Coagulation testing has evolved during the COVID 19 pandemic. First it was increased routine PT and aPTT testing, fibrinogen and D-dimer. We then moved to Heparin levels, HIT testing, and into Antithrombin, and markers of inflammation including von Willebrand factor (vWF). Endothelial derived vWF may play an important role in COVID-19 associated coagulopathy.
Von Willebrand factor is a multimeric protein that can be released from endothelium and platelets upon activation. Its main function is to support platelet adhesion to injured subendothelium to form a hemostatic plug.1 The two functions of vWF include carrying factor VIII and to facilitate binding of platelets to arteries and veins. Low levels are associated with bleeding and high levels may be associated with blood clots.2 There are three types of vWD associated with bleeding. Type 1 in which patients present with both a decreased antigen and ristocetin cofactor, type 2, vWF:Ag that is largely normal or mildly decreased, with vWF:RCo of less than 30-40% and type 2 with severe deficiency or absence of antigen and activity.1
Reference ranges are based on ages and blood type O versus non-blood type O, since vWF is cleared faster in subjects with blood type O. Additionally, levels of VWF are 20% higher in African Americans when compared to the white population, and levels also increase with age.1
- Newborn < 6 mo: 60-190% (blood type O); 75-230% (non-O blood type)
- Children 1-10 years: 50-150% (blood type O); 60-160% (non-O blood type)
- Adults: 60-160% (blood type O); 70-200% (non-O blood type)1
What happens in SARs-CoV-2
The SARs-CoV-2 virus can cause an inflammatory response is some people due to the virus attaching to the cells that line blood vessels resulting in endothelialitis. Blood type may play a role in the susceptibility and severity of symptoms with blood type O appearing to be more resistant while those with type A being more susceptable and experience more severe symptoms. It is well known that type O individuals have 25-35% lower levels of vWF with the highest levels found in patients with type AB.2 The blood group may play a role in its association with high levels of vWF, most important is the inflammatory response in the blood cells causing them to release proteins including vWF.
The viral pathophysiology of SARs-CoV-2 results in its binding to host cells which express angiotensin converting enzyme-2 receptor (ACE2) via the viral spike protein structure. The initial infection targets the cells of the respiratory system and progresses to a systemic inflammatory phase. Endothelial cells also express ACE2 receptors which are activated leading to endothelial dysfunction and coagulopathy and a prothrombotic tendency.3 The increased release of vWF may lead to an increased adhesiveness of platelets while decreasing ADAMTS-13 cleavage. This can lead to a severe and fatal blood clotting disorder known as thrombotic thrombocytopenic purpura (TTP). ADAMTS-13 role is to decreases the vWF molecules into smaller sizes resulting in them becoming less adhesive and less dangerous. Increased levels of vWF due to severe inflammation of blood vessels is further worsened by an ADAMTS-13 deficiency which in turn contributes to elevated vWF. Studies have shown that 5 out of 6 patients with low levels of ADAMTS-13 died.2
The primary cause of acute lung injury in COVID-19 is thought to be alveolar damage and pulmonary microvascular thrombi. Plasma vWF levels appear to be a significant independent predictor of death in COVID-19 patients.4 However, it is not clear if increased vWF factor levels are due to endothelial injury as a result of the virus attaching to or invading endothelial cells, or endothelial as part of the immune response or both.4
Levels of vW factor in COVID 19 patients
Studies have demonstrated that patients diagnosed with COVID-19 have high levels of vWF and factor VIII and contribute to increased venous thromboembolism. A report that included 24 ICU patients found that the median level of vWF;Ag was 350% this elevation was also confirmed by a meta-analysis of 17 publications. Deceased patients were found to have the highest concentration up to 449%.1 These levels contribute to an increased risk of thrombosis seen in COVID coagulopathy, with higher levels resulting in worse outcomes.3
In a study of 143 patients (34 classified as mild, 36 moderate, 36 severe and 37 were critical), 4 days post symptom onset it was observed that baseline markers increased as COVID severity increased. VWF levels independently correlated with both severity of disease and survival. In this cohort, 14 patients had normal VWF levels. In the 34 patients with mild disease, vWF levels were in the normal range in 13 patients, and it was noted that having levels above 332.6% was a significant predictor of mortality. Additionally older age, male, and the presence of any co-morbidity were also seen in increasing severity.4
Disorders such as HIT and lupus can trigger endothelial cell activation with increases in vWF. COVID-19 patients who presented with HIT were evaluated for levels of vWF. It was found that when compared to normal controls, these patients had markedly elevated VWF (range 2.1–10.1 U/ml; mean = 5.9 U/ml; normal range 0.5–1.5 U/ml) compared to healthy controls (range 0.9–1.5 U/ml; mean = 1.2 U/ml). Ristocetin activity, as a marker of VWF activity, was also significantly increased (range 2.2–8.52 U/ml; mean 4.6 U/ml; normal range 0.8–1.8 U/ml) compared to healthy controls (range 0.53–1.67 U/ml, mean = 1.18 U/ml.5
Further studies are needed to evaluate the exact role of VWF in pathogenesis and severity of COVID-19 infection. Current data suggests that plasma VWF levels are associated with poor prognosis. It is not known whether strategies to reduce plasma VWF levels will alter the natural course of disease. As time progresses and COVID evolves more information and outcomes will become available.
- Kostousov, V., von Willebrand Factor Antigen (Factor VIII:R Antigen) von Willebrand Factor Antigen (Factor VIII:R Antigen): Reference Range, Interpretation, Collection and Panels (medscape.com)
- Valentino, L., COVID-19 and VWF, July 2020 https://www.hemophilia.org/news/covid-19-and-vwf
- Zhen W Mei 1, Xander M R van Wijk 2, Huy P Pham 3, Maximo J Marin Role of von Willebrand Factor in COVID-19 Associated Coagulopathy, J Appl Lab Med, April 2021.
- Thomas VV1, Kumar SE2, Alexander V2, Nadaraj A3, Vijayalekshmi B4>, Prabhu S4, Kumar S5, Murugabharathy K1, Thomas SM1, Hansdak S1, Carey R1, Iyyadurai R1, Pichamuthu K6, Abhilash KPP7, Varghese GM8, Nair S5, Goel A2, Jeyaseelan L3, Zachariah U2, Zachariah A1, et al, Plasma Von Willebrand Factor Levels Predict Survival in COVID-19 Patients Across the Entire Spectrum of Disease Severity, Indian Journal of Hematology & Blood Transfusion : an Official Journal of Indian Society of Hematology and Blood Transfusion, 20 Jun 2021, :1-8
- Ishac Nazy, Stefan D. Jevtic, Jane C. Moore, Angela Huynh, James W. Smith, John G. Kelton, Donald M. Arnold, Platelet-activating immune complexes identified in critically ill COVID-19 patients suspected of heparin‐induced thrombocytopenia, J Thromb Haemost. 2021 Mar 14