Patients with COVID-19 infection present hematological changes depending on the patient’s immune response and the severity of the infection [1]. We presented above two different manifestations of thrombotic disorders related to COVID-19: one severe form of immune thrombocytopenia in a young woman with no comorbidities and a severe form of thrombocytopenia along with CID and acute urinary obstructive disease. Interestingly, both patients presented no signs of COVID-19 pneumonia.

According to specialty literature, mild thrombocytopenia is present in 45–55% of COVID-19 positive patients [9,10]. In a meta-analysis, which processed the clinical and paraclinical data of 5636 COVID-19-positive patients, it was concluded that there is a direct relationship between the clinical form of SARS-CoV-2 infection and the onset of thrombocytopenia. Thrombocytopenia occurs predominantly in patients with a severe form of SARS-CoV-2 infection [11].

Thrombocytopenia has been reported more frequently in patients with moderate or severe forms of COVID-19 infection. It usually occurs more than 10 days after the onset of symptoms [12]. Thus, thrombocytopenia may be a potential biomarker of negative prognosis in patients with COVID-19 [11]. There are several pathophysiological mechanisms that may be involved in the development of thrombocytopenia in patients with COVID-19 infection. In those with moderate or severe forms, the SARS-CoV-2 virus causes hyperinflammation and hypercoagulability. As a result, thrombocytopenia may be caused by platelet consumption during hypercoagulability and hyperinflammation.

For consumption thrombocytopenia, the risk factors are advanced age, male gender, high APACHE II score, neutropenia, lymphopenia, elevated CRP, and a low PaO₂/FiO₂ ratio. Thrombocytopenia can also be caused by a decrease in thrombopoietin (a regulator of megakaryopoiesis and platelet production) following damage caused to hepatocytes in SARS-CoV-2 infection [11]. In bone marrow, the viral infection of megakaryocytes can cause apoptosis and can reduce platelet maturation [11]. However, in the specialty literature, several cases have been presented showing that COVID-19 infection is associated with the onset or recurrence of immune thrombocytopenia (ITP), which is characterized by isolated thrombocytopenia, without any tendency to thrombosis [13,14]. The first case illustrates an ITP in a patient with a mild COVID-19 infection, who responded well to corticoid therapy. This severe immune thrombocytopenia in COVID-19 infection is a different entity, as it is milder than consumption thrombocytopenia, with a good prognosis. It can be associated with any degree of severity of COVID-19 infection, but it has been more commonly reported as associated with moderate and severe forms of the disease [15]. ITP is an autoimmune disease—with seasonal fluctuations—characterized by persistent thrombocytopenia secondary to autoantibodies absorbed on the surface of platelets, which generates premature destruction of the platelets by the reticuloendothelial system (especially the spleen) [16]. The mechanism of ITP in COVID-19 may be explained by molecular mimicry. The infection with the SARS-CoV-2 virus can cause antibodies to cross-act with certain platelet glycoproteins. Platelets coated with these antiplatelet antibodies will thus be eliminated by the reticuloendothelial system. These antibodies can also inhibit the development of bone marrow megakaryocytes and they can promote their apoptosis, thereby inhibiting platelet production [17].

Platelets do not have ACE2 receptors. However, a recent study suggests that platelets may take up SARS-CoV-2 mRNA independently/irrespective of ACE2. The diversification of an antigen-induced immune response to new T-cells and/or antibody specificities targeting new target epitopes of the same or different antigen is known as “epitope spread” [17]. CD8-positive cytotoxic T-cells can directly cause platelet lysis, induce platelet apoptosis, and inhibit platelet production by the maturation of megakaryocytes [18]. Low level or dysfunctional regulatory CD4-positive T-cells can also be seen in patients with ITP, indicating their possible role [19]. SARS-CoV-2 infection can lead to a recurrence of thrombocytopenia in patients with a history of thrombocytopenia caused by other diseases, such as systemic lupus erythematosus [20].

In adult patients, ITP has a sudden onset with variable symptoms ranging from nasal bleeding, gingivorrhagia, or purpuric skin lesions. Hemorrhages occur in rare cases of severe ITP when platelets number drops below 30,000/mmc; the lower the platelets, the higher the risk of major bleeding events such as cerebral bleeding (usually taking place if platelets are below 5000/mmc) [16]. There is no specific test for ITP; the presence of antiplatelet antibodies is not mandatory for a positive diagnosis. The clinical context, the presence of thrombocytopenia, the exclusion of other pathologies, and the response to corticoid therapy are usually enough for the diagnosis of ITP [16]. A short mention regarding the antiplatelet antibodies is in order. Antiplatelet antibodies target various platelet glycoproteins (GP), notably GPIIb/IIIa (fibrinogen receptor), GPIb/IX (von Willebrand factor), and, less frequently, GPIa/IIa (collagen receptor) and GPIV. Direct monoclonal antibody immobilization of platelet antigens assay (MAIPA) allows the detection of antiplatelet antibodies in up to 60% of ITP patients [21]. Unfortunately, antiplatelet antibody testing has low sensitivity and does not correlate with clinical outcomes. Some of the titers of antiplatelets antibodies are too low to be detected (false negative results). On the other hand, a positive result cannot be used as a unique diagnosis tool, but more as a screening test. Thus, these tests are not recommended to aid in the diagnosis or management of ITP [16]. It is worth mentioning that antiplatelet antibodies can be used to distinguish between immune and non-immune thrombocytopenia in complex cases associated with inappropriate platelet production in bone marrow and ITP, in cases of treatment-resistant ITP, or in cases of drug induced ITP [16].

Thus, ITP is a diagnosis of exclusion, which means that it is mandatory to exclude other viral infections that may cause thrombocytopenia. Exclusion should also be applied to other immune conditions that may cause thrombocytopenia. ITP is thought to be a consequence of viral infections of hepatitis B/C virus, cytomegalovirus, varicella zoster virus, HIV, and, more recently, secondary zika virus [22,23].

The appearance of ITP in the context of COVID-19 infection requires a positive diagnosis of SARS-CoV-2 infection. In the first case, the diagnosis of SARS-CoV-2 infection was made in concordance with international and national guidelines: in the epidemiological context, first of all, the detection of viral antigens through rapid diagnostic tests or Ag-RDTs is based on immunodiagnostic techniques and confirmed by the detection of viral RNA through automated nucleic acid amplification tests (NAAT) and reverse-transcription polymerase chain reaction (RT-PCR) [24]. No other laboratory testing is specific for COVID-19 positive diagnosis, but there are inflammatory markers that can be used for the classification of disease severity, such as D-dimer > 1000 ng/mL (normal range: <500 ng/mL), CRP > 100 mg/L (normal range: <8.0 mg/L), LDH > 245 units/L (normal range: 110 to 210 units/L), Troponin > 2 × the upper limit of normal (normal range for troponin T high sensitivity: females 0 to 9 ng/L; males 0 to 14 ng/L), Ferritin > 500 mcg/L (normal range: females 10 to 200 mcg/L; males 30 to 300 mcg/L), CPK > 2 × the upper limit of normal (normal range: 40 to 150 units/L), and lymphopenia [25].

Most patients with ITP responded to the treatment with intravenous immunoglobulins and corticosteroids. Erythrocyte mass transfusions were performed in those with significant bleeding [19]. Mention must be made that the reported bleeding was rare, most of it being minor (epistaxis), while the intracranial bleeding was reported as being major.

It has been observed that elderly patients with multiple comorbidities are more prone to severe forms of COVID-19 and have a higher risk of thrombosis. Elevated levels of D-Dimers, although nonspecific, demonstrate an increased risk of thrombosis in patients with COVID-19, while decreased platelets, fibrinogen, or antithrombin are more commonly associated with an increased risk of DIC. In contrast, bleeding events have been reported less frequently in patients with COVID-19 [26]. The presence of thrombocytopenia at the onset of the disease is rare, and the number of platelets has been significantly lower in patients with severe disease [7]. It was also observed that the majority of patients who met the diagnostic criteria for DIC established by the ISTH did not survive (71.4%) and only 0.6% of patients with COVID-19 who met these criteria are among the survivors [7].

DIC is a diagnosis of exclusion, and the clinical picture and general condition of the patient were inconsistent with laboratory investigations, which is why, before establishing this diagnosis, all possible steps were taken to rule out other causes. In this sense, considering that the patient did not show central nervous system, joint, or kidney damage and was not known to have any underlying pathology, thrombocytopenic thrombosis, vasculitis, and autoimmune diseases were excluded. Imaging examinations and blood smear contributed to the exclusion of liver pathology, immune thrombocytopenia, and myelodysplastic syndromes, thus preserving a possible diagnosis of DIC in the context of SARS-CoV-2 infection. It appears that patients with COVID-19 rarely meet the diagnostic criteria for DIC. DIC is usually defined by the criteria of the ISTH [27]. The laboratory presentation of DIC from COVID-19 is different than that from bacterial sepsis or trauma. In COVID-19 the coagulation markers such as aPTT or PT prolongation are only mildly modified. Low platelet count, low fibrinogen levels, and markers of hyperfibrinolysis are not common [28]. This spectrum of coagulation changes is called COVID-19-associated coagulopathy and it has three stages [29]:

• Stage 1: elevated D-dimers;
• Stage 2: D-dimers and mild thrombocytopenia and/or mildly prolonged PT and aPTT;
• Stage 3: critical illness and classic DIC.

The prognosis of patients with COVID-19 appears to be closely related to platelet counts, as Asakura et al. showed in a study on 1476 patients, 16.1% of whom died. The authors found that the mortality rate was 92.1% for patients who had platelet counts of 0–50,000/mm³, 61.8% for those with counts of 50,000–100,000/mm³, 17.5% for those with counts of 100,000–150,000/mm³, and only 4.7% in patients with counts > 150,000/mm³ [30].

The spectrum of hematological manifestation of COVID-19 is wide and frequently unpredictable. The researchers presented two different extremes of severe thrombocytopenia (ITP and DIC), both precipitated by COVID-19 inflammation, without pulmonary manifestations and with good response to systemic corticosteroid therapy. Failure to diagnose it rapidly may lead to severe complications. Management with immunosuppressive corticosteroids in high doses should carefully balance the risk of bleeding versus deterioration due to infection.