The two main functions of VWF in hemostasis include platelet adhesion and Factor VIII stabilization. Exposed VWF bound to collagen from vascular injury and endothelial damage adheres to the GPIb receptor on platelets to initiate signaling pathways for platelet activation, the next step in primary hemostasis. VWF acts as a major carrier protein for Factor VIII, and both circulate as a noncovalent complex in blood plasma to aid in coagulation down the intrinsic pathway.[6][7][8]

VWF released by Weibel-Palade bodies or alpha-granules can enter circulation or accumulate in the subendothelial matrix binding to collagen through its A3 domain. Once exposed under high shear stress conditions in the arterial circulation, VWF can bind to platelets via its A1 domain. The conformation of VWF may have further implications. Under high shear forces, VWF multimers unfold to change from a globular to an extended conformation, which aids in self-aggregation and additional platelet adhesion.[3][9]

VWF binds to Factor VIII with high affinity via its D’D3 domains. Factor VIII’s half-life becomes significantly increased upon interactions with VWF. The mechanisms behind this include Factor VIII structure stabilization, protection against protease cleavage, and modulation of cellular interactions and removal from circulation.[7]

Insufficient or dysfunctional VWF could lead to various bleeding disorders, as will be described in detail below. Testing should include the following to assess for quantitative or qualitative platelet or coagulation disorders:[10] 

• Platelet counts and bleeding time
• Activated partial thromboplastin time (aPTT)
• Prothrombin time and International Normalized Ratio (PT/INR)
• Thrombin time (TT)
• Specific factor assays such as VWF and Factor VIII
• ADAMST13 activity assay could help in case of hereditary TTP[11]

Genotyping of vWF is useful in determining the types that need desmopressin (vasopressin analog) treatment, which mainly includes Type 1.[2]

Due to the complex biosynthesis of VWF, genetic mutations account for most of the bleeding disorders. The most common inherited bleeding disorder is Von Willebrand’s disease, of which there are three types. It is inherited in an autosomal pattern with high heterogeneity in pathophysiology and clinical presentation.

• Type 1 disease is the most common, representing about 80% of cases, and is due to a quantitative deficiency of normal functioning VWF. Due to a reduction in protein synthesis, the type 1 phenotype primarily results from missense mutations and, to a lesser extent, null alleles.
• Type 2 disease is inherited mostly in an autosomal dominant pattern and results in a dysfunctional VWF, also largely due to missense mutations.
• Type 3 disease is rare and results in the complete absence of VWF; however, those with heterozygous carriers may have mild disease.
• There are other genetic determinants of VWF levels that include ABO blood groups with type O demonstrating reduced levels. Physiological factors such as age or the menstrual cycle, and pregnancy in women can also affect VWF levels.[3][12][13]

According to vWF genotyping, the types are[2]:

• Type 1: partial decrease in the quantity of vWF, either low or severe.
• Type 2A, 2B, and 2M: decrease in GP1b either due to decreased quantity of vWF or mutation, leading to an increase in spontaneous binding.
• Type 2M: decrease in the factor VIII binding.

Thrombotic thrombocytopenic purpura (TTP) is due to an inherited or acquired deficiency of ADAMST13. With deficient ADAMST13, there will be deficient or loss of proteolysis, thus the ultra-large VWF multimers build up in the vasculature to induce platelet aggregation and cause thrombosis. The blood film will show diagnostic schistocytes along with the decreased platelet count. Acquired TTP occurs due to HIV, malignancy, or as a part of the hemolytic uremic syndrome.[14]

Bernard-Soulier syndrome is a rare autosomal recessive inherited bleeding disorder resulting from a deficient or dysfunctional GpIb-IX-V complex on platelets. Therefore, VWF cannot bind to the GpIb receptors on platelets via the A1 domain to induce platelet aggregation and further hemostasis. This condition can lead to bleeding as well as macrothrombocytopenia (abnormally large platelets), but platelet count could be normal.[15]

In patients presenting with a personal or family history of bleeding or bruising, one can try to differentiate between quantitative or qualitative disorders and primary or secondary hemostasis.

Von Willebrand’s disease is the commonest inherited bleeding disorder; usually presents mildly with mucosal bleeding or excess blood loss following trauma or surgery. Females can present with menorrhagia. There are disturbances in primary and secondary hemostasis due to platelet defects not allowing adhesion to the site of endothelial injury and coagulation defects with lack of protection of Factor VIII, respectively. The following tests are diagnostic of the type of disease the patient is suffering from (quantitative versus qualitative).[12]

• Decreased VWF and Factor VIII levels
• Increased bleeding time but with normal platelet counts
• Normal or increased PTT due to decreased Factor VIII
• Normal PT

Thrombotic thrombocytopenic purpura is rare and can present with the classic pentad of clinical signs and symptoms:[14]

• Microangiopathic hemolytic anemia
• Thrombocytopenia
• Neurological problems
• Kidney problems
• Fever

Bernard-Soulier syndrome is rare and usually presents with easy bruising, excessive bleeding, petechiae, epistaxis, and heavy menstrual flow. The following tests may be representative of Bernard-Soulier syndrome:[15]

• Increased bleeding time with normal or decreased platelet counts due to the large platelet size
• Normal PT and PTT
• No platelet aggregation in ristocetin assay (an antibiotic that will aggregate normal platelets)