Autoimmune Antibody and Coagulation Testing

Number: 0662

Table Of Contents

Policy

Scope of Policy

This Clinical Policy Bulletin addresses autoimmune antibody and coagulation testing.

1. Medical Necessity

   Aetna considers the following coagulation tests medically necessary when criteria are met:

   1. von Willebrand factor - collagen binding (VWF:CB/VWF:Ag) assay (e.g., Versiti VWF Collagen III Binding, Versiti VWF Collagen IV Binding) to diagnose type 2 von Willebrand disease (VWD) for members suspected of type 2A, 2B, or 2M in need of additional testing;
   2. von Willebrand factor - factor VIII (VWF:FVIII) binding assay (e.g., Versiti VWD Type 2N Binding) to diagnose type 2N VWD for members suspected of type 2N VWD in need of additional testing;
   3. von Willebrand factor - multimer analysis and ristocetin-induced platelet aggregation (RIPA) (e.g., Versiti VWD Type 2B Evaluation) to determine VWD type in members diagnosed with VWD.
      

2. Experimental, Investigational, or Unproven

   Aetna considers the following autoimmune antibody and coagulation tests experimental, investigational, or unproven because its clinical value has not been established (not an all-inclusive list):

   1. Antiprothrombin antibody testing
   2. Detection of elevated factor VIII and von Willebrand factor (VWF) levels for assessment of acute ischemic stroke risk 
   3. Versiti Heparin-Induced Thrombocytopenia-PEA
   4. von Willebrand factor propeptide antigen (VWFpp)/VWF:Ag assay (e.g., Versiti VWF Propeptide Antigen) for diagnosis of VWD type 1C.
      

3. Related Policies

   The CPBs below include other types of antibody testing:

   1. CPB 0038 - Allergy and Hypersensitivity
   2. CPB 0340 - Antibody Tests for Neurologic Diseases
   3. CPB 0348 - Recurrent Pregnancy Loss
   4. CPB 0542 - HIV Testing
   5. CPB 0561 - Celiac Disease Laboratory Testing.

   For genetic testing see CPB 0140 - Genetic Testing.

Background

Antiprothrombin Antibody Testing

Anti-phospholipid syndrome (APS) is an autoimmune condition characterized by moderate-to-high levels of circulating anti-phospholipid antibodies and the presence of venous and arterial thromboses, autoimmune thrombocytopenia, fetal loss, and other clinical features, including transient ischemic attacks, amaurosis fugax, Coombs-positive hemolytic anemia, and livedo reticularis.

Most patients with APS have lupus anti-coagulant and anti-cardiolipin antibodies.  However, some patients with APS have either lupus anti-coagulant or anti-cardiolipin antibodies, but not both.  Thus, tests for both antibodies should be performed to confirm the diagnosis of APS (ACOG, 1998).  Anti-cardiolipin antibodies are detected by conventional immunoassays.  There is no direct test for the lupus anti-coagulant (LA); detection is based upon its inhibitory actions on coagulation.

Other autoantibodies have been associated with APS, including those reactive with prothrombin.  However, current guidelines state that the clinical significance of anti-prothrombin antibodies has not been defined (British Committee for Standards in Haematology, 2000; ACOG, 1998).  The Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology reached the following conclusion: "Antiprothrombin antibodies generally exhibit poor specificity for venous thrombosis and recurrent fetal loss and may be found in patients with infection.  Their precise clinical significance is not yet clear.  One report has claimed an association with myocardial infarction, but more work is required to clarify the clinical importance of this observation."

In a review of the literature, Galli and Barbui (1999) stated that "[t]he question whether antiprothrombin antibodies increase the risk of thromboembolic events remains unanswered .…The retrospective nature of these studies [of antiprothrombin antibody and antiphospholipid syndrome] prevents from drawing definite conclusions.  Only 1 prospective study has been performed that confirmed the association between high titers of antiprothrombin antibodies and an increased risk of developing myocardial infarction, which is not one of the typical features of the antiphospholipid syndrome.  Therefore, more "cross-sectional" or prospective clinical studies are warranted to establish the clinical relevance of antiprothrombin antibodies."

Donohoe (2001) has concluded that "[l]ongitudinal studies are required to asses the predictive value of these antibodies.  Pending those results, testing for antiprothrombin antibodies should remain a research procedure, as the detecting of those antibodies adds little to the clinical diagnosis and management of individual patients."

Identification of APS means that many patients who were in the past diagnosed as suffering from a "vasculitis" and treated with anti-inflammatory regimes and high-dose corticosteroids, will, if found to be suffering from APS, respond better to anti-coagulation therapy (GP Notebook, 2001).  First-line treatment for APS is low-dose aspirin.  Patients with APS who have had a documented major thrombotic event require long-term treatment with warfarin or coumarin anti-coagulation.

Women with APS should be treated during pregnancy with thromboprophylactic doses of heparin and low-dose aspirin.  Close obstetric care is indicated in all cases because of an increased risk of pregnancy-induced hypertension, fetal growth restriction, and a non-reassuring fetal heart rate pattern (ACOG, 1998).

von Landenberg et al (2003) documented the association of IgG anti-prothrombin antibodies with pregnancy loss and in particular early pregnancy loss in a large group of young female patients with APS.  These researchers recommended routine testing for anti-prothrombin antibodies in young female patients with APS.  However, they also stated that there is a need for further prospective studies to confirm the association between anti-prothrombin antibodies and pregnancy loss.  Furthermore, Lopez et al (2004) reported weak predictive value and association with pregnancy morbidity of 4 anti-phospholipid antibodies (e.g., anti-prothrombin antibodies) in patients with systemic lupus erythematosus and patients with APS.

Guidelines on APS from the American College of Obstetricians and Gynecologists (ACOG, 2005) stated that testing for anti-prothrombin antibodies "cannot be recommended for clinical use at this time."

Tincani et al (2007) stated that prothrombin (PT) is a target for antibodies with LA activity, suggesting the possible application of anti-prothrombin antibody (aPT) assays in patients with APS.  Different methods – both homemade and commercial – for the detection of aPT are available, but they seem to produce conflicting results.  These researchers compared the performance of different assays on a set of well-characterized serum samples.  Sera were gathered from 4 FIRMA institutions, and distributed to 15 participating centers.  A total of 45 samples were from patients positive for LA and/or anti-cardiolipin antibodies (aCL) with or without APS, and 15 were from rheumatoid arthritis (RA) patients negative for anti-phospholipid antibodies.  The samples were evaluated for IgG and IgM antibodies using a homemade direct aPT assay (method 1), a homemade phosphatidylserine-dependent aPT assay (aPS/PT, method 2), and 2 different commercial kits (methods 3 and 4).  In addition, a commercial kit for the detection of IgG-A-M aPT (method 5) was used.  Inter-laboratory results for the 5 methods were not always comparable when different methods were used.  Good inter-assay concordance was found for IgG antibodies evaluated using methods 1, 3, and 4 (Cohen k greater than 0.4), while the IgM results were discordant between assays.  In patients with thrombosis and pregnancy losses, method 5 performed better than the others.  The authors concluded that while aPT and aPS/PT assays could be of interest from a clinical perspective, their routine performance can not yet be recommended because of problems connected with the reproducibility and interpretation of the results.

Oku et al (2008) stated that aCL, anti-beta2 glycoprotein I antibodies, and LA are the only laboratory tests considered within the revised criteria for the classification of the APS.  Recently, antibodies against aPS/PT have been detected, and these antibodies, rather than antibodies against PT alone, are closely associated with APS and LA.  The sensitivity and specificity of aPS/PT for the diagnosis of APS were assessed in a population of patients with a variety of autoimmune disorders; aCL and aPS/PT have similar diagnostic value for APS, therefore aPS/PT should be further explored, not only for research purposes but also as a candidate for one of the laboratory criteria for the classification of the APS.

Sater et al (2012) examined the association of antibodies to β2-glycoprotein I (anti-β2GPI), cardiolipin (ACA), phosphatidylserine (anti-PS) and prothrombin (anti-PT) with recurrent spontaneous miscarriage (RSM).  This was a case-control study involving 277 RSM cases and 288 controls.  Autoantibody levels were measured by ELISA.  Differences between cases and controls were analyzed by non-parametric Mann-Whitney test, and logistic regression was used in analyzing the association of autoantibodies with RSM.  Anti-PS IgG, ACA IgM and IgG, and anti-PT IgM were significantly associated with RSM risk, and differential antibody association was noted according to BMI and primary and secondary RSM.  Higher prevalence of elevated anti-PS IgG was seen in cases, with the strongest risk above the 99th percentile.  For ACA IgM, 28 cases (10.1 %) and 5 controls (1.7 %) were positive, with increasing OR for increasing cut-off points, which was significant at antibody titers greater than 99th percentile.  For ACA IgG, 101 cases (36.5 %) and 13 controls (4.5 %) were positive, with graded increase in OR for increasing cut-off points, which was significant at titers greate than 90th percentile (maximal at titers greater than 99th percentile).  For anti-PT, 23 cases (12.0 %) and 9 controls (6.1 %) were positive, with increased OR at titers greater than 90th percentile.  Regression analyses confirmed the independent association of anti-PS IgG, ACA IgM and IgG with RSM, and significant RSM risk was associated with high anti-PS IgG (p < 0.001) and ACA IgM (p < 0.001) titers, and a dose-dependent increase in RSM risk was seen with progressively increased ACA IgG titers.  No significant association existed between anti-PT IgM and RSM.

Zigon et al (2013) stated that anti-prothrombin antibodies, measured with phosphatidylserine/prothrombin complex (aPS/PT) ELISA, have been reported to be associated with APS.  They are currently being evaluated as a potential classification criterion for this autoimmune disease, characterized by thromboses and obstetric complications.  Given the present lack of clinically useful tests for the accurate diagnosis of APS, these researchers evaluated in-house and commercial assays for determination of aPS/PT as a potential serological marker for APS.  They screened 156 patients with systemic autoimmune diseases for antibodies against PS/PT, β₂-glycoprotein I, cardiolipin and for lupus anticoagulant activity.  These investigators demonstrated a high degree of concordance between the concentrations of aPS/PT measured with the in-house and commercial assays.  Both assays performed comparably relating to the clinical manifestations of APS, such as arterial and venous thromboses and obstetric complications.  IgG aPS/PT represented the strongest independent risk factor for the presence of obstetric complications, among all tested aPL.  Both IgG and IgM aPS/PT were associated with venous thrombosis, but not with arterial thrombosis.  Most importantly, the association between the presence of IgG/IgM aPS/PT and lupus anticoagulant activity was highly significant.  The authors concluded that aPS/PT antibodies detected with the in-house or commercial ELISA represent a promising serological marker for APS and its subsets.

Furthermore, an UpToDate review on "Pathogenesis of the antiphospholipid syndrome" (Bermas and Schnur, 2014) states that "Future studies and further refinement of APS assays are likely to clarify the role of antibodies to prothrombin, annexin V, phosphatidylserine, and other aPL targets".

An UpToDate review on "Diagnosis of the antiphospholipid syndrome" (Erkan and Schur, 2015) lists antiprothrombin antibodies and antibodies to the phosphatidylserine-prothrombin complex as one of the non-criteria laboratory findings that may be associated with APS.

Amengual and colleagues (2017) noted that a task force of scientists at the International Congress on Antiphospholipid Antibodies recognized that phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT) might contribute to a better identification of APS.  Accordingly, initial and replication retrospective, cross-sectional multi-center studies were conducted to ascertain the value of aPS/PT for APS diagnosis.  In the initial study (8 centers, 7 countries), clinical/laboratory data were retrospectively collected.  Serum/plasma samples were tested for IgG aPS/PT at Inova Diagnostics (Inova) using 2 ELISA kits.  A replication study (5 centers, 5 countries) was performed afterwards.  In the initial study (n = 247), a moderate agreement between the IgG aPS/PT Inova and MBL ELISA kits was observed (k = 0.598).  IgG aPS/PT were more prevalent in APS patients (51 %) than in those without (9 %), OR 10.8, 95 % CI: 4.0 to 29.3, p < 0.0001.  Sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratio of IgG aPS/PT for APS diagnosis were 51 %, 91 %, 5.9 and 0.5, respectively.  In the replication study (n = 214), a moderate/substantial agreement between the IgG aPS/PT results obtained with both ELISA kits was observed (k = 0.630).  IgG aPS/PT were more prevalent in APS patients (47 %) than in those without (12 %), OR 6.4, 95 % CI: 2.6 to 16, p < 0.0001.  Sensitivity, specificity, LR + and LR- for APS diagnosis were 47 %, 88 %, 3.9 and 0.6, respectively.  The authors concluded that IgG aPS/PT detection is an easily performed laboratory parameter that might contribute to a better and more complete identification of patients with APS.

Nagi et al (2022) noted that auto-antibody testing has contributed to both biological and clinical insights in managing patients with liver disease.  These auto-antibodies often have clinical value for the diagnosis, disease activity and/or prognosis.  In a cross-sectional study, these investigators examined the potential use of auto-antibodies in different etiologies of non-autoimmune liver diseases.  This study was carried out on 53 infants and children with chronic liver diseases.  The patients were subjected to clinical history and examination, laboratory investigations and abdominal ultrasound (US).  Serum of all infants and children was tested for measurement of anti-prothrombin antibody and anti-b2-glycoprotein I (ab2GPI) and anti-cardiolipin (ACL) auto-antibodies using a fully-automated enzyme linked immunosorbent assay (ELISA) system.  The mean age of the infants with cholestatic liver diseases was significantly lower than those with metabolic liver diseases, hepatitis C virus (HCV) and vascular liver diseases (p < 0.05).  The gender distribution was proportionate in all groups (p = 0.703).  Auto-antibodies showed significant variations among different etiologies of chronic liver diseases.  The incidence of ab2GPI and ACL was significantly increased in both HCV (94.7 % and 78.9 %, respectively) and vascular liver diseases patients (90.9 % and 72.7 %, respectively) (p < 0.05).  Anti-prothrombin antibodies were found in 81.8 % of vascular liver disease patients.  Interestingly, all types of auto-antibodies were deficient in cholestatic and metabolic liver diseases.  The authors concluded that testing for liver-related auto-antibodies should be included in the work-up of patients with chronic liver diseases.  Moreover, these researchers stated that further studies are needed to explain the cause-effect association of ACL, ab2GPI and anti-prothrombin with chronic HCV and vascular liver diseases.

The authors stated that this study had several drawbacks.  First, this was a cross-sectional study; thus, it could not explain the cause-effect association of ACL, aβ2GPI and anti-prothrombin with liver diseases.  Second, multiple measurements of the antibodies were lacking.  Third, titers of the antibodies were not quantitatively measured.  Fourth, IgM and IgG types were not clarified.

Factor VIII and von Willebrand Factor Levels in Acute Ischemic Stroke

Samai et al (2014) stated that despite clear roles of factor VIII (FVIII) and von Willebrand factor (vWF) in thrombosis, few studies have examined the relationship of these factors with acute ischemic stroke (AIS).  These investigators examined if concurrent elevation in FVIII and vWF was associated with adverse events and outcomes.  From the authors’ prospective stroke registry, patients consecutively admitted with AIS between July 2008 and October 2013 were included if both FVIII and vWF were measured during admission.  The primary outcome was the modified Rankin Scale score on discharge.  Among 1,453 cases in the authors’ stroke registry, 148 patients with AIS met inclusion criteria; 62 patients (41.9 %) had FVIII-/vWF-, 16 patients (10.8 %) had FVIII+/vWF-, and 51 patients (34.5 %) had FVIII+/vWF+.  In the fully adjusted model, patients with FVIII+/vWF+ had increased odds of inpatient complications (odds ratio [OR], 8.6; 95 % CI: 1.58 to 46.85; p = 0.013) and neuro-worsening (OR, 3.2; 95 % CI: 1.18 to 8.73; p = 0.022) than patients with FVIII-/vWF-.  Adjusted for age, baseline stroke severity, and glucose, patients with FVIII+/vWF+ had increased odds of poor functional outcome (modified Rankin Scale greater than 2; OR, 2.87; 95 % CI: 1.16 to 7.06; p = 0.021) than patients with FVIII-/vWF-.  The authors concluded that concurrent FVIII/vWF elevation predicted higher odds of inpatient complications, neuro-worsening, and worse functional outcomes for patients with AIS compared with patients with normal levels.  They stated that these findings suggested that FVIII and vWF levels may serve as clinically useful stroke biomarkers by providing risk profiles for patients with AIS.

Furthermore, an UpToDate review on "Overview of ischemic stroke prognosis in adults" (Edwardson, 2023) does not mention the use of factor VIII or von Willebrand factor as biomarkers for stroke.

Measurement / Monitoring of Factor VIII and Factor IX Replacement

Van den Bossche and colleagues (2018) noted that several recombinant factor VIII and factor IX concentrates with extended half-life (EHL) have recently been validated by clinical studies.  The availability of these novel concentrates is expected to significantly facilitate the treatment of patients with hemophilia A and B.  However, the modification applied to these molecules has introduced variations in their activity measurement in routine coagulation assays.  Depending on the assays, under-estimations of up to 10-fold or over-estimations of up to approximately 30-fold in the measurements of the recovery have been reported in some factor concentrates.  Such biases in monitoring may lead to major under- or over-treatment, as well as unnecessary searching for inhibitor antibodies.  These investigators discussed the guidelines and recommendations that allowed the selection of optimal strategies to monitor patients treated with these novel factor concentrates.  Based on the specificities of the assays and on local regulations, different chromogenic substrate assays in addition to 1-stage clotting assays may be validated to allow the accurate measurement of all novel products.  An efficient communication between the clinical laboratory and the clinicians is essential to ensure that the appropriate assays are performed in laboratories and that the clinicians correctly evaluate the data.  The authors concluded that further laboratory and clinical studies are needed for the optimization of the laboratory assays that can be used in the measurement of novel factor VIII and factor IX concentrates with EHL.

Platelet-Binding Activity of Von Willebrand Factor (VWF)

The von Willebrand Factor ristocetin cofactor activity assay (VWF:RCo) has been a mainstay in the assessment of VWF binding to platelets. Ristocetin, an antibiotic, is used to cause a conformational change and ensuing VWF A1 domain exposure to allow platelet GPIbα binding. Notably, the high coefficient of variation and poor sensitivity of VWF:RCo poses difficulty in the assessment of patients with very low VWF levels. The recent development of VWF platelet-binding activity assays (e.g., [VWF:GPIbR] and [VWF:GPIbM]), which do not require the use of ristocetin, have shown less variability, more sensitivity, and excellent correlation with VWF:RCo (Sharma and Haberichter, 2019). In the ASH ISTH NHF WFH 2021 guidelines on the diagnosis of VWD, James and colleagues (2021) suggest newer assays that measure the platelet-binding activity of VWF (e.g., [VWF:GPIbM], [VWF:GPIbR]) over the VWF:RCo assay for the diagnosis of VWD.

Versiti Heparin-Induced Thrombocytopenia-PEA

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder mediated by platelet-activating antibodies that target complexes of platelet factor 4 (PF4) and heparin. Versiti Heparin-Induced Thrombocytopenia-PEA test (Versiti Diagnostic Laboratories) was developed to detect heparin-dependent platelet antibodies in the serum from patients suspected of having HIT. The test includes a PF4-dependent P-Selectin Expression Assay (PEA) to identify patients likely to have HIT.

Nicolas and colleagues (2023) state that the PF4 ELISA is an immunoassay used to detect the presence of antibodies in persons suspected of HIT. If this test is negative, then HIT can be ruled out. If the PF4 ELISA is positive, the result should be confirmed with the Serotonin Release Assay (SRA), the gold standard test for confirming HIT with high sensitivity and specificity. The authors do not mention the utility of P-Selectin Expression Assay (PEA).

In an UpToDate review on "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" Pishko and Crowther (2023) state that PEA is a functional HIT assay that does not require radioactive reagents. Unlike the SRA, the PEA involves incubation of patient serum with washed test platelets pre-treated with PF4 (rather than heparin). The PEA measures expression of P-selectin on the platelet surface rather than release of radiolabeled 14C-serotonin to detect platelet activation by HIT antibodies. The authors cite a 2016 study by Padmanabhan et al that compared the results of the novel PEA assay to the gold standard SRA assay using banked serum from 91 patients who had results for the 4 Ts score available. The test found that the PEA had greater accuracy for HIT than the SRA (area under the receiver operator curve: 0.92 versus 0.82). However, as the authors noted, it was not clear whether the 16 individuals with a negative SRA and a positive PEA actually had clinically important HIT. The authors also cite a prospective multicenter study (per Versiti website) evaluating 409 adults with suspected HIT, the PEA had high diagnostic accuracy (area under the curve [AUC], 0.94, 95% confidence interval [CI] 0.87-1.0), which was similar to the SRA (SRA AUC, 0.91, 95% CI 0.82-1.0). The assay was performed in one laboratory in the United States, and results have not yet been validated outside of this laboratory.

Versiti VWD Type 2B Evaluation

The Versiti VWD Type 2B Evaluation test is a platelet-VWF binding assay that includes VWD type 2B binding and VWD type 2B quantitative multimer used to differentiate type 2B VWD from platelet-type VWD. In this assay, a monoclonal antibody to VWF is used to monitor the ability of patient plasma VWF to bind to formalin fixed platelets in the presence of low dose ristocetin. To assist in the interpretation, VWF multimer analysis is also performed.

The 2021 guidelines of the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH), recommend either VWF multimer analysis or VWF collagen binding (VWF:CB)/VWF:Ag) to diagnose type 2 VWD for patients suspected of type 2B in need of additional testing. The panel also suggest targeted genetic testing over low-dose ristocetin-induced platelet aggregation (RIPA) to diagnose type 2B VWD for patients suspected of type 2A or 2B in need of additional testing. Both recommendations are considered conditional based on very low certainty in the evidence from diagnostic accuracy studies (James et al, 2021).

In a review in UpToDate on "Clinical presentation and diagnosis of von Willebrand disease" James (2024) state persons diagnosed with VWD should complete additional assays to determine the type of VWD. Further, the distinction among the VWD subtypes of types 2A, 2B, and 2M is made using results of VWF multimer analysis (or VWF:CB) and RIPA.

Von Willebrand Factor-Collagen Binding Assay

A functionality of von Willebrand factor (VWF) lies in its binding capability to exposed collagen a site of vascular trauma. Specifically, VWF can bind to many different types of collagen (e.g., type 1, 3, 4, and 6). The purpose of the von Willebrand factor-collagen binding (VWF:CB) assay is to study the VWF-collagen interaction. The significance of this interaction is that patients with defective VWF multimers (type 2A or type 2B) have diminished VWF:CB (Sharma and Haberichter, 2019). Although, most clinical laboratories perform the type 1 and/or type 3 collagen assay, Versiti offers the VWF Collagen III Binding (VWF:CB3) and VWF Collagen IV Binding (VWF:CB4) assays. In the ASH ISTH NHF WFH 2021 guidelines on the diagnosis of VWD, James and colleagues (2021) suggest either VWF multimer analysis or VWF:CB/VWF:Ag (ratio of VWF collagen binding to antigen) to diagnose type 2 VWD for patients suspected of type 2A, 2B, or 2M in need of additional testing.

Von Willebrand Factor-Factor VIII Binding Assay

In the ASH ISTH NHF WFH 2021 guidelines on the diagnosis of VWD, James and colleagues (2021) suggest using either von Willebrand Factor-Factor VIII (VWF:FVIII) binding assay or targeted genetic testing (when available) for patients with suspected type 2N VWD in need of additional testing.

Versiti Diagnostic Laboratories offers the VWD Type 2N Binding assay which uses ELISA method to distinguish type 2N-von Willebrand disease from mild hemophilia A and hemophilia A carriers.

Per UpToDate review in "Clinical presentation and diagnosis of von Willebrand disease" (James, 2024), abnormal binding of VWF to factor VIII specifies VWD type 2N. This can be determined by genetic testing and/or a binding assay. The binding assay is usually performed in an ELISA format.

Von Willebrand Factor Propeptide Antigen

Sharma and Haberichter (2019) noted that von Willebrand Factor propeptide (VWFpp) has most utility in identifying the subset of type 1 VWD patients with very low VWF:Ag owing to increase clearance of plasma and is commonly known as type 1C. In the ASH ISTH NHF WFH 2021 guidelines on the diagnosis of VWD, James and colleagues (2021) suggest against using the VWFpp/VWF:Ag (ratio of VWF propeptide to antigen) and instead administer a desmopressin trial with 1- and 4-hour postinfusion blood work to confirm increased VWF clearance for patients with VWD suspected of type 1 C should be used.

References