Oral manifestations of thrombocytopaenia.

The appearance in the mouth of haemorrhagic petechiae, ecchymoses or blood blisters with spontaneous bleeding is suggestive of a haemorrhagic disorder that may be caused either by functional impairment of platelets or of blood vessel walls, by an abnormal decrease in the number of circulating platelets (thrombocytopaenia), or by defects in the blood clotting mechanism. Thrombocytopaenia from decreased production or increased destruction of platelets may be caused by multiple factors including immune mediated mechanisms, drugs or infections. A diagnosis of thrombocytopaenic purpura can be made when any other disease entity that might be causing the purpura is excluded on the basis of the medical history, the physical examination, a complete blood count and a peripheral blood smear. In this paper, we outline the clinical features of oral thrombocytopaenic purpura and briefly discuss some aspects of its aetiopathogenesis and treatment.

Introduction

Thrombocytopaenic purpura is a haemorrhagic disorder characterized by an abnormal reduction in the number of circulating platelets with the extravasation of blood from small blood vessels, affecting particularly the mucous membranes of the aerodigestive and the genitourinary tracks, and the skin (Rajendran and Nooh, 2012, Parke et al., 2013, Mccarthy and Shklar, 1964, Aster, 2005, Rodeghiero et al., 2013). Melaena, haematuria, epistaxis, gingival bleeding or excessive menstrual flow may be the first signs of the disease (Aster, 2005); intracranial bleeding caused by thrombocytopaenia is a life-threatening condition (Aster, 2005).

According to the severity, oral thrombocytopaenic purpura manifests as small single or multiple petechial haemorrhages, as ecchymosis, as haemorrhagic blisters or as spontaneous bleeding (Fig. 1, Fig. 2, Fig. 3, Fig. 4) (McCarthy and Shklar, 1964). In the mouth, the thrombocytopaenic lesions are usually on the soft tissues most susceptible to trauma, such as the buccal mucosa from cheek biting, the junction between the hard and soft palate in denture wearing subjects or the gingiva (Regezi and Sciubba, 1989). The extravasated blood is gradually resorbed over a period of a few days, but in larger lesions resolution will take longer, and in the case of haemorrhagic blisters the overlying epithelium may slough and the resulting erosion may become secondarily infected (McCarthy and Shklar, 1964).

Fig. 1

A 42-year-old female attended for multiple haemorrhagic bullae affecting her lower labial mucosa and dorsum of the tongue (a); right buccal mucosa (b) and palate (c). There was spontaneous bleeding of the lower lingual gingiva (d) and upper palatal gingiva. A full blood count was normal excepting for her platelet count: 4000/mm3 (normal range: 150,000–400,000) and MCHC was marginally low: 29.9 g/dl (normal range: 31.5–34.5). She reported that two days previously she had had continuous bleeding from the mouth and she then noticed the oral lesions. She was treated in the Department of Haematology but the details of the treatment are not available: the spontaneous bleeding resolved and 48 h later the oral lesions were in the process of healing. The cause of her thrombocytopaenia remains unknown.

Fig. 2

A 24-year-old female attended for multiple haemorrhagic bullae affecting the left buccal mucosa (a), multiple scattered petechiae of the tongue, lower lip and elsewhere (b), and a haemorrhagic vesicle on the lower lip (c). Some of the lesions were bleeding (d). A full blood count is given in the above table. She reported that bleeding from her mouth had started three days before the consultation when she had also noticed the oral lesions which she thought were becoming worst. After a blood transfusion, the oral bullae and petechiae started to get better.

Fig. 3

41-year-old HIV-seropositive female on HAART with a CD4+ T cell count of 402 cells/mm3 was referred by the Department of Haematology with multiple petechiae and bullae of the lower lip and dorsum of the tongue (a) and dried out bullae on the soft palate (b). A full blood count was given in the above table. The patient reported that her mouth had started bleeding about two weeks previously and that the lesions in her mouth had become more numerous and widespread since she first noticed them. She was then treated with a blood transfusion in the Department of Haematology and by the time of our consultation a few days later, the lesions were already somewhat better and the bleeding had stopped.

Fig. 4

A 42-year-old HIV-TB co-infected HAART-naïve female with multiple haemorrhagic bullae on the dorsum of the tongue (a) and lower labial mucosa (b), reported that the lesions had been present for three weeks and were getting progressively worst. Patient was referred to the Department of Haematology, where she was diagnosed with idiopathic thrombocytopaenia and was treated with a blood transfusion. She was also referred to the local HIV clinic for treatment of HIV-TB co-infection. The results of her blood test were not available.

Oral haemorrhagic purpura can be brought about not only by diminution in the number of circulating platelets but also by impairment of their functional activity, by defects in blood clotting or by abnormalities of blood vessel walls. Exclusion of other haemorrhagic disorders will enable prompt diagnosis of the thrombocytopaenia and its treatment (McCarthy and Shklar, 1964).

There are no clear-cut guidelines to the management of thrombocytopaenic patients who are going to receive dental or oral surgical treatment; but in general if the platelet count is below 50,000/mm3, it is advisable to administer an infusion of platelets and to treat any oral or dental condition that may cause local bleeding in hospital (Scully et al., 2007).

The purpose of this paper is to inform the general dental practitioner about the clinical presentation, diagnosis, course, aetiopathogenesis and management of oral thrombocytopaenic purpura.

Thrombocytopaenia

The normal count of platelets in the blood ranges from 150,000 to 450,000/mm3 (Konkle, 2010, Handin, 2005) and the average lifespan of platelets ranges from 7 to 12 days (Scully, 2014). Thrombocytopaenia is defined as a platelet count below 150,000/mm3 (Ganda, 2008) and it has been classified into mild, moderate, severe and life threatening based on the platelet count (Table 1) (Scully, 2014, Scully et al., 2007). However, there is no direct correlation of platelet count with clinical signs and symptoms, so such a classification is not of great clinical value (Vinholt et al., 2014, Handin, 2005, Aster, 2005). Regardless of the platelet count, recurrent spontaneous bleeding is the determinant of whether treatment is necessary (Aster, 2005, Rodeghiero et al., 2013, Rodeghiero et al., 2009). Despite prolonged bleeding time, protrombin time (PT) and partial tromboplastin time (PTT) remain normal in thrombocytopaenic subjects (Aster, 2005).

Table 1

The severity of thrombocytopaenia in relation to oral manifestations.

Platelet count × 103/mm3	Severity of thrombocytopaenia	Manifestations
100–150	Mild	Normal mucosaSometimes slight increase in postoperative bleeding
50–100	Moderate	Postoperative bleedingPossible petechial and ecchymosis
30–50	Severe	Sometime spontaneous bleedingMultiple petechial haemorrhageEcchymosis, blood blisters
<30	Life-threatening	Spontaneous bleeding

There is a dynamic equilibrium between the number of platelets produced in the bone marrow and the number sequestered in the spleen, maintaining a stable pool of circulating platelets. A decrease in the number of circulating platelets brings about an increase in the production of the hormone thrombopoietin by the liver. This in turn stimulates bone marrow megakaryocytes, increasing the production and the release of platelets into the circulation (Kuter, 2014, Handin, 2005, Grozovsky et al., 2015). Splenomegaly, whatever its cause, results in an increase in the sequestration of platelets, and if this exceeds the rate of production, thrombocytopaenia will develop (Konkle, 2010).

Causes of thrombocytopaenia

Thrombocytopaenia may be brought about by decreased production of platelets by megakaryocytes in the bone marrow, by increased destruction of platelets in the circulation, and by abnormal sequestration of platelets in the spleen (Table 2) (Konkle, 2010, Rajendran and Nooh, 2012). Bone marrow aplasia, fibrosis, infiltration by malignant cells, and the effect of cytotoxic drugs or infective agents are the most common causes of bone marrow suppression (Table 2). Although thrombocytopaenia may occur as the sole outcome of bone marrow dysfunction, more often than not bone marrow suppression also affects the production of white and red blood cells, so that thrombocytopaenia is accompanied by anaemia and leukopaenia (Rajendran and Nooh, 2012).

Table 2

Some causes of thrombocytopaenia. Certain drugs and infective agents may cause thrombocytopaenia by both decreasing production and increasing destruction of platelets.

1. Decreased production of platelets by the bone marrow

• Hypoplasia or aplasia of megakaryocytes

○ Ionizing radiation

○ Drugs and chemicals (e.g. cytotoxic drugs, certain antibiotics, antidiabetic, anticonvulsive, sedative and tranquilizers, insecticides, heavy metals and a variety of other agents)

○ Congenital conditions

○ Idiopathic

• Infiltration of bone marrow

○ Leukaemia, multiple myeloma, histiocytosis, metastatic tumours

• Metabolic disorders

○ Hypothyroidism, azothemia

• Infections

○ Bacterial, viral, protozoan and metazoan diseases

2. Sequestration of platelets, usually in an enlarged spleen

3. Increased destruction of platelets

• Infection - induced thrombocytopenia

• Drug - induced thrombocytopenia

• Immune - mediated thrombocytopenia

• Idiopathic thrombocytopenia

Increased destruction of circulating platelets is common in persons with established thrombotic thrombocytopaenic purpura, haemolytic uraemic syndrome and as a manifestation of disseminated intravascular coagulation. In addition, destruction of circulating platelets can be induced by drugs or infections, may be immune-mediated or may be idiopathic (Konkle, 2010). Certain drugs can directly affect platelets, but most drugs that cause thrombocytopaenia do so by eliciting an anti-platelet immune response (Konkle, 2010, Liu et al., 2013): in cases of infections, the infective agent may induce the production of antibodies that cross react with platelet surface antigens causing their elimination (Bettaieb et al., 1992). Drug- and infection-induced thrombocytopaenia usually resolves after withdrawal of the drug, or after resolution of the infection (Konkle, 2010).

Immune thrombocytopaenia with purpura is an acquired auto-immune disorder (Liu et al., 2013) that is considered ‘secondary’ when it is associated with other autoimmune diseases particularly lupus erythematosus and autoimmune lymphoproliferative syndrome, or with certain infective agents such as HIV, hepatitis C virus, cytomegalovirus and Helicobacter pylori (Konkle, 2010).

Autoantibodies directed against the glycoprotein (GP) GPIIb-IIIa on the platelet surface, or against as yet an unidentified platelet antigen, or the formation of immune complexes on platelet surfaces result in increased platelet clearance (Scully, 2014, Louache et al., 1991). In those persons with immune thrombocytopaenic purpura who do not have autoantibodies against platelets, activated cytotoxic T cells probably destroy the platelets (Cines et al., 2014, Olsson et al., 2003). As megakaryocytes express some antigenic glycoproteins identical to those of platelets, the same immune response against megakaryocytes will also cause impairment of platelet production bringing about thrombocytopaenic purpura (Konkle, 2010). Thus, immune-mediated thrombocytopaenia is caused both by a decrease in production of platelets in the bone marrow, and by an increase in clearance of circulating platelets (Kashiwagi and Tomiyama, 2013).

Diagnosis, evaluation and management of a patient with thrombocytopaenia

A diagnosis of thrombocytopaenia is predicated by a count of circulating platelets below 150,000/mm3 (Grozovsky et al., 2015). A comprehensive history of drug usage, illnesses, a thorough physical examination, a complete blood count and a peripheral blood smear are all essential for the initial evaluation of the thrombocytopaenic patient (Konkle, 2010, Provan et al., 2010). Importantly, there are no clinical or laboratory predictors of the course of thrombocytopaenia (Rodeghiero and Ruggeri, 2014), and the differential diagnosis of purpura is more complex for elderly, ill persons on medications, than for otherwise healthy young adults (Konkle, 2010).

Serological testing for antibodies against platelets is seldom helpful because of the low specificity and sensitivity of the tests; and bone marrow investigation is usually necessary for those who do not respond to treatment. The diagnosis of primary immune thrombocytopaenic purpura is based on the exclusion of other causes of purpura. A peripheral blood smear allows for identification of abnormalities in size and morphology of platelets: in immune thrombocytopaenic purpura the morphology of the platelets is normal, but they may be abnormally large (Aster, 2005, Provan et al., 2010). If there has been significant bleeding owing to thrombocytopaenia there will be microcytic anaemia; however, if the thrombocytopaenia is the result of bone marrow suppression of whatever cause, then there may be macrocytic anaemia (Provan et al., 2010).

Thrombocytopaenic purpura manifests clinically as mucocutaneous petechiae, ecchymoses and haemorrhagic blisters with spontaneous bleeding (Fig. 1, Fig. 2, Fig. 3, Fig. 4). The severity of the clinical manifestations does not always correlate with the platelet count (Vinholt et al., 2014), but the presence of a haemorrhagic blister in the oral cavity may serve as an indicator for spontaneous intracranial haemorrhage (Konkle, 2010).

Thrombocytopaenia should be treated when there is spontaneous bleeding or if the platelet count falls below 30,000/mm3 (Konkle, 2010). In the absence of spontaneous bleeding, the decision as to the treatment of thrombocytopaenia when the platelet count is above 30,000/mm3 is dictated by the patient’s age, gender, medications and comorbidities (Rodeghiero and Ruggeri, 2014, Provan et al., 2010).

Severe thrombocytopaenia not of immune origin should be treated with transfusion of platelets. On the other hand immune thrombocytopaenia should be treated with systemic glucocorticoids, or with cytotoxic chemotherapy, but not with platelet transfusion because the host anti-platelet immunoglobulins will destroy the transfused platelets (Ganda, 2008, Scully et al., 2007). However, regardless of the pathogenesis, established thromboctyopaenic bleeding must be treated by transfusion of platelets (Scully, 2014).

Thrombocytopaenia in relation to HIV infection

Thrombocytopaenia is the most frequent haematological disorder associated with HIV infection. Cross reaction of antibodies in response to HIV gp120 with certain platelet glycoproteins will promote clearance of the platelets, and the direct effect of HIV on megakaryocytes in the bone marrow may impair platelet production (Scully, 2014). Thus both increased platelet destruction and diminished platelet production are implicated in the pathogenesis of HIV-associated thrombocytopaenia (Bettaieb et al., 1992, Louache et al., 1991).

Conflict of interest

The authors declared that there is no conflict of interest.

Funding

No funding was received for this paper.

Competing interest

None.

Ethical approval

Approved: SMUREC/D/295/2015: Case Presentation (J).