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Review article

Thrombocytopenia and COVID-19: differential diagnosis and therapy

Mirjana Mitrović1,2, Nikola Pantić1
  • University Clinical Center of Serbia, Clinic for Hematology, Belgrade, Serbia
  • University of Belgrade, Faculty of Medicine, Belgrade, Serbia

ABSTRACT

Thrombocytopenia represents a common manifestation of COVID-19 with a prevalence of up to 35% in certain studies. A low platelet count is an unfavorable prognostic marker in SARS-CoV-2 infected patients. Despite a large number of publications dealing with the prognostic significance of thrombocytopenia in COVID-19, data regarding the differential diagnosis and therapy are scarce. The most common causes of thrombocytopenia in COVID-19 are shown in this review, namely: SARS-CoV-2-induced thrombocytopenia; disseminated intravascular coagulopathy (DIC); immune thrombocytopenia; drug-induced thrombocytopenia, with a special insight into heparin-induced thrombocytopenia (HIT). Although a majority of patients suffer from mild thrombocytopenia and do not require any particular treatment, there are some cases of severe thrombocytopenia which may cause life threatening bleeding. On the other hand, some forms of thrombocytopenia, such as DIC or HIT, carry a high risk of the development of thrombotic events, which is why anticoagulant prophylaxis is required in these patients. At the end of each section of this review, treatment recommendations are given for each aforementioned type of thrombocytopenia developing in COVID-19.


INTRODUCTION

Over the past two years, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led to the infection of millions of people all over the world, and, according to data from November 2021, it has also led to more than five million deaths worldwide [1]. Although COVID-19 is primarily an infectious disease, systemic manifestations develop particularly frequently in patients with severe clinical presentation. The first reports from Wuhan, China, as well as large meta-analyses, have highlighted numerous hematologic abnormalities in patients suffering from the disease [2],[3]. Anemia, leukopenia with lymphopenia, thrombocytopenia, elevated D-dimer, LDH and ferritin are often found in blood test results. The aforementioned disorders are the result of a cytokine storm, macrophage and endothelial activation, increased tissue factor release, coagulation activation, as well as the forming of microthrombi in the blood vessels of the entire body [2],[3]. In this process, venous and arterial thromboses are the most prominent clinical manifestations, while bleeding is significantly less frequent [2],[3].

The results of meta-analyses, which included several thousand COVID-19 patients, showed thrombocytopenia to be a very frequent manifestation of the disease, which, in certain groups, amounted to as much as 35% [4],[5]. A meta-analysis, with a systematic overview of 7,000 patients, showed significant association between thrombocytopenia and the severe from of COVID-19 (OR = 3.46, 95% CI 1.72 – 6.94, I2 = 91.8%), as well as association between thrombocytopenia and the lethal outcome of COVID-19 (OR = 11.75, 95% CI 3.51 – 39.31, I2 = 88.9%) [4].

Despite the large number of publications on the prognostic significance of thrombocytopenia in COVID-19, data on differential diagnosis and the treatment of thrombocytopenia are limited. The differential diagnosis of thrombocytopenia during COVID-19 infection includes preexisting thrombocytopenia. Also, during the infection itself, diseases causing thrombocytopenia, such as myelodysplastic syndrome, acute leukemia, liver cirrhosis, and others, may be diagnosed. Bearing in mind that the aforementioned causes are rare, in this paper, emphasis will be placed on the most frequent causes of thrombocytopenia in COVID-19, which are as follows: SARS-CoV-2-induced thrombocytopenia, disseminated intravascular coagulopathy (DIC), immune thrombocytopenia (ITP), and drug-induced thrombocytopenia (DITP), with a special insight into heparin-induced thrombocytopenia (HIT).

SARS-COV-2 INDUCED THROMBOCYTOPENIA

Thrombocytopenia in COVID-19 is mediated by a series of complex pathophysiological processes, which result in decreased production or increased consumption of circulating platelets (Figure 1). It occurs as the result of a cytokine storm, direct viral invasion of hematopoietic cells, as well as the result of pulmonary tissue damage [5].

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Figure 1. SARS-CoV-2-induced thrombocytopenia (adapted from: Xu P. et al. [6])

DECREASED PLATELET PRODUCTION

Cytokine storm

A cytokine storm is defined as the state of an extremely elevated level of circulating cytokines, and it most commonly occurs during excess activation of the immune system, caused by systemic infection [7]. It is this phenomenon that explains thrombocytopenia in a certain number of patients infected by the SARS-CoV-2 virus [8]. Namely, it has been shown that the activity of proinflammatory cytokines, such as interleukins IL2R, IL-6, IL-10, as well as of tumor necrosis factor α, is significantly increased in patients suffering from the severe form of COVID-19 [9]. An elevated concentration of cytokines leads to further amplification of the immune response, to damage to the bone marrow microenvironment, as well as to the suppression of hematopoiesis [8]. Also, tumor necrosis factor α is a direct inhibitor of megakaryocytopoiesis [10].

Direct viral invasion of hematopoietic cells

Although the expression of the angiotensin-converting enzyme 2 (ACE2) receptor, which has been identified as the point of entry of the SARS-CoV-2 virus into the cells, has not been registered on megakaryocytes, the virion of this virus has been detected with electron microscopy in megakaryocytes, while the application of the polymerase chain reaction (PCR) method has proven the presence of viral genetic material in the platelets of patients infected with SARS-CoV-2 [11]. There is a number of possible paths of entry of the virus into megakaryocytes. For instance, human coronavirus 229E also causes thrombocytopenia, which is explained by direct viral invasion into bone marrow cells and platelets via CD13 molecules [6]. Bearing in mind the level of similarity between these two viruses, as well as the fact that the presence of SARS-CoV-2 has been proven in the megakaryocyte lineage, numerous authors have marked this as one of the mechanisms of megakaryopoiesis suppression.

DECREASE IN THE NUMBER OF CIRCULATING PLATELETS

Damage to the lungs

Bilateral pneumonia is a frequent characteristic of patients hospitalized for COVID-19. Namely, the SARS-COV-2 virus causes alveolar damage, pulmonary congestion, the formation of hyaline membranes, and fibrosis [10]. It has been shown that the damage to lung parenchyma affects the decrease in the platelet count, which is mediated through a number of mechanisms. Primarily, it has been proven that there are two types of megakaryocyte populations in the lungs: intravascular megakaryocytes, originating from bone marrow, which produce circulating platelets, and sessile, interstitial megakaryocytes of unknown origin, which participate in immunologic reactions [12]. At the same time, an increased number of megakaryocytes has been found in in the pulmonary parenchyma of COVID-19 patients with diffuse damage to alveolar membranes [13]. As normal microvasculature of the lungs, which is in this case damaged, is necessary for megakaryocyte cytoplasm fragmentation and platelet production, thus the production of circulating thrombocytes is reduced [14]. A decreased number of platelets, together with elevated inflammatory factors, leads to the rise in the level of thrombopoietin with consequently elevated mobilization of megakaryocytes into the lung tissue [15].

Additionally, damaged endothelium is also a pathohistological substrate of the pulmonary tissue in COVID-19 patients. Namely, the SARS-CoV-2 virus directly infects the vascular endothelium via the ACE-2 receptors, causing cellular damage and apoptosis. In this way, degranulation of endothelial cells occurs as well as the release of the Von Willebrand factor (vWF) and factor VIII into the circulation [16]. The released vWF activates thrombocytes via the GPIb-IX-V complex, which leads to endothelial cell degranulation. Also, the greater the pulmonary cell damage, the more intensive the activation and consumption of platelets, thus resulting in more severe thrombocytopenia [8].

TREATMENT

In the treatment of COVID-19-induced thrombocytopenia, it is most important to treat the main source of the thrombocytopenia. It is primarily advised to treat the infection itself according to the National Protocol [17]. Timely administration of corticosteroids, in the appropriate dose, has proven effective in reducing systemic inflammatory response. Thereby, not only is the platelet count increased, but a faster resolution of the damaged pulmonary parenchyma is achieved [8]. Other treatment options, such as monoclonal antibodies which antagonize the effect of IL-6 (tocilizumab, sarilumab, siltuximab), also the IL-1 receptor antagonist (anakinra), the complement component inhibitor (eculizumab), as well as the chemokine and chemokine receptor inhibitors and the human recombinant soluble ACE2 inhibitor, are the object of research in numerous studies, whose aim is better control of COVID-19, and, consequently, more effective treatment of thrombocytopenia in COVID-19 [8]. Platelet transfusions in these patients are recommended only in case of hemorrhage, while prophylactic transfusions are not recommended [8].

COVID-19 ASSOCIATED COAGULOPATHY (CAC)

According to the definition of the International Society on Thrombosis and Haemostasis (ISTH), disseminated intravascular coagulopathy (DIC) is an acquired syndrome, characterized by disseminated intravascular coagulation activation, which may occur due to different causes [18]. DIC is, at the same time, both a laboratory and a clinical diagnosis, characterized by D-dimer elevation, a reduced concentration of fibrinogen, a fall in the platelet count and the consumption of the clotting factor. The main clinical manifestation of DIC is multiorgan dysfunction resulting from microischemias, while bleeding is significantly rarer [18]. In COVID-19 patients, disseminated intravascular coagulopathy may be caused by hemostatic disturbance occurring as a part of the viral infection (COVID-19-associated coagulopathy – CAC) or by bacterial sepsis, which complicates treatment (SIC – sepsis-induced coagulopathy) [3],[4]. It is necessary to stress that every cause of coagulopathy has its own particular evolution and consequent laboratory parameter dynamics. For instance, CAC is characterized by a higher D-dimer and a higher platelet count, as compared to SIC. Data up to date indicate that CAC manifests through activated coagulation and thromboses, rather than as overt DIC. However, all forms of coagulopathy may gradually progress towards overt DIC, which is characterized by thrombocytopenia, a fall in the concentration of the clotting factor and a tendency towards bleeding [3],[4].

In the first stages of the SARS-CoV-2 viral infection, the disease is limited to the lungs. Namely, due to alveolar damage, extravasation and extravascular coagulation activation occur, with the conversion of fibrinogen into fibrin and disease containment [3],[4]. This initial phase is characterized by D-dimer elevation [3],[4]. Increased inflammation and disease activation in the lungs themselves with vascular endothelial damage are the cause of in situ thromboses, typical for COVID-19. In case of disease progression and the occurrence of a cytokine storm, intravascular coagulation activation occurs in the whole body, primarily through macrophage activation, as well as through endothelial damage and increased expression of tissue factor (Figure 2) [3],[4].

09 02

Figure 2. Progression from COVID-19-associated coagulopathy (CAC) to disseminated intravascular coagulopathy (DIC) (adapted from: Ida T. et al. [37])

According to the definition by Iba et al, CAC is diagnosed if there is proven SARS-CoV-2 infection, as well as one of the following criteria: (1) platelet count < 150 ×109 /L; (2) D‐dimer increase > twice above the normal value; (3) prolonged prothrombin time (PT) by > 1 second or international normalized ratio (INR) > 1.2; (4) fibrinogen depletion; (5) thrombosis. Risk of developing CAC is present in patients with the following: (1) elevated fibrinogen level; (2) increased vWF (more than twice above the normal level); (3) presence of antiphospholipid antibodies [3].

Patients with CAC, or those at risk of developing CAC, may progress to overt DIC. As there is no reliable diagnostic test for DIC, dynamic monitoring of coagulation parameters and the application of a scoring system is advised. The most frequently applied scoring system for the diagnosis of DIC are the ISTH criteria (Table 1), while in intensive care units, the SIC score is also used (Table 2). The criteria for overt DIC are the value of the ISTH DIC score of ≥ 5 or the value of the SIC score of ≥ 4. It is necessary to point out that with each rise of the score by 1 point, patient mortality significantly rises. Namely, the lethal outcome for patients with overt DIC and COVID-19 is more than 70%. Also, in the conditions of overt DIC, the possibility of bleeding increases, which is why, in addition to treatment for the underlying disease, replacement of the clotting factor and platelets through the transfusion of blood derivatives and components is recommended [18],[19].

Table 1. ISTH DIC score [19]

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Table 2. SIC score [3]

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Bearing in mind the high frequency of thrombotic complications, as the main manifestation of CAC, discontinuation of anticoagulant therapy is recommended only if the platelet count is < 25 x 109 /L and in case of bleeding. Platelets should be kept at > 25 x 109 /L, with platelet transfusions. On the other hand, if the patient is bleeding, it is necessary to maintain fibrinogen at > 1.5 g/L, the platelet count at > 50 x 109 /L, and the PT ratio (not the same as INR) at < 1.5, with transfusions [20].

IMMUNE THROMBOCYTOPENIA

Immune thrombocytopenia (ITP) is defined as isolated platelet count of < 100 x 109 /L, in the absence of other potential causes of thrombocytopenia [21]. The diagnosis of ITP is established through excluding other causes of thrombocytopenia (negative virological and immunological analyses, normal values of CRP and IL-6, absence of signs of consumption coagulopathy, exclusion of drugs as the cause of thrombocytopenia). In the group of patients with COVID-19 and ITP, there are two subgroups: patients with newly diagnosed immune thrombocytopenia and patients with previously diagnosed immune thrombocytopenia.

Newly diagnosed immune thrombocytopenia

Viral infections are a known trigger for the development of ITP. However, although the number of published cases or smaller series of cases of ITP following COVID-19 is significant, so far there are no data on the frequency of ITP after COVID-19. From reports on cases published so far, it may be concluded that this type of ITP is more frequent in patients older than 60 years. It can present as severe thrombocytopenia (< 20 x 109 /L), wherein life-threatening bleeding has been recorded (intracerebral hemorrhage, gastrointestinal bleeding), which is why this state must never be overlooked. Thrombocytopenia most commonly occurs during the second or third week of COVID-19 (when synthesis of anti-COVID-19 antibodies begins) [22].

Previously diagnosed immune thrombocytopenia

Different infections often lead to the relapse of primary immune thrombocytopenia. According to the results of a Spanish group of authors, SARS-CoV-2 viral infection increases the frequency of relapse in patients with a preexisting ITP diagnosis [23]. Also, it has been shown that the relapse rate is greater in patients with more severe initial clinical presentation [23]. On the other hand, in patients in whom, through the application of thrombopoietin receptor agonists (TPO-RA), stable remission has been achieved prior to COVID-19, thrombocytosis has been recorded, during the illness [24],[25],[26].

Treatment

As first-line therapy in treating ITP, application of corticosteroids and intravenous immunoglobulins is recommended. Normally, first-line therapy is prednisolone in the dose of 1 mg/kg bw (maximum 80 mg), for two weeks, and then it is necessary to start with gradual discontinuation of treatment [27]. However, according to some guidelines, in case of COVID-19, if the platelet count is < 20 x 109 /L, in patients who are not bleeding, prednisolone treatment should be started in lower doses (20 mg/day), with an increase of the dose, if therapeutic response is lacking [28],[29]. If the patient is bleeding, it is necessary to administer intravenous immunoglobulins immediately (total dose 2 g/kg bw for two or five days) and/or corticosteroids (dexamethasone 40 mg/day, for four days, or prednisolone 1 mg/kg bw) [28],[29]. Cases of ITP in COVID-19 have been reported, which did not respond to the previously described therapy and where control of bleeding was established only after thrombopoietin receptor agonists had been administered (TPO-RA) [30],[31]. The application of rituximab is not recommended during COVID-19 infection [28],[29].

If relapse occurs in patients with previously diagnosed ITP, the application of TPO-RA should be considered. In case of acute bleeding in these patients, first-line therapy may be applied – corticosteroids and intravenous immunoglobulins. In patients already receiving TPO-RA, the dose should be adjusted to the current platelet count with more frequent control of the number of thrombocytes. The application of rituximab is not recommended in this patient group [28],[29].

Platelet transfusions in patients with ITP are recommended only in case of life-threatening bleeding [27].

DRUG-INDUCED THROMBOCYTOPENIA

Drugs are one of the most common causes of thrombocytopenia, especially in hospitalized patients. So far, thrombocytopenia has been registered during the application of more than 1,300 different drugs [30]. A precise list of these drugs can be found on the following website: www.ouhsc.edu/platelets. The frequency of drug-induced thrombocytopenia is estimated at 10/1,000,000 per capita a year [30]. In intensive care units, 30% of patients suffer from some level of drug-induced thrombocytopenia [31].

Based on the mechanism of development, drug-induced thrombocytopenia can be categorized as immune and non-immune (cytotoxic).

Cytotoxic drug-induced thrombocytopenia

Drugs such as cytostatics and antineoplastics – linezolid, ganciclovir, aspirin, vancomycin, and ethanol, may cause thrombocytopenia through direct cytotoxic or proapoptotic effect on megakaryocytes [31].

Immune drug-induced thrombocytopenia

Drug-induced immune thrombocytopenia (DIIT) is most commonly caused by antibodies specific to the particular drug, which, in the presence of the drug, bind to platelets, leading to their accelerated clearance. Drugs most commonly leading to DIIT are the following: abciximab, acetaminophen, amlodipine, amiodarone, ampicillin, carbamazepine, cotrimoxazole, chlorpropamide, cimetidine, digitalis, drospirenone, gentamicin, eptifibatide, danazol, moxonidine, ethambutol, diclofenac, tirofiban, haloperidol, efalizumab, ibuprofen, irinotecan, gold-based drugs, phenytoin, triamterene/hydrochlorothiazide, naproxen, hydrochlorothiazide, oxaliplatin, interferon A, methyldopa, nalidixic acid, quinidine, quinine ranitidine, rifampin, simvastatin, tirofiban, sulfisoxazole, vancomycin, valproic acid [30],[31].

The time from the beginning of treatment until the development of thrombocytopenia varies from several hours to several months (most commonly 10 - 15 days). Thrombocytopenia occurs acutely and may be severe, accompanied by life-threatening bleeding. In fact, as many as 67% of patients hemorrhage, and as many as 9% experience life-threatening bleeding. Occasionally, febrility, nausea, vomiting, hypotension, and syncope may occur [30],[31].

Treatment

The most important step in treating this condition is considering the possibility of drug-induced thrombocytopenia. It is necessary to immediately discontinue the drug suspected of causing the condition and replace it with a drug of different chemical structure. Since, in COVID-19 treatment, the patient is exposed to a large number of drugs at the same time, which are introduced concomitantly, it is recommended that the entire drug regimen is changed. As recovery is expected within an average of 7 days (range: 1 – 15 days), if the patient is bleeding, it is recommended to apply platelet transfusion, corticosteroids, intravenous immunoglobulins, and therapeutic plasma exchange [30],[31].

HEPARIN-INDUCED THROMBOCYTOPENIA

Heparin-induced thrombocytopenia (HIT) is an acquired prothrombotic disorder caused by the administration of the anticoagulant heparin [32],[33]. The pathophysiology of HIT is based on the production of IgG antibodies to the platelet factor 4 (PF4)/heparin complex. The binding of this complex to thrombocytes leads to their accelerated clearance and to thrombocytopenia, one the one hand, but also to platelet activation and thrombin production, on the other [32],[33]. Thus, discontinuation of anticoagulant therapy in patients with HIT is a professional error.

According to the meta-analysis including 7 studies with 5,849 patients, the overall incidence of HIT in COVID-19 was 0.8% (95% confidence interval (CI) = 0.2 – 3.2%; I2 = 89%). The estimated incidence for the group of patients receiving a therapeutic dose of low-molecular-weight heparin (LMWH) was 1.2% (95% CI, 0.3 – 3.9%; I2 = 65%), as opposed to 0.1% (95% CI, 0.0 – 0.4%; I2 = 0%) in the prophylaxis group. The incidence of HIT was significantly higher in critically ill patients (2.2%, 95% CI; 0.6 – 8.3%; I2 = 72.5%), as compared to patients who were not critically ill (0.1%, 95% CI, 0.0 – 0.4%; I2 = 0%). Although, the frequency of HIT in COVID-19 patients is not too high, the absolute number of patients, when the scale of the pandemic is taken into consideration, is massive [34].

Table 3. 4Ts HIT score (adapted from: Linkins LA et al. [36])

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In case of the development of thrombocytopenia in patients treated with heparin, it is important to calculate the 4Ts HIT score (Table 3) [17],[35],[36]. Namely, if the 4Ts HIT score is low (≤ 3), the probability of HIT is small, which is why heparin need not be discontinued. However, if the score is intermediate or high (≥ 4), it is necessary to discontinue patient exposure to any type of heparin, including the flushing of venous catheters and the use of extracorporeal membrane oxygenators, and to introduce fondaparinux (Arixtra®) as well as determine anti-heparin antibodies. If anti-heparin antibodies are negative, discontinuation of fondaparinux and the continuation of heparin application are advised. On the other hand, in case of a positive titer of anti-heparin antibodies, treatment with fondaparinux is continued [17],[35],[36]. The overview of the diagnostics and treatment of HIT in the COVID-19 hospital Batajnica, is presented in Figure 3. Apart from fondaparinux, the application of the following anticoagulants is possible: (1) argatroban: 1 – 2 mcg/kg/min, with the achievement of the prolongation of activated partial thromboplastin time (aPTT) 1.5 to 3 times the normal value; (2) danaparoid: bolus 2.250 units, 400 units/h for 4 h, followed by 300 units/h for 4 h, then 200 units/h; (3) bivalirudin: 0.15 mg/kg per hour, (aPTT 1.5 to 2.5 times the normal value); (4) rivaroxaban (Xarelto®, Rivaroksaban SK®): 2 x 15 mg for 21 day, then 20 mg/day; (5) apixaban (Eliquis®): 2 x 10 mg/day for 7 days, then 2 x 5 mg per day; (6) dabigatran (Pradaxa®): 2 x 150 mg/day (after the period of parenteral anticoagulation, for 5 – 10 days). It is possible to start Warfarin upon the reestablishing of the normal platelet count [17],[35],[36].

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Figure 3. Protocol applied when heparin-induced thrombocytopenia is suspected

If the patient with HIT has had a thrombotic event, anticoagulant therapy must be applied for a minimum of three months. On the other hand, if HIT in a patient passes without thrombotic events, treatment is carried out for a period of four weeks [17],[35],[36].

A patient diagnosed with heparin-induced thrombocytopenia must not be exposed to heparin again, unless monitored by a hematologist [17],[35],[36].

CONCLUSION

The development of thrombocytopenia is an unfavorable prognostic factor in COVID-19 treatment. Although thrombocytopenia is mainly mild and does not require treatment, the development of severe forms of thrombocytopenia is possible, which, due to bleeding, may be life-threatening for the patient. On the other hand, some forms of thrombocytopenia, such as HIT and CAC, carry a high risk of thrombosis, which is why it is necessary to continue anticoagulant prophylaxis. The understanding of the algorithm of diagnostics and treatment of these conditions is essential.

  • Conflict of interest:
    None declared.

Informations

Volume 3 No 1

Volume 3 No 1

March 2022

Pages 87-99
  • Received:
    13 December 2021
  • Revised:
    22 December 2021
  • Accepted:
    27 December 2021
  • Online first:
    25 March 2022
  • DOI:
Corresponding author

Mirjana Mitrović
Clinic for Hematology, University Clinical Center of Serbia
2 Koste Todorovića Street, 11000 Belgrade, Serbia
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.


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    23. Mingot-Castellano ME, Alcalde-Mellado P, Pascual-Izquierdo C, Perez Rus G, Calo Pérez A, Martinez MP, et al.; on behalf GEPTI (Grupo Español de Trombocitopenia Inmune). Incidence, characteristics and clinical profile of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in patients with pre-existing primary immune thrombocytopenia (ITP) in Spain. Br J Haematol. 2021 Aug;194(3):537-541. doi: 10.1111/bjh.17506.[CROSSREF]

    24. Pantić N, Mitrović M, Virijević M, Sabljić N, Pravdić Z, Suvajdžić N. SARS-KoV-2 infection in a patient with Evans syndrome: A silent enemy or an ally?. Vojnosanitetski pregled. 2020;77(12):1348-1350.[CROSSREF]

    25. de la Cruz-Benito B, Rivas-Pollmar MI, Álvarez Román MT, Trelles-Martínez R, Martín-Salces M, Lázaro-Del Campo P, et al. Paradoxical effect of SARS-CoV-2 infection in patients with immune thrombocytopenia. Br J Haematol. 2021 Mar;192(6):973-977. doi: 10.1111/bjh.17077.[CROSSREF]

    26. Pantic N, Suvajdzic-Vukovic N, Virijevic M, Pravdic Z, Sabljic N, Adzic-Vukicevic T, Mitrovic M. Coronavirus disease 2019 in patients with chronic immune thrombocytopenia on thrombopoietin receptor agonists: new perspectives and old challenges. Blood Coagul Fibrinolysis. 2022 Jan 1;33(1):51-55. doi: 10.1097/MBC.0000000000001109.[CROSSREF]

    27. Pantić N, Suvajdžić-Vuković N. Treating ITP: What are the options in the era of new guidelines and new drugs?. Medicinski podmladak. 2020;71(4):40-6.[CROSSREF]

    28. Rodeghiero F, Cantoni S, Carli G, Carpenedo M, Carrai V, Chiurazzi F, et al. Practical Recommendations for the Management of Patients with ITP During the COVID-19 Pandemic. Mediterr J Hematol Infect Dis. 2021 May 1;13(1):e2021032. doi: 10.4084/MJHID.2021.032.[CROSSREF]

    29. Pavord S, Thachil J, Hunt BJ, Murphy M, Lowe G, Laffan M, et al. Practical guidance for the management of adults with immune thrombocytopenia during the COVID-19 pandemic. Br J Haematol. 2020 Jun;189(6):1038-1043. doi: 10.1111/bjh.16775.[CROSSREF]

    30. Suvajdžić-Vuković N, Miljić P, Mitrović M. Vodič za dijagnostiku i lečenje odraslih bolesnika sa ITP-om. Aktiv za ITP, SLD. Beograd, Srbija; 2016.

    31. Bakchoul T, Marini I. Drug-associated thrombocytopenia. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):576-583. doi: 10.1182/asheducation-2018.1.576.[CROSSREF]

    32. Coutre S, Crowther M. Management of heparin-induced thrombocytopenia. Up to date. [Pristupljeno: 2021 Mart]

    33. Greinacher A. CLINICAL PRACTICE. Heparin-Induced Thrombocytopenia. N Engl J Med. 2015 Jul 16;373(3):252-61. doi: 10.1056/NEJMcp1411910[CROSSREF]

    34. Uaprasert N, Tangcheewinsirikul N, Rojnuckarin P, Patell R, Zwicker JI, Chiasakul T. Heparin-induced thrombocytopenia in patients with COVID-19: a systematic review and meta-analysis. Blood Adv. 2021 Nov 9;5(21):4521- 4534. doi: 10.1182/bloodadvances.2021005314.[CROSSREF]

    35. Cuker A, Arepally GM, Chong BH, Cines DB, Greinacher A, Gruel Y, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv. 2018 Nov 27;2(22):3360-3392. doi: 10.1182/bloodadvances.2018024489.[CROSSREF]

    36. Linkins LA, Dans AL, Moores LK, Bona R, Davidson BL, Schulman S, et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e495S-e530S. doi: 10.1378/chest.11-2303.[CROSSREF]


References

1. COVID-19 live update. [Internet]. [Pristupljeno: 2021 Novembar 1] Dostupno na: https://www.worldometers.info/coronavirus/. [HTTP]

2. Terpos E, Ntanasis-Stathopoulos I, Elalamy I, Kastritis E, Sergentanis TN, Politou M, et al. Hematological findings and complications of COVID-19. Am J Hematol. 2020 Jul;95(7):834-847. doi: 10.1002/ajh.25829.[CROSSREF]

3. Iba T, Levy JH, Levi M, Connors JM, Thachil J. Coagulopathy of Coronavirus Disease 2019. Crit Care Med. 2020 Sep;48(9):1358-1364. doi: 10.1097/CCM.0000000000004458.[CROSSREF]

4. Jiang SQ, Huang QF, Xie WM, Lv C, Quan XQ. The association between severe COVID-19 and low platelet count: evidence from 31 observational studies involving 7613 participants. Br J Haematol. 2020 Jul;190(1):e29-e33. doi: 10.1111/bjh.16817.[CROSSREF]

5. Zong X, Gu Y, Yu H, Li Z, Wang Y. Thrombocytopenia Is Associated with COVID-19 Severity and Outcome: An Updated Meta-Analysis of 5637 Patients with Multiple Outcomes. Lab Med. 2021 Jan 4;52(1):10-15. doi: 10.1093/labmed/lmaa067.[CROSSREF]

6. Xu P, Zhou Q, Xu J. Mechanism of thrombocytopenia in COVID-19 patients. Ann Hematol. 2020 Jun;99(6):1205-1208. doi: 10.1007/s00277-020-04019-0.[CROSSREF]

7. Tang XD, Ji TT, Dong JR, Feng H, Chen FQ, Chen X, et al. Pathogenesis and Treatment of Cytokine Storm Induced by Infectious Diseases. Int J Mol Sci. 2021 Nov 30;22(23):13009. doi: 10.3390/ijms222313009.[CROSSREF]

8. Delshad M, Safaroghli-Azar A, Pourbagheri-Sigaroodi A, Poopak B, Shokouhi S, Bashash D. Platelets in the perspective of COVID-19; pathophysiology of thrombocytopenia and its implication as prognostic and therapeutic opportunity. Int Immunopharmacol. 2021 Oct;99:107995. doi: 10.1016/j.intimp.2021.107995.[CROSSREF]

9. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020 May 1;130(5):2620-2629. doi: 10.1172/JCI137244.[CROSSREF]

10. Zhang Y, Zeng X, Jiao Y, Li Z, Liu Q, Ye J, et al. Mechanisms involved in the development of thrombocytopenia in patients with COVID-19. Thromb Res. 2020 Sep;193:110-115. doi: 10.1016/j.thromres.2020.06.008.[CROSSREF]

11. Gu SX, Tyagi T, Jain K, Gu VW, Lee SH, Hwa JM, et al. Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nat Rev Cardiol. 2021 Mar;18(3):194-209. doi: 10.1038/s41569-020-00469-1.[CROSSREF]

12. Lefrançais E, Ortiz-Muñoz G, Caudrillier A, Mallavia B, Liu F, Sayah DM, et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature. 2017 Apr 6;544(7648):105-109. doi: 10.1038/nature21706.[CROSSREF]

13. Valdivia-Mazeyra MF, Salas C, Nieves-Alonso JM, Martín-Fragueiro L, Bárcena C, Muñoz-Hernández P, et al. Increased number of pulmonary megakaryocytes in COVID-19 patients with diffuse alveolar damage: an autopsy study with clinical correlation and review of the literature. Virchows Arch. 2021 Mar;478(3):487-496. doi: 10.1007/s00428-020-02926-1.[CROSSREF]

14. Mandal RV, Mark EJ, Kradin RL. Megakaryocytes and platelet homeostasis in diffuse alveolar damage. Exp Mol Pathol. 2007 Dec;83(3):327-31. doi: 10.1016/j.yexmp.2007.08.005.[CROSSREF]

15. Battina HL, Alentado VJ, Srour EF, Moliterno AR, Kacena MA. Interaction of the inflammatory response and megakaryocytes in COVID-19 infection. Exp Hematol. 2021 Dec;104:32-39. doi: 10.1016/j.exphem.2021.09.005.[CROSSREF]

16. Iba T, Connors JM, Levy JH. The coagulopathy, endotheliopathy, and vasculitis of COVID-19. Inflamm Res. 2020 Dec;69(12):1181-1189. doi: 10.1007/ s00011-020-01401-6.[CROSSREF]

17. Pelemiš M, Stevanović G, Turklov V, Vučinić V, Matijašević J, Milošević B, i sar. Nacionalni protokol za lečenje pacijenata sa COVID-19, Verzija 13. Beograd (Srbija): Ministarstvo zdravlja Republike Srbije; 2020. [Interni izveštaj]. Neobjavljen.

18. Wada H, Thachil J, Di Nisio M, Mathew P, Kurosawa S, Gando S, et al.; The Scientific Standardization Committee on DIC of the International Society on Thrombosis Haemostasis. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost. 2013 Feb 4. doi: 10.1111/jth.12155.[CROSSREF]

19. Iba T, Levy JH, Warkentin TE, Thachil J, van der Poll T, Levi M; Scientific and Standardization Committee on DIC, and the Scientific and Standardization Committee on Perioperative and Critical Care of the International Society on Thrombosis and Haemostasis. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Thromb Haemost. 2019 Nov;17(11):1989-1994. doi: 10.1111/jth.14578.[CROSSREF]

20. Thachil J, Tang N, Gando S, Falanga A, Cattaneo M, Levi M, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020 May;18(5):1023-1026. doi: 10.1111/jth.14810.[CROSSREF]

21. Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009 Mar 12;113(11):2386-93. doi: 10.1182/ blood-2008-07-162503.[CROSSREF]

22. Bhattacharjee S, Banerjee M. Immune Thrombocytopenia Secondary to COVID-19: a Systematic Review. SN Compr Clin Med. 2020;2(11):2048-2058. doi: 10.1007/s42399-020-00521-8.[CROSSREF]

23. Mingot-Castellano ME, Alcalde-Mellado P, Pascual-Izquierdo C, Perez Rus G, Calo Pérez A, Martinez MP, et al.; on behalf GEPTI (Grupo Español de Trombocitopenia Inmune). Incidence, characteristics and clinical profile of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in patients with pre-existing primary immune thrombocytopenia (ITP) in Spain. Br J Haematol. 2021 Aug;194(3):537-541. doi: 10.1111/bjh.17506.[CROSSREF]

24. Pantić N, Mitrović M, Virijević M, Sabljić N, Pravdić Z, Suvajdžić N. SARS-KoV-2 infection in a patient with Evans syndrome: A silent enemy or an ally?. Vojnosanitetski pregled. 2020;77(12):1348-1350.[CROSSREF]

25. de la Cruz-Benito B, Rivas-Pollmar MI, Álvarez Román MT, Trelles-Martínez R, Martín-Salces M, Lázaro-Del Campo P, et al. Paradoxical effect of SARS-CoV-2 infection in patients with immune thrombocytopenia. Br J Haematol. 2021 Mar;192(6):973-977. doi: 10.1111/bjh.17077.[CROSSREF]

26. Pantic N, Suvajdzic-Vukovic N, Virijevic M, Pravdic Z, Sabljic N, Adzic-Vukicevic T, Mitrovic M. Coronavirus disease 2019 in patients with chronic immune thrombocytopenia on thrombopoietin receptor agonists: new perspectives and old challenges. Blood Coagul Fibrinolysis. 2022 Jan 1;33(1):51-55. doi: 10.1097/MBC.0000000000001109.[CROSSREF]

27. Pantić N, Suvajdžić-Vuković N. Treating ITP: What are the options in the era of new guidelines and new drugs?. Medicinski podmladak. 2020;71(4):40-6.[CROSSREF]

28. Rodeghiero F, Cantoni S, Carli G, Carpenedo M, Carrai V, Chiurazzi F, et al. Practical Recommendations for the Management of Patients with ITP During the COVID-19 Pandemic. Mediterr J Hematol Infect Dis. 2021 May 1;13(1):e2021032. doi: 10.4084/MJHID.2021.032.[CROSSREF]

29. Pavord S, Thachil J, Hunt BJ, Murphy M, Lowe G, Laffan M, et al. Practical guidance for the management of adults with immune thrombocytopenia during the COVID-19 pandemic. Br J Haematol. 2020 Jun;189(6):1038-1043. doi: 10.1111/bjh.16775.[CROSSREF]

30. Suvajdžić-Vuković N, Miljić P, Mitrović M. Vodič za dijagnostiku i lečenje odraslih bolesnika sa ITP-om. Aktiv za ITP, SLD. Beograd, Srbija; 2016.

31. Bakchoul T, Marini I. Drug-associated thrombocytopenia. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):576-583. doi: 10.1182/asheducation-2018.1.576.[CROSSREF]

32. Coutre S, Crowther M. Management of heparin-induced thrombocytopenia. Up to date. [Pristupljeno: 2021 Mart]

33. Greinacher A. CLINICAL PRACTICE. Heparin-Induced Thrombocytopenia. N Engl J Med. 2015 Jul 16;373(3):252-61. doi: 10.1056/NEJMcp1411910[CROSSREF]

34. Uaprasert N, Tangcheewinsirikul N, Rojnuckarin P, Patell R, Zwicker JI, Chiasakul T. Heparin-induced thrombocytopenia in patients with COVID-19: a systematic review and meta-analysis. Blood Adv. 2021 Nov 9;5(21):4521- 4534. doi: 10.1182/bloodadvances.2021005314.[CROSSREF]

35. Cuker A, Arepally GM, Chong BH, Cines DB, Greinacher A, Gruel Y, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv. 2018 Nov 27;2(22):3360-3392. doi: 10.1182/bloodadvances.2018024489.[CROSSREF]

36. Linkins LA, Dans AL, Moores LK, Bona R, Davidson BL, Schulman S, et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e495S-e530S. doi: 10.1378/chest.11-2303.[CROSSREF]

1. COVID-19 live update. [Internet]. [Pristupljeno: 2021 Novembar 1] Dostupno na: https://www.worldometers.info/coronavirus/. [HTTP]

2. Terpos E, Ntanasis-Stathopoulos I, Elalamy I, Kastritis E, Sergentanis TN, Politou M, et al. Hematological findings and complications of COVID-19. Am J Hematol. 2020 Jul;95(7):834-847. doi: 10.1002/ajh.25829.[CROSSREF]

3. Iba T, Levy JH, Levi M, Connors JM, Thachil J. Coagulopathy of Coronavirus Disease 2019. Crit Care Med. 2020 Sep;48(9):1358-1364. doi: 10.1097/CCM.0000000000004458.[CROSSREF]

4. Jiang SQ, Huang QF, Xie WM, Lv C, Quan XQ. The association between severe COVID-19 and low platelet count: evidence from 31 observational studies involving 7613 participants. Br J Haematol. 2020 Jul;190(1):e29-e33. doi: 10.1111/bjh.16817.[CROSSREF]

5. Zong X, Gu Y, Yu H, Li Z, Wang Y. Thrombocytopenia Is Associated with COVID-19 Severity and Outcome: An Updated Meta-Analysis of 5637 Patients with Multiple Outcomes. Lab Med. 2021 Jan 4;52(1):10-15. doi: 10.1093/labmed/lmaa067.[CROSSREF]

6. Xu P, Zhou Q, Xu J. Mechanism of thrombocytopenia in COVID-19 patients. Ann Hematol. 2020 Jun;99(6):1205-1208. doi: 10.1007/s00277-020-04019-0.[CROSSREF]

7. Tang XD, Ji TT, Dong JR, Feng H, Chen FQ, Chen X, et al. Pathogenesis and Treatment of Cytokine Storm Induced by Infectious Diseases. Int J Mol Sci. 2021 Nov 30;22(23):13009. doi: 10.3390/ijms222313009.[CROSSREF]

8. Delshad M, Safaroghli-Azar A, Pourbagheri-Sigaroodi A, Poopak B, Shokouhi S, Bashash D. Platelets in the perspective of COVID-19; pathophysiology of thrombocytopenia and its implication as prognostic and therapeutic opportunity. Int Immunopharmacol. 2021 Oct;99:107995. doi: 10.1016/j.intimp.2021.107995.[CROSSREF]

9. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020 May 1;130(5):2620-2629. doi: 10.1172/JCI137244.[CROSSREF]

10. Zhang Y, Zeng X, Jiao Y, Li Z, Liu Q, Ye J, et al. Mechanisms involved in the development of thrombocytopenia in patients with COVID-19. Thromb Res. 2020 Sep;193:110-115. doi: 10.1016/j.thromres.2020.06.008.[CROSSREF]

11. Gu SX, Tyagi T, Jain K, Gu VW, Lee SH, Hwa JM, et al. Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nat Rev Cardiol. 2021 Mar;18(3):194-209. doi: 10.1038/s41569-020-00469-1.[CROSSREF]

12. Lefrançais E, Ortiz-Muñoz G, Caudrillier A, Mallavia B, Liu F, Sayah DM, et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature. 2017 Apr 6;544(7648):105-109. doi: 10.1038/nature21706.[CROSSREF]

13. Valdivia-Mazeyra MF, Salas C, Nieves-Alonso JM, Martín-Fragueiro L, Bárcena C, Muñoz-Hernández P, et al. Increased number of pulmonary megakaryocytes in COVID-19 patients with diffuse alveolar damage: an autopsy study with clinical correlation and review of the literature. Virchows Arch. 2021 Mar;478(3):487-496. doi: 10.1007/s00428-020-02926-1.[CROSSREF]

14. Mandal RV, Mark EJ, Kradin RL. Megakaryocytes and platelet homeostasis in diffuse alveolar damage. Exp Mol Pathol. 2007 Dec;83(3):327-31. doi: 10.1016/j.yexmp.2007.08.005.[CROSSREF]

15. Battina HL, Alentado VJ, Srour EF, Moliterno AR, Kacena MA. Interaction of the inflammatory response and megakaryocytes in COVID-19 infection. Exp Hematol. 2021 Dec;104:32-39. doi: 10.1016/j.exphem.2021.09.005.[CROSSREF]

16. Iba T, Connors JM, Levy JH. The coagulopathy, endotheliopathy, and vasculitis of COVID-19. Inflamm Res. 2020 Dec;69(12):1181-1189. doi: 10.1007/ s00011-020-01401-6.[CROSSREF]

17. Pelemiš M, Stevanović G, Turklov V, Vučinić V, Matijašević J, Milošević B, i sar. Nacionalni protokol za lečenje pacijenata sa COVID-19, Verzija 13. Beograd (Srbija): Ministarstvo zdravlja Republike Srbije; 2020. [Interni izveštaj]. Neobjavljen.

18. Wada H, Thachil J, Di Nisio M, Mathew P, Kurosawa S, Gando S, et al.; The Scientific Standardization Committee on DIC of the International Society on Thrombosis Haemostasis. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost. 2013 Feb 4. doi: 10.1111/jth.12155.[CROSSREF]

19. Iba T, Levy JH, Warkentin TE, Thachil J, van der Poll T, Levi M; Scientific and Standardization Committee on DIC, and the Scientific and Standardization Committee on Perioperative and Critical Care of the International Society on Thrombosis and Haemostasis. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Thromb Haemost. 2019 Nov;17(11):1989-1994. doi: 10.1111/jth.14578.[CROSSREF]

20. Thachil J, Tang N, Gando S, Falanga A, Cattaneo M, Levi M, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020 May;18(5):1023-1026. doi: 10.1111/jth.14810.[CROSSREF]

21. Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009 Mar 12;113(11):2386-93. doi: 10.1182/ blood-2008-07-162503.[CROSSREF]

22. Bhattacharjee S, Banerjee M. Immune Thrombocytopenia Secondary to COVID-19: a Systematic Review. SN Compr Clin Med. 2020;2(11):2048-2058. doi: 10.1007/s42399-020-00521-8.[CROSSREF]

23. Mingot-Castellano ME, Alcalde-Mellado P, Pascual-Izquierdo C, Perez Rus G, Calo Pérez A, Martinez MP, et al.; on behalf GEPTI (Grupo Español de Trombocitopenia Inmune). Incidence, characteristics and clinical profile of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in patients with pre-existing primary immune thrombocytopenia (ITP) in Spain. Br J Haematol. 2021 Aug;194(3):537-541. doi: 10.1111/bjh.17506.[CROSSREF]

24. Pantić N, Mitrović M, Virijević M, Sabljić N, Pravdić Z, Suvajdžić N. SARS-KoV-2 infection in a patient with Evans syndrome: A silent enemy or an ally?. Vojnosanitetski pregled. 2020;77(12):1348-1350.[CROSSREF]

25. de la Cruz-Benito B, Rivas-Pollmar MI, Álvarez Román MT, Trelles-Martínez R, Martín-Salces M, Lázaro-Del Campo P, et al. Paradoxical effect of SARS-CoV-2 infection in patients with immune thrombocytopenia. Br J Haematol. 2021 Mar;192(6):973-977. doi: 10.1111/bjh.17077.[CROSSREF]

26. Pantic N, Suvajdzic-Vukovic N, Virijevic M, Pravdic Z, Sabljic N, Adzic-Vukicevic T, Mitrovic M. Coronavirus disease 2019 in patients with chronic immune thrombocytopenia on thrombopoietin receptor agonists: new perspectives and old challenges. Blood Coagul Fibrinolysis. 2022 Jan 1;33(1):51-55. doi: 10.1097/MBC.0000000000001109.[CROSSREF]

27. Pantić N, Suvajdžić-Vuković N. Treating ITP: What are the options in the era of new guidelines and new drugs?. Medicinski podmladak. 2020;71(4):40-6.[CROSSREF]

28. Rodeghiero F, Cantoni S, Carli G, Carpenedo M, Carrai V, Chiurazzi F, et al. Practical Recommendations for the Management of Patients with ITP During the COVID-19 Pandemic. Mediterr J Hematol Infect Dis. 2021 May 1;13(1):e2021032. doi: 10.4084/MJHID.2021.032.[CROSSREF]

29. Pavord S, Thachil J, Hunt BJ, Murphy M, Lowe G, Laffan M, et al. Practical guidance for the management of adults with immune thrombocytopenia during the COVID-19 pandemic. Br J Haematol. 2020 Jun;189(6):1038-1043. doi: 10.1111/bjh.16775.[CROSSREF]

30. Suvajdžić-Vuković N, Miljić P, Mitrović M. Vodič za dijagnostiku i lečenje odraslih bolesnika sa ITP-om. Aktiv za ITP, SLD. Beograd, Srbija; 2016.

31. Bakchoul T, Marini I. Drug-associated thrombocytopenia. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):576-583. doi: 10.1182/asheducation-2018.1.576.[CROSSREF]

32. Coutre S, Crowther M. Management of heparin-induced thrombocytopenia. Up to date. [Pristupljeno: 2021 Mart]

33. Greinacher A. CLINICAL PRACTICE. Heparin-Induced Thrombocytopenia. N Engl J Med. 2015 Jul 16;373(3):252-61. doi: 10.1056/NEJMcp1411910[CROSSREF]

34. Uaprasert N, Tangcheewinsirikul N, Rojnuckarin P, Patell R, Zwicker JI, Chiasakul T. Heparin-induced thrombocytopenia in patients with COVID-19: a systematic review and meta-analysis. Blood Adv. 2021 Nov 9;5(21):4521- 4534. doi: 10.1182/bloodadvances.2021005314.[CROSSREF]

35. Cuker A, Arepally GM, Chong BH, Cines DB, Greinacher A, Gruel Y, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv. 2018 Nov 27;2(22):3360-3392. doi: 10.1182/bloodadvances.2018024489.[CROSSREF]

36. Linkins LA, Dans AL, Moores LK, Bona R, Davidson BL, Schulman S, et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e495S-e530S. doi: 10.1378/chest.11-2303.[CROSSREF]


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