J Clin Periodontol 2004; 31: 1019–1023 doi: 10.1111/j.1600-051X.2004.00617.x Copyright r Blackwell Munksgaard 2004 Printed in Denmark. All rights reserved

Matthias Fenner1, Roland Frankenberger2, Katharina Life-threatening thrombotic 3 3 Pressmar , Stefan John , Friedrich Wilhelm Neukam1 and thrombocytopenic purpura Emeka Nkenke1 Departments of 1Oral & Maxillofacial Surgery, 2Operative Dentistry and associated with dental foci Periodontology and 3Medicine IV, University of Erlangen-Nuremberg, Germany Report of two cases

Fenner M, Frankenberger R, Pressmar K, John S, Neukam FW, Nkenke E: Life- threatening thrombotic thrombocytopenic purpura associated with dental foci. Report of two cases. J Clin Periodontol 2004; 31: 1019–1023. doi: 10.1111/j.1600-051X. 2004.00617.x. r Blackwell Munksgaard, 2004.

Abstract Background: Thrombotic thrombocytopenic purpura (TTP) is a rare haematological disease of unknown aetiology. This thrombotic microangiopathy is characterized by microvascular lesions with platelet aggregation. It is found in adults and can be associated with pregnancy, cancer, autoimmune diseases, bone marrow transplantation, drugs and bacterial as well as viral infections. The therapy requires a multi-disciplinary team approach involving dentistry. Even if TTP is immediately treated in an adequate manner, it still shows a mortality of up to 20%. Aim: To define a specific treatment concept for periodontal disease and decayed teeth in patients suffering from TTP based on the experiences gained from two cases. Conclusion: The two patient cases revealed a possible association of TTP with dental foci. Because of the severity and mortality of this disease, both prognosis evaluation Key words: dental foci; periodontal disease; and treatment standards of periodontologically compromised or decayed teeth have to systemic disease; thrombotic thrombocytopenic purpura be strictly followed in patients suffering from TTP. In order to avoid recurrence of TTP, it seems important to remove radically teeth of questionable prognosis. Accepted for publication 24 February 2004

Thrombotic thrombocytopenic purpura purpura, ecchymosis or spontaneous circulation and causes organ dysfunc- (TTP) is a life-threatening multi-system bleeding. Subsequently, haematuria tion like renal failure or hemiparesis by disease characterized by the classic pen- and renal failure occur. Neurological cerebral ischaemia. tad of thrombocytopenia, microangio- symptoms appear transiently and range The majority of TTP cases occur pathic haemolytic anaemia (MAHA), from headache and confusion to sei- without a known precipitating factor. neurological symptoms, progressive re- zures, hemiparesis and coma (Quasim & They are referred to as primary or nal failure and fever. Partridge 2001). idiopathic TTP. Secondary TTP shows The incidence of TTP is estimated to The aetiology and pathogenesis of an association with connective tissue be 3–7 cases per year per 1 million TTP are still not fully understood. Cur- disease, pregnancy, cancer and certain persons (Bell et al. 1991, Moake 1994). rently, it is assumed that an endothelial drugs like immunosuppressants. More- The reported mortality rate has drama- damage triggers processes leading to over, viral and bacterial infections have tically decreased during the past two microvascular lesions with platelet fi- been identified to be relevant aetiologi- decades. However, still up to 20% of the brin microthrombi occluding arterioles cal factors (Neild 1994, Creager et al. patients affected by this disease die and capillaries. Recent reports have 1998, Lara et al. 1999). A PUBMED despite adequate treatment (Quasim & shown that a deficiency regarding a query of the literature was performed to Partridge 2001). The clinical presenta- specific plasma protease (ADAMTS13) identify publications reporting an ex- tion may vary considerably as the being responsible for cleaving of the plicit association of TTP and dental classic pentad is seen only in less than von Willebrand factor plays a crucial infection (http://www.pubmed.de, date: half of the patients. A prodromal period role in microthrombi formation (Furlan 10–10–2003, keywords: TTP1foci/ resembling a viral, flue-like syndrome is et al. 1998, Tsai & Lian 1998, Remuzzi dental infection/oral infection/perio- common. Thrombocytopenia can lead to et al. 2002). The latter hinders micro- dontal). The recherche´ yielded no results. 1020 Fenner et al.

Actually, none of the reports dealing The patient showed no history of Ultracain-DS 1:200,000, Aventis, Bad with TTP evaluates the role of dental bone marrow transplantation or intake Soden, Germany). A single-shot intra- foci in the occurrence and recurrence of of drugs like immunosuppressants caus- venous antibiotic prophylaxis with 10 the disease. Nevertheless, the detrimen- ing TTP. Different examinations were million IU penicillin G (Penicillin G tal effect of chronic dental infections on carried out to detect other factors that ‘‘Gru¨nenthal’’ 10 Mega, Gru¨nenthal, general health is well known. These are have been reported to be associated with Aachen, Germany) was administered considered to deteriorate the condition TTP. For detection of infectious foci perioperatively. At that time, platelet of medically compromised patients and cancerous lesions, a thorough phy- counts had normalized (285,000/ml). (Golder & Drinnan 1993, Meurman sical examination was carried out in- Surgical treatment involved removal of 1997). It has been shown that perio- cluding neurological and urological the five teeth showing mobility of grade dontal disease is a risk factor for status. Moreover, an ultrasound exam- II as well as scaling and root planing at atherosclerosis and other chronic dis- ination of the abdomen and a computed a single appointment. Excavation and eases (Seymour & Steele 1998, Garcia tomography of the chest were per- restoration of carious lesions were et al. 2001). As chronic diseases reveal formed. As no factors associated with performed at a second appointment. a slow progression over time, dental TTP could be detected, the patient was After the patient was discharged from treatment is focussed on preventive care scheduled for a dental examination by the hospital, he received further restora- to avoid dental infections. In contrast to the Department of Oral and Maxillofa- tive and prosthetic therapy and was chronic diseases, TTP exhibits a fulmi- cial Surgery of the University of Erlan- restored with a removable partial den- nant progression leading to death if it is gen-Nuremberg. Unfortunately, he ture. During a follow-up of 14 months, diagnosed or treated on delay (Rock et refused any further examination and there was no recurrence of TTP. al. 1991, Lau & Wun 1993). treatment. The patient was discharged Therefore, the aim of this presenta- from the hospital after a total of six tion is to highlight the differences plasma exchanges (platelet count in concepts of treatment of dental 285,000/ml) on day 8. At that time, all Case Report 2 foci between TTP and other systemic symptoms of TTP had disappeared. A 40-year-old non-smoking female was diseases. Ten days after discharge, the patient referred to the Department of Medicine again complained about increasing IV of the University of Erlangen- headache, nausea and arthralgies. On Nuremberg after a gynaecological ex- re-admission, the patient was disorien- amination because of massive vaginal Case Report 1 tated and showed a focal neurological bleeding. The patient reported a feeling A 51-year-old non-smoking male pre- deficit. Laboratory studies revealed a of lethargy and malaise for several days sented at the Department of Medicine platelet count of 4000/ml, as well as before the bleeding suddenly occurred. IV of the University of Erlangen- schistocytes in the peripheral blood The previous medical history was un- Nuremberg complaining of general ma- smear. The patient was diagnosed with eventful. laise and fever over a period of 1 week. a relapse of TTP and was transferred to On admission, the patient was dis- The patient reported two episodes of the ICU, where he received plasma orientated and developed cerebral palsy. thrombocytopenia that had occurred 1 exchange therapy for 10 days. At that Within a few hours, she became coma- and 2 years ago. There was no history of time, the patient was referred to the tose, and had to be put on a respirator. other general diseases. Department of Oral and Maxillofacial Physical examination revealed pete- On initial examination, the patient Surgery of the University of Erlangen- chiae and ecchymoses on the tibial was alert, oriented and did not show any Nuremberg. Intraoral examination re- regions as well as multiple carious le- signs of bleeding. Intraoral examination vealed poor oral hygiene, characterized sions, mobile teeth and desolate oral hy- showed multiple mobile and decayed by massive plaque deposits along the giene. Laboratory examinations showed teeth. Laboratory examinations revealed cervical margins of the dentition. In a platelet count of 4000/ml (reference a platelet count of 10,000/ml (reference both the mandible and maxilla, the range 140,000–400,000/ml), a haemo- range 140,000–400,000/ml) and a hae- gingiva displayed redness, swelling globin of 7.8 g/dl (reference range 12.0– moglobin value of 9.1 g/dl (reference and bleeding on gentle probing as well 15.0 g/dl) and schistocytes in the range 13.6–17.2 g/dl). Fragmented red as increased probing depth and attach- peripheral blood smear. TTP was diag- blood cells (schistocytes) were observed ment loss. Supragingival calculus was nosed, based on clinical symptoms and in the peripheral blood smear. These present on the lingual surfaces of the the results of laboratory examination. cells were pathognomonic for MAHA. lower incisors. An increased mobility of The patient was transferred to the ICU Based on the history of thrombocytope- grade II according to Miller’s classifica- where a plasma exchange was carried nia, the presence of fever and the tion was observed in the lower central out with 2500 ml of FFP. Platelet counts laboratory studies showing MAHA the and lateral incisors and the lower right gradually returned to normal values, clinical diagnosis of TTP was estab- canine. Carious lesions were found in whereas the neurological deficit re- lished. The patient was transferred to 14 of the remaining 20 teeth. A Water’s solved very slowly. Plasma exchange the intensive care unit (ICU) where a view and a panoramic radiograph were therapy continued for 18 days. In order therapeutic plasma exchange was car- assessed. The latter revealed an ad- to detect infectious causes of secondary ried out immediately with 2500 ml of vanced alveolar bone loss in both jaws. TTP, a thorough physical examination fresh frozen plasma (FFP). Platelet Oral surgical treatment was per- was carried out including neurological counts returned to normal values after formed under local anaesthesia using and gynaecological examination. Con- three additional plasma exchanges in 5 ml of local anaesthetic (articain ventional radiological studies, ultra- the following days. 0.4 mg/ml, epinephrine 0.006 mg/ml; sound examination of the abdomen, TTP and dental foci 1021

Discussion

The occurrence of TTP is a haematolo- gical emergency situation. It is a multi- system disease that can cause rapid deterioration of the patient’s neurologi- cal, renal and haematological status. TTP is an uncommon disease with high mortality if untreated or misdiagnosed. Fig. 1. Preoperative panoramic radiograph Rapid diagnosis and aggressive treat- showing a root fragment (#) in the upper left ment by therapeutic plasma exchange alveolar process and an opaque mass in the n are necessary to reduce the risk of fatal left maxillary sinus ( ). outcome (Bell et al. 1991, Lara et al. 1999). However, 20–40% of surviving patients have relapses. These can occur computed tomography scans of the as early as a few months after recovery, chest and magnetic resonance imaging but also after an interval of many years scans of the neurocranium were per- (Real et al. 1998). formed, but yielded no pathological Fig. 2. Clinical situation after the removal Initially, TTP is sometimes difficult results. Subsequently, the patient was of the left lateral antral wall showing to diagnose because the patient’s symp- referred to the Department of Oral and granulation tissue within the left maxillary toms can be non-specific. Often, the n Maxillofacial Surgery of Erlangen-Nur- sinus ( ) and the root fragment in the patient does not exhibit the complete emberg University. On examination, the alveolar process (#). characteristic pentad of thrombocyto- gingiva was swollen and showed bleed- penia, MAHA, neurological symptoms, ing on gentle probing. Decayed root progressive renal failure and fever. fragments were found in the position of Other haematological diseases may the first and second upper right molars, have some of the same symptoms. the left upper lateral and central incisors However, in the presence of MAHA and the left upper canine. Nine out of (schistocytes, elevated lactate dehydro- 18 teeth showed carious lesions. A genase, and indirect hyperbilirubinae- panoramic radiograph revealed ad- mia) as well as thrombocytopenia in vanced resorption of the alveolar crest. the absence of other obvious causes Panoramic radiograph and Water’s view (disseminated intravascular coagulation showed an opaque mass of 2 cm dia- Fig. 3. Postoperative panoramic radiograph (DIC), malignant hypertension), TTP meter on the floor of the left maxillary after removal of decayed teeth and revision has to be considered a potential diag- sinus (Fig. 1). A computed tomography of the left maxillary sinus. nosis and total plasma exchange has to was carried out for further evaluation of be started immediately. this process. In the two present cases, none of the At the time the oral surgical treat- factors previously associated with sec- ment was performed, the patient was in ondary TTP like connective tissue good physical condition and platelet disease, pregnancy, cancer and the use counts as well as other laboratory of certain drugs could be detected. Yet, findings had normalized. A single-shot both patients showed a large number of intravenous antibiotic prophylaxis with decayed or periodontologically compro- 10 million IU penicillin G (Penicillin G) mised teeth with extensive probing was administered perioperatively. Oral depths and tooth mobility. The desolate surgical treatment comprised removal of dental status as a cause of chronic the root fragments and the partially infection remained the potentially ae- erupted right lower third molar under tiological factor. Further studies are local anaesthesia using 7 ml of local needed to evaluate the role of dental anaesthetic (articain 0.4 mg/ml, epi- foci in the pathogenesis of TTP. nephrine 0.006 mg/ml; Ultracain-DS Generally, the strategy for treatment 1:200,000, Aventis). Revision of the of dental foci depends on the patient’s left maxillary sinus was carried out by general health and the severity of the an approach through the lateral antral underlying systemic disease. Conflicting wall (Fig. 2). A root fragment that had Fig. 4. Clinical situation after removal of opinions can be found in the literature been dislocated into the sinus during an the root fragment and the granulation tissue. regarding the intensity of the treatment extraction performed previously alio of dentogenic foci. In many chronic loco was removed together with poly- On day 29, the patient was dischar- systemic diseases, more conservative pous antral mucosa (Figs 3 and 4). ged from the hospital (platelet count therapy concepts are adopted, while Histological examination revealed a 200,000/ml). During a subsequent fol- patients undergoing radiotherapy still chronic inflammation of the antral low-up of 6 months, TTP did not seem to require a more radical approach mucosa without signs of malignancy. re-occur. (Meyer et al. 1999, Thorn et al. 2000, 1022 Fenner et al.

exclude pathology of the maxillary Furlan, M., Robles, R. & Galbusera, M. (1998) sinuses. In cases of doubt, computed Von Willebrand factor-cleaving protease in tomography has to be considered for thrombotic thrombocytopenic purpura and further analysis of accompanying infec- the hemolytic–uremic syndrome. New Eng- tious diseases of the head and neck. land Journal of Medicine 339, 1578–1584. Often, this examination can be com- Garcia, R. I., Henshaw, M. M. & Krall, E. A. (2001) Relationship between periodontal Fig. 5. Course of treatment concept. bined with computed tomography of disease and systemic health. Periodontology other regions also carried out for detec- 2000 25, 21–36. Groetz et al. 2001, Lund et al. 2002). tion of cancerous lesions or infectious Golder, D. T. & Drinnan, A. J. (1993) Dental The same seems to be true for TTP, foci. In Case Report 2, a root fragment aspects of cardiac transplantation. Transplan- because the oral surgical treatment for was found having been dislocated pre- tion Proceedings 25, 2377–2380. elimination of dental infection sources viously into the maxillary sinus during Gregg, G. H., Shelton, B. J., Chavers, L. C. & as potential aetiological factors of TTP an extraction alio loco. It caused an Bradford, E. H. (2002) Predicting tooth loss has to be taken into consideration facing infection of the maxillary sinus, which during a population-based study: role of the mortality rate of this particular had to be treated by an approach attachment level in the presence of other disease. The possible significance of through the lateral antral wall. dental conditions. Journal of Periodontology 73, 1427–1436. evaluation and complete removal of During the removal of teeth, a Groetz, K. A., Riesenbeck, D., Brahm, R., dental foci in TTP patients is shown in bacteraemia is likely to occur in a high Seegenschmiedt, M. H., al-Nawas, B., Dorr, Case Report 1. The patient had suffered percentage of cases, which may harm W., Kutzner, J., Willich, N., Thelen, M. & three episodes of TTP within 3 con- the patient. Therefore, administration of Wagner, W. (2001) Chronic radiation effects secutive years. Even though platelet antibiotics and extraction of only one on dental hard tissue (radiation caries). counts had recovered completely during tooth at each appointment have been Classification and therapeutic strategies. the current episode, the disease reap- recommended (Okabe et al. 1995). Strahlentherapie Onkologie 177, 96–104. peared within a few days after dismis- However, in an urgent situation like in Kanj, N. A., Mikati, A. R. & Kfoury Baz, E. M. sal, while the patient refused to receive the two patient cases, 10 million IU (2003) Early relapse of thrombotic thrombo- a radical extraction therapy of the com- penicillin G (Penicillin G) can be given cytopenic purpura during therapeutic plasma promised teeth. Early recurrence of TTP intravenously as a single-shot prophy- exchange associated with Acinetobacter ani- tratus bacteremia. Therapeutic Apheresis and has also been described previously for laxis, while we recommend the extrac- Dialysis 7, 119–121. other remaining infectious foci that had tion therapy to be performed at a single Lara, P. N., Coe, T. L. & Zhou, H. (1999) not been eradicated completely during appointment. As no relapse of the Improved survival with plasma exchange in the course of the disease (Creager et al. disease occurred, this treatment strategy patients with thrombotic thrombocytopenic 1998, Niv et al. 2000, Kanj et al. 2003). seems to be appropriate. purpura-hemolytic uremic syndrome. Amer- Therefore, a conservative approach to ican Journal of Medicine 107, 573–579. dental rehabilitation in TTP may not be Lau, D. H. & Wun, T. (1993) Early manifestation appropriate and severely compromised Conclusion of thrombotic thrombocytopenic purpura. American Journal of Medicine 95, 544–545. teeth should not be maintained. As the mortality of TTP accounts for Dental treatment of the affected Lund, J.-P., Drews, T., Hetzer, R. & Reichart, 20% of the cases and a high risk of P. A. (2002) Oral surgical management of patient should be started a soon as recurrence arises from inadequate treat- patients with mechanical circulatory support. possible, as the patient’s prognosis is ment of infectious foci, it seems that International Journal of Oral Maxillofacial fundamentally dependent on early diag- teeth with questionable prognosis should Surgery 31, 629–633. nosis and treatment without delay (Qua- be removed radically using antibiotic Meurman, J. H. (1997) Dental infections and sim & Partridge 2001). However, a prophylaxis after a minimal platelet general health. Quintessence International minimal platelet count of 50,000/ml count of 50,000/ml has been reached. 28, 807–811. should be re-established to prevent the This hypothesis, however, has to be Meyer, U., Weingart, D., Deng, M. C. & occurrence of haemorrhage after extrac- proven by follow-up of a larger series Scheld, H. H. (1999) Heart transplants – assessment of dental procedures. Cinical tion therapy (British Committee for of cases. Standards in Hematology 2003) (Fig. 5). Oral Investigation 3, 79–83. Moake, J. L. (1994) Haemolytic–uraemic syn- The potential dental sources of infec- drome: basic science. Lancet 343, 393–397. References tion are well known (Siminoski 1993, Neild, G. H. (1994) Haemolytic–uraemic Wang et al. 1996, Seymour et al. 2003). Bell, W. R., Braine, H. G. & Ness, P. M. (1991) syndrome in practice. Lancet 343, 398–401. They comprise periapical abscesses, Improved survival in thrombotic thrombocy- Niv, E., Segev, A. & Ellis, M. H. (2000) periodontal abscesses, deep vertical topenic purpura-hemolytic uremic syndrome. Staphylococcus aureus bacteremia as a cause periodontal bone pockets exceeding Clinical experience in 108 patients. New of early relapse of thrombotic thrombocyto- 6 mm in probing depth, furcation lesions England Journal of Medicine 325, 398–403. penic purpura. Transfusion 40, 1067–1070. of multi-rooted teeth, deep carious British Committee for Standards in Hematol- Okabe, K., Nagakawa, K. & Yamamoto, E. lesions, pericoronitis of erupted or ogy, Blood Transfusion Task Force (2003) (1995) Factors affecting the occurrence of retained teeth such as third molars, Guidelines for the use of platelet trans- bacteremia associated with tooth extraction. International Journal of Oral and Maxillo- cysts and mucosal ulcers (Meurman fusions. British Journal of Hematology 122, 10–23. facial Surgery 24, 239–242. 1997, Gregg et al. 2002). Creager, A. J., Brecher, M. E. & Bandarenko, Quasim, Z. A. & Partridge, R. A. (2001) Prior to dental treatment, a radiolo- N. (1998) Thrombotic thrombocytopenic Thrombotic thrombocytopenic purpura pre- gical examination should be carried out purpura that is refractory to therapeutic senting as bilateral flank pain and hematuria: involving single-tooth radiographs, pano- plasma exchange in two patients with occult a case report. The Journal of Emergency ramic radiographs and Water’s views to infection. Transfusion 38, 419–423. Medicine 21, 15–20. TTP and dental foci 1023

Remuzzi, G., Galbusera, M., Noris, M., Cancia- Seymour, R. A. & Steele, J. G. (1998) Is there a acute thrombotic thrombocytopenic purpura. ni, M. T., Daina, E., Contaretti, S., Caprioli, link between periodontal disease and coron- New England Journal of Medicine 339, J., Gamba, S., Ruggenenti, P., Perico, N. & ary heart disease? British Dental Journal 1585–1594. Mannucci, P. M. (2002) Von Willebrand 184, 33–38. Wang, T. D., Chen, Y. C. & Huang, P. J. (1996) factor cleaving protease (ADAMTS13) is Seymour, R. A., Preshaw, P. M., Thomason, J. Recurrent vertebral osteomyelitis and psoas deficient in recurrent and familial thrombo- M., Ellis, J. S. & Steele, J. G. (2003) Cardio- abscess caused by Streptococcus constellatus cytopenic thrombotic purpura and haemolytic vascular diseases and periodontology. Jour- and Fusobacterium nucleatum in a patient uremic syndrome. Blood 100, 778–785. nal of Clinical Periodontology 30, 279–292. with atrial septal defect and an occult dental Real, E., Pastor, E., Perella, M. & Grau, E. Siminoski, K. (1993) Persistent fever due to oc- infection. Scandinavian Journal of Infectious Diseases 28, 309–310. (1998) Elective splenectomy in relapsing cult dental infection: case report and review. thrombotic thrombocytopenic purpura. Hae- Clinical Infectious Diseases 16, 550–554. Address: matologica 83, 959–960. Thorn, J. J., Hansen, H. S., Specht, L. & Matthias Fenner Rock, G. A., Shumak, K. H. & Buskard, N. A. Bastholt, L. (2000) Osteoradionecrosis of the Glueckstr. 11 (1991) Comparison of plasma exchange with jaws: clinical characteristics and relation to 91054 Erlangen plasma infusion in the treatment of thrombo- the field of irradiation. Journal of Oral Germany tic thrombocytopenic purpura. Canadian Maxillofacial Surgery 58, 1088–1095. Fax: 149(0)9131 8534219 Apheresis Study Group. New England Jour- Tsai, H. M. & Lian, E. C. (1998) Antibodies to E-mail: [email protected] nal of Medicine 325, 393–397. von Willebrand factor-cleaving protease in erlangen.de