Clinical Spectrum of Autoerythrocyte Sensitization Syndrome: A Series of Five Cases.

Autoerythrocyte sensitization syndrome (Gardner Diamond syndrome or GDS) is a rare syndrome characterized by painful and spontaneous purpura commonly affecting adult women, and is mostly associated with psychiatric illness. Diagnosis is mainly based on clinical presentation, exclusion of other simulating diseases, and psychiatric evaluation. Only few cases have been reported till date. We report five cases of spontaneous purpura with a normal investigation profile, except for iron deficiency anemia in 1 patient, of which three had associated underlying psychiatric illness. Autoerythrocyte sensitization test was positive in all our cases. Patients presenting with painful bruises without significant medical history such as underlying bleeding disorder or drug history or history of trauma should be considered for autoerythrocyte sensitization syndrome, and managed accordingly. The present study is a case series of patients with characteristic features of autoerythrocyte sensitization syndrome, considering the rarity of the reports on its clinical spectra.

Introduction

Autoerythrocyte sensitization syndrome was first described by Gardner and Diamond in 1955 in four women with painful spontaneous bruising.[1] Though exact cause remains unknown, it is regarded as an autoimmune vasculopathy with sensitization to phosphatidylserine, a component of erythrocyte stroma. It is characterized by recurrent, painful, and spontaneous purpuramainly affecting adult females, and is associated with psychiatric illness. We herein present five cases of autoerythrocyte sensitization syndrome.

Table 1 depicts the clinical spectrum of all our cases.

Table 1

Clinical spectrum of the cases

Case Reports

Case 1

A 29-year-old biparous woman presented with 1 week duration of painful spontaneous skin bruises over the lower extremities for the first time [Figure 1]. The lesions were described as multiple edematous, red to bluish black rashes which were preceded by pain and burning sensation. There was no personal or family history of bleeding disorders. There was no history of trauma or recent drug intake.

Figure 1

Multiple edematous, red to bluish black macules on the lower limb

On examination, there were multiple, well-defined, irregularly shaped tender ecchymosis over bilateral thighs and legs. Psychiatric evaluation revealed previous episodes of anxiety and depression before marriage which were relieved with psychotherapy. She had mild anxiety and depression at the time of presentation. Routine investigations including complete hemogram, coagulation profile, thyroid, kidney, and liver function tests were within normal limits.

An intradermal test for autoerythrocyte sensitization was performed by injecting 0.1 ml of the patient's washed red blood cells on the flexural aspect of the left forearm. There was burning sensation at the injection site followed 2 hours later by the development of an oval, purpuric lesion [Figure 2]. Intradermal injection of 0.1 ml saline used as control on the same arm caused no reaction.

Figure 2

Autoerythrocyte Sensitisation Test showing an oval, purpuric lesion on the test site while control was normal

Case 2

A 25-year-old uniparous woman, presented with 1-month history of first episode of painful spontaneous bruises all over the body. There was no personal or family history of bleeding disorders. There was no history of trauma or significant drug history. Her medical history revealed recurrent depressive mood for which she had not received any treatment. She also complained of headache, myalgia, arthralgia, and fatigue. Physical examination revealed multiple, irregularly shaped, tender ecchymoses of varying sizes over bilateral upper limbs and legs, forehead, neck, and right retroauricular areas. Autoerythrocyte sensitization test was positive. Routine laboratory parameters were normal; however, low hemoglobin (6.4 g/dl), altered iron profile (ferritin-4.3 ng/ml, Serum iron– 20 μg/dl, TIBC – 385 μg/dl) and a very high ESR (122 mm/1st h) was noted. Peripheral smear showed moderate anisopoikilocytosis and microcytic hypochromic anemia with a few elliptocytes and pencil cells. Transferrin saturation index was 5.1. Bone marrow examination showed ineffective erythropoiesis suggestive of iron deficiency anemia.

Case 3

A 22-year-old unmarried female presented with a 1-year history of frequent episodes of painful skin bruises over the lower limbs. The lesions were sudden in onset, aggravated in severity and frequency when she was depressed or stressed, and were not associated with any injury, self-harm, or drug intake. She had not received any treatment for previous episodes. Examination revealed single oval-shaped tender ecchymosis over the thigh of 4 × 3 cm size. Autoerythrocyte sensitization test was positive. Routine investigations including coagulation profile were within normal limits.

Case 4

A 38-year-old biparous woman presented with 3-month history of recurrent, spontaneous, painful skin bruises over the lower limbs. There was no significant positive medical or personal history. It was not associated with emotional fluctuations, and psychiatric mental examination was normal. Physical examination showed oval-shaped, tender ecchymosis over the right leg of 3 × 4 cm size. Autoerythrocyte sensitization test was positive. Routine investigations including coagulation profile were within normal limits.

Case 5

A 45-year-old multiparous woman presented with a 1-month history of spontaneous skin bruises. There was no significant positive history or psychiatric comorbidities. Physical examination revealed multiple, oval-shaped tender ecchymosis over the thighs, legs, and upper chest of varying sizes. Autoerythrocyte sensitization test was positive. Routine investigations including coagulation profile were within normal limits.

Discussion

Autoerythrocyte sensitization syndrome (AES) is a rare clinical syndrome of unknown etiology characterized by recurrent bruising, usually following a physical or psychosocial stress. It is most prevalent among women 19–72 years of age.[1] All our cases were of women aged 22–45 years. However, many cases have been reported in men and children as well. AES in men accounts for 5% of all cases as reported by Ratnoff et al.[2]

Duration of the complaints ranged from 1 week to 1 year, with an average of 3.45 months among our patients. In other Indian reports, duration ranged from 1½ months to 3 years.[34] Two patients had recurrent symptoms whereas other three were diagnosed during the first episode itself. Only 1 patient reported pain and burning sensation preceding the ecchymosis. A prodrome stage consisting of malaise, fatigue, etc., has been described. In one case report, frontal headache was preceded by each episode.[5] Furthermore, other symptoms such as fever, arthralgia, myalgia, epistaxis, gastrointestinal hemorrhages, hemarthrosis, menorrhagia, hematuria, and intracranial bleed have been reported.[4] One patient in the present series complained of headache, myalgia, arthralgia, and fatigue prior to skin symptoms.

None of the patients gave a history of trauma as a trigger factor. Only 1 patient revealed the association of emotional stress before each episode of bruising. It has been reported that the development of bruises usually is preceded by slight mechanical injuries, stress, surgical procedures, and hard physical work, though they can develop spontaneously as well.[4] None of the patients had any bleeding diathesis or any recent medication intake. Routine blood parameters and coagulation profiles were within normal limits, except for a single patient who showed features suggestive of iron deficiency anaemia. However, several hematological findings have been described associated with AES such as thrombocytosis, defective thrombocyte aggregation, increased activated partial thromboplastin time, morphological abnormalities in RBCs, functional platelet defect, idiopathic thrombocytopenic purpura, and abnormally increased tissue plasminogen activator (tPA)-dependent cutaneous fibrinolytic activity.[16]

Autoerythrocyte sensitization test (AEST) was positive in all the cases. In their original pioneer work, Gardner and Diamond evoked the typical lesions by intradermal injection of erythrocytic stroma. This led them to suggest an association of the disease with auto-sensitization of patients to their own blood, mainly to phosphatidylserine [phosphoglyceride of red blood cell (RBC) membrane].[1] However, Groch et al. failed to elicit a positive reaction by injecting phosphatidylserine directly.[7] Some authors have revealed auto-sensitization to hemoglobin and deoxyribonucleic acid as well as disturbance in the tonus regulation of the venous capillaries due to fluctuations in the kallikrein–kinin system as the probable pathogenesis of AES.[18] However, in the largest series of 71 patients of GDS, Ratnoff et al. observed AEST positivity in 59% patients only.[9] Therefore, a negative AEST does not eliminate the diagnosis of GDS. Biopsy was not taken as it is nonspecific to the diagnosis.

Lack of clarity in the pathogenesis of AES led investigators to suggest psychiatric comorbidities as an important contributing factor. Three of our patients were suffering from psychiatric diseases with depression among all three and anxiety in one. According to Agle and Ratnoff, AES can be a reaction of the body to psychosomatic conditions to attain relief from symptoms, and the autonomic nervous system may play a pivotal role in the process.[10] However, Zhao et al. suggested the pathogenesis as synergism between the psycho-immunology and mechanical injury of the skin in which pre-existing psychosomatic instabilities might disturb the skin's immunological function and weaken the skin's blood capillaries, so that even a mild trauma of the skin would damage the capillary walls and eventually result in the permeation of red corpuscles.[10] Such psychosomatic instabilities include emotional stress, hysteria, masochism, egoistic characters, emotional liabilities, self-injuries, difficulty in suppression of aggression, depression, aphonia, paralysis, paresthesia, dissociative disorders with convulsions, hallucinations, and syncope.[411] All three of our patients with psychiatric conditions were managed exclusively with cognitive behavioral therapy. Numerous medications have been proposed according to the type and severity of psychiatric symptoms, however, better responses have been observed with psychotherapy.[12]

Conclusion

Autoerythrocyte sensitization syndrome is a rare disorder with only few cases reported till date. Because of the benign nature, most cases could have been ignored, unreported, or underdiagnosed. Patients presenting with painful bruises without any history of trauma or bleeding disorder and normal hematological findings should be referred for proper psychiatric evaluation, and AEST can be done to aid early diagnosis. It will save patients from undergoing unnecessary and costly investigations.

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Conflicts of interest

There are no conflicts of interest.