Ristocetin Cofactor (Functional von Willebrand Factor) 

Updated: Feb 12, 2020
Author: Vadim Kostousov, MD; Chief Editor: Eric B Staros, MD 

Reference Range

Reference ranges for age groups are as follows[1, 2] :

  • Newborn (< 6 mo) - 50-200% (IU/dL)

  • Children (1-10 y) - 40-130% (blood type O); 50-180% (non-O blood type)

  • Adults - 50-150% (blood type O); 60-180% (non-O blood type)

 

Interpretation

von Willebrand factor deficiency (inherited)

See the list below:

  • Type 1 - Decreases are noted in both von Willebrand factor (vWF) antigen (vWF:Ag) and vWF ristocetin cofactor (vWF:RCo) levels (vWF:RCo to vWF:Ag ratio >0.7).

  • Type 2 - Decrease only noted in vWF:RCo levels. vWF:Ag levels are largely normal (vWF:RCo to vWF:Ag ratio < 0.7) in von Willebrand disease (vWD) types 2A and 2B but vWF:RCo may be normal or decreased in types 2N and 2M.

  • Type 3 - Severe deficiency or absence of both vWF:RCo and vWF:Ag (< 5%).

von Willebrand factor deficiency (acquired)

Autoimmune clearance or inhibition causes are as follows:

  • Lymphoproliferative diseases (lymphoma, leukemia)

  • Monoclonal gammopathies (multiple myeloma, Waldenstrom macroglobulinemia)

  • Systemic lupus erythematosus and other autoimmune disorders

  • Some cancers (Wilms tumor, Ewing sarcoma, carcinoma)

Causes of vWF deficiency due to increased shear-induced proteolysis are as follows:

  • Small-sized (pinhole) ventricular septal defect

  • Severe aortic stenosis

  • Primary pulmonary hypertension

  • Extracorporeal life support

Other causes include the following:

  • Hypothyroidism

  • Drug-induced (hydroxyethyl starch, valproic acid)

  • Myeloproliferative diseases (polycythemia, thrombocythemia)

  • Angiodysplasia, glycogen storage disease

Increased vWF:RCo activity and increased vWF:Ag are observed in acute phase reactions, which can be associated with the following:

  • Stress, extensive exercise

  • Inflammation

  • Cancer

  • Obesity

  • Postoperative period

  • Diabetes

  • Atherosclerosis and atherothrombosis

  • Pregnancy

 

Collection and Panels

Collection and panel details are as follows:

  • Specimen - Citrated plasma

  • Collection - Tube with sodium citrate 3.2% citrate, blue top

  • Centrifugation - 2000-2500 g for 15 minutes or similar regime to produce platelet-poor plasma

  • Storage - As long as 6 hours at 18-25ºC or plasma sample should be frozen; specimen stable for 1 month at -20ºC (Whole blood after collection should not be stored at refrigerator temperature [2-4ºC] due to cold-induced binding of vWF to platelets and selective loss of vWF:RCo activity in plasma.[3] )

 

Background

Description

von Willebrand factor (vWF) is multimeric glycoprotein (molecular weight varies from 1000-20,000 kDa) that is assembled from identical monomers in endothelial cells and megakaryocytes possibly released from endothelium and platelets upon their activation. The half-life of vWF is approximately 12 hours (range, 9-15 h) and its clearance is faster in persons with blood type 0.[4]

The main function of vWF is to support platelet adhesion to injured subendothelium in order to form hemostatic plug. Also vWF is a carrier protein for factor VIII and prevents its proteolysis degradation in plasma. vWF:RCo assay evaluates protein functional activity; platelet aggregation to vWF in the presence of ristocetin is proportional to hemostatically active fraction of vWF.[5, 3]

In order to overcome poor sensitivity of the standard assay at lower activity of vWF:RCo (less than 20-30%), a modified protocol of vWF:RCo assay was implemented and validated.[6, 7] Also, assays of vWF activity measurement were developed that utilize microparticles covered with recombinant platelet receptors to glycoprotein Ib, which bind to vWF (vWF:GPIb) in the presence or absence of ristocetin;[8] these could replace the standard vWF:RCo activity assay in the future.

Indications/Applications

vWF:RCo (in conjunction with vWF:Ag and factor VIII activity) is indicated for the following:

  • Diagnosis of vWD

  • Differentiation of vWD subtypes

  • Differentiation of vWD from hemophilia A

  • Monitoring therapy of vWD

For more information, see the Medscape Drugs & Diseases article von Willebrand Disease.

Considerations

Repeated vWF:RCo activity testing is sometimes needed to identify low levels of vWF compatible with vWD. A retrospective study showed that up to 30% of pediatric patients required a second test for vWD before the diagnosis was established.[9]  A vWF:RCo level of less than 30% is designated as the level for a definitive diagnosis of vWD, although some patients with type 1 or type 2 vWD have vWF:RCo levels of 30-50%.[4] Bucciarelli et al reported that adults with initial vWF:RCo levels of 30-40% were very likely to have vWD, which was confirmed in these patients by second‐level tests. In the same study, among individuals with vWF:RCo levels of 40-60%, vWD was diagnosed in 20-30%, with female gender and non-O blood type being independent predictors of vWD diagnosis.[10]

vWF ristocetin binding–site polymorphism, which is more frequently detected in African Americans, can cause artificially low vWF:RCo activity and lead to a misdiagnosis of vWD type 2;[6] other tests (vWF collagen-binding assay, vWF:GPIb without ristocetin, vWF multimer analysis) may be useful to confirm the diagnosis in these patients.

During the third trimester of pregnancy, the vWF:RCo level can reach normal ranges in the majority of patients with vWD type 1. However, vWF:RCo activity is usually low in pregnant women with vWD type 2 or 3.[11, 12]

 

Questions & Answers