Severe course of COVID-19 may be associated with the von Willebrand factor


Anna Aksenova, a senior research associate at the Laboratory of Amyloid Biology at St Petersburg University, has advanced a hypothesis that the severe course of COVID-19 may be associated with the von Willebrand factor, one of the main components of the blood coagulation system.

As the researcher suggests, the replication of the virus stimulates the development of microdamage on vessel walls. In its response to this, the body releases von Willebrand factor into the blood, trying to ‘patch’ possible holes. As a result, the risk of thromboses increases.

It is with this clotting that a significant part of the deaths from COVID-19 are associated.

Nowadays, doctors throughout the world report that the novel coronavirus infection COVID-19 occurs in different people in completely different ways.

Combinations of symptoms that are dissimilar, ranging from coughing to digestive disorders, make diagnosis difficult. Additionally, scientists and doctors still do not understand why people of the same age and with comparable health indicators can transmit the infection so differently from each other: some require ventilator support to stay alive, while others do not feel sick at all.

One of the possible causes of this phenomenon may be a different level of von Willebrand factor (VWF) in the blood of patients.

“This protein is synthesized in endothelial cells and platelets, and its main function is to form a framework for platelet adhesion,” explains Anna Aksenova.

“To date, the way in which the level of VWF is regulated in the blood has not yet been fully studied. However, it is known to be stored in vascular endothelial cells in special organelles, where it secretes in the form of multimers.

As soon as some damage to the vessel occurs, then in order to eliminate it, a cascade of blood coagulability is launched in the body, in which VWF takes an active part.”

The level and activity of VWF in the blood in people can be different. The lowest values are associated with von Willebrand disease.

It is a hereditary blood disease that is characterized by spontaneous bleeding. Additionally, it differs markedly among healthy people.

For example, it is higher among: African Americans than among Europeans; in men than in women; in adults than in children; and in the elderly than in middle-aged people.

Also, academic papers have described the VWF and blood group relationship – its level is lower among people with blood group 0, and is higher among those with blood group A.

The different amount and activity of VWF in people with different blood groups has a very interesting explanation: this protein is modified by oligosaccharide chains of antigenic determinants of the AB0 system (one of the blood group systems), and this affects its stability and activity.

Earlier, it was believed that the new type of coronavirus SARS-CoV-2 affects mainly the lungs by binding with ACE2 receptors on the surface of alveolocytes (cells lining the lungs).

Today, there is more and more information that something similar happens with endothelial cells – the internal surface of blood vessels. Anna Aksenova explains that since the ACE2 receptor belongs to the renin-angiotensin system (it regulates blood pressure), the virus cannot but affect the blood vessels.

Apparently, it is capable of causing local inflammation of the walls of blood vessels and capillaries. This results in an increased release of VWF into the blood, which, in turn, provokes clotting.

“Acute respiratory distress syndrome, which often develops in patients with COVID-19, can also be associated with VWF,” said Aksenova. “There are studies that use the example of model animals and people and suggest: the higher VWF, the higher the probability of respiratory distress.

Why does this happen? Because capillaries run through the lungs, and if any thrombotic events occur there, this adversely affects the tissue functions. Excessive production of VWF can lead to the development of thrombosis, including in the capillaries of the lungs.”

Additionally, as Anna Aksenova notes, this hypothesis explains why the drug chloroquine, which is usually used to treat malaria, in preliminary trials has shown efficacy in COVID-19 treatment as well.

The fact is that chloroquine affects the process of autophagy in cells. This process regulates the secretion of certain factors into the extracellular environment, including the secretion of VWF.

“I hypothesize that the level and activity of VWF might be important predictors for COVID-19 morbidity and mortality. It might also itself be involved in the disease process,” said Anna Aksenova.

“In order to confirm this hypothesis, it is necessary to carry out large-scale and comprehensive research into the level and activity of VWF in people infected with SARS-CoV-2, who have a mild or severe course of infection.”

In different countries throughout the world, academic papers currently continue to come out in favor of this hypothesis. For example, there have recently been reports that VWF is significantly increased in patients with severe COVID-19 who receive mechanical ventilation or who have thromboembolic complications.

Moreover, rigorous research using GWAS (genome-wide association study) has confirmed the association of COVID-19 complications with a locus that determines AB0 blood groups.

Also, the ways to reduce the amount of VWF in the blood plasma for the treatment of COVID-19 complications has begun to be discussed in scientific literature.

The attention of researchers from all over the world is now starting to focus on VWF, its role in COVID-19, and new treatment regimens that will take into account the individual characteristics of the human body associated with von Willebrand factor.

COVID-19 coagulopathy and thromboembolic complications
Severe COVID-19 causes a specific coagulopathy that is reminiscent of, but also distinct from, other systemic coagulopathies associated with severe infections, such as disseminated intravascular coagulation or thrombotic microangiopathy.7a

Pro-inflammatory cytokines, in particular interleukin-6, stimulate mononuclear cells to express tissue factor, leading to thrombin generation, thereby initiating a systemic coagulopathy.

Superimposed on this low-grade coagulation activation, direct infection of endothelial cells causes release of plasminogen activator (explaining the very high D-dimer levels in severe COVID-19) and large von Willebrand factor multimers.8a

The massive release of these multimers overwhelms the cleaving capacity of its physiological regulator ADAMTS13 (a disintegrin and metalloprotease) resulting in high levels of uncleaved von Willebrand factor mediating the consequent deposit of microvascular platelet thrombi, especially in affected pulmonary vessels.9a

• Direct viral infection of endothelial cells, which express ACE2 enabling entry of the virus, can result in widespread endothelial dysfunction associated with recruitment of a vascular inflammatory response, which is more exaggerated in patients with pre-existent vascular disease.8a

The simultaneous presence of vascular inflammation and coagulopathy might explain the high incidence of thromboembolic complications in patients with COVID-19.

Indeed, markers of coagulopathy, such as D-dimer, have been closely associated with thrombotic complications and increased mortality.10a

These systemic inflammatory responses manifest as a varied and wide-ranging clinical syndrome. Lung, heart, brain and kidneys are the organs with major clinicopathological manifestations requiring ICU management in order to support life.


Von Willebrand factor is a glycoprotein that plays a part in hemostasis. It is synthesized in endothelial cells and megakaryocytes.

After transcription and translation, pro-vWF is covalently linked to form dimers in the endoplasmic reticulum, and subsequently, large dimers form in the Golgi complex and secretory granules.

The pro-von Willebrand factor propeptide then undergoes cleavage and then both the propeptide and mature von Willebrand factor are secreted into the vessel lumen. It functions as a carrier for factor VIII to maintain its levels, as well as help in platelet adhesion and binding to endothelial components after a vascular injury.

Any qualitative or quantitative deficiency of pro-von Willebrand factor will lead to an increased bleeding tendency, and this syndrome is called Von Willebrand disease.[1][2][3]


Von Willebrand disease (VWD) can be inherited or acquired.[4][5]

Inherited phenotypic forms of Von Willebrand disease are:

  • Type 1: This is an autosomal dominant disease (AD, incomplete penetrance approximately 60%) and is caused by a partial quantitative deficiency of von Willebrand factor.
  • Type 2: This is an autosomal dominant disease and is caused by several qualitative defects in von Willebrand factor. It has four subtypes (2A-AD or AR, 2B-AD, 2N-AR, 2M-AD). 2A is the most common variant.
  • Type 3: This is an autosomal recessive disease (AR) and is caused by a complete quantitative defect. The von Willebrand factor levels are not detectable, and the severe bleeding disorder characterizes this variant.

The VWF gene is highly polymorphic, and this polymorphism leads to a big variation in the normal spectrum of von Willebrand levels function. Subsequently, there is a spectrum of presentations and disease severity.

Acquired von Willebrand disease occurs when secondary (acquired) processes lead to a functional impairment of von Willebrand factor, either by decreasing its available quantity or by interfering with the physiological hemostasis pathway.

The most commonly associated conditions are lung cancer, Wilm’s tumor, gastric cancer, MGUS, multiple myeloma, chronic lymphocytic leukemia, hairy cell leukemia, myeloproliferative neoplasms (MPN), plasma cell dyscrasias, lymphomas, systemic lupus erythematosus (SLE), Felty syndrome, autoimmune hemolytic anemia, or other autoimmune disorders, metabolic disorders (hypothyroidism), drug side effects, and states of high-vascular flow such as AS, VSD, VAD (ventricular assist devices), extracorporeal membrane oxygenation (ECMO), or metallic cardiac valves. The von Willebrand factor is a large multimeric glycoprotein, and it is susceptible to the shear stress associated with high flow states.

The autoimmune spectrum can be quite varied as von Willebrand factor occurs as a multimer, and this heterogeneity means that certain multimer sizes may escape the immune-mediated antibody response.

The mechanism in malignancy includes the formation of non-specific antibodies that bind the von Willebrand factor forming an immune complex and hence increase clearance by the reticular endothelial system.

The other mechanism is the absorption of the von Willebrand factor on the surface of malignant cells such as the case in multiple myeloma or solid tumors or proteolysis of von Willebrand factor multimers as is usually seen in MPN.


Von Willebrand disease is estimated to affect approximately 1% of the unselected population, but clinically significant disease prevalence is estimated to be about 125 per million, with severe disease affecting up to five per million.

There is an equal distribution between males and females. Acquired von Willebrand disease prevalence is unknown but may represent 1% to 5% of all von Willebrand disease.

Its prevalence is higher in certain groups. For example, it has been reported in up to 20% of malignancies, and up to 100% of certain high flow states such as extracorporeal membrane oxygenation (ECMO) and metallic cardiac valves.[6]


Von Willebrand factor is a multimer formed from a basic dimer subunit. It is produced in megakaryocytes and endothelial cells. The physiological hemostatic effect is determined by the size of the multimer. Bigger multimers are more active and even prothrombic. They are cleaved by circulating proteases into smaller units. These larger multimers are stored in cytoplasmic granules, and released in response to a trigger such as thrombin, fibrin, and histamine.

Larger multimers have more available sites for binding to platelets and endothelium. Von Willebrand factor increases factor VIII half-life by preventing its degradation. With regards to the subtypes, type I is characterized by a mild decrease in von Willebrand factor antigen (Ag), von Willebrand factor activity, and VIII:C. 

Of note, von Willebrand factor levels of less than 30% are required for a diagnosis of Von Willebrand disease. Conversely, type III  is characterized by a significant decrease in the parameters above.

Type II disease is characterized by a qualitative decrease with specific variations: 

Type 2A: variable decrease in von Willebrand factor Ag and VIII:C with a significant decrease in von Willebrand factor activity and absence of large and intermediate size multimers. 

Type 2B: variable decrease in von Willebrand factor Ag and VIII:C and a significant decrease in von Willebrand factor activity and absence of large multimers. However, most importantly this type is hypersensitive to ristocetin-induced platelet aggregation (RIPA).

Type M: vWF activity is decreased relative to Ag and multimers are present. 

Type N: this is characterized variably by a decrease in vWF Ag and activity but is distinguished from the other types by the significant decrease in VIII:C, albeit usually more than 5%. This specific subtype can be confused with hemophilia A.

History and Physical

Low von Willebrand factor is quite common in the general population, but not all patients have clinically significant bleeding issues. Therefore, a significant proportion of the patient population goes undiagnosed. Most cases are diagnosed formally after investigating for significant bleeding problems such and recurrent and excessive bruising, prolonged bleeding from minor skin trauma, and prolonged bleeding from mucosal surfaces (epistaxis, dental extractions, menstruation).

Physical examination can be often normal. Sometimes evidence of bleeding/bruising (petechiae, hematomas) may be noted.

In the case of a qualitative defect, von Willebrand disease may mimic hemophilia and presents predominantly with bleeding into soft tissues, joints, and hematuria rather than mucocutaneous bleeding. Sometimes, type 2N von Willebrand disease is misdiagnosed as hemophilia.


Patients with a clinical history consistent with von Willebrand disease are investigated further with the following labs:

  • Complete blood count (CBC): Platelet levels tend to be normal
  • Coagulation profile: aPTT may be prolonged due as there would be increased factor VIII degradation in von Willebrand disease. PT should be normal
  • Von Willebrand factor antigen: von Willebrand factor protein levels are measured. This is a test for a quantitative defect
  • Von Willebrand factor activity: This is a qualitative analysis for von Willebrand factor physiological function. This is tested through Ristocetin cofactor activity (vWF:RCo) and collagen binding activity (vWF:CB). Normal Ristocetin cofactor activity levels are above 50 IU/dL. Levels below 30 are diagnostic for von Willebrand disease
  • Factor VIII Activity: Decreased von Willebrand factor leads to increased degradation of factor VIII
  • Von Willebrand factor activity/antigen ratio: This helps identify cases with a significant qualitative deficit. A low ratio should raise suspicion for type 2 von Willebrand disease, however, absolute normal values have yet to be determined.

Patients with von Willebrand disease activity/antigen levels between 30 and 50 should be designated as “low-von Willebrand factor” and be considered for treatment in high bleeding risk scenarios.

Treatment / Management

Stable patients with type 1, some type 2 (except type 2B) and acquired von Willebrand disease patients are given a trial of Desmopressin (DDAVP), this is a synthetic analog of vasopressin to check for a response. This is usually performed when patients are not actively bleeding.[7][8][9]

Type 1 usually shows a good response to DDAVP trial. Type 2A shows a variable and transient response which is often clinically adequate. Type 2M and Type 2N usually show a poor or minimal response. Type 3 von Willebrand disease does not respond to Desmopressin as there is a complete lack of von Willebrand factor. A successful trial sees von Willebrand factor activity levels of at least 30 IU/dL (ideally 50 IU/dL).

Desmopressin causes von Willebrand factor release from endothelial cells. DDVAP can be administered subcutaneously, intravenously and via intranasal spray. It leads to increased von Willebrand factor and factor VIII levels with response persisting for up to 12 hours. It is useful for minor bleeding episodes (including epistaxis and menses) and elective minimally invasive surgical procedures.

Von Willebrand factor replacement can be considered in patients with type 3 von Willebrand disease, or severe variants of type 1 and two that do not demonstrate a sufficient DDAVP response in serious bleeding scenarios.

There are many different preparations available, including factor VIII concentrates that also include von Willebrand factor. Von Willebrand factor replacement therapy often is used in serious bleeding scenarios such as trauma or major surgery. Usually, it is administered as a short course.

Examples of intermediate-purity vWF concentrates include Wilate, alphanate, and Humate-P which contain both vWF and FVIII. Patients with von Willebrand disease type III need the products mentioned above for episodes of bleeding or surgery, conversely, for mild type I and type II A disease (or minor procedures in this category) DDAVP might suffice, however, other scenarios might require von Willebrand and FVIII factors mentioned previously.

Tranexamic acid can also be used as an anti-fibrinolytic agent. It prevents the break down of fibrin clots. It is useful in case of mucosal bleeding.[10]

Differential Diagnosis

  • Factor X deficiency
  • Factor XI deficiency
  • Hemophilia A
  • Hemophilia B
  • Bernard-Soulier syndrome
  • Platelet function defects
  • Antiplatelet drug ingestion
  • Fibrinolytic defects  


For the majority of patients, vWD is a mild, manageable bleeding disorder. Clinically severe hemorrhage is usually only seen with trauma or invasive procedures.

Pearls and Other Issues

Von Willebrand disease in females is often a more clinically severe disease due to menorrhagia.

Von Willebrand factor levels vary with physiological stress. Some patients may occasionally be noted to have normal von Willebrand factor levels. A clinically suspect patient should be retested in a few weeks if initial von Willebrand factor levels are normal.

Von Willebrand factor levels are adjusted according to ABO blood grouping.

Sodium levels should be measured in patients taking DDAVP as multiple doses along with free fluid intake can cause severe Hyponatremia. Similarly, NSAIDs should be used with caution as they can worsen hyponatremia.

Prolonged DDAVP use can lead to tachyphylaxis.

DDAVP and anti-fibrinolytic agents carry a thrombosis risk. Von Willebrand factor replacement therapy is preferable in patients with cardiovascular or cerebrovascular disease.

Tranexamic acid is not recommended in gross haematuria. Clots can form and cause ureteric or urethral obstruction.

Though generally avoided due to viral transmission risk, cryoprecipitate and fresh frozen plasma (FFP) can be used in life-threatening scenarios.

DDAVP dosing is 0.3 micrograms/Kg administered over 20 to 30 minutes.


7a.Levi M., Thachil J., Iba T., Levy J. Coagulation abnormalities and thrombosis in patients with COVID-19 infection. Lancet Haematology. 2020 in press/online. [update] [Google Scholar]

8a.Varga Z., Flammer A.J., Steiger P. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020 (17 April, online) [Google Scholar]

9a. Levi M., Scully M., Singer M. The role of ADAMTS-13 in the coagulopathy of sepsis. J Thromb Haemost. 2018;16(4):646–651. [PubMed] [Google Scholar]

10a. Tang N., Li D., Wang X., Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844–847. [PMC free article] [PubMed] [Google Scholar]

1.Yaghmour KM, Peng Y, Chisari E, Khan W, McDonnell SM. Management of von Willebrand disease in patients undergoing total hip and knee arthroplasty. J Perioper Pract. 2019 Sep;29(9):266-269. [PubMed]

2.Katneni UK, Ibla JC, Hunt R, Schiller T, Kimchi-Sarfaty C. von Willebrand factor/ADAMTS-13 interactions at birth: implications for thrombosis in the neonatal period. J. Thromb. Haemost. 2019 Mar;17(3):429-440. [PubMed]

3.Bury L, Malara A, Momi S, Petito E, Balduini A, Gresele P. Mechanisms of thrombocytopenia in platelet-type von Willebrand disease. Haematologica. 2019 Jul;104(7):1473-1481. [PMC free article] [PubMed]

4.Mezzano D, Quiroga T. Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research. J. Thromb. Haemost. 2019 Feb;17(2):257-270. [PubMed]

5.Petricevic M, Knezevic J, Samoukovic G, Bradaric B, Safradin I, Mestrovic M, Papestiev V, Hodalin A, Madzar T, Mihalj M, Rotim A, Biocina B. Diagnosis and Management of Acquired von Willebrand Disease in Heart Disease: A Review of the Literature. Thorac Cardiovasc Surg. 2020 Apr;68(3):200-211. [PubMed]

6.De Larochellière H, Puri R, Eikelboom JW, Rodés-Cabau J. Blood Disorders in Patients Undergoing Transcatheter Aortic Valve Replacement: A Review. JACC Cardiovasc Interv. 2019 Jan 14;12(1):1-11. [PubMed]

7.Lavin M, O’Donnell JS. How I treat low von Willebrand factor levels. Blood. 2019 Feb 21;133(8):795-804. [PubMed]

8.Kreuziger LB, Massicotte MP. Adult and pediatric mechanical circulation: a guide for the hematologist. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):507-515. [PMC free article] [PubMed]

9.Charlebois J, Rivard GÉ, St-Louis J. Management of acquired von Willebrand syndrome. Transfus. Apher. Sci. 2018 Dec;57(6):721-723. [PubMed]

10.Chapin J. Von Willebrand disease in the elderly: clinical perspectives. Clin Interv Aging. 2018;13:1531-1541. [PMC free article] [PubMed]

More information: Anna Yi. Aksenova, von Willebrand factor and endothelial damage: a possible association with COVID-19, Ecological Genetics (2020). DOI: 10.17816/ecogen33973


Please enter your comment!
Please enter your name here

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.