[Glycocalyx Awareness! Part 3] From SARS-infection to COVID

Juvenile COVID-19 thrombotic microangiopathy shows how SARS-coronaviruses put all ages at thrombotic risk (and the complement MAC is key)

COVID-19 is known to impose thrombotic risk and a risk of hyperinflammatory (systemic) syndromes on all age groups, but until recently, few studies assessing the actual characteristics of thrombotic events and risks in juvenile SARS-CoV-2 infected patients have been published.

What has been acknowledged, is that COVID-19 can cause hyperinflammatory syndrome in children during the period of infection or after recovery, characterized by symptoms similar to Kawasaki (SARS-CoV-2-Induced Kawasaki-Like Hyperinflammatory Syndrome: A Novel COVID Phenotype in Children, Pediatrics Vol. 146, Issue 2, August 1, 2020; An outbreak of severe Kawasaki-like disease at the Italian epicenter of the SARS-CoV-2 epidemic: an observational cohort study, Lancet Vol. 395, Issue 10239 , P1171-1178, June 6, 2020).

MIS-C and Kawasaki-like or Toxic Shock Syndrome, leukemia and brain death in paediatric COVID-19
International studies report that previously healthy children and adolescents show Multisystemic Inflammatory Syndromes with features of Kawasaki or Toxic Shock Syndrome associated with COVID-19 (Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City, JAMA 2020 ; 324 (3): 294-296; see also "Autoimmune and inflammatory diseases following COVID-19, Nature Reviews Rheumatology 2020, 4 June 2020: 1-2"). There has been a shocking report of a three-year-old child who has contracted lymphocytic leukemia from coronavirus infection (Acute lymphoblastic leukemia onset in a 3-year-old-child with COVID-19, Pediatric Blood & Cancer Vol. 67, Issue 11 , November 2020). This child has no underlying medical condition, which underlines the toxicity of the coronavirus.

 

A French study reports the records of a 16-year-old boy and 6-year-old child with no medical condition, diagnosed with COVID-related brain death (Severe and fatal forms of COVID-19 in children, Archives de Pédiatrie Vol. 27, Issue 5, July 2020 , P235-238). In systemic conditions, such as PIMS and MIS-C, the damage caused by SARS-CoV-2 can only be fully determined in the longer term.

Complement MAC (C5b-9) associated Thrombotic Microangiopathy
The December 2020 study provides evidence of thrombotic microangiopathy (TMA) in SARS-CoV-2 infected children, with COVID-19 ranging from minimal to severe. In children with minimal COVID as well as severe COVID and post-COVID MIS-C, markers for TMA were found to be elevated significantly. It is confirmed that complement activation is a major marker for thrombotic microangiopathy. Specifically, the complement C5b-9 Membrane Attack Complex (MAC) that is released by the body in order to lyse pathogens, is associated with TMA in juvenile COVID-19 patients (Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations, Blood Advances Vol. 4, Issue 23, December 08 2020).

 

The immune complex can most likely be ruled out as a driving force for complement activation in patients with COVID-TMA. In autopsy specimens and pathologic reports, published between 2010 and July 2020, evidence was found for activation of the Lectin Pathway through Mannose Binding Lectin (MBL). MAC C5b9 deposits were found in body tissue of SARS-CoV-1 (2003) and SARS-CoV-2 infected patients. Direct viral activation of this Lectin Pathway is a repeatedly and probable hypothesized cause of the MAC deposition.

Relevance
The recent findings are of great relevance, as once again it shows that the complement MAC (C5b-9) is a key feature in COVID-19 thrombotic risk that warrants further exploration. Complement activation is not the sole cause, as many factors are involved in the thrombotic risks that are characteristic for SARS-coronaviruses. Complement inhibitors should be considered as therapeutic options for COVID-infected children as well as adults. While there are specific therapeutics targeting the MAC, a side note is that complement inhibition should not become detrimental to the body's ability to perform pathogen clearance. The graphic shows some examples of complement inhibitors to target C5b9 (the MAC) and  complement C5.

Overview: therapeutic options for targeting the Complement cascade in COVID-19

The Complement system and its relation with coagulation: how complement cascades enhance thrombotic risk

Reports: evidence of MAC depositions in SARS-coronavirus infections have been provided since 2003

SARS-CoV-2/COVID-19 Hypercoagulation, thrombosis, embolism and urokinase pathways: an up-to-date research collection

Haemostasis and vasculature: COVID-19 characterized by thrombosis and hypercoagulability

 
Below is a classic collection of verified and updated thrombosis research. I have selected sources that are applicable to COVID-19 as well as to mechanisms of coagulopathy in general.

ADAMTS-13's failure to cut Von Willebrand Factor (VWF)
ADAMTS13 activity, Von Willebrand Factor, Factor VIII and D-dimers in COVID-19 inpatients, Thrombosis Research 2020 Aug; 192: 174-175;
Targeting VWF levels and macrophage activation in severe COVID-19: Consider low volume plasma exchange and low dose steroid, Thrombosis Research 2020 Aug; 192:2;

Aspirin (Acetylsalicylic acid) use and cardiovascular management of COVID-19
Apirin Use is Associated with Decreased Mechanical Ventilation, ICU Admission, and In-Hospital Mortality in Hospitalized Patients with COVID-19, Anesthesia & Analgesia: October 21, 2020;
Is Acetylsalicylic Acid a Safe and Potentially Useful Choice for Adult Patients with COVID-19?, Drugs 80, 1383-1396(2020);

Antiviral agents and interaction with anticoagulant drugs
Direct oral anticoagulants (DOAC) plasma levels' striking increase in severe COVID-19 patients treated with antiviral agents: The Cremona experience, Journal of Thrombosis and Haemostasis 2020 May 6;

Capillary hypertension
Effect of Coronavirus Disease 2019 in Pulmonary Circulation. The Particular Scenario of Precapillary Pulmonary Hypertension, Diagnostics (Basel) 2020 Aug; 10(8): 548;

Cardiovascular complications in COVID-19
Right Atrial Thrombus in Transient in a COVID-19 Patient: Clinical Echocardiographic Features--Case Report and Literature Review, SN Comprehensive Clinical Medicine 2020 Oct 8: 1-3;
Cardiovascular Implications of Patients with COVID-19, JAMA Cardiology 2020 Jul;5(7):1-8;
Coronavirus and Cardiovascular Disease, Myocardial Injury and Arrhytmia (all factors explained), JACC 2020 Oct 27; 76(17): 2011-2023;
COVID-19, myocardial edema and dexamethasone, Medical Hypotheses Vol. 145, December 2020;
Rescue venoarterial extracorporeal membrane oxygenation (ECMO) after cardiac arrest in COVID-19 myopericarditis, Cardiovascular Revascularization Medicine, 30 September 2020;

Acute myocardial injury is common in patients with COVID-19 and impairs their prognosis, BMJ Heart 2020 Aug; 106(15): 1154-1159;

COVID-19 Coagulopathy (CAC)
Coagulopathy in COVID-19: Focus on vascular thrombotic events, Journal of Molecular Cell Cardiology 2020 Sep; 146: 32-40;
SARS-CoV-2 and coagulation disorders in different organs, Life Science 2020 Nov 1; 260: 118431;
The coagulopathy, endotheliopathy and vasculitis of COVID-19, Inflammation Research 2020 Sep 12: 1-9;
Coagulopathy in COVID-19, Journal of Thrombosis and Haemostasis Vol. 18, Issue 9, September 2020, p2103-2109;
Systemic Inflammatory Response Syndrome is a Major Contributor to COVID-19-Associated Coagulopathy, Circulation 2020 Aug 11; 142(6): 611-614 (Note: PAI-1 and procoagulants are significantly elevated in COVID-19 as compared to other viruses);
Comment: checking for hyperhomocysteinemia in COVID-19, Journal of Thrombosis and Haemostasis, 08 October 2020;
Pulmonary intravascular coagulopathy in COVID-19 pneumonia, Lancet Rheumatology Vol. 2, Issue 8, E458, August 01, 2020;
The unique characteristics of COVID-19 coagulopathy, Critical Care 2020; 24: 360;

Coagulation markers
Specific coagulation markers may provide more therapeutic targets in COVID-19 patients receiving prophylactic anticoagulant (thrombin-antithrombin complex levels, TAT and plasmin-antiplasmin (PAP)), Journal of Thrombosis and Haemostasis, Vol. 18, Issue 9, September 2020, p2428-2430;

COVID-19 thrombotic activity: pathogenesis of coronavirus SARS-CoV-2
Characterization of heparin and SARS-CoV-2 Spike glycoprotein binding interactions, Antiviral Research Vol. 181, September 2020, 104873;
Multifactorial pathogenesis of COVID-19-related coagulopathy. Can defibrotide have a role in the early phases of coagulation disorders?, Journal of Thrombosis and Haemostasis, 21 July 2020;
Thrombotic Complications in Patients with COVID-19: Pathophysiological Mechanisms, Diagnosis and Treatment, Cardiovascular Drugs and Therapy Journal 2020 Oct 19: 1-15;
Pulmonary Arterial Thrombosis in COVID-19: Results from a Prospective, Single-Center, Clinicopathologic Case Series, Annals of Internal Medicine 2020 May 14;

Deep Vein Thrombosis (DVT)
Incidence of deep vein thrombosis among non-ICU patients hospitalized for COVID-19 despite pharmacological thromboprophylaxis, Journal of Thrombosis and Haemostasis Vol. 18, Issue 9, September 2020, p2358-2363;
Response to: Incidence of DVT among non-ICU patients hospitalized for COVID-19 despite thromboprophylaxis: hypoxia as a clinically relevant risk for DVT needs further investigation;

Embolism
Late Pulmonary Embolism after COVID-19 Pneumonia Despite Adequate Rivaroxaban Treatment, European Journal of Case Reports in Internal Medicine 2020; 7(7): 001790;
Pulmonary embolism: A complication of COVID-19 infection, Thrombosis Research 2020 Sep; 193: 79-82;
A Review of Venous Thromboembolism Phenomena in COVID-19 Patients, Current Problems in Cardiology 2020 Aug 28; 100692;
Pulmonary embolism in acute medicine: a case-based review incorporating latest guidelines in the COVID-19 era, British Journal of Hospital Medicine Vol. 81, Issue 6, 2 June 2020;
Pulmonary Embolism in Patients With COVID-19: Awareness of an Increased Prevalence (thrombosis in coronavirus is similar to SARS-1 (2003), differs from influenza; low incidence of DVT suggests pulmonary thrombosis rather than embolism), Circulation, Vol. 142, Issue 2, July 14, 2020;
COVID-19 Complicated by Acute Pulmonary Embolism, Radiology: Cardiothroracic Imaging Vol. 2, nr. 2, 2020;
Diagnosis and Treatment of Pulmonary Embolism During the COVID-19 Pandemic, Chest Journal, August 26, 2020;

Fibrinolysis
Fibrinolysis and COVID-19: A plasmin paradox, Journal of Thrombosis and Haemostasis Vol. 18, Issue 9, September 2020, p2118-2122;
Study of alteplase for respiratory failure in SARS-CoV-2/COVID-19: Study design of the phase IIa STARS trial, Journal of Research and Practice in thrombosis and haemostasis Vol. 4, Issue 6, August 2020, p984-996;

Hypercoagulability
In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID-19 patients on anticoagulation, Journal of Thrombosis and Haemostasis Vol. 18, Issue 10, October 2020, p2646-2653;
COVID-19 versus HIT (heparin-induced thrombocytopenia) hypercoagulability, Thrombosis Research  2020 Dec; 196: 38-51;
Hypercoagulability of COVID-19 patients in Intensive Care Unit: A report of thromboelastography findings and other parameters of hemostasis, Journal of Thrombosis and Haemostasis Vol. 18, Issue 7, July 2020, p1738-1742;
Immunothrombosis in the Pathogenesis of COVID-19 Coagulopathy (CD177 and NET upregulation in severe COVID-19), NEJM Journal Watch, August 17, 2020;

Immunothrombosis
Immunothrombotic Dysregulation in COVID-19 Pneumonia is Associated With Respiratory Failure and Coagulopathy (granulocytes, neutrophils and platelets), Circulation Vol. 142, Issue 12, September 22, 2020;

Interleukin-1 (IL-1) and Thromboxane induction
IL-I induces Thromboxane-A2 (TxA2) in COVID-19 causing inflammation and micro-thrombi: inhibitory effect of the IL1-receptor antagonist (IL-1Ra), Journal of Biological Regulators and Homeostatic Agents 2020 Aug 3;34(5);
Mast cells activated by SARS-CoV-2 release histamine which increases IL-1 levels causing cytokine storm and inflammatory reaction in COVID-19, Journal of Biological Regulators and Homeostatic Agents 2020 Sep 18;34(5);

Long-term cardiovascular damage by COVID-19
Outcomes of Cardiovascular MRI'ing in Patients Recently Recovered from COVID-19, JAMA Cardiology, July 27, 2020;
Long-term Health Consequences of COVID-19, JAMA, October 5, 2020;

Microthrombosis in COVID-19
The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications, Circulation Research 2020 Jul 31; 127(4): 571-587;

Platelet responses
COVID-19 patients exhibit reduced procoagulant platelet responses, Journal of Thrombosis and Haemostasis, 18 September 2020;

RAAS (Renin-Angiotensin-Aldosterone System) and cardiovascular circulatory disease
β-Arrestin-Biased Angiotensin II (Ang II) Receptor Agonists for COVID-19, Circulation Vol. 142, Issue 4, July 28, 2020;

Sepsis
The Role of Microvascular Thrombosis in Sepsis, Anaesthesia and Intensive Care Vol. 32, Issue 5, October 1, 2004;

Stroke
SARS-CoV-2 infection and its association with thrombosis and ischemic stroke: A review, The American Journal of Emergency Medicine, 30 September 2020;

Thrombocytopenia
Exploring possible mechanisms for COVID-19 induced thrombocytopenia: Unanswered questions, Journal of Thrombosis and Haemostasis Vol. 18, Issue 6, June 2020, p1514-1516;

Treatment options and management
Management of the thrombotic risk associated with COVID-19: guidance for the hemostasis laboratory, Thrombosis Journal 2020; 18: 17;
Plasminogen improves lung lesions and hypoxemia in patients with COVID-19, QJM: An International Journal of Medicine Vol. 113, Issue 8, August 2020, p539-545;
Tissue plasminogen activator (tPA) treatment for COVID-19 associated ARDS: A case series, Journal of Thrombosis and Haemostasis Vol. 18, Issue 7, July 2020, p1752-1755;
The Anticoagulant Nafamostat Potently Inhibits SARS-CoV-2 S Protein-Mediated Fusion in a Cell Fusion Assay System and Viral Infection in Vitro in a Cell-Type-Dependent Manner, MDPI Viruses 2020 Jun; 12(6):629;
Anticoagulation with argatroban in patients with acute antithrombin deficiency in severe COVID-19, British Journal of Haematology Vol. 190, Issue 5, September 2020, p286-288;
IL-1 induces thromboxane-A2 (TxA2) in COVID-19 causing inflammation and micro-thrombi: inhibitory effect of the IL-1 receptor antagonist (IL-1Ra), Journal of Biological Regulators and Homeostatic Agents 2020 Aug 3;34(5);
Rescue venoarterial extracorporeal membrane oxygenation (ECMO) after cardiac arrest in COVID-19 myopericarditis, Cardiovascular Revascularization Medicine, 30 September 2020;
Apirin Use is Associated with Decreased Mechanical Ventilation, ICU Admission, and In-Hospital Mortality in Hospitalized Patients with COVID-19, Anesthesia & Analgesia: October 21, 2020;
Is Acetylsalicylic Acid a Safe and Potentially Useful Choice for Adult Patients with COVID-19?, Drugs 80, 1383-1396(2020);

Urokinase pathways towards thrombotic activity
Hypoxia Stimulates Urokinase Receptor Expression Through a Heme Protein-Dependent Pathway, ASH Blood Journal Vol. 91, Issue 9, May 1, 1998;

V and X Factors and therapeutic inhibition options
(Xa Factor) Response to "Studies on hemostasis in COVID-19 careful reporting of the laboratory methods, their significance and their limitation": don't throw the baby out with the bathwater (on testing with anti-Xa kit), Journal of Thrombosis and Haemostasis, 28 August 2020;
Dual inhibition of Factor XIIa and Factor XIa as a therapeutic approach for safe thromboprotection, Journal of Thrombosis and Haemostasis, 12 October 2020;
COVID-19 and Blood Clots (Factor V activity strongest among all clinical parameters), Harvard News & Research September 09, 2020;

Thromboinflammation and hypercoagulation in COVID-19 patients: slides

COVID-19 is known for its highly (pro)thrombotic events following SARS-CoV-2 infection. Ultimately, disruption of the vasculature results in multiple organ failure and long-term COVID-19 related cardiorespiratory damage. While both host immunity and inflammatory and pathogenic features of this SARS-Coronavirus contribute to vascular injury, it is the virus that is the cause of the thromboinflammatory state that characterizes COVID-19. In the following slides, I will describe the mechanisms underlying thrombotic events in COVID-19 patients.

Markers to assess the thromboinflammatory state of COVID-19 patients

Thrombocyopenia in COVID-19: while values are normal at the time of hospital admission, thrombocytopenia appears as a progressive feature

Dysregulation of thrombin and fibrin in COVID-19

Urokinase pathway involvement in COVID-19 thrombosis

A remaining challenge: hypercoagulability characterizing COVID-19, despite anticoagulation practices

Mechanisms of coagulation and thrombosis in COVID-19

 

Over the past eight months it has become increasingly clear that COVID-19 is characterized by hypercoagulation and thromboinflammation. The pathogen SARS-CoV-2 itself, the innate host immunity response, haemostatic factors, the Renin-Angiotensin-Aldosterone System (RAS/RAAS) and the complement system are wired up to evoke a procoagulant, thromboinflammatory state in COVID-19 affected patients. The mechanisms enhance thromboinflammation and reduce fibrinolysis (the breakdown of clots). 

A few reports indicate that the hypercoagulant state in COVID-19 remains, in spite of thromboprophylaxis. In an early report, Deep Venous Thrombosis (DVT) was observed among non-Intensive Care Unit patients receiving thromboprophylaxis with either enoxaparin or fondaparinux (Incidence of deep vein thrombosis among non-ICU patients for COVID-19 despite pharmacological thromboprophylaxis, Journal of Thrombosis and Haemostasis 2020;18:2358-2363). 

Another, more recent study reports ongoing activation of coagulation and fibrinolysis despite low therapeutic anticoagulation in COVID-19 patients. Hypofibrinolytic states (impairment of the breakdown of fibrin clots) occur, even in the presence of Low Molecular Weight Heparin (LMWH). It is hypothesized that low therapeutic anticoagulant therapies are insufficient to downregulate coagulation activation in COVID-19 (In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID-19 patients on anticoagulation, Journal of Thrombosis and Haemostasis 2020;18:2646-2653). 

Keeping it simple: is it just the case that prophylaxis at hospital admission is too late?
One key factor, a major factor, might be explanatory for ongoing thromboinflammation, the occurrence of Deep Venous Thrombosis (even after hospital discharge) and hypercoagulation in spite of prophylaxis: time. 

I hypothesize that the administration of thromboprophylaxis might be too late to curb already ongoing thrombotic activity in the vasculature, as thromboprophylaxis is received at the time of hospital admission, which is a main of 4 to 5 days after SARS-CoV-2 infection. If thromboinflammation occurs before or a few days from the onset of symptoms, thromboprophylaxis fails to break down fibrin accumulation and stabilized fibrin structures in the microvasculature. Markedly, a study involving 107 SARS-CoV-2 infected patients, chronic use of anticoagulation is associated with decreased thrombotic complications typical for COVID-19. Only 17 out of 107 chronically anticoagulated patients required Intensive Care (Chronic therapeutic anticoagulation is associated with decreased thrombotic complications in SARS-CoV-2 infection, Journal of Thrombosis and Haemostasis Vol. 18, Issue 10, October 2020, p2640-2645).

Nevertheless, questions on timing of thromboprophlaxis and therapeutic options for non-chronic anticoagulated COVID-19 remain to addressed. This is further complicated by a recent finding.

Pathogenesis of SARS-CoV-2: how this coronavirus impairs anticoagulation therapies
A recent finding is that the S-protein (spike) of SARS-CoV-2 binds heparin and heparan sulfate (Characterization of heparin and SARS-CoV-2 spike glycoprotein binding interactions, Antiviral Research Vol. 181, September 2020, 104873), which explains why heparin prophylaxis according to standard-dose LMWH or Unfractioned Heparin (UFH) is insufficient to reduce thrombotic activity in COVID-19 patients. The effect of nebulized heparin is under investigation.

A key role for hypoxia?
There are several topics to address. The timing and dose of anticoagulation therapies or thromboprophylaxis are essential, but mechanisms underlying thromboinflammation might offer insight into the presumed ongoing procoagulant state in COVID-19. Hypoxia and Hypoxia-inducible transcription factors (HIF) are a possible link between viral sepsis and thrombosis (Hypoxia and HIF activation as a possible link between sepsis and thrombosis, Thrombosis Journal 2019; 17: 16). The need for research of hypoxia as a trigger for thrombosis is expressed (Hypoxia- an overlooked trigger for thrombosis in COVID-19 and other critically ill patients, Journal of Thrombosis and Haemostasis, 29 July 2020; Incidence of Deep Vein Thrombosis among non-ICU Patients Hospitalized for COVID-19 Despite Pharmacological Prophylaxis: Response).

Making the shift towards more distinctive parameters to assess hypercoagulation: urokinase markers
Shifting towards distinctive parameters is recommended to provide more therapeutic targets. The urokinase pathway offers specific markers to assess the fibrinolytic state of a patient. PAP (plasmin-antiplasmin) and TAT (thrombin-antithrombin) as well as tPAI-C (tissue plasminogen activator-plasminogen activator inhibitor 1 complex) are the suggested specific markers to improve anticoagulation practice (Specific coagulation markers may provide more therapeutic targets in COVID-19 patients receiving prophylactic anticoagulant, Journal of Thrombosis and Haemostasis, 25 June 2020).

Noteworthy, an article published in ASH Blood from 1 May 1998 reviews the role of hypoxia in stimulating the urokinase-type plasminogen activator (uPAR) receptor, thereby enhancing cellular invasion (Hypoxia Stimulates Urokinase Receptor Expression Through a Heme Protein-Dependent Pathway, ASH Blood (1998) 91 (9):3300-3307).

Extensive reading recommendations on SARS-CoV-2/ COVID-19: all mechanisms (Part 3)

So much to it! A non-exhaustive overview of factors involved in COVID-19

ARDS-like
Co-aerosolized Pulmonary Surfactant and Ambroxol for COVID-19 ARDS Intervention: What are we waiting for?, Frontiers in Bioengineering and Biotechnology, 25 September 2020;

Asymptomatic transmission
Asymptomatic patients as a source of COVID-19 infections: A systematic review and meta-analysis, International Journal of Infectious Diseases Vol. 98, P180-186, September 01, 2020;

Cardiopulmonary complications caused by COVID-19
The emerging spectrum of cardiopulmonary pathology of COVID-19: Report of 3 autopsies from Houston, Texas, and review of autopsy findings from other US cities, Cardiovascular Pathology 2020 September-October; 48: 107233;

Central Nervous System (CNS)
Interactions between Olfaction and the Trigeminal System: what can be learned from olfactory loss, Cerebral Cortex (Journal), Vol. 17, Issue 10, October 2007;
Sympathetic Nervous System Activation and its Modulation: Role in Atrial Fibrillation, Frontiers in Neuroscience, 23 January 2019;
Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19, Neurology, September 22, 2020; 95(12);
New onset neurologic events in people with COVID-19 in 3 regions in China, Neurology, September 15, 2020; 95 (11);
Potential of SARS-CoV-2 to Cause CNS Infection: Biological Fundamental and Clinical Experience, Frontiers Neurology, 18 June 2020;
Neurologic Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China, Jama Neurology 2020; 77 (6):683-690;
Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System?, MDPI Viruses, 20 December 2019, Viruses 2020, 12(1), 14;
Neuromechanisms of SARS-CoV-2: A Review, Frontiers Neuroanatomy, 16 June 2020;
COVID-19: A Global Threat to the Nervous System (microthrombi and acute infarctions in the brain), Annals of Neurology Vol. 88, Issue 1, July 2020;
Involvement of the Nervous System in SARS-CoV-2 Infection, Neurotoxicity Research 2020, May 13 :1-7;
The Neurology of COVID-19 revisited: A Proposal from the Environmental Neurology Specialty Group of the World Federation of Neurology to implement international neurological registries, Journal of Neurological Science 2020 July 15; 414: 116884;
Multiple Neuroinvasive Pathways in COVID-19, Molecular Neurobiology 2020 September 29: 1-12;
Coronavirus infection of the central nervous system: host-virus stand-off, Nature Reviews Microbiology 4, 121-132(2006);
Pathophysiology of the COVID-19- entry to the CNS through the nose, Acta Oto-Laryngologica Vol. 140, 2020, Issue 10;
COVID-19 associated acute necrotizing encephalopathy (ANE) succesfully treated with steroids and polyvalent immunoglobulin with unusual IgG targeting the cerebral fibre network, Journal of Neurology, Neurosurgery & Psychiatry Vol. 91, Issue 9, 2020;
COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia, Journal of Neuroimmunology & Neuroinflammation, September 2020; 7(5);
Brain abnormalities in COVID-19 acute/subacute phase: A rapid systematic review, Brain Behavior and Immunology 2020 Oct; 89: 543-554;
Neuropathology of COVID-19: a spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology, Acta Neuropathologica 2020; 140(1): 1-6;

Coagulation
Anticoagulant treatment in COVID-19: a narrative review (in COVID-19 patients, thrombotic lesions in pulmonary vessels have a prevalence twice higher than in non-COVID-19 patients), Journal of Thrombosis and Thrombolysis 2020, 18 August 2020;
Hypercoagulability of COVID-19 patients in IC Unit: A report of thromboelastography findings and other parameters of hemostasis, Journal of Thrombosis and Haemostasis Vol. 18, Issue 7, July 2020, p1738-1742;

Cytokine storms/cascade/cytokine release syndrome
COVID-19: In the Eye of the Cytokine Storm, Frontiers Immunology, 24 September 2020;
T-Cell Hyperactivation and Paralysis in Severe COVID-19 Infection Revealed by Single-Cell Analysis, Frontiers Immunology, 08 October 2020;

Embolism
Occurrence of pulmonary embolism related to COVID-19, Journal of Thrombosis and Thrombolysis 2020, 06 October 2020;
Acute pulmonary embolism in COVID-19 related hypercoagulability, Journal of Thrombosis and Thrombolysis 2020, 30 May 2020;
Risk of venous thromboembolism in patients with COVID-19: A systematic review and meta-analysis (22,7% of ICU patients and non-ICU patients), Research and Practice in Thrombosis and Haemostasis, 25 September 2020;
Left ventricular thrombus and pulmonary embolism: A case series of thrombosis in COVID-19 in Thai patients, Research and Practice in Thrombosis and Haemostasis, 18 September 2020

Endothelium
The Enigma of Endothelium in COVID-19 (and sepsis), Frontiers in Physiology, 04 August 2020;

Long-term complications of COVID-19 and SARS-CoV-2 infection
Anticipating the long-term cardiovascular effects of COVID-19, Journal of Thrombosis and Thrombolysis 50, 512-524(2020);
Long-Haul COVID, Neurology, September 29, 2020, 95 (13);

Markers to assess severity of COVID
Serum Activity of Liver Enzymes is Associated with Higher Mortality in COVID-19: A Systematic Review and Meta-Analysis, Frontiers in Medicine, 22 July 2020;
Specific coagulation markers may provide more therapeutic targets in COVID-19 patients receiving prophylactic anticoagulant (TPA, TAT and PAP), Journal of Thrombosis and Haemostasis Vol. 18, Issue 9, September 2020, p2428-2430;

Monocytes
Increased Serum Levels of sCD14 and sCD163 Indicate a Preponderant Role for Monocytes in COVID-19 Immunopathology, Frontiers Immunology, 23 September 2020;

Macrophages
Targeting Macrophages as a therapeutic option in COVID-19, Research Article to be published, Frontiers Pharmacology;

Matrix Metalloproteinase (MMPs)
Matrix Metalloproteinase-9 Inhibition Reduces Inflammation and Improves Motility in Murine Models of Post-Operative Ileus, Gastroentology 2011 Oct: 141(4): 1283-1292.e4.;

NETs (Neutrophil Extracellular Traps) and neutrophil profiles
Neutrophils and Neutrophil Extracellular Traps Drive Necroinflammation in COVID-19, MDPI Cells 2020, Jun; 9(6)1383;

Pathogenicity and structure of SARS-CoV-2
Free fatty acid binding pocket in the locked structure of SARS-CoV-2 Spike protein, AAAS 21 September 2020;
COVID-19 is Distinct from SARS-CoV-2 Negative Community Acquired Pneumonia (= COVID pneumonia differs from other pneumonias), Frontiers in Cellular and Infection Microbiology, 16 June 2020;
ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19, Frontiers in Immunology, 07 October 2020;
Host/genetic factors associated with COVID-19 call for medicine, Precision Clinical Medicine Vol. 3, Issue 3, September 2020, p228-234;
The unique characteristics of COVID-19 coagulopathy, Critical Care 2020; 24: 360;

Red Blood Cells
Association of Red Blood Cell Distribution Width With Mortality Risk in Hospitalized Adults With SARS-CoV-2 Infection, Jama Critical Care, September 23, 2020;3(9);

Stroke as a frequent feature in COVID-19
Acute Ischemic Stroke and COVID-19: Experience from a Comprehensive Stroke Center in Midwest US, Frontiers in Neurology, 20 August 2020;
Stroke risk, phenotypes and death in COVID-19: Systematic review and newly reported cases, September 15, 2020;
Risk of Acute Cerebrovascular Events in patients with COVID-19 Infection (COVID-19-related stroke is not age or comorbidity related), American Journal of Neuroradiology, August 27, 2020;

T lymphocytes
Decreased T cell populations contribute to the increased severity of COVID-19, Clinica Chimica Acta, Vol. 508, September 2020, p110-114;
Mapping the T cell response to COVID-19, Signal Transduction and Targeted Therapy 5, Art. No. 112(2020);

Treatment of COVID-19
An open-label, randomized trial of the combination of IFN-k plus TFF2 (Treefoil Factor Family member 2) with standard care in the treatment of patients with moderate COVID-19, EClinicalMedicine, September 20, 2020;
Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D, Quercetin and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells, Biomedicines 2020 May; 8(5): 129;
Dupilumab and COVID-19: What should we expect?, Dermatologic Therapy Vol. 33, Issue 4, July/August 2020;
COVID-19-related encephalopathy responsive to high-dose glucocorticoids, Neurology September 22, 2020; 95(12);
How nicotine can inhibit cytokine storm in the lungs and prevent or lessen the severity of COVID-19 infection?, Immunology Letters Vol. 224, August 2020, p28-29;
Nicotine and the nicotinic cholinergic system in COVID-19, The FEBS Journal Vol. 287, Issue 17, September 2020, p3656-3663;
COVID-19 associated acute necrotizing encephalopathy succesfully treated with steroids and polyvalent immunoglobulin with unusual IgG targeting the cerebral fibre network, Journal of Neurology, Neurosurgery & Psychiatry Vol. 91, Issue 9, 2020;
SARS-associated Coronavirus Nucleocapsid Protein Interacts with Smad3 and Modulates Transforming Growth Factor-β (TGF-β) Signaling (and the role of PAI-1 in fibosis), Journal of Biological Chemistry, February 8, 2008, 283; 3772-3280;
Low mortality of hospitalized patients with COVID-19 in a tertiary Danish hospital setting, Internation Journal of Infectious Diseases, October 12, 2020;

Urokinase
Urokinase plasminogen activator independent early experimental thrombus resolution: MMP2 as an alternative mechanism, Thrombosis and Haemostasis 2010 Dec;104(6):1174-83;

Vitamin D Immunomodulation
A Basic Review of the Preliminary Evidence that COVID-19 Risk and Severity is Increased in Vitamin D Deficiency, Frontiers in Public Health, 10 September 2020;

Extensive reading recommendations on SARS-CoV-2/ COVID: all mechanisms involved (Part 2)

Mechanisms involved in SARS-CoV-2 / COVID-19

It has been clear since the SARS epidemic of 2003 that coronavirus diseases caused by SARS-CoV infections are thromboinflammatory diseases. As of March 2020, when SARS-CoV-2 was politically (finally) declared a pandemic, COVID-19 was still treated like a main pulmonary disease. Reseachers have been pointing out that the underlying mechanisms are characterized by hyperinflammation, hypercoagulation, complement cascades and dysregulation of the Renin-Angiotensin-Aldosterone System, ultimately leading to thromboembolic events in multiple organs (MOF), stroke and post-COVID systemic diseases, such as Guillain-Barré and cardiomyopathy. 

To provide a view into the complexity of COVID-19, I share with you the most prominent research papers on the mechanisms and pathogenicity of SARS-CoV-2. Some of the research papers of the biggest relevance for COVID-19 complications are as old as 60 years. This is why the paradigm should be that "Lots of the mechanisms causing COVID-19 are well-known, but we have to find the best practices to treat its complications".

I only refer to verified and reviewed research and scientific viewpoint papers citing verified references. If paper has already been peer reviewed but still awaitens the editory process (early release), I will mention this. To retrieve these papers from the PubMed/NCBI and Wiley database, I narrowed my search process to combinations of "SARS-CoV-2", "Thrombosis", "Pulmonary embolism", "Complement" and "Coagulation".

ACE and ACE2
Angiotensin Converting Enzyme defects in shock: implications for future therapy, Critical Care 22, Art. No. 274 (2018);

ADAM17
TMPRSS2 and ADAM17 Cleave ACE2 Differentially and Only Proteolysis by TMPRSS2 Augments Entry Driven by the SARS-Coronavirus Spike Protein, Journal of Virology, January 2014 Vol. 88, No. 2, P1293-1307;

Aquaporins
Aquaporin-mediated transport, Pathway R-HSA-445717, PubChem, 08 July 2020;

ARDS
Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study, Lancet Infectious Diseases Vol. 20, Issue 4, P425-434;
The evolving role of the Renin-angiotensin system in ARDS, Critical Care 21, Art. No. 329 (2017);

Asymptomatic SARS-CoV-2 Infection
Natural History of Asymptomatic SARS-CoV-2 Infection, NEJM 2020; 383:885-886, August 27, 2020;

B- and T-cell immunological memory (CD4+ and CD8+)
COVID-19 and the Path to Immunity, JAMA, September 11, 2020;
Depletion of CD4 and CD8 Positive T Cells Impairs Venous Thrombus Resolution in Mice, MDPI International Journal of Molecular Sciences 2020 March;21(5): 1650;

Call for better screening
Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection, The American Journal of Medicine, August 06, 2020;

Cardiovascular complications
Outcomes of Cardiovascular MRI in Patients Recently Recovered from COVID-19 (coronavirus causes myocardial inflammation independent of preexisting conditions), JAMA Cardiology, July 27, 2020;

Coagulation
Immunothrombotic Dysregulation in COVID-19 Pneumonia is Associated with Respiratory Failure and Coagulopathy, Journal of Circulation, 28 July 2020;
Coagulation biomarkers are independent predictors of increased oxygen requirements in COVID-19, Journal of Thrombosis and Haemostasis, 17 August 2020;
Coagulation parameters and venous thromboembolism in patients with and without COVID-19 admitted to the Emergency Department for acute respiratory insufficiency, Thrombosis Research Vol. 196, P209-212, December 2020;

Complement
Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis, Nature 2020, 29 July 2020;
COVID-19: A collision of complement, coagulation and inflammatory pathways, Journal of Thrombosis and Haemostasis Vol. 18, Issue 9, September 2020, P2110-2117;

Comparative tropism and transmission (profiling of SARS-CoV-2)
Distinct conformational states of SARS-CoV-2 Spike protein, Science 21 July 2020;
Coronavirus surprise from cryo-EM data, Wiley Analytical Science, 22 July 2020;
Single-Cell Sequencing of Peripheral Mononuclear Cells Reveals Distinct Immune Response Landscapes of COVID-19 and Influenza Patients, Immunity Vol. 53, Issue 3, 15 September 2020, P685-696;
Enhanced Binding of SARS-CoV-2 Spike Protein Receptor by Distal Polybasic Cleavage Site, ACS Nano 2020, 14, 8, 10616-10623;
Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and hydrophobic interactions, Proceedings of the National Academy of Sciences of the US (PNAS) June 23, 2020 117 (25), 13967-13974;
Pathogenicity, Transmission, Diagnosis and Treatment of COVID-19, JAMA 2020;324(8):782-793;
Risk of Ischemic Strole in Patients with COVID-19 vs. Patients With Influenza, JAMA Neurology, July 2, 2020;

Central Nervous System (CNS) complications
A case of malignant cerebral infarction associated with COVID-19 infection, British Journal of Neurosurgery, 05 August 2020;

Critical Care
Association of Noninvasive Oxygenation Strategies with All-Cause Mortality in Adults with Acute Hypoxemic Respiratory Failure: A Systematic Review and Analysis, JAMA 2020;324(1):57-67;
Anti Xa activity after high dose Low Molecular Weight Heparin (LMWH) thrombosis prophypaxis in COVID-19 patients at the IC Unit, Thrombosis Research Vol. 196, P1-3, December 01, 2020;
Impact of implementation of an individualised thromboprophylaxis protocol in critically ill ICU patients with COVID-19: A longitudinal controlled before and after study, Thrombosis Research Vol. 194, October 2020, P209-215;
Scientific and Standardization Committee communication: Clinical guidance on the diagnosis, prevention and treatment of Venous Thromboembolism (VTE) in hospitalized patients with COVID-19, Journal of Thrombosis and Haemostasis Vol. 18, Issue 8, August 2020, P1859-1865;
Inaccuracy of point-of-care international normalized ratio in Rivaroxaban-treated patients, Annals of Pharmacotherapy Vol. 47, Issue 9, September 1, 2013;
How I treat recurrent Venous Thromboembolism in patients receiving anticoagulant therapy, Blood Vol. 129, Issue 25, June 22, 2017;

Deep Vein Thrombosis (DVT)
Deep vein thrombosis in SARS-CoV-2 pneumonia-affected patients within standard care units: Exploring a submerged portion of the iceberg, Thrombosis Research Vol. 194, October 2020, P216-219;
Incidence of deep vein thrombosis among non-ICU patients hospitalized for COVID-19 despite pharmacological thromboprophylaxis, Journal of Thrombosis and Haemostasis Vol. 18, Issue 9, September 2020;

DIC (Disseminated Intravascular Coagulopathy) and differentiations of DIC
Clotting abnormalities in critically ill COVID-19 patients are inconsistent with overt Disseminated Intravascular Coagulation, Thrombosis Research Vol. 196, P272-275, December 01, 2020;
Higher procoagulatory potential but lower DIC score in COVID-19 ARDS patients compared to non-COVID-19 ARDS patients, Thrombosis Research Vol. 196, P186-192, December 01, 2020;

Endothelialitis/Endotheliitis
Pulmonary Vascular Endothelialitis, Thrombosis and Angiogenesis in COVID-19, New England Journal of Medicine (NEJM) 2020; 383:120-128, July 9, 2020;

Fibrinolysis
Fibrinolytic abnormalities in ARDS and versatility of thrombolytic drugs to treat COVID-19, Journal of Thrombosis and Haemostasis Vol. 18, Issue 7, July 2020;
Hypofibrinolytic state and high thrombin generation may play a major role in SARS-CoV-2 associated thrombosis, Journal of Thrombosis and Haemostasis Vol. 18, Issue 9, September 2020;

Interferons (IFN)
Role of IFN-γ responsiveness in CD8 T cell-mediated viral clearance and demyelination in coronavirus-infected mice, Journal of Neuroimmunology 2008 February; 194(1): 18-26;
Type I and Type III Interferons- Induction, Signaling, Evasion and Application to combat COVID-19, Cell Host & Microbe Vol. 27, Issue 6, p870-878, June 10, 2020;

Megakaryocytes
Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: A case series, EClinicalMedicine Vol. 24, 100434, July 01, 2020;

Monocytes
Monocyte activation in systemic COVID-19 infection: Assay and rationale, EBioMedicine Vol. 59, 102964, September 01, 2020;

Neutrophils and NETs (& platelet interaction)
Immunothrombosis in severe COVID-19, EBioMedicine Vol. 59, 102942, September 01, 2020;

Pathogenicity of SARS-CoV-2: PROS1 and PL proteins
Identification of the antithrombotic protein S as a potential target of the SARS-CoV-2 palpain-like protease, Thrombosis Research Vol. 196, P257-259, December 01, 2020;

Pathogenicity of SARS-CoV-2: RNA and Spike protein
Circulating endothelial progenitors are increased in COVID-19 patients and correlate with SARS-CoV-2 RNA in severe cases, Journal of Thrombosis and Haemostasis, 06 August 2020;
Cleavage of spike protein of SARS coronavirus by protease factor Xa is associated with viral infectivity, Biochemical and Biophysical Research Communications 2007, July 20; 359(1): 174-179;

Platelets
Intravascular Platelet Aggregation in the Heart Induced by Norepinephrine, Journal of Circulation, 1972;46:698-708;
Platelet protein S limits venous but not arterial thrombosis propensity by controlling coagulation in the thrombus, Blood Vol. 135, Issue 22, May 28, 2020;

Pulmonary Embolism
Subsegmental Thrombus in COVID-19 Pneumonia: Immunothrombosis or Pulmonary Embolism? Data Analysis of Hospitalized Patients with Coronavirus Disease, Heart, Lung and Circulation, 24 August 2020;
Late Pulmonary Embolism after COVID-19 Pneumonia Despite Adequate Rivaroxaban Treatment, European Journal of Case Reports in Internal Medicine Vol. 7, No. 7, June 18, 2020;

Pyroptosis
Inflammasomes and Pyroptosis as Therapeutic Targets for COVID-19, The Journal of Immunology Vol. 205, Issue 2, 15 July 2020, P307-312;

RAAS (Renin-Angiotensin-Aldosterone) - KKS (Kallikrein-Kinin), Angiotensins and Bradykinin
Involvement of bradykinin B1 and B2 receptors in human PMN elastase release and increase in endothelial cell monolayer permeability, Immunopharmacology, 1996 June;33(1-3):325-9;
The Renin-Angiotensin System: An integrated view of lung disease and coagulopathy in COVID-19 and therapeutic implications, Journal of Experimental Medicine (2020) 217 (8):e20201000;
The evolving role of the Renin-angiotensin system in ARDS, Critical Care 21, Art. No. 329 (2017);

Stroke (and prevalence in young people due to SARS-CoV-2 infection)
Acute cerebral stroke with multiple infarctions and COVID-19, France, 2020, CDC Research Vol. 26, No. 9, September 2020;
A case of malignant cerebral infarction associated with COVID-19 infection, British Journal of Neurosurgery, 05 August 2020;
COVID-19 related stroke in young individuals, Lancet Neurology Vol. 19, Issue 9, P713-715, September 01, 2020;
Risk of Ischemic Strole in Patients with COVID-19 vs. Patients With Influenza, JAMA Neurology, July 2, 2020;
Stroke as a complication and prognostic factor of COVID-19, Neurologia Vol. 35, Issue 5, June 2020, P318-322;
Mechanisms of Stroke in COVID-19, Cerebrovascular Diseases Vol. 49, No. 4,  September 2020;

Systemic diseases following SARS-CoV-2 infection
Autoimmune and inflammatory diseases following COVID-19, Nature Reviews Rheumatology 16, 413-414(2020);

Thrombosis
Arterial Mesentric Thrombosis as a Complication of SARS-CoV-2 Infection, European Journal of Case Reports in Internal Medicine 2020; 7(5): 001690;
Multisystemic Infarctions in COVID-19: Focus on the Spleen, European Journal of Case Reports in Internal Medicine 2020; 7(7): 001747;
Clotting abnormalities in critically ill COVID-19 patients are inconsistent with overt Disseminated Intravascular Coagulation, Thrombosis Research Vol. 196, P272-275, December 01, 2020;
Asymptomatic Deep Vein Thrombosis (DVT) in critically ill COVID-19 patients despite therapeutic levels of anti-Xa activity, Thrombosis Research Vol. 196, P268-271, December 01, 2020;
Extensive pulmonary perfusion defects compatible with microthrombosis and thromboembolic disease in severe COVID-19 pneumonia, Thrombosis Research Vol. 196, P135-137, December 01, 2020;
Systemic thromboemboli in patients with COVID-19 may result from paradoxical embolization, Thrombosis Research Vol. 196, P206-208, December 01, 2020;
Circulating endothelial progenitors are increased in COVID-19 patients and correlate with SARS-CoV-2 RNA in severe cases, Journal of Thrombosis and Haemostasis, 06 August 2020;
Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2, International Journal of Laboratory Hematology 2020 June;42:19-20;

Treatment/therapeutic options for treating COVID
Treatment of patients with acute Deep Vein Thrombosis and/or pulmonary embolism: efficacy and safety of non-VKA oral anti-coagulants in selected populations, Thrombosis Research Vol. 134, Issue 2, p227-233, August 01, 2014;
Ig-like ACE2 protein therapeutics: a revival in development during a pandemic, Journal of mAbs (antibodies) Vol. 12, Issue 1, December 2020;
Therapeutic blockade of granulocyte macrophage colony-stimulating factor (GM-CSF) in COVID-19 associated hyperinflammation: challenges and opportunities, Lancet Respiratory Medicine Vol. 8, Issue 8, p822-830, August 2020;
Fibrinolytic abnormalities in ARDS and versatility of thrombolytic drugs to treat COVID-19, Journal of Thrombosis and Haemostasis Vol. 18, Issue 7, July 2020;
Dynamic changes in fibrinogen and D-dimer levels in COVID-19 patients on nafamostat mesylate, Journal of Thrombosis and Thrombolysis 2020, 12 September 2020 (note: trial from Tokyo Hospital, coagulation dynamics might differ in non-Asian people);
Kallikrein-kinin blockade in patients with COVID-19 to prevent ARDS, Radboud UMC, April 27, 2020;
Accumulating evidence suggests anti-TNF therapy needs to be given trial priority in COVID-19 treatment, Lancet Rheumatology, September 04, 2020;
GM-CSF Blockade during Chimeric Antigen Receptor T Cell Therapy Reduces Cytokine Release Syndrome and Neurotoxicity and May Enhance Their Effector Functions, ASH Blood Vol. 132, November 29, 2018;
GM-CSF Neutralization With Lenzilumab in Severe COVID-19 Pneumonia: A Case-Control Study, Mayo Clinic Proceedings, 03 September 2020;
Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe ARDS and COVID-19: the CoDEX Randomized Clinical Trial, JAMA, September 2, 2020;
Effect of Hydrocortisone Among Critically Ill Patients With COVID-19: A Randomized Clinial Trial, JAMA, September 2, 2020;
The Role of Anticoagulation in COVID-19 Induced Hypercoagulability, Current Cardiology Reports 22, Art. No. 53(2020);

Viral load and antibody responses
Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study, Lancet Infectious Diseases Vol. 20, Issue 5, P565-574;

Pathways to deterioration in SARS-CoV-2 (Part II): coagulation disorders/haemostatic imbalance: COVID is thromboinflammation and pulmonary fibrosis

Hemostatic imbalance in SARS-CoV-2
In this series, I discuss the haemostatic imbalance typically involved in SARS-CoV-2, the virus that causes COVID-19. As can be learned from the SARS-CoV-1 epidemic (2003) and its massive body of knowledge still expanding since 2003, the topic of deterioration should not mainly focus on "SARS as a lung disease"; under no condition the key role of coagulation disorders as a response to inflammation should be underestimated. 

 

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-β₂-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).

 

Next feature: interactions of MMPs, notably MMP9, ADAMTS-13 and VWF in severe SARS-CoV-2 cases
In this "deterioration series", I have mentioned the involvement of Von Willebrand Factor platelet binding to the injured endothelium and the role of ADAMTS-13 in taming down the release of overactive ULVWF into the plasma. There is more to it. Upregulated MMPs are notable contributors to pulmonary fibrosis. In next feature, I will elaborate on the influence of overexpression of MMP-9 on thrombus formation and the role of ADAMTS-13 in thrombosis. While a lack of ADAMTS-13 does not consitute TTP or ischemic stroke by itself, deficiency of ADAMTS-13 induces a prothrombotic state to be enhanced by other metalloproteases and inflammatory cytokines.