Managementul trombocitopeniei imune: o provocare între protocoalele standard și cazurile refractare, între formele primare idiopatice și formele secundare – prezentare de caz

Introduction

Immune thrombocytopenia (ITP) is a rare autoimmune disorder characterized by isolated thrombocytopenia (platelet count below 100,000/mm³), which can be classified as primary or secondary, based on the existence of underlying diseases or a triggering factor⁽¹⁾. The pathogenesis of ITP is complex and still not completely understood. Multiple mechanisms, such as autoantibodies, complement and T cells, have been described in ITP, highlighting the heterogeneous nature of this disease^(2-5).

Clinical features of primary and secondary immune thrombocytopenia are generally similar, manifested by mucocutaneous bleeding. Different clinical characteristics and pathophysiology still need to be evaluated in different subsets of ITP patients for a better management of immune thrombocytopenia^(4,6).

Positive diagnosis is still a real challenge, and it is based on clinical history, clinical examination and the exclusion of other causes of thrombocytopenia (infections, autoimmune disorders, hematologic malignancies, liver diseases). Failure in demonstrating the presence of an underlying pathology leads to the diagnosis of primary immune thrombocytopenia⁽⁷⁾.

Association of rheumatoid arthritis (RA) with immune thrombocytopenia is a very rare condition; very few cases have been reported in the literature, mostly patients from Japan. ITP can be diagnosed before the onset of RA, simultaneously with or after the diagnosis of rheumatoid arthritis^(8-10).

In this article, we report the case of a middle-aged male patient, with a background of undifferentiated connective tissue disease. He was diagnosed with immune thrombocytopenia, without response to corticotherapy.

Case presentation

We present the case of a 51-year-old patient who was diagnosed with undifferentiated connective tissue disease, treated with steroids and anti-inflammatory drugs. Two years later, he was diagnosed with immune thrombocytopenia. Different types of steroids were administered (dexamethasone, methylprednisolone, prednisone), but with no rise in the platelet count. Immunotherapy with azathioprine was also administered as a second-line therapy, without result. During treatment, he developed type 2 diabetes mellitus and Cushing’s syndrome secondary to prolonged steroid administration.

Six months after the immune thrombocytopenia diagnosis, he was admitted in our hematology department. The clinical evaluation revealed generalized hemorrhagic syndrome with extensive purpuric rash (legs, abdominal, thorax etc.), muscular weakness, myalgia and important Cushing syndrome’s signs (weight gain, fatty deposits on midsection, face and between the shoulders and the upper back, purple stretch marks on abdomen and thighs), without organomegaly or lymphadenopathy.

A complete blood count (CBC) revealed severe thrombocytopenia, with a platelet (PLT) count of 26,000/µL and leukocytosis (11,300/µL), probably secondary to corticotherapy. A peripheral blood smear (PBS) revealed no morphological abnormalities in leukocytes, erythrocytes and platelets. The platelets were scanty on the PBS.

Bleeding time, prothrombin time and partial thromboplastin time were all normal.

Serology of platelet autoantibodies was equivocal for glycoprotein IIb/IIIa.

Bone marrow biopsy revealed trilineage maturing hematopoiesis with markedly increased megakaryopoiesis, regenerative pattern.

TSH level was normal. Also, hepatitis C and B, HIV, CMV and EBV serologies were all negative.

He presented an elevated erythrocyte sedimentation rate (ESR=60 mm/1h), normal C-reactive protein level (CRP=0.2 mg/dl) and a positive rheumatoid factor, HLA-B27 negative, in the absence of swelling, redness or warmth of any joints. During hospitalization in the hematology department, our patient didn’t meet the criteria for a positive diagnosis of rheumatoid arthritis.

The positive diagnosis was primary ITP – persistent phase, unresponsive to corticotherapy and with an increased hemorrhagic risk evaluated on Bleeding Assessment Tool evaluation.

Helicobacter pylori (HP) stool antigen was positive, and triple therapy was administered (proton pomp inhibitor, amoxicillin and clarithromycin), with no impact on platelet count after treatment.

Second-line treatment with azathioprine was administered, according to the rheumatologist advice regarding the inflammatory background.

An initial rise of platelet count was observed after nine days of treatment (PLT=86,000/µL), followed by a rapid decline starting on day 13 (PLT=34,000/µL).

Considering the bleeding risk (purpura, eye hemorrhage), the adverse reactions of corticotherapy (osteopenia, myotonia, skin impregnation), the prolonged hospitalization since ITP onset, the patient’s age and preferences, splenectomy became a very good option, although the current recommendation of the International Working Group (IWG) did not fit other treatment options like thrombopoietin receptor agonists or monoclonal therapy with anti-CD20 antibodies (rituximab), which were not available and advisable at that moment.

Before splenectomy, intravenous immunoglobulins were administered for a therapeutic increase in platelet count (110,000/µL), along with antibiotic prophylaxis and immunization against Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae.

Splenectomy was performed, without side effects. Postoperative prophylactic antibiotherapy and thromboprophylaxis with low-molecular-weight heparin were administered. Immediately after surgery, the platelet count started to increase, and the patient was discharged with a platelet count of 682,000/µL. He has not presented any other relapse for the past five years.

Discussion

Immune thrombocytopenia occurs in 2 to 4/100,000 adults, with a peak among males over 75 years old (9/100,000 person-year), resulting in variable bleeding symptoms and thrombocytopenia⁽¹¹⁾.

The therapy’s goal is to maintain a hemostatic platelet count and minimize the toxicity of the treatment. There are no controlled studies demonstrating the superiority of any specific treatment algorithm, but the risk of bleeding increases when the platelet count is below 30,000/µL⁽¹²⁾.

The factors initiating immune thrombocytopenia are unknown, but seasonal fluctuations have been observed. However, there are other factors involved, such as genetic predisposition and innate lymphoid cells alteration^(2,13). Secondary ITP afflicts 20% of patients, and it is most often associated with chronic diseases. It is characterized by disturbed immune function, which can be caused by persistent infections, lymphoproliferative and myeloproliferative disorders, pregnancy, immunodeficiency, autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis and antiphospholipid syndrome) or drug-induced⁽⁶⁾. Primary ITP, in about 80% of cases, is favored by a rupture in the immune tolerance, leading to an autoimmune process involving both innate and adaptive immune responses^(2,5).

Undifferentiated connective tissue disease is a term used for an autoimmune condition that does not meet the criteria for established illnesses like systemic lupus erythematosus, dermatomyositis, Sjögren’s syndrome or rheumatoid arthritis. The recognition of this entity is a challenge, being an early manifestation of one of the above groups⁽¹⁴⁾.

Patients with undifferentiated connective tissue disease who do not present with any organ-specific problems are usually not treated. Myalgia, as our patient developed, arthralgia or arthritis require analgesic treatment with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs). Our patient has been taking these drugs daily in the last two years⁽¹⁵⁾.

NSAIDs can induce thrombocytopenia either by inhibiting megakaryopoiesis in the bone marrow, or by immunological depletion of platelets. The best proof of drug-induced thrombocytopenia can be a prompt increase in the platelet count when the suspected drug is discontinued⁽¹⁶⁾. In our patient, thrombocytopenia persisted despite discontinuation of NSAIDs.

On presentation, an extensive evaluation for secondary causes of immune thrombocytopenia was performed.

The first symptom developed by our patient was myalgia, followed by persistent fatigue with a pronounced alteration in his quality of life. Anamnesis and physical examination did not reveal signs of arthralgia or arthritis, Sjögren syndrome (dryness of eyes and mouth, sicca syndrome or keratoconjunctivitis), no fever or signs of infection and no lymphadenopathy or hepatosplenomegaly. Patient denied exposure to toxins, new medication or vaccines.

Except for the Helicobacter pylori antigen, which was positive, the paraclinical examination excluded other viral or bacterial infections and malignancies (normal CT scan, normal bone marrow evaluation). The autoimmune panel revealed only a positive rheumatoid factor.

The positivation of the rheumatoid factor raised the question whether he developed rheumatoid arthritis (RA), and if there may be a connection between immune thrombocytopenia and rheumatoid arthritis. A literature review shows that ITP associated with RA might be more refractory to corticotherapy than ITP alone⁽⁸⁾. However, the rheumatoid factor may also be detected in some healthy people, and our patient did not meet the criteria for a rheumatologic pathology. Acknowledging the absence of a positive diagnosis of rheumatoid arthritis, we treated our patient according to the available guidelines for primary immune thrombocytopenia.

The International Working Group on Immune Thrombocytopenia and the guidelines of the American Society of Hematology suggest that patients with ITP lasting over three months, who are corticosteroid dependent or have no response to corticotherapy, should undergo treatment either with thrombopoietin receptor agonists (TPO-RA), rituximab or splenectomy^(12,17). This treatment options were not available at that moment.

Good practice statements guidelines recommend to individualize the treatment. This should be based on the duration of immune thrombocytopenia (the frequency of bleeding episodes requiring hospitalization or rescue medication), on comorbidities, the patient’s age, the medication adherence and, very importantly, the patient’s values and preferences^(12,17).

Our patient was young, with a history of many treatment lines, with frequent previous hospital admissions, with a poor quality of life and with significant corticotherapy-related comorbidities such as type 2 diabetes mellitus and Cushing syndrome. Ultimately, there was the patient’s option with its importance.

All these factors contributed to the decision of elective splenectomy.

In this particular case, splenectomy was a good option, with no complications, no future relapse and no need of another therapeutic intervention.

Conclusions

Thrombocytopenia may be associated with many underlying disorders, challenging the diagnosis. A complete clinical and laboratory workup can be helpful toward a clear etiology.

Regarding our clinical case, the etiology of the thrombocytopenia was still a debate. Nevertheless, there was a higher chance of developing another autoimmune disorder due to the presence of underlying mixed connective tissue disease.

Moreover, it was hard to demonstrate if immune thrombocytopenia preceded the rheumatoid arthritis diagnosis. However, secondary ITP diagnosis is unlikely in the absence of full clinical picture of RA.

Despite the existence of an underlying autoimmune disorder, the positive response to the elective splenectomy along with the lack of future relapses represent strong arguments in favor of primary immune thrombocytopenia.  

Ethical considerations. The informed consent was obtained from the patient to report the case.

Conflict of interest. The authors declare no conflicts of interest.

Authors’ contribution. A.M. reviewed the literature and developed the manuscript; A.M.V. reviewed the literature and provided substantial editing of the manuscript; M.C.O. and E.A.L. critically reviewed the manuscript; and all authors reviewed the manuscript and gave the final approval.

Corresponding author: Alina Mititelu E-mail: ahmititelu@yahoo.com

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.