bleeding into the skin in the form of petechiae is characteristic, ranging with petechiae from the size of a pinpoint to that of a pinhead. These may be generalized, appearing as a rash, or they may occur as clusters in areas subjected to trauma from restrictive clothing or minor injuries. The most frequent form of external bleeding includes gingival bleeding and epistaxis. Other forms include subconjunctival hemorrhage, heavy menstrual flow, gastrointestinal bleeding, and hematuria. Large purple superficial ecchymoses are seen, although external bleeding from these sites is uncommon. Hemarthrosis is not frequently encountered in ATP unless precipitated by injury. Oral hemorrhagic bullae have been reported on the tongue, palate, and vestibular regions. These are usually seen in situations in which the platelet count is below 20,000 per cubic millimeter. Bleeding from the gingival sulcus can occur on mastication of food

666

Fotos et al.

2. Excessivegingival hemorrhage following oral prophylaxis.

Fig.

Fig. 3. Painlesssubmucosalhemorrhageon dorsal-lateral surfaceof the tongue.

in such cases.Excessive hemorrhage following tooth extractions or other surgical procedures may first attract attention to thrombocytopenia. In contrast to the hereditary coagulation disorders, bleeding is seldom rapid or in large volumes; rather, it takes the form of a persistent oozing. Intracranial hemorrhage, usually subarachnoid in location, is the most serious complication of ATP and can result in retardation or death. Fortunately, this is rare, with one patient survey placing the incidence at about 1 percent.3 The present caseappears to have been precipitated by contact with a common environmental antigen (upper respiratory viral infection) which resulted in the production of an IgG (7s) antibody reactive with the platelet membrane. One might speculate that a polyclonal rather than a specific antibody is responsible. Whenever poly-

Oral Surg. June, 1983

clonal IgG production is stimulated (as in responseto colds, infections, or immunizations), then there is a recurrent platelet decreasewhich persists as long as the antibody level overrides compensatory platelet production. Various drugs, including ampicillin4 may be capable of acting as haptens in conjunction with damaged host tissues or other foreign proteins, such as viruses, causing ATP. The importance of the spleen in the pathogenesis of ATP has been established by the therapeutic effectivenessof its removal in this disorder. This can be attributed to the spleen’s role as a major site of antibody production and its function as the primary location of antibody-labeled platelet sequestration and removal. Interestingly, splenomegaly is generally not evident in true ATP. Bone marrow aspirations usually exhibit a moderate increase in megakaryocyte numbers, demonstrating attempted compensation for decreased platelet survival time. In addition to decreasedplatelet counts and defective platelet function5 there is also some evidence of direct vascular injury. This is supported by failure in some cases of the platelet count to correspond well with bleeding severity as compared with cases of secondary thrombocytopenia that exhibit similar platelet counts6 It has been suggestedthat numerous persons with normal platelet counts who display “easy bruising syndrome,” in fact, suffer from ATP. Most cases of ATP will respond favorably to treatment with corticosteroids through depression of splenic and hepatic sequestration of antibody-labeled platelets, stabilization of the vascular epithelium, and diminished antibody synthesis. In refractive cases splenectomy is performed and permanent remission is achieved in 50 to 80 percent of the patients studied.’ As was the case with the patient in this report, splenectomy failure has been manifested through chronic drops in the platelet count with corresponding clinical symptoms. Appreciable amounts of hepatic platelet destruction in persons who have undergone splenectomy have been documented and correlate well with platelet specific antibody levels.’ Treatment of chronic ATP is primarily one of steroid titration governed by the severity of hemorrhagic symptoms rather than by the platelet count.* This is reflective of the role that antibody plays in altering capillary fragility. In the most difficult situations, or where cushingoid syndromes develop, vincristine or cyclophosphamide has been used to suppresstotal antibody production. Platelet transfusions are of little benefit for other than the very short

ATP case study

Volume 55 Number 6

term becauseof their highly efficient removal via the reticuloendothelial system when tagged with antibody. Recent work suggests the use of high-dose intravenous polyclonal immunoglobulins as a positive treatment in acute casesin which steroids are contraindicated or some surgical procedure is required. Here polyvalent IgG interferes with phagocyte Fc receptor-mediated immune clearance in the spleen and liver, thus decreasing platelet sequestration.g Transplacental transfer of platelet specific antibody in the infant is demonstrated in this caseand is found frequently in mothers who are in remission following splenectomy.lo Treatment of these infants is usually deferred except in the presence of acute bleeding, where exchange transfusions or fresh frozen platelets may be of some value. Otherwise, maternal antibody is largely eliminated by the fourth month postpartum. Possible passageof platelet antibody through nursing (passive platelet immunization) has been suggested, although evidence fails to support its significance here. Genetic factors have been shown to influence predisposition to various autoimmune diseases,such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and ATP. It has been reported that clinical SLE is preceded by ATP (one survey places this frequency at 16 percent).7v” While little is known about the genetic predisposition of ATP, in numerous reported cases of hereditary thrombocytopenia there have been diagnostic criteria compatible with ATP. In one study, thirty-eight patients with ATP were typed for the HLA-A, B, and C loci antigens.‘* Twenty percent of these were also typed for the HLA-DRw locus antigens. Using matched controls, it was shown that fifteen of the twenty were positive for the HLA-DRw2 locus antigen and six of the twenty were positive for the HLA-DRw3 locus antigen. It was also noted that a high linkage disequilibrium exists between the haplotype A26Bw38 and DRw2. Furthermore, investigators suggest a relationship of systemic lupus erythematosus and ATP with a corresponding high incidence of the HLA-DRw2 locus antigen. SLE is described with an increase in HLA-DRw3 as well as the DRw2 locus antigen.‘) The patient in this study was found to have the following HLA locus antigens: A2, Aw24, B13, Bw22, Cwl, Cw6, DRw3, and DRw7, indicating some consistency with previous findings. Perhaps the genetically predisposed person contacts a triggering environmental antigen, which results in the expression of clinical ATP. In any case,

567

the patient in this study is probably destined to an indefinite “subclinical compensated thrombolytic state.“14It would be expected that any stress (viral, infectious, alcohol, nutritional deficiency, etc.) placed on the hematopoietic tissues would result in intermittent clinical relapses. Appreciationis extended to the following individuals for their assistance or consultation in preparing this report: LesterVlahos,Departmentof Communications,University of Dayton, Dayton, Ohio; Carl Srodes, West Penn Hospital, Pittsburgh, Pennsylvania; and Nathaniel Rodman, Department of Pathology, West Virginia University Medical Center, Morgantown, West Virginia. REFERENCES 1. Wintrobe, M. M., Lee, D. R., Boggs, D. R., Bithell, T. C., Foerster, J., Athens, J.W., and Lukens, J.N.: Clinical Hematology, ed. 8, Philadelphia, 1981, Lea & Febiger, pp. 10901127. 2. Lackner, H., and Karpatkin, S.: On the Easy Bruising Syndrome With Normal Platelet Count: A Study of 75 Patients. Ann. Intern. Med. 83: 190, 1975. 3. Choi, S. I., and McClure, P. D.: Idiopathic Thrombocytopenic Purpura in Childhood, Can. Med. Assoc. J. 97: 562, 1967. During Treatment With 4. Brooks, A. P.: Thrombocytopenia Ampicillin, Lancet 2: 723, 1974. 5. Clancy, R., Jenkins, B., and Firkin, B.: Qualitative Platelet Abnormalities in Idiopathic Thrombocytopenic Purpura. N. Eng. J. Med. 286: 622, 1972. 6. Morrison, F. C. and Baldwin, M. G.: Antigenic Relationship Between Blood Platelets and Vascular Endothelium. Blood 33: 46, 1969. 7. Karpatkin, S.: Autoimmune Thrombocytonpenia. Blood 56: 329, 1980. 8. Cooper, M. R., Hansen K. S., Maynard, C. D., Elrod, I. W., and Spurr, C. L.: Platelet Survival and Squestration Patterns in Thrombocytopenic Disorders. Radiology 102: 89, 1972. 9. Fehr, J., Hofmann, V., and Kappler, U.: Transient Reversal of Thrombocytopenic Purpura by High Dose Gamma Globulin. N. Eng. J. Med. 306: 1254, 1982. 10. Kernoff, L. M., Malan, E., and Guson, K.: Neonatal Thrombocytopenia Complicating Autoimmune Thrombocytopenia in Pregnancy. Ann. Intern. Med. 90: 55. 1979. Il. Rabinowitz, Y. and Dameshek, W.: Systemic Lupus Erythematosus After ITP. Ann. Intern. Med. 52: 1, 1960. 12. Karpatkin, S., Fotino, M., Gibofsky, A., and Winchester, R.J.: Association of HLA DRw2 with Autoimmune Thrombocytopenic Purpura. J. Clin. Invest. 63: 1085, 1979. 13. Reinerstein, J. L., Klippel, J. H., Johnson, A. H., Steinberg, A. D., Decker, J. L., and Mann, B. L.: A Lymphocyte Alloantigens Associated with Systemic Lupus Erythematosus. N. Eng. J. Med. 299: 515, 1978. 14. Karpatkin, S., Garg, S. K., and Siskind, G. W.: Autoimmune Thrombocytopenic Purpura and the Compensated Thrombolytic State. Am. J. Med. 51: 1, 1975. Reprint requests to: Dr. Pete G. Fotos Departments of Oral Diagnosis and Microbiology West Virginia University Medical Center Morgantown, W. Va. 26506