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Gingival hemorrhage secondary to uremia
Gingival hemorrhage secondary to uremia Review
and
report
of a case
Arthur Merril, B.S., D.D.S., P.R.S.H.,* and Larry J. Peterson, B.S., D.D.S.,** Washington, D. C.
T
he hemorrhagic manifestations of uremia were first described by Richard Bright in the early nineteenth century. In discussing this secondary complication of renal disease, many author9, lg* 31 allude to the gingiva as a rather common site of uremic bleeding. However, we found the dental literature devoid of information concerning the recognition and therapy as well as the mechanism of uremia-induced hemorrhage. The purpose of the present article is to describe a case of uremic hemorrhage, the unsuccessful attempt at its treatment, and the mechanism by which this hemorrhagic disorder is caused. CASE
REPORT
A 547year-old Negro man was admitted to the District of Columbia General Hospital on Feb. 19, 1969, with the chief complaint of hemorrhage from the gingiva for 3 weeks prior to admission. He had first been treated at this hospital in June, 1967, when a diagnosis of chronic pyelonephritis, obstructive uropathy, and salt-losing nephritis was made. He had been treated at other hospitals for his disease, beginning in March, 1966. Previous admissions to the District of Columbia General Hospital were for treatment of symptoms secondary to the primary renal insufficiency-anemia, pleuritis, pericarditis, and acidosis. Treatment during these admissions was essentially supportive. One admission was for dyspnea secondary to upon paracentesis, 11.5 liters of fluid was removed. During the time from 1967 ascites; until the current admission in 1969, the patient’s blood urea nitrogen ranged from 53 to 216 mg. per cent; the hematocrit fell steadily from a high of 17 per cent in 1967 to 11 per cent at the time of this admission, in spite of multiple transfusions of packed red blood cells during the two previous periods of hospitalization. At the time of the current admission, physical examination revealed a well-developed but poorly nourished Negro man who was lethargic and somewhat disoriented. The blood pressure was llO/SO, the pulse rate was 112, and the temperature was 98.6” F. The general appearance of the skin was normal, with no petechiae or ecchymotic areas. The conjunctivae were very *Chief **Oral
530
Dental Surgery
Officer, District of Columbia General Hospital. Resident, Georgetown University School of Dentistry.
Volume Number
Gingival
29 4
hemorrhage
secondary
to uremia
531
pale; there was marked arterial narrowing in the fundi. There was brisk hemorrhage from the gingiva. The trachea was in the midline. Lungs were clear, with no rLles or rubs. Thi> heart had a normal sinus rhythm, with a Grade 4 systolic murmur. Examination of the abdomen revealed massive ascites. The patient demonstrated bilateral costal vertebral anqltx tenderness. He also had bleeding hemorrhoids. blood urea nitrogen, 248 mg. per cent (norma.1, A blood work-up revealed the following: 31.2 mg. per cent (normal, 1 to 2 mg. per cent) ; uric 9 to 19 mg. per cent) j creatinine, acid, 16.5 mg. per cent (normal, 3 to 6 mg. per cent) ; glucose, 160 mg. per cent (normal, 70 to 110 mg. per cent) ; moderate acidosis with a carbon-dioxide combining power of 1 G m&l. per liter (normal, 27 to 35 mEq. per liter) ; hematocrit, 11 per cent (normal, 42 to 47 per cent) ; reticulocyte count, 1.6 per cent (normal, 0.5 to 1.0 per cent) ; platelet count, 275,000 (normal, 250,000 to 300,000) ; prothrombin time, 15.8 seconds (e011tr01, 11.6 scc011ds) ; fibrinogen, 280 mg. per cent (normal, 200 to 400 mg. per cent) ; Ivy bleeding time, grc:rt.cbl than 30 minutes (normal, 8 to 14 minutes) ; clot retraction, alwxt with a wry frial)ltk (+ll+t (normal begins in 30 to 120 minutes, complete in 24 hours). For 3 days the patient was given supportive therapy consisting of packed red l~lood cc,11 transfusions, sodium bicarbonate for the acidosis, and N(bosporin citrate mouth rinsc>s. ‘l’lic gingival hemorrhage continued. On Feb. 23, 1969, a dental consultation was requested. Oral examination revealed that the maxilla mas edentulous, with a normal-appearing but very pale ridge. The m:~ndibul:~r dent,ition was intact except for the absence of the first and third molars bilatrrally. ‘Tile teeth were caries free and slightly mobile. There was a brisk hemorrhagic oozing from tl;e lingual and labial marginal gingivae surrounding the mandibular teeth. Close inspection revealed a lvhite, necrotic, marginal gingiva which would become hidden by hemorrhage soon a diagnosis of uremic si.orn:rl.il is :?fter it 11a.d been dried. In view of the patient’s history, complicated by uremic bleeding was made. Therapy consisted of hydrogen peroxide mouthwashes followed Iby saline rinscbs. ;tu attempt was made to control the hemorrhage by means of direct, pressure with moist gnu/.tx sponges. After 10 minutes the hemorrhage slowed substantially. The patient was tetnruld to his room with a gauze pack in place, to return to the clinic on the following day. The next day the condition was unchanged. The hemorrhage was again slowed I)y tllc application of direct pressure. The teeth and gingiva were tlricd and Orahesive batndag~~” was placed on the labial and lingual surfaces of the antclrior teeth. The bleeding was f:ririy well controlled and the patient was returned to his room? to be seen again on thf~ follo\\ing day. The next day we found the hemorrhage to be as brisk as originally. The procedure of tilt, day before was repeated, but this time dental tape was applied in a figure-of-eight tic LO hold the Orahesire bandage more securely to the teeth. This routine was followed for t,he nctxt 4 days, with no appreciable results. On the seventh day, a periodontal pack was placed :IIIII secured by figure-of-eight wiring with 26.gauge wire. Although the pack remained sccur~lg iu place, the bleeding continued but at a less rapid rate. It was thought by members of the dental service, the medical service, and the rc1::11 scrvico that the hemorrhage was uncontrollable by local measures and that dialysis of sol type was necessary. During the 19 days since admission, the patient had rezreivetl five ullits of packed red blood cells. The resultant hematoerit was 1’0.4 per cent. Peritoneal dialysis was started on March 10, 1969, and was completed on March -12, 19~0, after twenty-nine exchanges. The blood urea nitrogen fell from 255 to 86 mg. per cent. The hemorrhage stopped completely on the morning of March 12, and the patient was much more alert and well oriented by that evening. When the patient was seen in the dental clinic on March 13, the gingiva appeared completely normal. The necrotic margin was no longer :ipparent. The color and texture were excellent. The patient was given transfusions of ih~t, additional unit.s of packed red blood cells which raised the hematocrit to 18 per c-ent. 111% was then discharged. *E.
K,. Squibb
Bi Sons,
New
York,
N. Y.
532
Me&l
and Peterscm
Oral
April,
Surg. 1970
DISCUSSION
Uremic stomatitis is a relatively uncommon complication of the uremic syndrome. In 1930 Hempstead and Hench’ reported that of 300 uremic patients treated at the Mayo Clinic, four had uremic stomatitis; Beaney3 reports that only four of 262 uremic patients had stomatitis complications. This lesion was first described by Lancereauxl in 1887. The treatment of uremic stomatitis itself, as reported by Halazonetis,7 is uncomplicated and can be accomplished in the face of untreated uremia. When uremic stomatitis is part of the clinical picture, it must be considered indicative of advanced uremia, with a poor prognosis. Hemorrhage may be initiated in patients with severe uremic stomatitis. The stomatitis itself is thought to be caused by the caustic action of ammonia,6 formed by bacterial urease4 produced by oral flora, acting on the salivary urea.G-s The bacteria which are the main agents in this conversion are in close association with calculus.5 The stomatitis can be t.reated locally7> Q by scaling of the teeth, hydrogen peroxide rinses to neutralize the ammonia, and application of a triple dye solution to suppress the oral flora growth and reduce the formation of urease. The stomatitis may be eliminated in spite of the continued systemic uremia. However, the hemorrhage invariably continues. The problem, of course, is not local but systemic. The hemorrhage tendency in uremic patients is well knownI* In fact, Stewart and Castaldi16 and Maher and Schreiner23 state that abnormal bleeding is the actual cause of death in nearly 10 per cent of patients with renal failure. Ze1man2’ reported a case in which the patient died of uncontrollable bleeding following needle biopsy of the liver. As stated earlier, the hemorrhagic tendency has been recognized since the nineteenth century. However, not until the mid-1950’s did serious study of the mechanism of the bleeding abnormality begin. Several plasma factors have been found deficient.1° Hypofibrinogenemia, lop I1 derangement of the prothrombin complex,11 prolonged thromconsumpbin time,lO thrombocytopenia,‘l? l2 and deficiency in prothrombin tionf2s I3 have been given as reasons for the clotting problem. In 1956 Lewis and associates10 and Larrain and Adelson,z.’ working independently, described the discovery of a qualitative defect in the function of blood platelets. Their reports mere the first in a series indicating a qualitative defect in platelets. ~9 17r*l Lewis reported that the prothrombin-consumption time is abnormal in uremic patients with bleeding tendencies. An abnormality in this test response in uremic patients thought to show a deficient platelet thromboplastic factor (PFs) , has been verified consistently.l’? I29 13*IQ, 24-2G Before we continue with the discussion of the mechanism of uremic bleeding, a brief review of postulated platelet function is necessary. The generally accepted order of events is as follows: After severance of the vessel, platelets adhere to collagen in a reaction requiring adenosine diphosphate (ADP). Degranulation of the plateletsz7 occurs with release of ADP, which enhances platelet aggregation. At the same time, the platelets reiease serotonin, catecholamineq and c.PF,. For platelet aggregation to occur properly, several factors must be in proper balance-ADP, calcium ions,?*’ ?g and a plasma protein, probably fibrinogen.2g-31 Platelet aggregation provides a large amount of PF, for
Volume Number
29 4
Gingival
hemwrhage secondary to wemia
533
coagulation32 ; in order to become active in coagulation, it must be available.3” As mentioned, decreased PF, function has been indicated as the cause of uremic bleeding. Cahalane and colleagues*3 caused defective PF, function 1)~. incubating normal platelets with uremic plasma. Horowitz and Papayoanon”’ were unable to produce decreased PF, function by direct action of urea. In the early 1960’s, urea metabolism was more closely examined. Certain guanidine compounds arc known metabolic precursors of urea and creatinine.:“’ In uremic patients, two compounds-guanidinoacetic acid (GAA) and guanidinosuccinic acid (GSA) ,-were found to haTe important relationships.36 In the normal patient GAA is present in relatively high concentrations in thn urine as compared to the uremic patient, whereas the urine concentration of GSA is much higher in the uremic than in the normal patient.37 A discussion of the altered pathway by which an excess of GSA is formed is beyond the scope of this article. Suffice it to say that, in the uremic patient, there is a blockage of the conversion of GAA to creatine and consequent conversion of urea precursors to GSA. In 1967 GSA was shown to be a potent inhibitor of ADP-induced PI;, activation.38 It is claimed that an increased GSA concentration is accompanied by a decrease in the ADP calcium ion complex needed for platelet function and an increase in the ADP-GSA complex.3il :(g Hence, the current thought on the mechanism of uremic hemorrhage is that there is an alternate pathway to urea metabolism which leads to the formatiou of GSA. GSA competes with the calcium for ADP, reducing the availability of the ADP-calcium comples which is needed for the release of PF:,.“” There is some controversy over the fine points, but the crux is that GSA is clearly indicated as the major offender in the etiology of “uremic thrombopathy.“,L” Virtually everyone agrees that dialysis or kidney transplantation will eliminate or greatly improve the hemorrhagic condition. In fact, Stewart and Castaldi16 state that “bleeding is an indication for dialysis.” The bleeding parameters are generally improved in all pre- and postdialysis studies,15,x6.23 and clinical hemorrhage is controlled in almost all cases.11l I6 Current research shows that the improvement is due to the removal of GSA and its inhibitory effect on PI?,. Routine screening tests in common use in hospitals today for blce(ling diathesis usually include the platelet count, Duke bleeding time, prothrombin time, and partial thromboplastin time determinations. These test.s will frcquently miss the active or potentially active uremic bleeder. A recommended presurgical screen for a possible bleeding abnormality should include the Ivy bleeding t,ime, clot retraction, and prothrombin consumption.20 Hutton a~(1 O’Sl~ea’8 believe, on the basis of their experience, that it is not consistently possible to predict the clinical hemostatic response of the patient by means of laboratory tests. They believe, however, that an attempt should indeed be made to investigate the hemostatic status of renal patients about to undergo a surgical procedure. The dentist, especially the oral surgeon, is faced daily with the problem of hemostasis. With the advent of the artificial kidney and the concurrent, yise
534
Merril
and
Peterson
Oral April,
Surg. 1970
in the number of persons surviving with chronic renal disease, it becomes increasingly important that the patient be asked about kidney function. Eknoyan and co-workerP suggest that when the blood urea nitrogen level is as low as 60 mg. per cent hemorrhage may become a problem. Routine admission blood urea nitrogen tests in hospital patients, especially those with a history of kidney ailments, should certainly be considered. SUMMARY
A case of gingival hemorrhage secondary to uremia has been reported, and the unsuccessful attempt at local control has been described. The probable mechanism of the hemorrhagic diathesis of uremia has also been described. This bleeding tendency is due to an altered pathway of urea metabolism with consequently increased levels of GSA, which inhibits platelet function. In view of the increased number of persons with chronic renal disease who are surviving as a result of repeated dialyses on the artificial kidney, the dentist must be acutely aware of the possible consequences of uremia. REFERENCES
Anatomie pathologigue et complications de I’uremie, Union Med. 44: 1. Lancereaux, M.: 829,1887 (cited by Hempstead and Hench). 2. Hempstead, B. E., and Hench, P. S.: Uremic Stomatitis, Trans. Amer. Laryng. Rhin. Otol. Soe., p. 516, 1930. 3. Beaney, G. P. E.: Otolaryngeal Problems Arising During the Management of Severe Renal Failure, J. Laryng. 78: 507, 1964. 4. Earlam, M. S. 8.: Urea-Splitting Staphylococci in Urinary Tract Infections, Brit. J. Urol. 2: 233, 1930. 5. Bliss, 8.: Cause of Sore Throat in Nephritis, J. Biol. Chem. 121: 425, 1937. 6. Afonsky, D.: Saliva and Its Relation to Oral Health, ed. 1, Montgomery, Ala., 1961, Paragon Press, pp. 126-139. 7. Halazonetis, J., and Harley, A.: Uremic Stomatitis; Report of a Case, ORAL SURG. 23: 573, 1967. 8. Hench, P. S., and Aldrich, M.: A Salivary Index to Renal Function, J. A. M. A. 81: 1997, 1933. 9. Black, D. R.: Nephritic Stomatitis, Ural. Cutan. Rev. 46: 75, 1942. 10. Lewis, J. H., Zucker, M. B., and Ferguson, J. H.: Bleeding Tendency in Uremia, Blood 11: 1073, 1956. 11. Kendall, A. G., Lowenstein, L., and Morgan, R. 0.: The Hemorrhagic Diathesis in Renal Disease With Special Reference to Acute Uremia, Canad. Med. Ass. J. 86: 406, 1961. 12. Rath, C. E., Mailliard, J. A., and Schreiner, G. E.: Bleeding Tendency in Uremia, New Eng. J. Med. 257: 808, 1957. 13. Cahalane, S. F., Johnson, S. A., Monto, R. W., and Caldwell, M. J.: Acquired Thrombocytopathy: Observations on the Coagulation Defect in Uremia, Amer. J. Clin. Path. 30: 507, 1958. 14. Nakamot,o, S., and Koliff, W.: Hemorrhagic Diathesis in Uremia and the Avoidance of Bleeding Problems During Dialysis, Ann. N. Y. Acad. Sei. 115: 348, 1964. 15. Von Kaulla, K. N., von Kaulla, E., Wasantopruck, D., Marchioro, T. L., and Starzl, T. E.: Blood Coagulation in Uremic Patients Before and After Hemodialysis and Transplantation of the Kidney, Arch. Surg. 92: 184, 1966. 16. Stewart, J. H., and Castaldi, P. A.: Uraemic Bleeding: A Reversible Platelet Defect Corrected by Dialysis, Quart. J. Med. 143: 409, 1967. 17. Willoughby, M. L. N., and Crouch, S. J.: An Investigation of the Hemorrhagic Tendency in Renal Failure, Brit. J. Haemat. 7: 315, 1961. 18. Hutton, R. A,, and O’Shea, M. J.: Haemostatic Mechanism in Uremia, J. Clin. Path. 21: 406, 1968. 19. Cheney, K., and Bonnin, J. A.: Haemorrhage, Platelet Dysfunction, and Other Coagulation Defects in Uremia, Brit. J. Haemat. 8: 215, 1962. 20. Castaldi, P. A., Rozenberg, M. D., and Stewart, J. H.: The Bleeding Disorder of Uremia: A Qualitative Platelet Defect, Lancet 2: 66, 1966. 21. Eknoyan, G., Wacksman, 8. J., Glueek, H. L., and Will, J. J.: Platelet Function in Renal Failure, New Eng. J. Med. 280: 677, 1969.
Volume Number
29 4
Gingival
hemorrhage
secondary
to uremia
535
22. Zelman, S.: Fatal Hemorrhage Following Needle Biopsy in Uremia; Report of a Case. J. A. M. A. 164: 997,19X 23. Maher. J. H.. and Schreiner. 0. E.: Cause of Death in Acute Renal Failure. Arch. Intern: Med. IChicago) 110: 493, 1962. 24. Larrain, Defect of Uremia, Blood 11: 1059, 1956. G., and Adelson, E.: The Hemostatic “5 Dormer, L., and Neuwirtova, R.: The Hemostatic Defect of Acute and Chronic Uremia, Thromb. Diath. Haemorrh. 5: 319. 1960. 26. Salzman, E. W., and Neri, L. L.: Adhesiveness of Blood Platelets in Uremia, ‘l’hroml~. Diath. Haemorrh. 15: 84, 1966. 27. Hovig.. T.: The Ultrastructure of Rabbit Blood Plat,elet Aggregates. Diath. YIIL I Thromb. Haemorrh. 3: 455, 1962. 28. Hovig, T.: The Effect of Cat+ and Mg++ on Rabbit Blood Platelet Aggregation 111 Vitro, Thromb. Diath. Haemorrh. 12: 179, 1964. 29. Born, G. V. R., and Cross, M. J.: Effects of Inorganic Ions and of Plasma Proteins on the Aggregation of Blood Platelets by Adenosine Diphosphate, J. Physiol. (London‘! 170: 397, 1964. 30. Born, G. V. R.: Mechanism of Platelet Aggregation and of Its Inhibition of Adenosine Derivatives, Fed. Proc. 26: 115, 1967. 31. Gross, R., Niemeyer, G., and Reater, H.: Localization of Platelet Aggregation by Incubation of Platelet Rich EDTA Plasma at 37” C., Thromb. Diath. Haemorrh. 19: 1, 196X. 32. Hardisty, R. M., and Hutton, R. A.: Platelet Aggregation and the Availability (if PF,, Brit. J. Haemat. 12: 764, 1966. 33. Marcus, A. J., Zucker-Franklin, D., Safier, L., and Ullman, H.: Studies on Humau Platelet Granules and Membranes, J. Clin. Invest. 45: 14, 1966. 34. Horowitz, H. I., and Papayoanou, M. F.: Activation of Platelet Factor Three 113. Adenosine 5’ Diphosphate, Thromb. Diath. Haemorrh. 19: 18, 196s. 35. Van Thoai, J., and Roche, J.: Biochemistry of Guanidine Derivatives, Expos. Anri. Biochim. Med. 18: 165, 1965. 36. Bon&s, J. E., Cohen, B. D., and Natelson, 8.: Separation and Estimation of Certain Guanidino Compounds: Application to Human Urine, Microchem. J. 7: 163, 1963. 37. Cohen, B. D., and Horowitz, H. I.: Carbohydrate Metabolism in Uremia: Inhibition of Phosphate Release, Amer. J. Clin. Nutr. 21: 430, 1968. 38. Horowitz, H. I., Cohen, B. D., Martinez, P., and Papayoanou! M. F.: Defective Adenosine Diphosphate-Induced Platelet Factor Three Activation in TJremia, Blood 30: 33 1, 1967. 39. Cohen, B. D., Stein, I., and Bonas, J. E.: Guanidinosuccinic Aciduria: A Possible Alternate Pathway for Urea Synthesis, Amer. 5. Med. 45: 63, 1968. 40. Marcus, A. J.: Platelet Function, New Eng. J. Med. 280: 1280, 1969.
and
report
of a case
Arthur Merril, B.S., D.D.S., P.R.S.H.,* and Larry J. Peterson, B.S., D.D.S.,** Washington, D. C.
T
he hemorrhagic manifestations of uremia were first described by Richard Bright in the early nineteenth century. In discussing this secondary complication of renal disease, many author9, lg* 31 allude to the gingiva as a rather common site of uremic bleeding. However, we found the dental literature devoid of information concerning the recognition and therapy as well as the mechanism of uremia-induced hemorrhage. The purpose of the present article is to describe a case of uremic hemorrhage, the unsuccessful attempt at its treatment, and the mechanism by which this hemorrhagic disorder is caused. CASE
REPORT
A 547year-old Negro man was admitted to the District of Columbia General Hospital on Feb. 19, 1969, with the chief complaint of hemorrhage from the gingiva for 3 weeks prior to admission. He had first been treated at this hospital in June, 1967, when a diagnosis of chronic pyelonephritis, obstructive uropathy, and salt-losing nephritis was made. He had been treated at other hospitals for his disease, beginning in March, 1966. Previous admissions to the District of Columbia General Hospital were for treatment of symptoms secondary to the primary renal insufficiency-anemia, pleuritis, pericarditis, and acidosis. Treatment during these admissions was essentially supportive. One admission was for dyspnea secondary to upon paracentesis, 11.5 liters of fluid was removed. During the time from 1967 ascites; until the current admission in 1969, the patient’s blood urea nitrogen ranged from 53 to 216 mg. per cent; the hematocrit fell steadily from a high of 17 per cent in 1967 to 11 per cent at the time of this admission, in spite of multiple transfusions of packed red blood cells during the two previous periods of hospitalization. At the time of the current admission, physical examination revealed a well-developed but poorly nourished Negro man who was lethargic and somewhat disoriented. The blood pressure was llO/SO, the pulse rate was 112, and the temperature was 98.6” F. The general appearance of the skin was normal, with no petechiae or ecchymotic areas. The conjunctivae were very *Chief **Oral
530
Dental Surgery
Officer, District of Columbia General Hospital. Resident, Georgetown University School of Dentistry.
Volume Number
Gingival
29 4
hemorrhage
secondary
to uremia
531
pale; there was marked arterial narrowing in the fundi. There was brisk hemorrhage from the gingiva. The trachea was in the midline. Lungs were clear, with no rLles or rubs. Thi> heart had a normal sinus rhythm, with a Grade 4 systolic murmur. Examination of the abdomen revealed massive ascites. The patient demonstrated bilateral costal vertebral anqltx tenderness. He also had bleeding hemorrhoids. blood urea nitrogen, 248 mg. per cent (norma.1, A blood work-up revealed the following: 31.2 mg. per cent (normal, 1 to 2 mg. per cent) ; uric 9 to 19 mg. per cent) j creatinine, acid, 16.5 mg. per cent (normal, 3 to 6 mg. per cent) ; glucose, 160 mg. per cent (normal, 70 to 110 mg. per cent) ; moderate acidosis with a carbon-dioxide combining power of 1 G m&l. per liter (normal, 27 to 35 mEq. per liter) ; hematocrit, 11 per cent (normal, 42 to 47 per cent) ; reticulocyte count, 1.6 per cent (normal, 0.5 to 1.0 per cent) ; platelet count, 275,000 (normal, 250,000 to 300,000) ; prothrombin time, 15.8 seconds (e011tr01, 11.6 scc011ds) ; fibrinogen, 280 mg. per cent (normal, 200 to 400 mg. per cent) ; Ivy bleeding time, grc:rt.cbl than 30 minutes (normal, 8 to 14 minutes) ; clot retraction, alwxt with a wry frial)ltk (+ll+t (normal begins in 30 to 120 minutes, complete in 24 hours). For 3 days the patient was given supportive therapy consisting of packed red l~lood cc,11 transfusions, sodium bicarbonate for the acidosis, and N(bosporin citrate mouth rinsc>s. ‘l’lic gingival hemorrhage continued. On Feb. 23, 1969, a dental consultation was requested. Oral examination revealed that the maxilla mas edentulous, with a normal-appearing but very pale ridge. The m:~ndibul:~r dent,ition was intact except for the absence of the first and third molars bilatrrally. ‘Tile teeth were caries free and slightly mobile. There was a brisk hemorrhagic oozing from tl;e lingual and labial marginal gingivae surrounding the mandibular teeth. Close inspection revealed a lvhite, necrotic, marginal gingiva which would become hidden by hemorrhage soon a diagnosis of uremic si.orn:rl.il is :?fter it 11a.d been dried. In view of the patient’s history, complicated by uremic bleeding was made. Therapy consisted of hydrogen peroxide mouthwashes followed Iby saline rinscbs. ;tu attempt was made to control the hemorrhage by means of direct, pressure with moist gnu/.tx sponges. After 10 minutes the hemorrhage slowed substantially. The patient was tetnruld to his room with a gauze pack in place, to return to the clinic on the following day. The next day the condition was unchanged. The hemorrhage was again slowed I)y tllc application of direct pressure. The teeth and gingiva were tlricd and Orahesive batndag~~” was placed on the labial and lingual surfaces of the antclrior teeth. The bleeding was f:ririy well controlled and the patient was returned to his room? to be seen again on thf~ follo\\ing day. The next day we found the hemorrhage to be as brisk as originally. The procedure of tilt, day before was repeated, but this time dental tape was applied in a figure-of-eight tic LO hold the Orahesire bandage more securely to the teeth. This routine was followed for t,he nctxt 4 days, with no appreciable results. On the seventh day, a periodontal pack was placed :IIIII secured by figure-of-eight wiring with 26.gauge wire. Although the pack remained sccur~lg iu place, the bleeding continued but at a less rapid rate. It was thought by members of the dental service, the medical service, and the rc1::11 scrvico that the hemorrhage was uncontrollable by local measures and that dialysis of sol type was necessary. During the 19 days since admission, the patient had rezreivetl five ullits of packed red blood cells. The resultant hematoerit was 1’0.4 per cent. Peritoneal dialysis was started on March 10, 1969, and was completed on March -12, 19~0, after twenty-nine exchanges. The blood urea nitrogen fell from 255 to 86 mg. per cent. The hemorrhage stopped completely on the morning of March 12, and the patient was much more alert and well oriented by that evening. When the patient was seen in the dental clinic on March 13, the gingiva appeared completely normal. The necrotic margin was no longer :ipparent. The color and texture were excellent. The patient was given transfusions of ih~t, additional unit.s of packed red blood cells which raised the hematocrit to 18 per c-ent. 111% was then discharged. *E.
K,. Squibb
Bi Sons,
New
York,
N. Y.
532
Me&l
and Peterscm
Oral
April,
Surg. 1970
DISCUSSION
Uremic stomatitis is a relatively uncommon complication of the uremic syndrome. In 1930 Hempstead and Hench’ reported that of 300 uremic patients treated at the Mayo Clinic, four had uremic stomatitis; Beaney3 reports that only four of 262 uremic patients had stomatitis complications. This lesion was first described by Lancereauxl in 1887. The treatment of uremic stomatitis itself, as reported by Halazonetis,7 is uncomplicated and can be accomplished in the face of untreated uremia. When uremic stomatitis is part of the clinical picture, it must be considered indicative of advanced uremia, with a poor prognosis. Hemorrhage may be initiated in patients with severe uremic stomatitis. The stomatitis itself is thought to be caused by the caustic action of ammonia,6 formed by bacterial urease4 produced by oral flora, acting on the salivary urea.G-s The bacteria which are the main agents in this conversion are in close association with calculus.5 The stomatitis can be t.reated locally7> Q by scaling of the teeth, hydrogen peroxide rinses to neutralize the ammonia, and application of a triple dye solution to suppress the oral flora growth and reduce the formation of urease. The stomatitis may be eliminated in spite of the continued systemic uremia. However, the hemorrhage invariably continues. The problem, of course, is not local but systemic. The hemorrhage tendency in uremic patients is well knownI* In fact, Stewart and Castaldi16 and Maher and Schreiner23 state that abnormal bleeding is the actual cause of death in nearly 10 per cent of patients with renal failure. Ze1man2’ reported a case in which the patient died of uncontrollable bleeding following needle biopsy of the liver. As stated earlier, the hemorrhagic tendency has been recognized since the nineteenth century. However, not until the mid-1950’s did serious study of the mechanism of the bleeding abnormality begin. Several plasma factors have been found deficient.1° Hypofibrinogenemia, lop I1 derangement of the prothrombin complex,11 prolonged thromconsumpbin time,lO thrombocytopenia,‘l? l2 and deficiency in prothrombin tionf2s I3 have been given as reasons for the clotting problem. In 1956 Lewis and associates10 and Larrain and Adelson,z.’ working independently, described the discovery of a qualitative defect in the function of blood platelets. Their reports mere the first in a series indicating a qualitative defect in platelets. ~9 17r*l Lewis reported that the prothrombin-consumption time is abnormal in uremic patients with bleeding tendencies. An abnormality in this test response in uremic patients thought to show a deficient platelet thromboplastic factor (PFs) , has been verified consistently.l’? I29 13*IQ, 24-2G Before we continue with the discussion of the mechanism of uremic bleeding, a brief review of postulated platelet function is necessary. The generally accepted order of events is as follows: After severance of the vessel, platelets adhere to collagen in a reaction requiring adenosine diphosphate (ADP). Degranulation of the plateletsz7 occurs with release of ADP, which enhances platelet aggregation. At the same time, the platelets reiease serotonin, catecholamineq and c.PF,. For platelet aggregation to occur properly, several factors must be in proper balance-ADP, calcium ions,?*’ ?g and a plasma protein, probably fibrinogen.2g-31 Platelet aggregation provides a large amount of PF, for
Volume Number
29 4
Gingival
hemwrhage secondary to wemia
533
coagulation32 ; in order to become active in coagulation, it must be available.3” As mentioned, decreased PF, function has been indicated as the cause of uremic bleeding. Cahalane and colleagues*3 caused defective PF, function 1)~. incubating normal platelets with uremic plasma. Horowitz and Papayoanon”’ were unable to produce decreased PF, function by direct action of urea. In the early 1960’s, urea metabolism was more closely examined. Certain guanidine compounds arc known metabolic precursors of urea and creatinine.:“’ In uremic patients, two compounds-guanidinoacetic acid (GAA) and guanidinosuccinic acid (GSA) ,-were found to haTe important relationships.36 In the normal patient GAA is present in relatively high concentrations in thn urine as compared to the uremic patient, whereas the urine concentration of GSA is much higher in the uremic than in the normal patient.37 A discussion of the altered pathway by which an excess of GSA is formed is beyond the scope of this article. Suffice it to say that, in the uremic patient, there is a blockage of the conversion of GAA to creatine and consequent conversion of urea precursors to GSA. In 1967 GSA was shown to be a potent inhibitor of ADP-induced PI;, activation.38 It is claimed that an increased GSA concentration is accompanied by a decrease in the ADP calcium ion complex needed for platelet function and an increase in the ADP-GSA complex.3il :(g Hence, the current thought on the mechanism of uremic hemorrhage is that there is an alternate pathway to urea metabolism which leads to the formatiou of GSA. GSA competes with the calcium for ADP, reducing the availability of the ADP-calcium comples which is needed for the release of PF:,.“” There is some controversy over the fine points, but the crux is that GSA is clearly indicated as the major offender in the etiology of “uremic thrombopathy.“,L” Virtually everyone agrees that dialysis or kidney transplantation will eliminate or greatly improve the hemorrhagic condition. In fact, Stewart and Castaldi16 state that “bleeding is an indication for dialysis.” The bleeding parameters are generally improved in all pre- and postdialysis studies,15,x6.23 and clinical hemorrhage is controlled in almost all cases.11l I6 Current research shows that the improvement is due to the removal of GSA and its inhibitory effect on PI?,. Routine screening tests in common use in hospitals today for blce(ling diathesis usually include the platelet count, Duke bleeding time, prothrombin time, and partial thromboplastin time determinations. These test.s will frcquently miss the active or potentially active uremic bleeder. A recommended presurgical screen for a possible bleeding abnormality should include the Ivy bleeding t,ime, clot retraction, and prothrombin consumption.20 Hutton a~(1 O’Sl~ea’8 believe, on the basis of their experience, that it is not consistently possible to predict the clinical hemostatic response of the patient by means of laboratory tests. They believe, however, that an attempt should indeed be made to investigate the hemostatic status of renal patients about to undergo a surgical procedure. The dentist, especially the oral surgeon, is faced daily with the problem of hemostasis. With the advent of the artificial kidney and the concurrent, yise
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Peterson
Oral April,
Surg. 1970
in the number of persons surviving with chronic renal disease, it becomes increasingly important that the patient be asked about kidney function. Eknoyan and co-workerP suggest that when the blood urea nitrogen level is as low as 60 mg. per cent hemorrhage may become a problem. Routine admission blood urea nitrogen tests in hospital patients, especially those with a history of kidney ailments, should certainly be considered. SUMMARY
A case of gingival hemorrhage secondary to uremia has been reported, and the unsuccessful attempt at local control has been described. The probable mechanism of the hemorrhagic diathesis of uremia has also been described. This bleeding tendency is due to an altered pathway of urea metabolism with consequently increased levels of GSA, which inhibits platelet function. In view of the increased number of persons with chronic renal disease who are surviving as a result of repeated dialyses on the artificial kidney, the dentist must be acutely aware of the possible consequences of uremia. REFERENCES
Anatomie pathologigue et complications de I’uremie, Union Med. 44: 1. Lancereaux, M.: 829,1887 (cited by Hempstead and Hench). 2. Hempstead, B. E., and Hench, P. S.: Uremic Stomatitis, Trans. Amer. Laryng. Rhin. Otol. Soe., p. 516, 1930. 3. Beaney, G. P. E.: Otolaryngeal Problems Arising During the Management of Severe Renal Failure, J. Laryng. 78: 507, 1964. 4. Earlam, M. S. 8.: Urea-Splitting Staphylococci in Urinary Tract Infections, Brit. J. Urol. 2: 233, 1930. 5. Bliss, 8.: Cause of Sore Throat in Nephritis, J. Biol. Chem. 121: 425, 1937. 6. Afonsky, D.: Saliva and Its Relation to Oral Health, ed. 1, Montgomery, Ala., 1961, Paragon Press, pp. 126-139. 7. Halazonetis, J., and Harley, A.: Uremic Stomatitis; Report of a Case, ORAL SURG. 23: 573, 1967. 8. Hench, P. S., and Aldrich, M.: A Salivary Index to Renal Function, J. A. M. A. 81: 1997, 1933. 9. Black, D. R.: Nephritic Stomatitis, Ural. Cutan. Rev. 46: 75, 1942. 10. Lewis, J. H., Zucker, M. B., and Ferguson, J. H.: Bleeding Tendency in Uremia, Blood 11: 1073, 1956. 11. Kendall, A. G., Lowenstein, L., and Morgan, R. 0.: The Hemorrhagic Diathesis in Renal Disease With Special Reference to Acute Uremia, Canad. Med. Ass. J. 86: 406, 1961. 12. Rath, C. E., Mailliard, J. A., and Schreiner, G. E.: Bleeding Tendency in Uremia, New Eng. J. Med. 257: 808, 1957. 13. Cahalane, S. F., Johnson, S. A., Monto, R. W., and Caldwell, M. J.: Acquired Thrombocytopathy: Observations on the Coagulation Defect in Uremia, Amer. J. Clin. Path. 30: 507, 1958. 14. Nakamot,o, S., and Koliff, W.: Hemorrhagic Diathesis in Uremia and the Avoidance of Bleeding Problems During Dialysis, Ann. N. Y. Acad. Sei. 115: 348, 1964. 15. Von Kaulla, K. N., von Kaulla, E., Wasantopruck, D., Marchioro, T. L., and Starzl, T. E.: Blood Coagulation in Uremic Patients Before and After Hemodialysis and Transplantation of the Kidney, Arch. Surg. 92: 184, 1966. 16. Stewart, J. H., and Castaldi, P. A.: Uraemic Bleeding: A Reversible Platelet Defect Corrected by Dialysis, Quart. J. Med. 143: 409, 1967. 17. Willoughby, M. L. N., and Crouch, S. J.: An Investigation of the Hemorrhagic Tendency in Renal Failure, Brit. J. Haemat. 7: 315, 1961. 18. Hutton, R. A,, and O’Shea, M. J.: Haemostatic Mechanism in Uremia, J. Clin. Path. 21: 406, 1968. 19. Cheney, K., and Bonnin, J. A.: Haemorrhage, Platelet Dysfunction, and Other Coagulation Defects in Uremia, Brit. J. Haemat. 8: 215, 1962. 20. Castaldi, P. A., Rozenberg, M. D., and Stewart, J. H.: The Bleeding Disorder of Uremia: A Qualitative Platelet Defect, Lancet 2: 66, 1966. 21. Eknoyan, G., Wacksman, 8. J., Glueek, H. L., and Will, J. J.: Platelet Function in Renal Failure, New Eng. J. Med. 280: 677, 1969.
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22. Zelman, S.: Fatal Hemorrhage Following Needle Biopsy in Uremia; Report of a Case. J. A. M. A. 164: 997,19X 23. Maher. J. H.. and Schreiner. 0. E.: Cause of Death in Acute Renal Failure. Arch. Intern: Med. IChicago) 110: 493, 1962. 24. Larrain, Defect of Uremia, Blood 11: 1059, 1956. G., and Adelson, E.: The Hemostatic “5 Dormer, L., and Neuwirtova, R.: The Hemostatic Defect of Acute and Chronic Uremia, Thromb. Diath. Haemorrh. 5: 319. 1960. 26. Salzman, E. W., and Neri, L. L.: Adhesiveness of Blood Platelets in Uremia, ‘l’hroml~. Diath. Haemorrh. 15: 84, 1966. 27. Hovig.. T.: The Ultrastructure of Rabbit Blood Plat,elet Aggregates. Diath. YIIL I Thromb. Haemorrh. 3: 455, 1962. 28. Hovig, T.: The Effect of Cat+ and Mg++ on Rabbit Blood Platelet Aggregation 111 Vitro, Thromb. Diath. Haemorrh. 12: 179, 1964. 29. Born, G. V. R., and Cross, M. J.: Effects of Inorganic Ions and of Plasma Proteins on the Aggregation of Blood Platelets by Adenosine Diphosphate, J. Physiol. (London‘! 170: 397, 1964. 30. Born, G. V. R.: Mechanism of Platelet Aggregation and of Its Inhibition of Adenosine Derivatives, Fed. Proc. 26: 115, 1967. 31. Gross, R., Niemeyer, G., and Reater, H.: Localization of Platelet Aggregation by Incubation of Platelet Rich EDTA Plasma at 37” C., Thromb. Diath. Haemorrh. 19: 1, 196X. 32. Hardisty, R. M., and Hutton, R. A.: Platelet Aggregation and the Availability (if PF,, Brit. J. Haemat. 12: 764, 1966. 33. Marcus, A. J., Zucker-Franklin, D., Safier, L., and Ullman, H.: Studies on Humau Platelet Granules and Membranes, J. Clin. Invest. 45: 14, 1966. 34. Horowitz, H. I., and Papayoanou, M. F.: Activation of Platelet Factor Three 113. Adenosine 5’ Diphosphate, Thromb. Diath. Haemorrh. 19: 18, 196s. 35. Van Thoai, J., and Roche, J.: Biochemistry of Guanidine Derivatives, Expos. Anri. Biochim. Med. 18: 165, 1965. 36. Bon&s, J. E., Cohen, B. D., and Natelson, 8.: Separation and Estimation of Certain Guanidino Compounds: Application to Human Urine, Microchem. J. 7: 163, 1963. 37. Cohen, B. D., and Horowitz, H. I.: Carbohydrate Metabolism in Uremia: Inhibition of Phosphate Release, Amer. J. Clin. Nutr. 21: 430, 1968. 38. Horowitz, H. I., Cohen, B. D., Martinez, P., and Papayoanou! M. F.: Defective Adenosine Diphosphate-Induced Platelet Factor Three Activation in TJremia, Blood 30: 33 1, 1967. 39. Cohen, B. D., Stein, I., and Bonas, J. E.: Guanidinosuccinic Aciduria: A Possible Alternate Pathway for Urea Synthesis, Amer. 5. Med. 45: 63, 1968. 40. Marcus, A. J.: Platelet Function, New Eng. J. Med. 280: 1280, 1969.