Thromboembolism: the secret lethal weapon of coronavirus disease 2019 : Reviews and Research in Medical Microbiology

Secondary Logo

Journal Logo

Univited Review Article

Thromboembolism: the secret lethal weapon of coronavirus disease 2019

Ahmed, Abdulrahman K.a; Moustafa, Eslam R.b; Abd EL-Monem, Aya M.a; Hasan, Galal A.a; Mohamed, Omar A.c; Ibrahim, Islam H.a; Batiha, Gaber El-Saberd; Al-Kadmy, Israa M.S.e; Hosni, Amalf; Hetta, Helal F.g

Author Information
Reviews and Research in Medical Microbiology ():10.1097/MRM.0000000000000336, January 12, 2023. | DOI: 10.1097/MRM.0000000000000336
  • Free
  • PAP

Abstract

Introduction

Coronavirus disease 2019 (COVID-19), a new disease of the coronavirus strain, has started to emerge in Wuhan, China, and has spread rapidly throughout China and successively worldwide [1,2]. Typically, COVID-19 presents as respiratory disease, but coagulopathy can result in high death rates [3–8]. Among the serious cases of SARS-CoV-2 infection, blood coagulation disorders, and serious respiratory failure are the major complications. COVID-19 has been associated with blood clots, pulmonary embolism, and pedal acro-ischaemia (’COVID-toes’), particularly in severe cases [9–14].

The potential mechanisms of the blood clotting disorders of coronavirus disease 2019

More than 70% of COVID-19-related deaths are linked to blood clotting processes. When coagulation management is inadequate, disseminated intravascular coagulation (DIC) can develop, resulting in a clinical condition that includes extensive microvascular thrombosis from increased blood clotting and increased bleeding from coagulation factor depletion [15]. In this study, we briefly describe the potential blood coagulation disorder mechanisms; highlighting the role of activation of coagulation factors associated with hypoxia; neutrophil activation; cytokine storm; and ICU-related risk factors and immobility; and coagulation factor VIII dysregulation [16,17].

Hypoxia-induced coagulopathy

Hypoxia reduces blood anticoagulation and activates pro-coagulation factors, which increases thrombosis [18]. Hypoxia decreases the amount of protein S in the body [19]. The amount of protein S is inversely proportional to the amount of hypoxia-inducible factor 1 (HIF1), which is continuously degraded in an O2-dependent manner [20]. Patients who have both protein S deficiency and the Factor V Leiden mutation have lower endogenous antithrombotic activity and are more susceptible to fibrin buildup at hypoxemic sites [21]. In severe COVID-19 conditions, D-dimer, a tiny protein fragment that is a clot-dissolving fibrin breakdown product, is considerably increased, and this protein is a sure indication of the disease's severity [5]. The D-dimer level is drastically elevated and highly connected with the severity of sickness in individuals who have been infected with many different viruses that can cause serious haemorrhage, such as Ebola and Hantavirus haemorrhagic fever with renal syndrome [22,23].

An enhanced immune system response ‘cytokine storm’ and neutrophil-derived extracellular traps in the lungs during coronavirus disease 2019

The response of immune cells shares in thrombotic risk [24]. A condition is known as ‘cytokine storm’ can develop in patients with a terrible disease, which contributes to damaging inflammatory responses by cytokine discharges of lymphocytes, monocytes, and alveolar macrophages. Acute respiratory distress syndrome, stroke, and myocardial injury are the terminal stages of SARS-CoV-2 infection in patients who die [25]. The activation of the blood coagulation pathway is caused by electrostatic interactions between platelet phospholipids and neutrophil extracellular trap (NET) histones [26]. One of the most essential enzymes involved in NET formation is neutrophil elastase (a serine protease) [27]. Dengue fever, or DHF, is revealed to have NETs in an aggressive case, resulting in multiorgan failures and death [28].

Coagulation factor VIII dysregulation

Coagulation laboratory testing showed a severe unexpected rising of factor V action at 248 IU/dl (normal value 60–150 IU/dl), and 4 days later, this patient highly developed a pulmonary embolism [16]. In the coagulation succession, active factor X interacts with activated factor V result in the formation of the prothrombinase complex, which catalyzes the formation of thrombin and leads to the formation of many fibrin clots [16]. Any dysregulation happens with factor V because of factor V Leiden is a famous cause of a prothrombotic state [29]. Co-occurrent raise in the activity of factor V and factor VIII have also been related to increased venous thromboembolism (VTE) risk [30]. Thus, we acknowledged that thromboembolism and maybe other complications related to COVID-19 are related to disturb of factor V activity.

Coronavirus disease 2019 and coagulation disorders

Fever (more than 80%), cough (more than 60%), and fatigue (more than 40%) are common in COVID-19 patients [31,32]. With a medium age of about 50 years, men are more often affected (around 60% of cases) [1,7,31]. The whole range of COVID-19-related symptoms and concerns is also not fully explained. Medical evidence ranges from asymptomatic to serious illness, sepsis, and death. Despite the fact that the majority of COVID-19 disorders are moderate, a study indicated that severe illness occurs in 16% of instances [7].

COVID-19 patients continue to be concerned about thrombotic problems. Infected patients frequently have thrombocytopenia (36.2%) and may have elevated D-dimer levels, according to preliminary COVID-19 disease outbreak statistics (46.4%) [7]. These rates are also higher in persons who have severe COVID-19 disease (57.7% and 59.6%, respectively) [7]. The rising body of evidence suggests that patients infected with this novel coronavirus are more likely to develop disseminated intravascular coagulation [7,33,34]. In individuals with new coronavirus illness, elevated D-dimer levels and a longer prothrombin time have been linked to poor outcomes [33].

According to Tang et al.[33], 15 of the 21 nonsurvivors (8% of the overall cohort) had an open DIC (five points) as determined by the International Society for Thrombosis and Haemostasis Diagnostic Criteria. A meta-analysis found that individuals with severe illness had somewhat lower platelet counts [mean difference: 31 109/l, 95% confidence interval (CI) 35–29 109/l]. Thrombocytopenia was connected to a five-fold greater risk of serious disease (OR: 5.13; 95% confidence interval: 1.81–14.58) [35]. The excessive activity of the cascade and platelet coagulation can indicate both thrombocytopenia and increased D-dimer. Infections with viruses trigger systemic inflammatory responses and disrupt the balance of homeostatic procoagulants and anticoagulants [36].

Platelets are aroused by antigen recognition and work with white blood cells to promote pathogen elimination by stimulating white blood cells and forming clots [37]. Via connecting cell surface receptors with pathogens or immune system products, platelets are constitutional mediators of inflammation and infectious agents (immunoglobulin Fc receptors and complement receptors). The activation and interactions of macrophage, monocyte, endothelial, platelet, and lymphocyte cells are critical for the procoagulant effect of viral infections [38,39].

Brief rundown of relativity markers between coronavirus disease 2019 and other coagulopathy-related disorders

The importance of hypercoagulability in COVID-19 and anticoagulation is highlighted in this review. However, the pathophysiology of COVID-19-associated coagulopathy (CAC) is complex, and it is likely to differ from conventional thrombus formation mechanisms seen in critically unwell patients. This study will compare and represent alternative well characterized forms of coagulopathy with CAC (Table 1) [40].

Table 1 - Commonalities and dissimilarities in thrombosis and laboratory data among coronavirus disease 2019 and differential diseases.
Primary cause and target of coagulopathy Thromboembolism Platelet count D-dimer PT/aPTT Antithrombin Fibrinogen Antiphospholipid antibody Activated complement system/VWF Inflammatory cytokines (IL-1β, IL-6)
COVID-19 Macrophage/endothelial cell Microthrombosis/venous thrombosis ↑↓ →↑ + +
DIC/SIC Macrophage/endothelial cell Microthrombosis →↓ -
APS Antiphospho-lipid antibody Arterial/venous thrombosis Pt→
aPTT↑
+
HPS Inflammatory cytokines Microthrombosis/venous thrombosis
TMA (aHUS/TTP) Complement system/ADAMTS13 Microthrombosis/arterial/venous thrombosis AHUS +/- TTP-/+
aHUS, atypical haemolytic uremic syndrome; APS, antiphospholipid syndrome; aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; HPS, haemophagocytic syndrome; IL, interleukin; PT, prothrombin time; SIC, sepsis-induced coagulopathy; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura; VWF, von Willebrand factor.

Sepsis-induced coagulopathy and disseminated intravascular coagulation and coronavirus disease 2019

Because the inflammatory response and blood clotting are both important host defence processes that are proportional to the severity of infection and can be harmful to the host [41]. Proinflammatory cytokines including interleukin (IL)-1 and IL-6, as well as complementing system proteins, are all found in the host defence system and can cause coagulopathy [42]. Furthermore, thromboembolism is influenced by monocyte/macrophage tissue factor expression, neutrophil stimulation, and NETs [43,44]. Endothelial damage is caused by this thromboinflammatory response, which increases thrombin generation when combined with extracellular vesicles [45,46].

Consumptive coagulopathy is a prevalent characteristic of SIC/DIC; however, the type of coagulopathy is rarely found in COVID-19 in its early stages. Thrombocytosis and hyper-fibrinogenaemia are known to be induced by IL-1 and IL-6, and the development of these factors may be aided by chronic inflammation [47]. Furthermore, inflammation and coagulation are extensively distributed inside the lungs in the early stages of the disease, but as the disease advances, hypercoagulability becomes widespread and progresses to SIC/DIC. The up-regulation of local alveoli fibrinolysis by urokinase-type plasminogen activator (u-PA) produced by alveolar macrophages explains the mismatched rise of the D- dimer [48].

Furthermore, direct virus invasion of endothelial cells [a strategy used by coronaviruses to enter cells via the ACE2 (angiotensin-converting enzyme 2, the SARS-CoV-2 receptor) receptor, which is widely distributed on the surface of endothelium] leads in a massive release of plasminogen activators [49]. Due to the high amount of fibrinogen and activated platelets, there is a procoagulant shift with an increase in the severity of illnesses and the amplification of fibrin formation. Inhibited fibrinolysis by PAI-1 production enhances clot formation in lung capillaries. Although ACE2 helps to mediate healthy vascular endothelium anticoagulation properties, SARS-CoV-2 binding to ACE2 enhances cell damage, alters tissue factor expression, and suppresses the C-protein system [50].

In a healthy condition, ACE2 converts angiotensin-II to angiotensin-I [1–7], which encourages endothelial cells to produce nitric oxide. NO aids in the dilation of blood arteries and inhibits platelet aggregation. SARS-CoV-2 occupies ACE2 in COVID-19, causing a rise in angiotensin-II levels, leading in vasoconstriction and decreased blood flow [40]. Weibel Palade's body contains Von Willebrand factor (VWF), which is released into circulation and aids in the production of clots. Reduced levels of ADAMTS13 (not yet shown in COVID-19) could lead to the formation of a thrombus [40].

Haemophagocytic syndrome/haemophagocytic lymphohistiocytosis and coronavirus disease 2019

Ferritin (1297.6 vs. 614.0 ng/ml, P = 0.01) and IL-6 (11.4 against 6.8 ng/ml, P = 0.0001) levels were found to be higher in nonsurvivors compared with survivors in the multicentre COVID-19 study [31]. Although there are some similarities between haemophagocytic syndrome and haemophagocytic lymphohistiocytosis and CAC, such as the incidence of cytokine storm in COVID-19, clinical and laboratory observations of standard HPS/HLH, such as fever and hyperferritinemia, are not common in COVID-19, and ferritin levels in COVID-19 do not always reach the elevated levels seen in HPS/HLH [51,52].

Bone marrow biopsy haemophagocytosis was not reported in COVID-19 [53]; chemotherapy is not approved for use. In comparison to HPS/HLH, the dominant features of COVID-19 are severe lung damage and coagulopathy direct infection with SARS-CoV-2 in pulmonary epithelial cells causes pulmonary capillary endothelial cell death and subsequent fibrin deposition in the alveoli, which may help distinguish between HPS/HLH and COVID-19 [54]. Anticytokine treatment can play a significant role in COVID-19 [55], based on the theory of hypercytokinemia.

However, as used for HPS/HLH, corticosteroids have not enhanced results in patients with severe acute respiratory syndrome (SARS), but have also resulted in delayed viral clearance [56].

Antiphospholipid syndrome and coronavirus disease 2019

Even in young individuals, thrombotic stroke has been described as a serious COVID-19 consequence, with the clinical significance of antiphospholipid antibodies being disputed [13,14]. Secondary antiphospholipid syndrome (APS) is a term used to describe acquired autoimmune thrombophilia, which is characterized by arterial and venous thrombosis in the presence of antiphospholipid antibodies (APS) [57]. Thrombocytopenia and prolonged aPTT are caused by antiphospholipid antibodies, that is, lupus anticoagulant, anticardiolipin, and antiβ2-glycoprotein (GP) I antibodies, and all these results are mostly the indications of APS [40].

Combination antiplatelet therapy and anticoagulant therapy can be used to avoid blood clots in people with APS but the benefit is still uncertain [58]; unfractionated heparin or low-molecular-weight heparin (LMWH) is a benefit of adding antiplatelet therapy to therapeutic therapy in COVID-19 patients and can increase bleeding incidence; corticosteroids, plasma exchange, and/or intravenous immunoglobulin are used to treat CAPS in addition to anticoagulant therapy. In the case of COVID-19 [59], although plasma treatment is being developed, there has been no research into the use of intravenous immunoglobulins.

A noteworthy COVID-19 study was documented by Escher et al.[60] Case admitted to hospital, followed by respiratory with an altered mental state. Anticardiolipin and anti2-GP I IgM antibodies were elevated in the patient, along with high levels of von Willebrand factor (VWF) and factor VIII [60]. The patient was given a preventive dose of LMWH at first, but after clinical improvement and incremental coagulation marker abnormalities, anticoagulation was switched to therapeutic-dose unfractionated heparin [60].

Thrombotic micro-angiopathy and coronavirus disease 2019

Thrombotic thrombocytopenic purpura (TTP), haemolytic uremic syndrome (HUS), and secondary TMAs are all examples of thrombotic microangiopathy (TMA). TMA is characterized by the formation of a microvascular thrombus (mostly in arterioles), as well as laboratory findings of microangiopathic haemolytic anaemia (MAHA) and thrombocytopenia [61]. COVID-19 autopsy cases have diffuse microvascular thrombosis in various organs, and changes in haematological markers are similar to those seen in mild MAHA, which are associated with decreased haemoglobin, increased lactate dehydrogenase (LDH), increased bilirubin, decreased haptoglobin, and the presence of schistocytosis [62].

A metalloprotease enzyme that cleaves big VWF multimers is type 1 motif thrombospondin, member 13 (ADAMTS13). Platelet/VWF microthrombi are present in TTP, associated with severe thrombocytopenia and MAHA. Although infection can cause acquired TTP, no evidence of ADAMTS13 deficiency in COVID-19 has been found to date [40]. Instead, higher VWF levels have been discovered in COVID-19. VWF activity, VWF antigen, and factor VIII were shown to be considerably elevated in COVID-19 [25]. In addition, nearly 90% of the patients tested positive for lupus anticoagulant, implying that COVID-19 has characteristics similar to TTP and APS. Increased VWF is thought to be the result of vascular injury because VWF and factor VIII are both deposited in the Weibel–Palade body in endothelial cells [40]. The release of these components can be triggered by SARS-CoV-2 endothelial cell infection, with levels growing independently of ADAMTS13 levels.

Dengue fever is a coronavirus-like RNA virus that causes endothelial cells to release VWF [63], Dengue fever has been linked to greater levels of VWF in the bloodstream as well as stroke [64]. Thrombocytopenia, fever, diminished awareness, and altered renal function are all TTP features that could be seen in COVID-19 [65], indicate that there could be potential similarities in pathophysiology.

Hemolytic uremic syndrome and coronavirus disease 2019

Complement system dysregulation, MAHA, acute kidney injury, and other organ dysfunctions can all induce HUS as a result of infection [54] are some of the most frequent HUS symptoms. According to a study, COVID-19 is more similar to the pathophysiology and phenotypic of HUS than SIC/DIC [66]. Platelets are triggered by active complement, which causes haemolysis and eventually creates membrane attack complexes [MAC (C5b9)] that destroy cell membranes.

MERS-CoV is reported to raise blood and lung tissue levels of C5a and C5b-9 in a mouse model, despite the lack of research articles on the complement system in COVID-19 [67]. The deposition of MAC, C4d, and mannose-binding lectin-associated serine protease (MASP) 2 in the pulmonary microvasculature of COVID-19 patients was further characterized in a research article [68]. These findings were also said to be consistent with long-term activation of the alternative and lectin-based complement pathways throughout the body. Endothelial damage in COVID-19 may play a role in complement activation, and the impact of anticomplement therapy is now being investigated [62].

Heparin-induced thrombocytopenia and coronavirus disease 2019

Heparin-induced thrombocytopenia (HIT) can be considered as a prothrombotic complication, which can happen after heparin therapy. Because heparin (unfractionated or LMWH) is becoming the primary treatment for VTE prophylaxis in COVID-19, patients may be at an increased risk of acquiring HIT [40]. This drug's adverse reaction is caused by platelet-activating antibodies that identify platelet factor 4 (PF4) and heparin multimolecular complexes. Patients may also have moderate-to-severe thrombocytopenia (possibly both at the same time) with venous or arterial thrombi [40]. Rarely, without heparin treatment, a condition similar to HIT on both clinical and laboratory grounds, spontaneous HIT syndrome happens after infection [69], but this has not been documented in COVID-19.

HIT has a 10-fold lower risk of thrombosis than LMWH and is, therefore, preferred for prophylaxis of thrombosis in COVID-19 [31,70]. LMWH is made from unfractionated heparin. For clinical diagnosis, the 4Ts score system, which includes thrombocytopenia, onset time, thrombosis, and other thrombocytopenia causes, is useful [71], However, with COVID-19 patients, it may be difficult to employ. Because greater baseline platelet counts in COVID-19 may hide HIT-related platelet count declines, clinical vigilance is essential, including thorough laboratory testing of HIT antibodies [40]. Anticoagulation using choices like fondaparinux or direct thrombin inhibitors is causing a lot of anxiety (e.g. bivalirudin) [71] should be altered.

In certain respects, CAC is similar to SIC/DIC, HPS/HLH, APS, and TTP/HUS but has specific characteristics that can be described as a new coagulopathy category (Fig. 1) [40]. As numerous factors are associated with the production of CAC, for proper management, it is important to further understand the underlying pathophysiology.

F1
Fig. 1:
Coronavirus disease 2019-related coagulopathy has distinct characteristics. COVID-19-associated coagulopathy (CAC) shares some clinical and laboratory characteristics with sepsis-induced coagulopathy (SIC)/disseminated intravascular coagulation (DIC), haemophagocytic syndrome (HPS)/haemophagocytic lymphohistiocytosis (HLH), antiphospholipid syndrome (APS), and thrombotic microangiopathy (TMA), but it does not perfectly match any of these other coagulopathies. Adapted from Toshiaki Iba et al. 2020 [40]. COVID-19, coronavirus disease 2019.

Anticoagulation management in venous thromboembolism: the rule heparin during coronavirus disease 2019

The use of heparin with anticoagulant treatment was revealed to decrease the death rate in patients with COVID-19 [32]. The preliminary Wuhan summary recorded a lower death rate in heparin-treated patients with D-dimer levels above 3.0 μg/ml (32.8 vs. 52.4% untreated) [32]. In another review that evaluated 2773 cases of COVID-19, of which only 28% were receiving anticoagulant treatment, patients receiving systemic anticoagulation had a lower hospital death rate of 29.1% with a median survival of 21 days, compared with 62.7% mortality with a median survival of 9 days in patients who did not receive anticoagulant treatment. That's two and a half times more survival rate in anticoagulant-treated patients than in nontreated patients [72].

The upregulation of pro-inflammatory cytokines in COVID-19 leads to severe inflammation in the lung and decreased pulmonary gas exchange [73]. It may be argued that the high D-dimer level may be because of the severe inflammation, which leads to intrinsic fibrinolysis in the lung tissue and leaking into the blood [74]. Heparin may reduce the inflammatory response by blocking thrombin, according to the immunothrombosis model, which explains the relationship between the immune system and the generation of thrombin [75]. Heparin has a nonanticoagulant property, which is its remarkable anti-inflammatory function. This nonanticoagulant property has been explained in many publications and the mechanisms described include binding heparin to inflammatory cytokines, neutralizing the positively charged peptide complement factor C5a, suppressing neutrophil chemotaxis, and sequestering acute-phase protein factor C5a [75–79]. In the clinical environment, a systematic review showed that heparin can reduce the level of biomarkers of the inflammatory process [80].

One of the most common complications of COVID-19 infection is acute respiratory distress syndrome (ARDS). The use of anticoagulants is significant in the pathogenesis of ARDS. The plasma concentrations of plasminogen activator inhibitor- 1 (PAI-1) and tissue factor were much greater than that at day 7 in patients with ARDS, as compared with normal values [81]. The increase in PAI-1 is involved in the mechanisms of this lung coagulopathy [81,82]. The use of heparin may thus be very helpful in reducing this pulmonary coagulopathy. A meta-analysis showed that treatment with LMWH during the first week of the onset of ARDS decreases the risk of 7-day mortality by 48% and improves the PaO2/FiO2 ratio [83]. In 42/355 (12.5%) of patients who had thrombosis, ARDS was a risk factor [84]. In this context, nebulized anticoagulation seems a reasonable choice in the treatment of coagulopathy in ARDS [85].

During the pathogen invasion, the vascular endothelium is affected, which results in endothelial dysfunction leading to marked organ failure [86]. In addition to the pathogen, damaged cells release histones, which cause also endothelial injury [86]. Heparin is used to antagonize histones; therefore, it can protect the endothelium [87,88]. This protective effect can be extended to the tight junctions between endothelial cells as explained in a sepsis model, in which unfractionated heparin could reduce lung edema, which follows lipopolysaccharide-induced injury [88]. Thus, there is an urgent need to use heparin to reduce microcirculatory dysfunction and the possible damage to organs.

Endothelial dysfunction greatly contributes to many effects on CVS, another possible complication in patients with COVID-19 [73]. As ischaemia hypoxia in the subendocardial layer can induce the loss of its natural anticoagulant qualities, heparin may assist in alleviating microvascular dysfunction in many cases of heart failure [89]. Heparin can reduce collagen deposition and decrease myocardial inflammation in an animal model of chronic myocarditis [90]. Almost all of these cardiovascular benefits should be noticed when treating patients with COVID-19.

The antiviral effect of heparin is another urgent aspect. The polyanionic nature of heparin enables it to bind to many proteins in order to act as an efficient inhibitor of viral attachment [83]. As an example, in the case of infection with herpes simplex virus, heparin competes with the virus for surface glycoproteins on the host cell to minimize infection and in the infection with Zika virus, it prevents the death of a certain type of cells called human neural progenitor cells after they get infected with the virus [91,92]. Heparin treatment reduced infection in experimental Vero cells inoculated with sputum from a patient with SARS-associated CoV strain pneumonia in an Italian investigation [93].

Prevention and risk assessment of thromboembolism associated with coronavirus disease 2019

Assessment of the risk of VTE is essential in COVID-19 patients to take prophylactic measures in high-risk groups, and for rapid management in case of occurrence of VTE or PE manifested by hypoxia, respiratory distress, or hypotension by antithrombotic measures throughout the prevention, control, and treatment of COVID-19 infection [94].

It would be considered in accordance with COVID-19 of the National Health Commission and the WHO's applicable diagnosis and treatment plans and clinical strategies [95–97], in addition to other global viral infection-related methods, clinical experience and medical evidence-based prevention and control of hospitalized VTE [94,98–101].

Risk assessment of venous thromboembolism

As mentioned in the fifth edition of the diagnosis and treatment plan, the national health programme divided COVID-19 cases into four classes based on clinical symptoms and laboratory findings: mild, moderate, severe, and critically sick [94].

Dehydration is a significant risk factor that contributes to the development of VTE. Tt may be caused by drugs; fever followed by physical cooling, which is reported to occur in most patients [1,102]; diarrhoea; and other GIT symptoms. Dehydration leads to hyperviscosity of the blood, which may be accompanied by other factors as bedridden patients, patients with concurrent infections, other diseases, and obesity [102] that hinders the peripheral venous return and predispose for thrombus formation. There are also catheterization and surgical manoeuvres that may lead to vascular endothelial damage, which increases the risk of DIC or fatal PE if added to the previous factors. Therefore, evaluation of VTE risk is strongly advised in all COVID-19 patients based on several different clinical conditions [94,100,103,104].

  • 1. Age at least 40 years, bedridden at least 3 days, reported with infection with COVID-19 and accompanied with one of the following signs and symptoms or risk factors: acute infection, respiratory failure, heart failure, obesity, previous history of VTE, lower limbs varicose veins, and other diseases, which are thought to contribute to a high VTE risk [94].
  • 2. When treating COVID-19 patients in an internal medicine department, the PADUA VTE risk assessment model (RAM) or the IMPROVE VTE RAM should be used [100,103], as well as the use of CAPRINI RAM for surgical operations [104].
  • 3. Pregnant women are also at risk because of conditions that aggravate the progress of COVID-19 such as preeclampsia, multiple pregnancies, obesity, postpartum haemorrhage, and infection [105,106].
  • 4. The inflammation that comes with a COVID-19 infection tends to make blood coagulation more common. As a result, a coagulation profile, which may indicate a quick rise in D-dimer levels or a rapid reduction in protein-C or antithrombin levels, can be used to assess the risk of developing VTE or PE [1,33,102].
  • In such cases, a radiological examination is done to exclude or confirm thrombosis.

Thromboembolism prevention in critically ill coronavirus disease 2019 patients

Depending on the risk assessment for thrombus formation, subcutaneous injection of LMWH appears to be the first-line agent for prophylaxis in patients with low risk for bleeding and good kidney function [94,100]. The recommended dosing regimens are enoxaparin 40 mg twice daily [107], enoxaparin 1 mg/kg daily [108], therapeutic doses of LMWH (a type of LMWH is not specified) [109,110], nadroparin 5700 IU daily [111], and nadroparin 2850 IU twice daily (bodyweight <100 kg) [112–114] which also must be monitored regularly because of its interaction with inflammatory mediators that decrease the drug's bioavailability [115,116].

In case of suspected or confirmed development of HIT, it is advised to use nonheparin anticoagulant drugs, such as danaparoid or bivalirudin [117]. It should be continued through the hospitalization period or till the management of the risk factors. If coagulation or bleeding side effects occurred during drug intake, it should be stopped immediately and the case is dealt with by the proper measures. It is suggested that prophylactic anticoagulants are continued for COVID-19 patients who are dismissed from the hospital and have one of the risk factors previously mentioned for at least 7 days [94].

Diagnosis and treatment thromboembolism associated with coronavirus disease 2019

Deep vein thrombosis is suspected in the occurrence of oedema, pain, redness, or unilateral limb cyanosis, also PE development is thought of on finding unexplained rapid falling in PaO2/FiO2 ratio and haemodynamic instability, also on occurrence of pulmonary hypertension and signs of right-sided heart problem in transition echocardiography, increase in troponin or B-type natriuretic levels [118].

Once DVT or PE is suspected, it should be confirmed by imaging using venous echo-Doppler ultrasound or echocardiography and computerized tomography pulmonary angiography ‘CTPA’, respectively. In case of difficulty in performing imaging because of high infectivity or difficult positioning of the patients for CT, assessment of VTE should be done depending on clinical examination and disease history of the patient and other laboratory assessments. Given that COVID-19 patients present a substantial increase in D-dimers at baseline [5], and there is no validated cut-off value for discriminating patients at risk of VTE [25], VTE diagnosis should not only be based on the D-dimer levels.

The use of LMWH in therapeutic dose is suggested for the treatment of acute VTE, also UFH or fondaparinux can be used instead depending on the patient's condition according to the current guidelines [119,120]. Therapeutic doses of LMWH, UFH and fondaparinux are demonstrated in Table 2[121].

Table 2 - Therapeutic dosage of low-molecular-weight heparin, unfractionated heparin, and fondaparinux and changes based on body weight and renal function.
Therapeutic dose Body weight Chronic kidney disease
Nadroparin <50 kg: 3800 IU SC twice daily
50 : 59 kg: 4750 IU s.c. twice a day
60 : 69 kg: 5700 IU s.c. twice a day
70 : 79 kg: 6650 IU s.c. twice a day
80 : 89 kg: 7600 IU s.c. twice a day
≥90 kg: 8550 IU s.c. twice a day
CrCl 30–50 ml/min:
Give 25% of the dose
CrCl < 30 ml/min: contraindicated
Enoxaparin 1 mg/kg SC twice a day CrCl 15–29 ml/min: 1 mg/kg
daily
or UFH
CrCl <15 ml/min: avoid,
consider UFH
Bemiparin 115 IU/kg s.c. daily CrCl = <30 ml/min:
contraindicated
Dalteparin Daily doses of 200 IU/kg s.c. for the first 30 days, then 150 IU/kg s.c. until the conclusion of treatment (maximum dose is 18 000 IU per day)
If the platelet count is less than 100 × 109/l, the dose should be lowered by 17–33%.
CrCl = <30 ml/min: (The dose must be adjusted according to anti-FXa activity with a target of 0.5–1.5 UI/ml)
Tinzaparin 175 IU/kg s.c. daily CrCl less than 20 ml/min: (contraindicated)
Fondaparinux <50 kg: 5 mg SC daily
50 : 100 kg: 7.5 mg s.c. daily
>100 kg: 10 mg s.c. daily CrCl less than 30 ml/min: (contraindicated)
UFH Loading dose: 80 IU/kg
Maintenance dose: 18 IU/kg/h continuous infusion
CrCl, creatinine clearance; IU, international unit; LMWH, low-molecular-weight heparin; s.c., subcutaneous; UFH, unfractionated heparin.

Considerations for pregnancy and lactation during coronavirus disease 2019

The American College of Obstetricians and the Gynecologists American Society of Hematology, have strategies that particularly report management of VTE during pregnancy [122,123]. There is a lack of information about how to use guidelines to expect VTE risk in pregnant women. Additionally, the level of D-dimer may not be a reliable indication of VTE during pregnancy, because during pregnancy, there is a physiological increase in D-dimer levels [124–126].

In general, heparin compounds are the preferred anticoagulants during pregnancy [127]. Because of its reliability, LMWH is highly recommended rather than nonfractionated heparin for prophylaxis and treatment of VTE in pregnant women [123]. Direct-acting anticoagulants are not usually used throughout pregnancy because of the deficiency of safety statistics in pregnant women [122]. Warfarin should be avoided in pregnant women, regardless of their COVID-19 status, particularly in the first trimester because of its teratogenic effects.

Treatment of thromboembolism during pregnancy

Given the possible risk of maternal haemorrhage, thrombolytic treatment during pregnancy should only be kept in reserve for acute pulmonary embolism, which can threaten the patient's life in spite of whether or not the patient has COVID-19 [122].

Lactation

No accumulation of warfarin and LMWH in breast milk.; therefore, they can be safely used in breastfeeding women who need VTE medication or prophylaxis [123]. In contrast, it is not recommended to use direct-acting oral anticoagulants because of the deficiency of safety pieces of information [122].

Vaccine-induced thrombotic thrombocytopenia

Thrombotic thrombocytopenia induced by vaccination in line with the hyperinflammatory and hypercoagulable state during severe SARS-COV-2 infections, we like to take a side step toward an exceptional but severe vaccine-induced thrombotic thrombocytopenia (VITT) [128].

Vaccination against SARS-COV-2 has been found to be the most effective way to reduce COVID-19's infectious burden [129]. However, after vaccination using adenovirus-based SARS-COV-2 vaccines, many cases of uncommon immunological thrombotic thrombocytopenia have been recorded (ChAdOx1 nCov-19; AstraZeneca and Ad26COV2.S, Janssen, Johnson & Johnson) [130]. Although no official cases of VITT have been documented following vaccination by Pfizer-BioNTech, one possible VITT case has been reported following immunization with Moderna [131]. VITT was anticipated to occur once in every 100 000 exposures [132]. Ischemic brain damage, subsequent haemorrhage, or both were the causes of death in almost 40% of the patients [132]. There is a link between the risk of VITT and being younger. In the UK VITT case series, the median age at diagnosis was 48 years, with 85% of patients being under 60 years old [133]. There was no evidence of a sex majority (54% were female individuals) or a link to certain medical disorders. Nonetheless, adenovirus-based immunizations are no longer recommended or available in numerous countries. Severe thrombocytopenia, aggressive thrombosis, and DIC were among the clinical symptoms of the vaccine-induced phenomena, which resembled the coagulopathy reported in patients with HIT [134]. Cerebral venous thrombosis was the most common thrombotic event, but arterial thrombosis and VTE also occurred. IgG autoantibodies that identify PF4 and heparin complexes induce HIT. These heparin/PF4/antibody immune complexes cause platelet activation and the release of procoagulant factors 5–10 days after heparin exposure. Platelet activation is not the only factor that contributes to the thrombotic process in HIT, as new research suggests that NETs play an important role in HIT-induced thrombosis [135]. Activated platelets and HIT-immune complexes can cause NETosis, which stimulates the production of thrombin. Despite this, only a tiny percentage of individuals with antiheparin/PF4 antibodies suffer thrombocytopenia and thrombosis in the long-run. The main risk factors for HIT include inflammation and tissue trauma, although more research is needed to fully understand the causes of HIT. In a recent study by Greinacher et al.[136], VITT is thought to be produced by a two-step mechanism. To make neoantigens, PF4 interacts with vaccination components (including the viral hexon protein). Second, 5–20 days after vaccination, anti-PF4 antibodies cause platelet and granulocyte activation, resulting in the production of NETs that trigger immunothrombotic pathways, potentially leading to clinical problems. Endogenous glycosaminoglycans found in the endothelium glycocalyx, which are similar to exogenous heparins, may also play a role in the abnormal immunological response seen in VITT patients. When the glycocalyx is damaged, fragmented glycosaminoglycans are released, which electrostatically bind with PF4 and activate an immunological response [137]. The most essential laboratory screening techniques are platelet count and D-dimer levels. The presence of anti-PF4 antibodies confirms the diagnosis of HIT. Because the sensitivity tests used to screen for HIT are not validated to rule in the diagnosis of VITT, the diagnosis must be verified by PF4 ELISA [138]. On the therapy of VITT, there is a scarcity of information. Given the similarities to HIT, nonheparin anticoagulants (DOACs and argatroban), the heparinoid danaparoid, which is also approved for use in HIT, are currently the preferred treatment options for VITT, in combination with immune suppressive or modulating measures such as glucocorticoids, intravenous immunoglobulins, and plasmapheresis [134]. Future research should focus on the cause of anti-PF4 antibody formation, the risk of VITT for each SARS-COV-2 vaccine, and the best therapeutic strategy.

Conclusion

COVID-19 is a pandemic disease caused by SARS-CoV-2 that has spread throughout the world. Dismantling of the coagulation cascade and intra-alveolar or systemic fibrin clot development is prominent. COVID-19 can result in the formation of a clot with negative impacts on the recovery and survival of the patient. Blood hypercoagulability has begun to appear as a key clinical symptom in serious COVID-19 patients. With time and experience, we learn more about the clinical features and disease cause of this new pathogen. Symptomatic therapy, as well as careful surveillance and evaluation of platelet counts and D-dimer, can aid in the early diagnosis of pulmonary embolism in COVID-19 patients. More observations and experimental research can help to provide a clear understanding of the pathophysiological, molecular, and cellular signalling pathways that contribute to SARS-CoV-2-related blood clot development.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

References

1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395:497–506.
2. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. China Novel Coronavirus Investigating and Research Team. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382:727–733.
3. Al-Samkari H, Karp Leaf RS, Dzik WH, Carlson JCT, Fogerty AE, Waheed A, et al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood 2020; 136:489–500.
4. Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020; 191:145–147.
5. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395:1054–1062.
6. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020; 180:934.
7. Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382:1708–1720.
8. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020; 135:2033–2040.
9. Oxley TJ, Mocco J, Majidi S, Kellner CP, Shoirah H, Singh IP, et al. Large-vessel stroke as a presenting feature of covid-19 in the young. N Engl J Med 2020; 382:e60.
10. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020; 383:120–128.
11. Zhang Y, Cao W, Xiao M, Li YJ, Yang Y, Zhao J, et al. Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia. Zhonghua Xue Ye Xue Za Zhi 2020; 41:E006.
12. 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; 95:834–847.
13. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al. Coagulopathy and antiphospholipid antibodies in patients with covid-19. N Engl J Med 2020; 382:e38.
14. Bowles L, Platton S, Yartey N, Dave M, Lee K, Hart DP, et al. Lupus anticoagulant and abnormal coagulation tests in patients with covid-19. N Engl J Med 2020; 383:288–290.
15. Kitchens CS. Thrombocytopenia and thrombosis in disseminated intravascular coagulation (DIC). Hematology 2009; 2009:240–246.
16. Stefely JA, Christensen BB, Gogakos T, Cone Sullivan JK, Montgomery GG, Barranco JP, et al. Marked factor V activity elevation in severe COVID-19 is associated with venous thromboembolism. Am J Hematol 2020; 95:1522–1530.
17. Pujhari S, Paul S, Ahluwalia J, Rasgon JL. Clotting disorder in severe acute respiratory syndrome coronavirus 2. Rev Med Virol 2020; 31:e2177.
18. Gupta N, Zhao Y-Y, Evans CE. The stimulation of thrombosis by hypoxia. Thromb Res 2019; 181:77–83.
19. Pilli VS, Datta A, Afreen S, Catalano D, Szabo G, Majumder R. Hypoxia downregulates protein S expression. Blood 2018; 132:452–455.
20. Semenza GL. Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE 2007; 2007:cm8.
21. Koeleman BP, van Rumpt D, Hamulyák K, Reitsma PH, Bertina RM. Factor V Leiden: an additional risk factor for thrombosis in protein S deficient families? Thromb Haemost 1995; 74:580–583.
22. Korva M, Rus KR, Pavletič M, Saksida A, Knap N, Jelovšek M, et al. Characterization of biomarker levels in crimean- congo hemorrhagic fever and hantavirus fever with renal syndrome. Viruses 2019; 11:686.
23. Sridhar A, Sunil Kumar BM, Rau A, Rau ATK. A correlation of the platelet count with D-dimer levels as an indicator for component therapy in children with dengue hemorrhagic fever. Indian J Hematol Blood Transfus 2017; 33:222–227.
24. Esmon CT, Xu J, Lupu F. Innate immunity and coagulation. J Thromb Haemost 2011; 9 (1S):182–188.
25. Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, et al. CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020; 46:1089–1098.
26. Oehmcke S, Mörgelin M, Herwald H. Activation of the human contact system on neutrophil extracellular traps. J Innate Immun 2009; 1:225–230.
27. Massberg S, Grahl L, von Bruehl M-L, Manukyan D, Pfeiler S, Goosmann C, et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010; 16:887–896.
28. Opasawatchai A, Amornsupawat P, Jiravejchakul N, Chan-in W, Spoerk NJ, Manopwisedjaroen K, et al. Neutrophil activation and early features of NET formation are associated with dengue virus infection in human. Front Immunol 2019; 9:3007.
29. Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85:1504–1508.
30. Saliba W, Warwar A, Kotler A, Cohen S, Stein N, Rennert G, et al. Association of factor V activity with risk of venous thromboembolism and atherothrombotic cardiovascular events: a retrospective population-based cohort study. Thromb Res 2018; 168:14–19.
31. 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; 18:1023–1026.
32. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020; 18:1094–1099.
33. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18:844–847.
34. Wang YD, Zhang SP, Wei QZ, Zhao MM, Mei H, Zhang ZL, et al. COVID-19 complicated with DIC: 2 cases report and literatures review. Zhonghua Xue Ye Xue Za Zhi 2020; 41:245–247.
35. Lippi G, Plebani M, Henry BM. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta 2020; 506:145–148.
36. Scharrer I. Procoagulant activity during viral infections. Front Biosci 2018; 23:4633.
37. Guo L, Rondina MT. The era of thromboinflammation: platelets are dynamic sensors and effector cells during infectious diseases. Front Immunol 2019; 10:2204.
38. Neumann F-J, Marx N, Gawaz M, Brand K, Ott I, Rokitta C, et al. Induction of cytokine expression in leukocytes by binding of thrombin-stimulated platelets. Circulation 1997; 95:2387–2394.
39. van Gorp ECM, Suharti C, ten Cate H, Dolmans WMV, van der Meer JWM, ten Cate JW, et al. Review: infectious diseases and coagulation disorders. J Infect Dis 1999; 180:176–186.
40. Iba T, Levy JH, Connors JM, Warkentin TE, Thachil J, Levi M. The unique characteristics of COVID-19 coagulopathy. Crit Care 2020; 24:360.
41. Iba T, Levy JH. Inflammation and thrombosis: roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis. J Thromb Haemost 2018; 16:231–241.
42. Chang JC. Sepsis and septic shock: endothelial molecular pathogenesis associated with vascular microthrombotic disease. Thromb J 2019; 17:10.
43. Iba T, Miki T, Hashiguchi N, Tabe Y, Nagaoka I. Is the neutrophil a ‘prima donna’ in the procoagulant process during sepsis? Crit Care 2014; 18:230.
44. Liaw PC, Ito T, Iba T, Thachil J, Zeerleder S. DAMP and DIC: the role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC. Blood Rev 2016; 30:257–261.
45. Østerud B, Bjørklid E. The tissue factor pathway in disseminated intravascular coagulation. Semin Thromb Hemost 2001; 27:605–618.
46. Wang Y, Luo L, Braun OÖ, Westman J, Madhi R, Herwald H, et al. Neutrophil extracellular trap-microparticle complexes enhance thrombin generation via the intrinsic pathway of coagulation in mice. Sci Rep 2018; 8:4020.
47. Yang M, Ng MHL, Li CK, Chan PKS, Liu C, Ye JY, Chong BH. Thrombopoietin levels increased in patients with severe acute respiratory syndrome. Thromb Res 2008; 122:473–477.
48. Gralinski LE, Bankhead A, Jeng S, Menachery VD, Proll S, Belisle SE, et al. Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. MBio 2013; 4:e00271-13.
49. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395:1417–1418.
50. Richardson MA, Gupta A, O’Brien LA, Berg DT, Gerlitz B, Syed S, et al. Treatment of sepsis-induced acquired protein C deficiency reverses angiotensin-converting enzyme-2 inhibition and decreases pulmonary inflammatory response. J Pharmacol Exp Ther 2008; 325:17–26.
51. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020; 395:1033–1034.
52. Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science 2020; 368:473–474.
53. Dimopoulos G, de Mast Q, Markou N, Theodorakopoulou M, Komnos A, Mouktaroudi M, et al. Favorable Anakinra responses in severe covid-19 patients with secondary hemophagocytic lymphohistiocytosis. Cell Host Microbe 2020; 28:117.e1–123.e1.
54. Azoulay E, Knoebl P, Garnacho-Montero J, Rusinova K, Galstian G, Eggimann P, et al. Expert statements on the standard of care in critically ill adult patients with atypical hemolytic uremic syndrome. Chest 2017; 152:424–434.
55. Radbel J, Narayanan N, Bhatt PJ. Use of tocilizumab for COVID-19-induced cytokine release syndrome. Chest 2020; 158:e15–e19.
56. Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 2017; 39:529–539.
57. Groot N, de Graeff N, Avcin T, Bader-Meunier B, Dolezalova P, Feldman B, et al. European evidence-based recommendations for diagnosis and treatment of paediatric antiphospholipid syndrome: the SHARE initiative. Ann Rheum Dis 2017; 76:1637–1641.
58. Garcia D, Erkan D. Diagnosis and management of the antiphospholipid syndrome. N Engl J Med 2018; 378:2010–2021.
59. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA 2020; 323:1582–1589.
60. Escher R, Breakey N, Lämmle B. Severe COVID-19 infection associated with endothelial activation. Thromb Res 2020; 190:62.
61. Wada H, Matsumoto T, Suzuki K, Imai H, Katayama N, Iba T, Matsumoto M. Differences and similarities between disseminated intravascular coagulation and thrombotic microangiopathy. Thromb J 2018; 16:14.
62. Campbell CM, Kahwash R. Will complement inhibition be the new target in treating COVID-19-related systemic thrombosis? Circulation 2020; 141:1739–1741.
63. Tadkalkar N, Prasad S, Gangodkar S, Ghosh K, Basu A. Dengue virus NS1 exposure affects von Willebrand factor profile and platelet adhesion properties of cultured vascular endothelial cells. Ind J Hematol Blood Transfus 2019; 35:502–506.
64. Roldán V, Marín F, García-Herola A, Lip GYH. Correlation of plasma von Willebrand factor levels, an index of endothelial damage/dysfunction, with two point-based stroke risk stratification scores in atrial fibrillation. Thromb Res 2005; 116:321–325.
65. Scully M, Hunt BJ, Benjamin S, Liesner R, Rose P, Peyvandi F, et al. British Committee for Standards in Haematology. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol 2012; 158:323–335.
66. Gavriilaki E, Brodsky RA. Severe COVID-19 infection and thrombotic microangiopathy: success does not come easily. Br J Haematol 2020; 189:e227–e230.
67. Jiang Y, Zhao G, Song N, Li P, Chen Y, Guo Y, et al. Blockade of the C5a-C5aR axis alleviates lung damage in hDPP4 -transgenic mice infected with MERS-CoV. Emerg Microbes Infect 2018; 7:1–12.
68. Magro C, Mulvey JJ, Berlin D, Nuovo G, Salvatore S, Harp J, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res 2020; 220:1–13.
69. Moores G, Warkentin TE, Farooqi MA, Jevtic SD, Zeller MP, Perera KS. Spontaneous heparin-induced thrombocytopenia presenting as cerebral venous sinus thrombosis. Neurology: Clinical Practice 2020.
70. Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106:2710–2715.
71. Warkentin TE. Clinical picture of heparin-induced thrombocytopenia (HIT) and its differentiation from non-HIT thrombocytopenia. Thromb Haemost 2016; 116:813–822.
72. Paranjpe I, Fuster V, Lala A, Russak AJ, Glicksberg BS, Levin MA, et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol 2020; 76:122–124.
73. Xiong T-Y, Redwood S, Prendergast B, Chen M. Coronaviruses and the cardiovascular system: acute and long-term implications. Eur Heart J 2020; 41:1798–1800.
74. Idell S. Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Crit Care Med 2003; 31: (Suppl): S213–S220.
75. Gaertner F, Massberg S. Blood coagulation in immunothrombosis—at the frontline of intravascular immunity. Semin Immunol 2016; 28:561–569.
76. Poterucha TJ, Libby P, Goldhaber SZ. More than an anticoagulant: do heparins have direct anti-inflammatory effects? Thromb Haemost 2017; 117:437–444.
77. Esmon CT. Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost 2013; 111:625–633.
78. Li JP, Vlodavsky I. Heparin, heparan sulfate and heparanase in inflammatory reactions. Thromb Haemost 2009; 102:823–828.
79. Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res 2008; 122:743–752.
80. Mousavi S, Moradi M, Khorshidahmad T, Motamedi M. Anti-inflammatory effects of heparin and its derivatives: a systematic review. Adv Pharmacol Sci 2015; 2015:507151.
81. Ozolina A, Sarkele M, Sabelnikovs O, Skesters A, Jaunalksne I, Serova J, et al. Activation of coagulation and fibrinolysis in acute respiratory distress syndrome: a prospective pilot study. Front Med 2016; 3:64.
82. Glas GJ, Van Der Sluijs KF, Schultz MJ, Hofstra JJH, Van Der Poll T, Levi M. Bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome. J Thromb Haemost 2013; 11:17–25.
83. Thachil J. The versatile heparin in COVID-19. J Thromb Haemost 2020; 18:1020–1022.
84. Hanify JM, Dupree LH, Johnson DW, Ferreira JA. Failure of chemical thromboprophylaxis in critically ill medical and surgical patients with sepsis. J Crit Care 2017; 37:206–210.
85. Camprubí-Rimblas M, Tantinyà N, Guillamat-Prats R, Bringué J, Puig F, Gómez MN, et al. Effects of nebulized antithrombin and heparin on inflammatory and coagulation alterations in an acute lung injury model in rats. J Thromb Haemost 2020; 18:571–583.
86. Xu J, Zhang X, Pelayo R, Monestier M, Ammollo CT, Semeraro F, et al. Extracellular histones are major mediators of death in sepsis. Nat Med 2009; 15:1318–1321.
87. Iba T, Hashiguchi N, Nagaoka I, Tabe Y, Kadota K, Sato K. Heparins attenuated histone-mediated cytotoxicity in vitro and improved the survival in a rat model of histone-induced organ dysfunction. Intensive Care Med Exp 2015; 3:36.
88. Zhu C, Liang Y, Li X, Chen N, Ma X. Unfractionated heparin attenuates histone-mediated cytotoxicity in vitro and prevents intestinal microcirculatory dysfunction in histone-infused rats. J Trauma Acute Care Surg 2019; 87:614–622.
89. Wojnicz R, Nowak J, Szyguła-Jurkiewicz B, Wilczek K, Lekston A, Trzeciak P, et al. Adjunctive therapy with low-molecular-weight heparin in patients with chronic heart failure secondary to dilated cardiomyopathy: one-year follow-up results of the randomized trial. Am Heart J 2006; 152:713.e1–713.e7.
90. Frizelle S, Schwarz J, Huber SA, Leslie K. Evaluation of the effects of low molecular weight heparin on inflammation and collagen deposition in chronic coxsackievirus B3-induced myocarditis in A/J mice. Am J Pathol 1992; 141:203–209.
91. Shukla D, Spear PG. Herpesviruses and heparan sulfate: an intimate relationship in aid of viral entry. J Clin Invest 2001; 108:503–510.
92. Ghezzi S, Cooper L, Rubio A, Pagani I, Capobianchi MR, Ippolito G, et al. Heparin prevents Zika virus induced-cytopathic effects in human neural progenitor cells. Antiviral Res 2017; 140:13–17.
93. Vicenzi E, Canducci F, Pinna D, Mancini N, Carletti S, Lazzarin A, et al. Coronaviridae and SARS-associated coronavirus strain HSR1. Emerg Infect Dis 2004; 10:413–418.
94. Zhai Z, Li C, Chen Y, Gerotziafas G, Zhang Z, Wan J, et al. Prevention Treatment of VTE Associated with COVID-19 Infection Consensus Statement Group. Prevention and treatment of venous thromboembolism associated with coronavirus disease 2019 infection: a consensus statement before guidelines. Thromb Haemost 2020; 120:937–948.
95. Pérez A, Santamaria EK, Operario D, Tarkang EE, Zotor FB, Cardoso SR de SN, et al. The Structure of Health Factors among Community-dwelling Elderly People. BMC Public Health [Internet] 2017; 5 (1):1–8.
96. World Health Organization. Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected. WHO 2020; 2019:12.
97. World Health Organization, World Health Organization. Clinical management of severe acute respiratory infection when Middle East respiratory syndrome coronavirus (MERS-CoV) infection is suspected: interim guidance. 2019.
98. Parikh F, Shah S. Ebola Virus Disease: Are We Prepared? JAPI 2014; 62:785.
99. Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing G-J, Harjola V-P, et al. ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41:543–603.
100. Schünemann HJ, Cushman M, Burnett AE, Kahn SR, Beyer-Westendorf J, Spencer FA, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv 2018; 2:3198–3225.
101. Levy MM, Baylor MS, Bernard GR, Fowler R, Franks TJ, Hayden FG, et al. National Heart Lung and Blood Institute Heart Failure Clinical Research Network. Clinical issues and research in respiratory failure from severe acute respiratory syndrome. Am J Respir Crit Care Med 2005; 171:518–526.
102. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395:507–513.
103. Barbar S, Noventa F, Rossetto V, Ferrari A, Brandolin B, Perlati M, et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost 2010; 8:2450–2457.
104. Cronin M, Dengler N, Krauss ES, Segal A, Wei N, Daly M, et al. Completion of the Updated Caprini Risk Assessment Model (2013 Version). Clin Appl Thromb 2019; 25:107602961983805.
105. Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet 2020; 395:809–815.
106. Leffert L, Butwick A, Carvalho B, Arendt K, Bates SM, Friedman A, et al. The Society for Obstetric Anesthesia and Perinatology Consensus statement on the anesthetic management of pregnant and postpartum women receiving thromboprophylaxis or higher dose anticoagulants. Anesth Analg 2018; 126:928–944.
107. Marietta M, Ageno W, Artoni A, De Candia E, Gresele P, Marchetti M, et al. COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET). Blood Transfus 2020; 18:167–169.
108. y Hemostasia SE. Recomendaciones de tromboprofilaxis y tratamiento antitrombótico en pacientes con COVID-19. Sociedad Española de Trombosis y Hemostasia. 2020.
109. Lodigiani C, Iapichino G, Carenzo L, Cecconi M, Ferrazzi P, Sebastian T, et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res 2020; 191:9–14.
110. Llitjos J-F, Leclerc M, Chochois C, Monsallier J-M, Ramakers M, Auvray M, et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost 2020; 18:1743–1746.
111. Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers D, Kant KM, et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res 2020; 191:148–150.
112. Middeldorp S, Coppens M, van Haaps TF, Foppen M, Vlaar AP, Müller MCA, et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18:1995–2002.
113. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign. Crit Care Med 2013; 41:580–637.
114. Duranteau J, Taccone FS, Verhamme P, Ageno W. European guidelines on perioperative venous thromboembolism prophylaxis. Eur J Anaesthesiol 2018; 35:142–146.
115. Thomas O, Lybeck E, Strandberg K, Tynngård N, Schött U. Monitoring low molecular weight heparins at therapeutic levels: dose-responses of, and correlations and differences between aPTT, anti-factor Xa and thrombin generation assays. PLoS One 2015; 10:e0116835.
116. Crowther M, Lim W. Use of low molecular weight heparins in patients with renal failure; time to re-evaluate our preconceptions. J Gen Intern Med 2016; 31:147–148.
117. 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; 2:3360–3392.
118. Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008; 29:2276–2315.
119. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report. Chest 2016; 149:315–352.
120. Witt DM, Nieuwlaat R, Clark NP, Ansell J, Holbrook A, Skov J, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv 2018; 2:3257–3291.
121. Orsi FA, De Paula EV, Santos F, de O, Teruchkin MM, Campêlo DHC, Mello TT, et al. Guidance on diagnosis, prevention and treatment of thromboembolic complications in COVID-19: a position paper of the Brazilian Society of Thrombosis and Hemostasis and the Thrombosis and Hemostasis Committee of the Brazilian Association of Hematology. Hematol Transfus Cell Ther 2020; 42:300–308.
122. Bates SM, Rajasekhar A, Middeldorp S, McLintock C, Rodger MA, James AH, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv 2018; 2:3317–3359.
123. ACOG Practice Bulletin No. 196 summary: thromboembolism in pregnancy. Obstet Gynecol 2018; 132:243–248.
124. Wang M, Lu S, Li S, Shen F. Reference intervals of D-dimer during the pregnancy and puerperium period on the STA-R evolution coagulation analyzer. Clin Chim Acta 2013; 425:176–180.
125. Réger B, Péterfalvi Á, Litter I, Pótó L, Mózes R, Tóth O, et al. Challenges in the evaluation of D-dimer and fibrinogen levels in pregnant women. Thromb Res 2013; 131:e183-7.
126. Hu W, Wang Y, Li J, Huang J, Pu Y, Jiang Y, et al. The predictive value of d-Dimer test for venous thromboembolism during puerperium: a prospective cohort study. Clin Appl Thromb Hemost 2020; 26:1076029620901786.
127. James AH. Pregnancy-associated thrombosis. Hematology 2009; 2009:277–285.
128. Goldman M, Hermans C. Thrombotic thrombocytopenia associated with COVID-19 infection or vaccination: possible paths to platelet factor 4 autoimmunity. PLoS Med 2021; 18:e1003648.
129. Dagan N, Barda N, Kepten E, Miron O, Perchik S, Katz MA, et al. BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting. New England Journal of Medicine 2021.
130. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. New Eng J Med 2021; 384:2092–2101.
131. Sangli S, Virani A, Cheronis N, Vannatter B, Minich C, Noronha S, et al. Thrombosis with thrombocytopenia after the messenger RNA-1273 vaccine. Ann Intern Med 2021; 174:1480–1482.
132. Cines DB, Bussel JB. SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia. Mass Med Soc 2021; 384:2254–2256.
133. Pavord S, Scully M, Hunt BJ, Lester W, Bagot C, Craven B, et al. Clinical features of vaccine-induced immune thrombocytopenia and thrombosis. New Eng J Med 2021; 385:1680–1689.
134. Scully M, Singh D, Lown R, Poles A, Solomon T, Levi M, et al. Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination. New Eng J Med 2021; 384:2202–2211.
135. Perdomo J, Leung HH, Ahmadi Z, Yan F, Chong JJ, Passam FH, et al. Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia. Nat Commun 2019; 10:1–14.
136. Greinacher A, Selleng K, Palankar R, Wesche J, Handtke S, Wolff M, et al. Insights in ChAdOx1 nCoV-19 vaccine-induced immune thrombotic thrombocytopenia. Blood 2021; 138:2256–2268.
137. Gill SE, Dos Santos CC, O’Gorman DB, Carter DE, Patterson EK, Slessarev M, et al. Lawson COVID19 Study Team. Transcriptional profiling of leukocytes in critically ill COVID19 patients: implications for interferon response and coagulation. Intensive Care Med Exp 2020; 8:1–16.
138. Greinacher A, Langer F, Makris M, Pai M, Pavord S, Tran H, Greinacher A. Vaccine-induced immune thrombotic thrombocytopenia (VITT): Update on diagnosis and management considering different resources. J Thromb Haemost 2022; 20:149–156.
Keywords:

coagulopathy; coronavirus disease 2019; thromboembolism

Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.