COVID-19-ASSOCIATED IMMUNE THROMBOCYTOPENIA

The coronavirus disease 2019 (COVID-19) is a contagious respiratory tract infection caused by the betacoronavirus SARS-CoV-2. The World Health Organization declared the COVID-19 outbreak a pandemic on March 11, 2020. Since the COVID-19 pandemic started, more than 166 million patients have been tested positive worldwide with more than 3.4 million related death recorded. COVID-19 has a wide range of signs and symptoms. Hematological changes such as lymphopenia, thrombocytopenia, and coagulation disturbances are not unusual in patients with COVID-19. However, the mechanisms causing these changes are partially comprehended. Immune thrombocytopenia was identified to be among the hematologic autoimmune diseases seen in patients infected with SARS-CoV-2. This review summarizes the evidence on COVID-19-associated immune thrombocytopenia and the underlying mechanisms involved in its development.


INTRODUCTION
The coronavirus disease 2019 (COVID-19) is a contagious respiratory tract infection caused by the beta-coronavirus SARS-CoV-2. It was first identified in Wuhan, the largest metropolitan area in China's Hubei Province, in late 2019, when a series of pneumonia cases of unknown cause emerged (1). The World Health Organization declared the COVID-19 outbreak a pandemic on March 11, 2020 (2). Since the COVID-19 pandemic started, more than 166 million patients have been tested positive worldwide with more than 3.4 million related death recorded (3).
SARS-CoV-2 infection tends to affect people of all ages, but the clinical manifestations vary depending on their age. Many infections, primarily in children and young adults, are asymptomatic or mild, but severe illness, respiratory failure, and death are more frequent in the elderly and/or people with comorbidities (4).
COVID-19 has a wide range of signs and symptoms. The most common symptoms at onset of illness are fever, fatigue and cough, but also myalgia, anorexia and in severe cases dyspnea. Headache, dizziness, sore throat, and chest pain are less common symptoms, as are gastrointestinal symptoms such as abdominal pain, diarrhea, nausea, and vomiting (4)(5)(6). Also, a significant number of patients complained of olfactory and taste disturbances. Anosmia and ageusia are nonspecific symptoms that may be the first or only sign of the condition (7,8).
Most patients reported symptoms of disease, after an incubation period of 1-14 days (typically about 5 days); dyspnea and pneumonia occurred within a median of 8 days from disease onset (8).
Hematological changes such as lymphopenia, thrombocytopenia, and coagulation disturbances are not unusual in patients with COVID-19. However, the mechanisms causing these changes are partially comprehended (9). Changes in immune system functions have recently been attributed to the SARS-CoV-2 infection. These changes could range from an abnormal immune response and excessive cytokine production to immune system hyperactivation and a significant increase in immune-inflammatory variables. Autoimmunity and cytokine storm may result from these excessive immune responses (10,11).
Furthermore, studies have identified many cases of COVID-19 patients who developed autoimmune events such as antiphospholipid syndrome, autoimmune cytopenia, Guillain-Barré syndrome and Kawasaki disease. These results suggest that SARS-CoV-2 infection is linked to the development of autoimmune diseases (11,12).
This review summarizes the evidence on COVID-19-associated immune thrombocytopenia and the underlying mechanisms involved in its development, based on the PubMed database.

MECHANISMS OF THROMBOCYTOPENIA IN COVID-19
The novel coronavirus disease has been linked to thrombocytopenia, which may have various mechanisms of occurrence and it may appear at any time during the disease course (14).
Coronaviruses can infect bone marrow cells, triggering abnormal hematopoiesis. Using various receptors, SARS-CoV-2 inhibits hematopoiesis in the bone marrow, resulting in reduced primary platelet formation and thrombocytopenia. Hemophagocytic lymphohistiocytosis is one of the secondary pathways that lead to the destruction of bone marrow progenitor cells. This is caused by excessive proliferation and activation of the mononuclear macrophage system, which results in a cytokine storm (14,15). SARS-CoV-2 also induces thrombocytopenia by increasing levels of autoantibodies and immune complexes, which causes the immune system to specifically destroy thrombocytes. Platelets with specific antigens can be coated by anti-platelet antibodies and immune complexes, resulting in immune-mediated destruction in the peripheral blood (ie. immune thrombocytopenia -ITP) (14).
Lung injury occurs as a consequence of viral infection and inflammation. Damaged lung tissues and pulmonary endothelial cells can stimulate platelets in the lungs, inducing aggregation and the formation of microthrombi, which enhances platelet consumption (14,16).

COVID-19-ASSOCIATED IMMUNE THROMBOCYTOPENIA
Immune thrombocytopenic purpura (ITP) is an uncommon autoimmune condition marked by platelet counts below 100,000 platelets per microliter and increased bleeding risk (17). Patients who exhibit thrombocytopenia without a known underlying cause are diagnosed with primary ITP. ITP caused by other disorders (autoimmune diseases, lymphoproliferative disorders), infectious agents or medications is known as secondary ITP (18). Environmental and genetic predisposition have been identified as risk factors for ITP. Among the environmental factors involved in the occurrence of autoimmune thrombocytopenia, several infectious agents are associated with the appearance of this condition, especially in children (eg Helicobacter pylori, hepatitis C virus, human immunodeficiency virus, cytomegalovirus, Epstein Barr virus, and other viruses) (19).
Molecular mimicry is one of the proposed mechanisms by which infections contribute to autoimmunity. To evade the immune response, viral proteins mimic platelet receptors. Cross reactivity against platelet receptors can arise as a result of an immune reaction to these viral proteins, resulting in autoantibodies specific for both the viral protein and platelet receptors (19,20).
Thrombocytopenia is among the most challenging disease entities for physicians to deal with on a daily basis. Mild thrombocytopenia has been reported in approximately 5-10% of patients with symptomatic SARS-CoV-2 infection (21). Other studies showed that nearly 36% of COVID-19 patients were found to have moderate thrombocytopenia (22). Deep throm-bocytopenia, on the other hand, is uncommon and is linked to disease severity (23). Huang et al. noted that COVID-19 non-survivors (20%) were more thrombocytopenic than COVID-19 survivors (1%) (24), while Tang et al. showed that thrombocytopenia is a negative prognostic factor during SARS-CoV-2 infection (25).
Several case reports of isolated thrombocytopenia linked to COVID-19 have recently been described (Table 1). Zulfiqar et al. published the first single case report indicating that COVID-19 infection could be linked to immune thrombocytopenia. He described a case of "de novo" ITP in a 65-year-old woman with COVID-19 who underwent a multi-drug treatment, including intravenous immunoglobulin (IVIG), prednisolone, and eltrombopag, to recover completely (26).
Most patients with bleeding symptoms reported manifestations such as epistaxis, purpuric and petechial rash, ecchymoses, or mucosal bleeding, according to our findings. Only 3 patients out of 16 suffered from intracerebral bleeding (28), intraventricular haemorrhage (31) and subarachnoid haemorrhage (26), one out of which died.
Diagnosing COVID-19-associated immune thrombocytopenia might be challenging because of various other possible causes, such as coagulation activation by COVID-19 infection leading to disseminated intravascular coagulation and subsequent thrombocytopenia. Also, medications used for treating COVID-19, including heparin, azithromycin, and hydroxychloroquine, may trigger thrombocytopenia (38). In the case report published by Zulfiqar et al., the patient had used amoxicillin-clavulanic acid and low-molecular-weight-heparin before the detection of thrombocytopenia, which might also be contributing to the decreasing of the platelet count (26).
The diagnosis of ITP is based on the patient's past medical history, systemic physical examination, and an extensive hematological workup that includes a complete blood count and a peripheral blood smear. To rule out viral-mediated thrombocytopenia, patients should be evaluated for HCV and HIV. In situations of isolated thrombocytopenia, bone marrow analysis is not indicated unless there is a suspicion for aplastic anemia, leukemia, or myelodysplastic syndrome (39).
ITP therapy seeks to minimize severe bleeding by ensuring a balanced platelet count. Treatment for COVID-19-related ITP might be complicated. Intravenous immunoglobulin, glucocorticoids, and thrombopoietin receptor agonists are all commonly used and effective treatments. IVIG is usually designated for individuals with ITP who require a quick rise in platelet levels. IVIG has the liability of not being curative and of being poorly tolerated (40). Because IVIG suppresses macrophage phagocytic functions, it may be effective in treating COVID-19 infection at an incipient phase (19,41).
Concerning the management of the documented cases, medications used were: steroids (prednisone, dexamethasone, and methylprednisone), intravenous immunoglobulin (IVIG), thrombopoietin receptor agonists (TPO-RA e.g. Romiplostim and Eltrombopag), and platelet transfusions. In several of the cases documented, intravenous immunoglobulin administration resulted in a favorable response relatively fast (Patient #2, #7, #8, #13, #15) (16,27,33,35). IVIG was administered for Patient #3 due to active bleeding and the relative contraindication of glucocorticoid medication, which may interact with his prior treatment (somatostatin analog therapy for the neuroendocrine tumor), and for Patient #4 due to dexamethasone treatment failure (28). Glucocorticoids comprise the main therapy of ITP (40). However, glucocorticoids are considered unsafe for patients with COVID-19 infection as they inhibit immune responses and clearance of the novel coronavirus (9,42).
Thrombopoietin receptor agonists have made a significant contribution to the treatment in patients with immune thrombocytopenia, which are refractory to first-line agents. About 30% of patients have shown a steady rise in platelet counts after treatment (43). Because TPO-RA therapy has demonstrated that the risk of venous thromboembolism has in-creased in selected patients, it should be used judiciously in COVID-19 infection (44).

CONCLUSIONS
Several hematological abnormalities that might lead to life-threatening bleeding complications were identified in COVID-19. Such manifestations must be included in the clinical evaluation of patients infected by SARS-CoV-2. Since the outbreak of the pandemic, there were several case reports of immunemediated thrombocytopenia linked to COVID-19. Thrombocytopenia may be attributed to different reasons and promptly diagnosis of the immunological cause is essential, so that proper immunosuppression may be initiated on time. Failure of timely recognition may eventually result in serious complications. The management of ITP should be decided upon the balance of the bleeding risk due to immune thrombocytopenia versus the prospective complication of COVID-19-infection due to immunosuppressive treatment.