CLINICAL
AND
LABORATORY OBSERVATIONS
Oral Pyogenic Granuloma in Hemophilia: A Report of 2 Cases Holly Lindsay, MD* and Lakshmi V. Srivaths, MDw
Summary: Pyogenic granulomas (PGs) are benign vascular lesions occurring in skin and mucous membranes, often secondary to trauma or chronic inflammation. Oral PGs have never been described previously in hemophilia. We describe 2 pediatric patients with hemophilia A, who developed PGs with inadequate factor therapy for bleeding. PG pathophysiology suggests an association with hemophilia given chronic vascular damage and low-grade inflammation at sites of bleeding in hemophilia patients. Knowledge about the occurrence of PGs in hemophilia patients is essential for prompt diagnosis and early institution of factor therapy, which in turn allows more rapid cessation of bleeding and lesion involution. Key Words: pyogenic granuloma, hemophilia, children
(J Pediatr Hematol Oncol 2014;36:e333–e334)
A
lthough pyogenic granulomas (PGs) are relatively common dermatologic lesions of childhood, there is a paucity of information in the literature about the presence of this complication in patients with hemophilia. We describe 2 patients with hemophilia A, one with previously undiagnosed mild disease and the other with severe disease, who developed oral PGs with inadequate factor therapy for bleeding. We present the etiologies and discuss the pathophysiology of PGs and highlight the need for prompt diagnosis and management of this condition in patients with hemophilia.
PATIENT PRESENTATIONS Patient 1 is a 4-year-old male child previously undiagnosed with a bleeding disorder who presented to our institution after developing 2 PGs of the tongue. Two painless hemorrhagic papules on each side of the patient’s tongue were noted by parents due to their intermittent bleeding and enlargement over 7 to 10 days (Fig. 1). The patient was initially seen in an urgent care center and then by his primary care physician, who subsequently referred the patient to our institution’s emergency center. The lesions were diagnosed as PGs based on their physical appearance. Because of the hemorrhagic appearance of the lesions, prolonged lesional bleeding, the patient’s history of easy bruising and bleeding, and a striking family history of heavy menses as well as prolonged bleeding after delivery and miscarriages in the mother and maternal aunt, respectively, a bleeding disorder evaluation was initiated. The laboratory work-up was significant for a partial Received for publication January 22, 2014; accepted February 19, 2014. From the *Fellow in Pediatric Hematology and Oncology; and wDepartment of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine/Texas Children’s Hospital, Houston, TX. The authors declare no conflict of interest. Reprints: Holly Lindsay, MD, Fellow in Pediatric Hematology and Oncology, Baylor College of Medicine, 1102 Bates, Ste 1030.20J, Houston, TX 77030 (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
J Pediatr Hematol Oncol
Volume 36, Number 5, July 2014
thromboplastin time of 42.7 seconds (normal, 24.9 to 34.3 s). Further coagulation work-up revealed low factor 8 level of 12% (normal, 47% to 169%), thereby confirming the diagnosis of mild hemophilia A. The patient’s PGs spontaneously involuted and slowly resolved over the subsequent weeks, leaving residual hypopigmentation and tissue atrophy at the sites. No factor replacement was given due to the delay in diagnosis of hemophilia and delayed presentation to a pediatric hematologist. Patient 2 was diagnosed with severe hemophilia A as a neonate after work-up of prolonged bleeding following a heel stick and otherwise routine circumcision. The patient was followed regularly at our institution’s Hemophilia Treatment Center for comprehensive hemophilia care and was not receiving prophylactic factor infusions as he had no history of major bleeding episodes or hemarthrosis. At 16 months, this patient developed intermittent bleeding at the upper frenulum likely caused by minor trauma. The intermittent bleeding, for which the patient presented to the emergency department thrice over a 2-month period, was treated with single doses of recombinant factor 8 infusions. Owing to parental concern about persistent bleeding, the patient was later evaluated by the treating hematologist, at which time he was diagnosed with a frenulum PG. Subsequently, therapy was initiated with daily factor 8 infusions and oral aminocaproic acid for 7 days which led to complete resolution of the lesion and cessation of bleeding. The patient has since been started on prophylactic factor infusions due to frequent bleeding episodes and large soft-tissue hematomas.
DISCUSSION PGs are benign acquired vascular lesions that occur most frequently on skin and mucous membranes, usually the head and neck region and extremities. They are commonly seen in children and young adults in the second or third decades of life and may also occur during pregnancy. The term PG is a misnomer as the vascular overgrowth is neither pyogenic nor a true granuloma; instead PGs are caused by inflammatory dermal capillary hyperplasia initiated by trauma, infection, hormonal changes, medications including immunosuppressants, or chronic low-grade local irritation. The lesions may initially grow rapidly and ulcerate; they are usually solitary and generally nontender, with size ranging from a few millimeters to 2.5 cm. Of the oral PGs reported, gingival lesions are the most common, followed by those on the lips, tongue, and buccal mucosa. As PGs are both vascular and fragile, the lesions bleed easily even in patients without underlying bleeding disorders.1–8 There is evidence that PG pathophysiology may be due to increased fibroblast synthetic activity leading to disordered protein metabolism.6 Other researchers hypothesize that PGs are triggered by the entry of infectious organisms into mucosa after minor trauma leading to disregulated proliferation of www.jpho-online.com |
e333
Lindsay and Srivaths
FIGURE 1. Pyogenic granuloma of the tongue in a patient (patient #1) with hemophilia.
surrounding vascular connective tissue.9 Other evidence suggests that the etiology of PG is stimulation of capillary angiogenesis from venules following upregulation of various vascular morphogenesis factors including angiopoeitin-1 and 2 and tie-2.10 Treatment options for PGs include cauterization, excision, cryotherapy, and laser therapy, although spontaneous resolution usually occurs within 6 months.1–8 Ours is the first report of oral PGs occurring in patients with hemophilia. A previous report by Heim and colleagues illustrates 3 patients with hemophilia who developed PGs of the toes secondary to trauma from ingrown nails. All patients had HIV in addition to hemophilia and were on chronic antiretroviral therapy.11 We believe the occurrence of oral PGs in our patients was at least in part due to the delayed diagnosis of hemophilia and/or inadequate therapy that led to continued lesional bleeding and recurrent tissue irritation. Animal data and clinical evidence suggest that patients with bleeding disorders have impaired wound healing with increased risk of hematoma formation, infections, skin necrosis, and wound dehiscence. The first phase of wound healing is hemostasis, and if circulating factors levels are insufficient to both initiate and sustain hemostasis, the subsequent phases of wound healing—inflammation, proliferation, and remodeling—cannot function appropriately.12,13 Poor wound healing and the resultant prolonged bleeding and tissue irritation likely potentiated the development of PGs in our patients. Optimal factor replacement is essential for hemophilia patients who develop PGs to achieve adequate hemostasis, which can in turn promote fast healing of the lesions and minimize the need for surgical interventions. In our first patient, the PGs developed before his diagnosis of hemophilia; consequently, hemostatic therapy
e334 | www.jpho-online.com
J Pediatr Hematol Oncol
Volume 36, Number 5, July 2014
was not provided, leading to continued enlargement and bleeding of the lesions. In our second patient, there was a delay in the diagnosis of PG; factor therapy was thus initially inadequate, leading to frequent reinjury at the site, increased bleeding events, and prolongation of the time to PG resolution. It is reassuring to note that the oral PG in patient 2 involuted once hemostasis was attained without the need for surgical intervention. This case report highlights the fact that it is important to institute appropriate treatment with continued factor replacement in a timely manner in hemophilia patients with PGs, to minimize the need for surgical interventions. Whereas simple mucosal bleeding in patients with hemophilia may resolve with antifibrinolytic agents with or without a single dose of factor infusion, PGs appear to need prolonged therapy for complete resolution. We hypothesize that PGs occur in hemophilia patients due to tissue inflammation from vascular trauma and prolonged bleeding; the resultant increase in circulating systemic inflammatory markers likely promotes the growth of these vascular lesions which in turn bleed easily, initiating a vicious cycle. In patients with hemophilia who develop oral PGs, early treatment with factor concentrate and antifibrinolytic agents can help break this cycle of oral injury and bleeding and lead to more rapid lesion resolution. Early institution of primary prophylaxis can reduce bleeding and tissue irritation and thereby prevent the development of complications such as PGs. In addition, in patients presenting with PGs, especially lesions with a hemorrhagic component, hemophilia, and other bleeding disorders should be considered as underlying predisposing conditions. REFERENCES 1. McMillan JA, Oski FA. Oski’s Pediatrics: Principles & Practice, XL. Philadelphia: Lippincott Williams & Wilkins; 2006:2808. 2. Habif TP. Clinical Dermatology: a Color Guide to Diagnosis and Therapy, XV. New York: Mosby, Edinburgh; 2004:1004. 3. Kliegman R, Nelson WE. Nelson Textbook of Pediatrics, LXVII. Philadelphia, PA: Elsevier/Saunders; 2011:2610. 4. Jafarzadeh H, Sanatkhani M, Mohtasham N. Oral pyogenic granuloma: a review. J Oral Sci. 2006;48:167–175. 5. Craig LM, Alster TS. Vascular skin lesions in children: a review of laser surgical and medical treatments. Dermatol Surg. 2013;39:1137–1146. 6. Bakshi J, Virk RS, Verma M. Pyogenic granuloma of the hard palate: a case report and review of the literature. Ear Nose Throat J. 2009;88:E4–E5. 7. Lee J, Sinno H, Tahiri Y, et al. Treatment options for cutaneous pyogenic granulomas: a review. J Plast Reconstr Aesthet Surg. 2011;64:1216–1220. 8. Gomes SR, Shakir QJ, Thaker PV, et al. Pyogenic granuloma of the gingiva: a misnomer?—A case report and review of literature. J Indian Soc Periodontol. 2013;17:514–519. 9. Kamal R, Dahiya P, Puri A. Oral pyogenic granuloma: various concepts of etiopathogenesis. J Oral Maxillofac Pathol. 2012;16:79–82. 10. Yuan K, Jin YT, Lin MT. Expression of Tie-2, angiopoietin-1, angiopoietin-2, ephrinB2 and EphB4 in pyogenic granuloma of human gingiva implicates their roles in inflammatory angiogenesis. J Periodontal Res. 2000;35:165–171. 11. Heim M, Schapiro J, Wershavski M, et al. Drug-induced and traumatic nail problems in the haemophilias. Haemophilia. 2000;6:191–194. 12. Rodriguez-Merchan EC. Surgical wound healing in bleeding disorders. Haemophilia. 2012;18:487–490. 13. Hoffman M, Monroe DM. Wound healing in haemophilia— breaking the vicious cycle. Haemophilia. 2010;16(suppl 3):13–18. r
2014 Lippincott Williams & Wilkins
AND
LABORATORY OBSERVATIONS
Oral Pyogenic Granuloma in Hemophilia: A Report of 2 Cases Holly Lindsay, MD* and Lakshmi V. Srivaths, MDw
Summary: Pyogenic granulomas (PGs) are benign vascular lesions occurring in skin and mucous membranes, often secondary to trauma or chronic inflammation. Oral PGs have never been described previously in hemophilia. We describe 2 pediatric patients with hemophilia A, who developed PGs with inadequate factor therapy for bleeding. PG pathophysiology suggests an association with hemophilia given chronic vascular damage and low-grade inflammation at sites of bleeding in hemophilia patients. Knowledge about the occurrence of PGs in hemophilia patients is essential for prompt diagnosis and early institution of factor therapy, which in turn allows more rapid cessation of bleeding and lesion involution. Key Words: pyogenic granuloma, hemophilia, children
(J Pediatr Hematol Oncol 2014;36:e333–e334)
A
lthough pyogenic granulomas (PGs) are relatively common dermatologic lesions of childhood, there is a paucity of information in the literature about the presence of this complication in patients with hemophilia. We describe 2 patients with hemophilia A, one with previously undiagnosed mild disease and the other with severe disease, who developed oral PGs with inadequate factor therapy for bleeding. We present the etiologies and discuss the pathophysiology of PGs and highlight the need for prompt diagnosis and management of this condition in patients with hemophilia.
PATIENT PRESENTATIONS Patient 1 is a 4-year-old male child previously undiagnosed with a bleeding disorder who presented to our institution after developing 2 PGs of the tongue. Two painless hemorrhagic papules on each side of the patient’s tongue were noted by parents due to their intermittent bleeding and enlargement over 7 to 10 days (Fig. 1). The patient was initially seen in an urgent care center and then by his primary care physician, who subsequently referred the patient to our institution’s emergency center. The lesions were diagnosed as PGs based on their physical appearance. Because of the hemorrhagic appearance of the lesions, prolonged lesional bleeding, the patient’s history of easy bruising and bleeding, and a striking family history of heavy menses as well as prolonged bleeding after delivery and miscarriages in the mother and maternal aunt, respectively, a bleeding disorder evaluation was initiated. The laboratory work-up was significant for a partial Received for publication January 22, 2014; accepted February 19, 2014. From the *Fellow in Pediatric Hematology and Oncology; and wDepartment of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine/Texas Children’s Hospital, Houston, TX. The authors declare no conflict of interest. Reprints: Holly Lindsay, MD, Fellow in Pediatric Hematology and Oncology, Baylor College of Medicine, 1102 Bates, Ste 1030.20J, Houston, TX 77030 (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
J Pediatr Hematol Oncol
Volume 36, Number 5, July 2014
thromboplastin time of 42.7 seconds (normal, 24.9 to 34.3 s). Further coagulation work-up revealed low factor 8 level of 12% (normal, 47% to 169%), thereby confirming the diagnosis of mild hemophilia A. The patient’s PGs spontaneously involuted and slowly resolved over the subsequent weeks, leaving residual hypopigmentation and tissue atrophy at the sites. No factor replacement was given due to the delay in diagnosis of hemophilia and delayed presentation to a pediatric hematologist. Patient 2 was diagnosed with severe hemophilia A as a neonate after work-up of prolonged bleeding following a heel stick and otherwise routine circumcision. The patient was followed regularly at our institution’s Hemophilia Treatment Center for comprehensive hemophilia care and was not receiving prophylactic factor infusions as he had no history of major bleeding episodes or hemarthrosis. At 16 months, this patient developed intermittent bleeding at the upper frenulum likely caused by minor trauma. The intermittent bleeding, for which the patient presented to the emergency department thrice over a 2-month period, was treated with single doses of recombinant factor 8 infusions. Owing to parental concern about persistent bleeding, the patient was later evaluated by the treating hematologist, at which time he was diagnosed with a frenulum PG. Subsequently, therapy was initiated with daily factor 8 infusions and oral aminocaproic acid for 7 days which led to complete resolution of the lesion and cessation of bleeding. The patient has since been started on prophylactic factor infusions due to frequent bleeding episodes and large soft-tissue hematomas.
DISCUSSION PGs are benign acquired vascular lesions that occur most frequently on skin and mucous membranes, usually the head and neck region and extremities. They are commonly seen in children and young adults in the second or third decades of life and may also occur during pregnancy. The term PG is a misnomer as the vascular overgrowth is neither pyogenic nor a true granuloma; instead PGs are caused by inflammatory dermal capillary hyperplasia initiated by trauma, infection, hormonal changes, medications including immunosuppressants, or chronic low-grade local irritation. The lesions may initially grow rapidly and ulcerate; they are usually solitary and generally nontender, with size ranging from a few millimeters to 2.5 cm. Of the oral PGs reported, gingival lesions are the most common, followed by those on the lips, tongue, and buccal mucosa. As PGs are both vascular and fragile, the lesions bleed easily even in patients without underlying bleeding disorders.1–8 There is evidence that PG pathophysiology may be due to increased fibroblast synthetic activity leading to disordered protein metabolism.6 Other researchers hypothesize that PGs are triggered by the entry of infectious organisms into mucosa after minor trauma leading to disregulated proliferation of www.jpho-online.com |
e333
Lindsay and Srivaths
FIGURE 1. Pyogenic granuloma of the tongue in a patient (patient #1) with hemophilia.
surrounding vascular connective tissue.9 Other evidence suggests that the etiology of PG is stimulation of capillary angiogenesis from venules following upregulation of various vascular morphogenesis factors including angiopoeitin-1 and 2 and tie-2.10 Treatment options for PGs include cauterization, excision, cryotherapy, and laser therapy, although spontaneous resolution usually occurs within 6 months.1–8 Ours is the first report of oral PGs occurring in patients with hemophilia. A previous report by Heim and colleagues illustrates 3 patients with hemophilia who developed PGs of the toes secondary to trauma from ingrown nails. All patients had HIV in addition to hemophilia and were on chronic antiretroviral therapy.11 We believe the occurrence of oral PGs in our patients was at least in part due to the delayed diagnosis of hemophilia and/or inadequate therapy that led to continued lesional bleeding and recurrent tissue irritation. Animal data and clinical evidence suggest that patients with bleeding disorders have impaired wound healing with increased risk of hematoma formation, infections, skin necrosis, and wound dehiscence. The first phase of wound healing is hemostasis, and if circulating factors levels are insufficient to both initiate and sustain hemostasis, the subsequent phases of wound healing—inflammation, proliferation, and remodeling—cannot function appropriately.12,13 Poor wound healing and the resultant prolonged bleeding and tissue irritation likely potentiated the development of PGs in our patients. Optimal factor replacement is essential for hemophilia patients who develop PGs to achieve adequate hemostasis, which can in turn promote fast healing of the lesions and minimize the need for surgical interventions. In our first patient, the PGs developed before his diagnosis of hemophilia; consequently, hemostatic therapy
e334 | www.jpho-online.com
J Pediatr Hematol Oncol
Volume 36, Number 5, July 2014
was not provided, leading to continued enlargement and bleeding of the lesions. In our second patient, there was a delay in the diagnosis of PG; factor therapy was thus initially inadequate, leading to frequent reinjury at the site, increased bleeding events, and prolongation of the time to PG resolution. It is reassuring to note that the oral PG in patient 2 involuted once hemostasis was attained without the need for surgical intervention. This case report highlights the fact that it is important to institute appropriate treatment with continued factor replacement in a timely manner in hemophilia patients with PGs, to minimize the need for surgical interventions. Whereas simple mucosal bleeding in patients with hemophilia may resolve with antifibrinolytic agents with or without a single dose of factor infusion, PGs appear to need prolonged therapy for complete resolution. We hypothesize that PGs occur in hemophilia patients due to tissue inflammation from vascular trauma and prolonged bleeding; the resultant increase in circulating systemic inflammatory markers likely promotes the growth of these vascular lesions which in turn bleed easily, initiating a vicious cycle. In patients with hemophilia who develop oral PGs, early treatment with factor concentrate and antifibrinolytic agents can help break this cycle of oral injury and bleeding and lead to more rapid lesion resolution. Early institution of primary prophylaxis can reduce bleeding and tissue irritation and thereby prevent the development of complications such as PGs. In addition, in patients presenting with PGs, especially lesions with a hemorrhagic component, hemophilia, and other bleeding disorders should be considered as underlying predisposing conditions. REFERENCES 1. McMillan JA, Oski FA. Oski’s Pediatrics: Principles & Practice, XL. Philadelphia: Lippincott Williams & Wilkins; 2006:2808. 2. Habif TP. Clinical Dermatology: a Color Guide to Diagnosis and Therapy, XV. New York: Mosby, Edinburgh; 2004:1004. 3. Kliegman R, Nelson WE. Nelson Textbook of Pediatrics, LXVII. Philadelphia, PA: Elsevier/Saunders; 2011:2610. 4. Jafarzadeh H, Sanatkhani M, Mohtasham N. Oral pyogenic granuloma: a review. J Oral Sci. 2006;48:167–175. 5. Craig LM, Alster TS. Vascular skin lesions in children: a review of laser surgical and medical treatments. Dermatol Surg. 2013;39:1137–1146. 6. Bakshi J, Virk RS, Verma M. Pyogenic granuloma of the hard palate: a case report and review of the literature. Ear Nose Throat J. 2009;88:E4–E5. 7. Lee J, Sinno H, Tahiri Y, et al. Treatment options for cutaneous pyogenic granulomas: a review. J Plast Reconstr Aesthet Surg. 2011;64:1216–1220. 8. Gomes SR, Shakir QJ, Thaker PV, et al. Pyogenic granuloma of the gingiva: a misnomer?—A case report and review of literature. J Indian Soc Periodontol. 2013;17:514–519. 9. Kamal R, Dahiya P, Puri A. Oral pyogenic granuloma: various concepts of etiopathogenesis. J Oral Maxillofac Pathol. 2012;16:79–82. 10. Yuan K, Jin YT, Lin MT. Expression of Tie-2, angiopoietin-1, angiopoietin-2, ephrinB2 and EphB4 in pyogenic granuloma of human gingiva implicates their roles in inflammatory angiogenesis. J Periodontal Res. 2000;35:165–171. 11. Heim M, Schapiro J, Wershavski M, et al. Drug-induced and traumatic nail problems in the haemophilias. Haemophilia. 2000;6:191–194. 12. Rodriguez-Merchan EC. Surgical wound healing in bleeding disorders. Haemophilia. 2012;18:487–490. 13. Hoffman M, Monroe DM. Wound healing in haemophilia— breaking the vicious cycle. Haemophilia. 2010;16(suppl 3):13–18. r
2014 Lippincott Williams & Wilkins
![[Pyogenic granuloma of the oral mucosa].](/assets/img/hold.png)
