The threefold mechanism involved in highly infectious diseases like SARS consists of haemostatic, inflammatory and thrombotic responses, which has become recognized only recently (The era of thromboinflammation: Platelets are dynamic sensors and effector cells during infectious diseases, Frontiers in Immunology, 13 September 2019). In this technical feature, I will discuss:
1. Determining factors of SARS-CoV-2 associated thromboinflammation;
2. Mechanisms underlying Thrombocytopenia;
2.1 Von Willebrand Factor- ADAMTS-13 (metalloprotease) mechanism in Thrombotic Thrombocytopenic Purpura;
3. Interaction of endothelial damage and platelet consumption;
3.1 NETs: Neutrophil Extracellular Traps: exaggeration of a normal inflammatory process?
4. Dynamics of (pro)thrombin and fibrin;
4.1 Inflammatory effects of thrombin, promoting microvascular thrombosis, DIC and MOF;
4.2 Fibrinolysis dysregulates the barrier function of fibrin, resulting in accumulation of leukocytes associated with ischemia;
4.3 Urokinase pathway: the role of Serpine1 overexpression in fibrin clotting and inflammation;
4.4 Diffuse Alveolar Damage (DAD);
4.5 Pulmonary fibrosis;
5. Rare cases of thrombosis: antiphospholipid antibodies (COVID-19);
6. Treatment with LMWH in hypercoagulant patients
1. Determining factors of SARS-CoV-2 associated thromboinflammation
1.1 Prognostic factors for severity of SARS-1 and SARS-2 cases
In a cohort study concerning 191 severely ill SARS-CoV-2 patients, low lymphocyte counts, severe lymphopenia, leukocytosis (elevated white blood cells), elevated alanine aminotransferase (ALT, severely elevated by a damaged liver), lactate dehydrogenase, high-sensitivity cardiac troponin I, creatinine kinase, elevated D-dimer levels, serum ferritin, IL-6, prolonged prothrombin time and procalcitonin were observed in cases of severe deterioration (Clinical course and risk factors for adult inpatients with COVID-19 in Wuhan: China: a retrospective cohort study, The Lancet, 9 March 2020).
Increased D-dimer levels of more than double the upper limit of normal is a prognostic marker for the risk of venous thromboembolism (
Pulmonary embolism in patients with COVID-19: Time to change the paradigm of CT, Thrombosis Research, June 2020). The level of inflammatory IL-6 was reported to be extremely high in critically ill COVID-19 patients (
Detectable Serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients, Clinical Infectious Diseases, 17 April 2020).
Similarities are found in a 2004 SARS-Cov study. Predictive factors for respiratory failure were initial absolute neutrophil count (ANC), peak CK level, peak CRP level. peak LDH level and lowest lymphocyte count. Most patients had elevated C-reactive protein levels and lymphopenia, other common abnormal findings included leukopenia, thrombocytopenia and elevated levels of aminotransferase, lactate dehydrogenase and creatinine kinase (
Clinical Manifestations, Laboratory Findings and Treatment Outcomes of SARS patients, Emerging Infectious Diseases, May 2004).
In a study involving 85 severe cases of SARS-CoV-2, 81,2% of patients had significantly low eosinophil (white blood cells) on admission, 60% had neutrophils above the normal range, 77,6% of patients had lymphocytes below the normal range and 78,8% of patients had albumin below the normal range. Elevated procalcitonin of more than 0,5 was associated with a death chance of 93%.It has been hypothesized that eosinophilopenia may be related to depletion of CD8 T-cells, rendering SARS-CoV-2 infected patients with lower levels of IL-5, an interleukin involved in proliferation of eosinophils (Clinical features of 85 fatal cases of COVID-19 from Wuhan: A retrospective observational study, 3 April 2020).
1.2 Most typical factors associated with SARS-CoV-2 thrombotic risk
On admission, patients with a severe progression of SARS-CoV-2 present with elevation of D-dimer levels and fibrin/fibrinogen degradation products, but abnormalities in prothrombin time, partial thromboplastin time and platelet counts are not common. While platelet counts progressively decrease, no bleeding has been reported, regardless of DIC occuring. The hypothesis is posed that this indicates a local expression of DIC, pulmonary vascular thrombosis with subsequent activation of fibrinolysis. Pulmonary thrombosis could induce prothrombotic endothelial dysfunction, which causes an inflammation cascade via complement and cytokine release and blood coagulation with vascular microthrombosis that induces local consumption coagulopathy (
Pulmonary thrombosis in 2019-nCoV pneumonia?, Journal of Thrombosis and Haemostasis, 15 April 2020).
Elevations in PT are limited, while aPTT is normal on admission. 10 days after admission, progressive DIC, decreased fibrinogen, increased D-dimer and increased PT have been reported. The level of inflammation on admission is indicated by elevated levels of IL-6, correlating with elevated fibrinogens (
COVID-19 and its implications for thrombosis and anticoagulation, American Society for Hematology, 27 April 2020). Thrombocytopenia is reported in 12% of cases. Fibrinolytic shutdown occurs in sepsis. However, the pattern of prothrombic coagulopathy noticed in SARS-CoV-2 patients differs from what is noticed in sepsis, where thrombocyte count is usually decreased (
The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome, Journal of Thrombosis and Haemostasis, 17 April 2020).
1.3 Platelet count: progressive decrease as a precursor for deterioration
Interestingly,
some case studies show that on admission of patients with SARS-CoV-2,
prothrombin time, platelet count and activated partial thromboplastin
time are within the normal range, while D-dimer levels are typically
elevated (
Acute
aorto-iliac and mesenteric arterial thromboses as presenting features
of COVID-19, Letter to British Journal of Haematology, 30 April 2020).
In 2003, the most prominent finding in severe clinical courses was
thrombocytopenia. Platelet count had progressively decreased in 90% of
the most severe cases, suggesting the occurrence of disseminated
intravascular coagulation following damage to the pulmonary capillary
membrane caused by inflammatory platelet aggregation and microthrombus
formation (
Prognostic factors for SARS: a clinical analysis of 165 cases, Clinical Infectious Diseases, Vol. 38 Issue 4, 15 Februari 2004).
Thrombocytopenia (low count of blood platelets that contribute to clotting following bleeding) and elevated D-dimer (fibrin degradation) levels can be explained by excessive activation of coagulation cascade and platelets. In addition to endothelial dysfunction, Von Willebrand Factor (VWF) activation, the release of tissue factors and activation of the Toll-like receptor (TLR) result in homeostatic imbalance. Platelets are key in inciting an inflammatory response through connection of white blood cells and clotting (
The era of thromboinflammation: platelets are dynamic sensors and effector cells during infectious diseases, Frontiers in Immunology, 13 September 2019). Upon triggering an inflammatory response, Toll-like receptor 2 (TLR2) is known for its promotion of thrombosis (Stimulation of Toll-like receptor 2 in human platelets induces a thromboinflammatory response through activation of phosphoinositide 3-kinase,
Circ Res. (2009) 104:346–54).
 |
| Markers to assess severity of SARS-CoV-2/COVID-19 |
2. Mechanisms underlying thrombocytopenia in SARS-CoV-2
Three
mechanisms by which coronaviruses interfere with the hematopoietic
system are hypothesized. They may interact.
1. The first hypothesis is that
SARS-CoV-2, like other coronaviruses, enter bone marrow cells and
platelets through aminopeptidase CD13, present on epithelial cells,
subsequently inducing growth inhibition and apoptosis, which leads to
inhibition of hematopoiesis (formation of blood cells and platelets),
resulting in thrombocytopenia. Activation of the macrophage system (the
recruitment and release of inflammatory cytokines) consumes red blood
cells. Following the activation of T-cells (transporter cells), an
inflammatory soup containing IL-6 causes immune damage to lung tissue.
Damage to capillary tissue ruptures megakaryocytes (in which platelets
are produced) and blocks platelets, impairing platelet release into the
pulmonary system. It should be noted that IL-6, SARS-proteins ORF3a and
ORF8a and a variety of cytokines contribute to epithelial and vascular
permeability, further increasing the inflammatory cascade.
2. A
second hypothesized mechanism is that antibodies are detected on
platelet surfaces by the reticuloendothelial system (RES), a part of the
immune system located in endothelial tissue. Platelet destruction is a
result of platelets being coated by anti-platelet antibodies.
3. A
third hypothesis explains common clinical findings in severe cases of
SARS-CoV-2. Damaged pulmonary endothelial cells activates platelets in
the lungs, aggregating microthrombi, followed by platelet consumption.
This seems to be compatible with DIC seen in SARS-CoV-2 cases (Mechanism
of thrombocytopenia in COVID-19 patients, Annals of Hematology, 30
March 2020).
Remarkably, when the Von Willebrand Factor
is knocked out of mice, adenovirus-induced thrombocytopenia does not
occur. Virus-induced thrombocytopenia most likely depends on the
interaction between platelets and Von Willebrand Factor, a clotting
factor involved in the adherence of platelets to the injured
subendohelium (
Adenovirus-induced
thrombocytopenia: the role of the van Willebrand factor and P-selectin
in mediating accelerated platelet clearance, Blood Vol. 109 Issue 7, 1
April 2007).
Activated endothelium upregulates VCAM-1, a protein
mediating the adhesion of leukocytes to vascular endothelium. Viral
inflammation activates endothelial cells, stimulates the generation of
endothelial cell-derived Microparticles (MPs), which are associated with
an elevated release of Ultra-Large molecular weight von Willebrand
Factor (ULVWF) plasma multimers. Endothelial Microparticles are involved in the
regulation of blood flow, inflammation, transport and coagulation (
Endothelial
Microparticle-Derived Reactive Oxygen Species: Role in endothelial
signaling and vascular function, Oxidative Medicine and Cellular
Longevity, 2016:5047954).
2.1 Von Willebrand Factor- ADAMTS-13 (metalloprotease) mechanism in Thrombotic Thrombocytopenic Purpura (TTP)
The hemostatic function of the Von Willebrand Factor (VWF), affixed to the subendothelium, is to recruit platelets to injured vessels by binding to the platelet GP Ib-IX-V complex. VWF is stored in megakaryocytes/platelets and in histamine-activated endothelial cells. Following stimulation of the endothelium, Ultra Large multimers of the VWF (ULVWF) are released, binding to platelets firmly.
The release of hyper-reactive ULVWF is moderated by ADAMTS-13, a metalloprotease with thrombospondin motif. ADAMTS-13 cleaves Von Willebrand Factors. If this mechanism fails due to deficiency of ADAMTS-13, thrombotic thrombocytopenic purpura (TTP) occurs. The acquired form of TTP is a result of antibodies directed against ADAMTS-13. An inherent 'weakness' of ADAMTS-13 is the absence of a transmembrane domain; a soluble form of ADAMTS-13 adheres to the A3 domain of VWF (ADAMTS-13 interacts with the endothelial cell-derived Ultra-large von Willebrand Factor,
Journal of Biological Chemistry, 8 August 2003, Vol. 278, No.32).
ADAMTS-13 prevents formation of thrombi. This metalloprotease is key in downregulating thrombosis and inflammation. Deficiency of ADAMTS-13 does not constitute TTP or ischemic stroke by itself, but it does induce the prothromobotic state to be enhanced by other ADAM metalloproteases, cytokines and MMPs.
3. Interaction of endothelial damage and platelet consumption
Endothelial
damage is associated with Multisystem Organ Failure (MOF), as recently
reported in a severe case of COVID-19. Endothelial dysfunction is
mentioned as a principal determinant of microvascular dysfunction, by
shifting towards enhanced vasoconstriction with subsequent organ
ischaemia, inflammation with tissue oedema and a pro-coagulant state. In
addition, induction of apoptosis and pyroptosis is hypothesized to have
a key role in endothelial cell injury, impairing microcirculation in
vascular beds (
Endothelial cell infection and endotheliitis in COVID-19, The Lancet, 20 April 2020).
Damaged lung tissue and pulmonary endothelial cells results in platelet
aggregation in the lungs, while thrombi formations at the injured site
might cause platelet consumption. Long term ventilation may result in
pulmonary fibrosis. Further increased platelet consumption and decreased
platelet production can result in thrombocytopenia (
Thrombocytopenia in patients with SARS, Immune Hematology, April 2005; 10(2)).
The
key role of ACE2 receptors as the entry site for SARS-CoV-2 is
explanatory. Found on epithelial cells, the ACE2 receptor is a
target for inflammatory cell infiltration and indirect endothelial cell apoptosis
(cell death). Induction of cell death and pyroptosis (inflammatory
programmed or caspase-1 cell death) is associated with microcirculatory
dysfunction in vascular beds (
Endothelial cell infection and endotheliitis in COVID-19, The Lancet, 20 April 2020).
3.1 NETs: Neutrophil Extracellular Traps: exaggeration of a normal inflammatory process?
Upon pathogen detection, activated platelets promote neutrophil extracellular traps (NETs). NETs contain chromatin, histone and granulate enzymes expelled by activated neutrophils. This process is called NETosis. P-selectin, derived from platelets, facilitates platelet-neutrophil interactions during the early stage of the NETosis process. Platelet GPIba and integrin aIIbb3 are mediators of NETosis. The release of cathepsin G and serine protease (among which TMPRSS2) by activated neutrophils can cause an exagerrated activation of platelets, coagulation and thrombosis as well as endothelial damage (The era of thromboinflammation: Platelets are dynamic sensors and effector cells during infectious diseases, Frontiers in immunology, 13 September 2019).
Eosinophils, mast cells and macrophages are reported to be capable of releasing NETs. Noteworthy is that neutrophils undergo programmed cell death that must be distinguished from apoptosis and necrotic cell death (
Regulation of Innate Immune Responses by Platelets, Frontiers in immunology, 2019; 10: 1320).
Uncontrolled NET formation contributes to arterial and venous thrombosis (
Neutrophil Extracellular Traps: Villains and targets in arterial, venous and cancer-associated thrombosis, Arteriosclerosis, Thrombosis and Vascular Biology September 2019, Vol. 39, Issue 9). NET formations were observed at the site of superficially eroded plaques to contribute to thrombus progression (
Platelet Interaction with Innate Immune Cells, Karger Transfusion Medicine and Hemotherapy, March 2016; 43(2)).
4. Dynamics of (pro)thrombin and fibrin
4.1 Inflammatory effects of thrombin promoting Microvascular thrombosis, DIC and MOF
Disseminated intravascular coagulation (DIC) and deep venous
thrombosis (DVT) are explicitly mentioned in a 1999 review concerning
the mechanism between infectious diseases and coagulation disorders (
Review: Infectious Diseases and Coagulation Disorders, The Journal of Infectious Diseases, 1 July 1999).
Microvascular thrombi are known to form (Pathogenesis of disseminated
intravascular coagulation in sepsis, JAMA, 1993 vol. 270) following the
conversion of fibrinogen into fibrin. Microvascular thrombosis,
multi-organ failure and hemorrhage occur due to consumption of
coagulation factors and activation of the fibrinolytic system. While DIC
is associated with both platelet and clotting factor consumption,
hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura
(TTP) are not associated with consumption of clotting factors; HUS and
TTP are characterized by thrombocytopenia (Par. 2.1 describes the mechanism of VWF and ADAMTS-13 underlying TTP).
The
function of prothrombin is to enhance clotting by activating platelets
and by converting fibrinogen to fibrin. Although thrombin is a necessary enzyme, thrombin also contributes to
further inflammation. The controlling of thrombins by antithrombin III,
tissue factor pathway inhibitor and protein C system is compromised by
infections such as SARS-CoV-2, promoting microthrombosis, DIC and
Multisystem Organ Failure. In addition to Deep Venous Thrombosis, high
prevalence of acute pulmonary embolism has been reported (
COVID-19 Complicated by Acute Pulmonary Embolism, Radiology: Cardiothoracic Imaging 2020:2(2):e200067).
4.2 Fibrinolysis dysregulates the barrier function of fibrin, resulting
in accumulation of leukocytes and neutrophils associated with ischemia
Thrombin activation of endothelial and immune effector cells induces production of growth factors, chemokines and cytokines and alters adhesion. Thrombin stimulation of endothelial cells results in the expression of chemokines including IL-6, IL-8, Platelet Activating Factor (PAT) and MCP-1, Monocyte Chemoattractant Protein, proangiogenic mediators (growth factor-beta), proadhesive factors such as ICAM-1, an intercellular adhesion molecule and P-selectin. PPACK-alpha-thrombin enhances leukocyte recruitment to injured endothelial sites.
The binding of thrombin to platelet GPIbα reduces platelet activation and early leukocyte migration. Fibrin binds alpha-thrombin and acts as a physical barrier to leukocyte migration. Following fibrinolysis, the migration of leukocytes to the site of injury is extensive, suggesting that fibrin retards leukocyte trafficking. Inducing fibrinolysis by rt-PA (Plasminogen Activator) dysregulates the physical barrier activity of fibrin, resulting in enhanced leukocyte migration and neutrophil accumulation, associated with ischemia. The finding that plasminogen activator-induced fibrinolysis induces thromboinflammation by dysregulation of the physical barrier function of fibrin poses a therapeutic target (
Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4, Nature Communications 6, Article 7835, July 2015).
4.3 Urokinase pathway: the role of Serpine1 overexpression in fibrin accumulation and inflammation
Patients with SARS have significantly lower counts of platelets and lymphocytes (
Role of vascular cell adhesion molecules and leukocyte apoptosis in the lymphopenia and thrombocytopenia of patients with SARS, Microbes and Infection, January 2006, 8(1)). It should be noted, though, that it is still unclear whether apoptosis is responsible for the reduction of blood cells. The urokinase pathway could be key. The function of the urokinase system is to regulate fibrinolytic and procoagulative responses to prevent hemorrhage and vascular permeability.
A 2013 study reports that, following SARS-CoV-1 infection, excess fibrin was likely mediated by Serpine1-driven inhibition of the urokinase and tissue type plasminogen activators (PLAU and PLAT) and by blocking of plasmin activity by α2-plasmin inhibitor. SARS dysregulates the profibrinolytic signaling of the urokinase system and increases Serpine1 (also: PAI-1 or Plasminogen activator-1) expression. Fibrin accumulation stimulates profibrotic growth factors and cytokines. Collagen deposition and fibrosis are result of fibroblast. Fibrin and fibrin breakdown products enhance vascular permeability, stimulating migration of inflammatory cells and recruiting neutrophils to the lungs.
PLAT serves as an anticlotting agent
Tissue plasminogen activator (PLAT or tPA), inhibited by Serpine, serves as an
anticlotting agent by promoting cleavage of plasminogen into plasmin
and stimulating the breakdown of fibrin clots. This explains why lack of Serpine1 leads to hemorrhage (bleeding). Serpine1-knockout mice succumb to SARS-CoV infection faster than control groups, while viral load is unaffected by Serpine1 (
Mechanisms of SARS Coronavirus-Induced Acute Lung Injury, American Society for Microbiology, July/August 2013, Volume 4 Issue 4).
A clotting problem due to overexpression of Serpine1
When working properly, the urokinase/coagulation system is balanced: upon detection of damage to the endothelium, cells induce te release of fibrin to the site of injury. During this stage in which the body needs to repair its tissue, Serpine1 prevents the premature breakdown of fibrin. Later on in the process, fibrin needs to be dissolved. This is where tPA/PLAT and plasminogen is bound to fibrin within the thrombus, to protect PLAT against inhibition by Serpine1, enabling plasmin generation and fibrinolysis (breakdown of fibrin clots). Inhibition of
Nitric Oxide induces expression of Serpine1, which ultimately results in fibrosis. Overexpression is caused by factors such as the release of inflammatory cytokines, Ang II, Transforming Growth Factor-beta (TGF-beta), aldosterone and lipoproteins (Serpins in thrombosis, hemostasis and fibrinolysis, Journal of Thrombosis and Haemostasis, July 2007; 5).
4.4. Diffuse Alveolar Damage (DAD)
Diffuse Alveolar Damage (DAD) has been observed as a characteristic feature in severe cases of SARS-CoV-2 (Pulmonary Fibrosis and COVID-19: the potential role for antifibrotic therapy, The Lancet Respiratory Medicine, 15 May 2020). Alongside DAD, the presence of microthrombi in pulmonary arteries is reported (
Thromboembolic Findings in COVID-19 Autopsies: Pulmonary Thrombosis or Embolism?, Annals of Medicine, 15 May 2020). Acute-phase DAD is characterized by hyaline membranes in the pulmonary alveoli.
In SARS-CoV-1 patients, exudative-phase DAD and increased macrophages, along with edema, hemorrhage and hyaline membrane formation were observed during the early stage of infection. 10 days post-infection, SARS-CoV-1 patients showed DAD occupying up to 100% of the lung, as well as pulmonary fibrosis resulting in long-term consistent loss of lung elasticity.
Hemorrhage indicates premature breakdown of fibrin products, indicated by vascular leakage into alveolar spaces and development of DAD. In mice models with severe cases of SARS-infection, an elevation of serum albumin was observed (Mechanisms of SARS-Coronavirus-Induced Acute Lung Injury, mBio Microbiology ASM, July/August 2013, Vol. 4 Issue 4, e00271-13); see also '
Serum prealbumin is a prognostic indicator in idiopathic pulmonary fibrosis', The Clinical Respiratory Journal, 18 May 2019..
4.5 Pulmonary fibrosis mechanisms
Impairment of STAT1, a key protein in interferon mediated immunity responses, causes SARS-CoV to induce an innate inflammatory cascade, including large amounts of macrophages, neutrophils and eosinophils (white blood cells). Excessive activation of M2 macrophages results in pulmonary fibrosis. In addition, impairment of ACE2 in the Renin-Angiotensin System (RAS) enables Ang II to induce pulmonary hypertension, increasing the risk of pulmonary fibrosis. While the RAS induces neutrophil recruitment to lung tissue, neutrophils, cytokines such as IL-6 and Tumor Necrosis Factor-alpha (TNF) and infected T cells can stimulate pulmonary fibrosis.
Upon detection of fluid, haemorrhage and fibrin in the alveoli, a coagulation cascade increases the release of factors, among which is F10 that cleaves prothrombin into thrombin (Blood clotting Factor 10. Thrombin activates fibrinogen to fibrin (
The coagulation factors fibrinogen, thrombin and Factor XII in inflammatory disorders, Frontiers in Immunology, 2018:9:1731). The accumulation of blood clots incites fibrinolysis, a system to clear fibrin formations by cleaving plasmins into plasminogens. These mechanisms underlying fibrosis and fibrin clearance explain why tiny clots are found in tissue from SARS-CoV-2 infected patients. A 2015 review stresses the importance of attention for pulmonary fibrosis in emerging coronavirus infections (Molecular pathology of emerging coronavirus infections, Journal of Pathology 2015: 235).
5. Rare cases of thrombosis: antiphospholipid antibodies in patients with COVID-19
A case study of three patients admitted to the ICU mentions the presence of anticardiolipin IgA antibodies and anti-β
2-glycoprotein I IgA and IgB antibodies. These antiphospholipid antibodies target phospholipid proteins, which may rarely result in thrombosis (
Coagulopathy and antiphospholipidantibodies in patients with COVID-19, NEJM, 2020;382:e38).
6. Treatment with LMWH- a Low Molecular Weight Heparin policy in hypercoagulant patients
Anticoagulant treatment with LMWH (heparin) is recommended in the early stage of the disease (
Hypothesis for potential pathogenesis of SARS-CoV-2 infection- a review of immune changes in patients with viral pneumonia, Emerging Microbes and Infections, 2020; 9(1)). Heparin has anti-inflammatory properties (
Anti-inflammatory effects of heparin and its derivates: a systemic review, Pharmacological Sciences, 12 May 2015). In patients with markedly elevated D-dimer levels, adjustment of LMWH is associated with lower 28-day mortality (
Anticoagulant treatment is associated with decreased mortality risk in severe coronavirus disease 2019 patients with coagulopathy, Journal of Thrombosis and Haemostasis, 27 March 2020). The International Society on Thrombosis and Haemostasis' guidance prescribes that all patients requiring hospital admission should receive LMWH (
Pulmonary embolism in patients with COVID-19: Time to change the paradigm of computed tomography, Thrombosis Research, June 2020; 190).
The risk of Heparin-Induced Thrombocytopenia (HIT) is a complicating factor. However, thrombosis-associated thrombocytopenia must be distinguished from HIT. Thrombosis and thrombocytopenia are not paradoxical: what is observed is VTE with consumption of platelets early on in the course of the disease, before the administration of heparin. Even in patients with HIT who need anticoagulants, lepirudin and argatroban are considered safe thrombin inhibitors (Thrombocytopenia due to acute venous thromboembolism and its role in expanding the differential diagnosis of Heparin-Induced Thrombocytopenia, American Journal of Hematology 76:69-73 (2004). In addition to its anticoagulant properties, heparin is mentioned to have antiarrhytmic effects
(Anticoagulant and antiarrhytmic effects of heparin in the treatment of COVID-19 patients, Journal of Thrombosis and Haemostasis, 14 May 2020).
