Protocol - Emicizumab Therapy: Individual Pharmacokinetic Study of Standard Half-life Factor VIII Products: Chromogenic Substrate Assay with Bovine Reagents

Description

This protocol provides instructions and guidance for collecting and processing samples for coagulation testing, performing an individual pharmacokinetic study using the chromogenic substrate assay with bovine reagents, and interpreting pharmacokinetic results in response to infusion of standard half-life Factor VIII products. Because there may be several comparable assays for performing the chromogenic assay, the protocol also provides basic guidelines to aid comparability among different studies.

Specific Instructions

The PhenX Hemophilia Inhibitor Research Working Group (WG) notes that these measures are intended for use in observational and interventional trials but are not sufficient to define hemophilia phenotypes when used in isolation.

The WG recommends that when measuring inhibitor recovery in non-severe patients, endogenous factor should be measured by the same assay that was optimized prior to inhibitor development.

The WG recommends that Factor VIII and IX assays, either by one-stage clotting factor or chromogenic substrate methodology, should be performed by a laboratory that is College American Pathologists (CAP) accredited or Clinical Laboratory Improvement Amendments of 1998 (CLIA) certified. For multi-center clinical trials, the use of a central laboratory is strongly encouraged.

Emicizumab is a bispecific antibody that mimics the cofactor function of activated factor VIII (FVIIIa) by bridging activated factor IX (FIXa) and factor X (FX). Factor VIII (FVIII) levels and inhibitors can be measured in the presence of emicizumab using chromogenic assays with bovine reagents. One-stage clot-based assays cannot be used for determination of FVIII levels and FVIII inhibitors in the presence of emicizumab because results will show artifactually elevated FVIII levels. For more information, see the Medical and Scientific Advisory Committee (MASAC) of the National Hemophilia Foundations MASAC Update on the Approval and Availability of the New Treatment: Emicizumab (Hemlibra), for Persons with Hemophilia A with Inhibitors to Factor VIII: Interim Guidance on Acute Bleed Management and Use of Laboratory Assays (https://www.hemophilia.org/sites/default/files/MASAC-Update-on-the-Approval-and-Availability-of-the-New-Treatment.pdf).

The PhenX Hemophilia Inhibitor Research Working Group (WG) notes the activity of FVIII extended half-life products in plasma determined by the chromogenic clotting factor assay can vary according to the reagents and instrumentation used (Kitchen et al., 2017). Investigators should select an assay that aligns with the one used to determine the potency of the product. Additionally, investigators should record the make and manufacturer of equipment, the repeatability and coefficients of variation for the assay, and the reagents used.

The WG expects that a pharmacokinetic study of standard and extended half-life FVIII products in the presence of emicizumab will primarily be used to guide prophylaxis for surgery and for episodic prophylaxis around peak activity.

The WG recommends that investigators wait at least 6 months from the patients last dose of emicizumab before using assays with regular (non-bovine) reagents.

Additionally, the WG notes that in the HAVEN 2 study, one patient developed an antibody to emicizumab which was associated with increased bleeding, decreased chromogenic factor VIII activity, and a prolonged activated partial thromboplastin time (aPTT).

If a washout is not performed, comparison of pharmacokinetic data between studies should be conducted under steady-state conditions. Steady-state is defined as a patient-specific condition during which a pharmacokinetic assessment remains valid over a clinically useful period of time. Examples of non-steady state conditions include:

Bleeding state
Peri- and immediate post-surgical states in which patients are receiving continuous or regular high (non-routine prophylactic) doses of FVIII
Immune tolerance induction during which inhibiter titers are in flux
Children in whom age- and weight-based clearance is still developing toward adult physiologic states.

Availability

Available

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Protocol

Emicizumab Therapy: Individual Pharmacokinetic Study of Standard Half-life Factor VIII Products: Chromogenic Substrate Assay with Bovine Reagents

Sample Collection

The PhenX Hemophilia Inhibitors Working Group (WG) recommends that investigators follow the sample collection procedures outlined in Lippi et al. (2012) to ensure quality specimens for coagulation testing. These recommendations include basic criteria for venipuncture (e.g., proper patient identification, use of correct techniques, appropriate devices and needles) as well as additional guidance for critical parameters which can affect the outcome of clot-based tests. These critical parameters include prevention of prolonged venous stasis, collection of nonhemolyzed samples, order of blood draw, and appropriate filling and mixing of collection tubes.

Additionally, the WG highlights that blood should be collected by direct venipuncture into 3.2% sodium citrate tubes and filled within 11% of fill line. A second tube should be collected. A discard tube should be drawn if using a winged butterfly collection system.

Sample Processing

The WG recommends that investigators follow the sample collection procedures outlined in Adcock Funk et al. (2012). The procedures include that:

unprocessed or processed sodium citrate samples remain capped and at room temperature until testing,
samples should not be refrigerated or stored on ice or in an ice bath,
samples should be transported vertically, and
processed samples should not be agitated during transportation to avoid remixing of components.

Additionally, samples can be transported and stored as:

unprocessed sodium citrate whole blood samples,
whole blood samples centrifuged and maintained in sodium citrate tubes, or
plasma processed by centrifugation and aliquoted into a second tube.

Ideally, whole blood samples should be processed to platelet poor plasma (PPP) within 1 hour of collection and assayed within 4 hours of collection.

If centrifuging samples, the centrifuge should be validated so that post-centrifuged samples contain less than 10,000 platelets/microliter. Centrifuged samples should be frozen immediately and can be stored at -20^o C for 2 weeks. Samples should be transferred to < -70^o C for longer storage, including shipment.

Emicizumab Therapy: Chromogenic Substrate Assay with Bovine Reagents for Determining Factor VIII Activity in Plasma

In patients being treated with emicizumab, Factor VIII inhibitors can only be measured using a chromogenic assay with bovine reagents. The WG notes that there may be a number of different assays and instruments that are appropriate to perform the chromogenic substrate assay. Once an assay is chosen for a particular study, the WG recommends that no changes in the protocol be made over the course of the study. Because results can vary with the instrumentation and reagents, the WG recommends that the investigator record the make and manufacturer of equipment, the repeatability and coefficients of variation for the assay, and the reagents used. Use of a central laboratory for multi-center clinical trials is strongly encouraged.

Standard Half-life Factor VIII Products: Individual Pharmacokinetic Study

The WG recommends that the pharmacokinetic assay using the chromogenic substrate assay be performed according to the parameters outlined by Subcommittee on Factor VIII and Factor VIII of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (Lee et al., 2001). This includes infusing a 100% correction dose of Factor VIII concentration after a treatment-free washout period lasting longer than five half-lives. Factor VIII activity is then tested at ten timepoints:

before infusion (baseline);
10-15 minutes after infusion;
30 minutes after infusion;
1 hour after infusion;
3 hours after infusion;
6 hours after infusion;
9 hours after infusion;
24 hours after infusion;
28 hours after infusion; and
32 hours after infusion.

A sample taken at 48 hours after infusion is optional.

Standard Half-life Factor VIII Products: Interpretation of Individual Pharmacokinetic Study Results

A Factor VIII half-life (t_1/2) less than 6 hours is considered abnormal and evidence of an inhibitor.

Personnel and Training Required

Phlebotomist

Equipment Needs

Laboratory with the ability to perform the chromogenic substrate assay with bovine reagents.

Requirements

Requirement Category	Required
Major equipment	No
Specialized training	No
Specialized requirements for biospecimen collection	Yes
Average time of greater than 15 minutes in an unaffected individual	Yes

Mode of Administration

Bioassay

Lifestage

Toddler, Child, Adolescent, Adult

Participants

Any age

Selection Rationale

The PhenX Hemophilia Inhibitors Working Group selected the recommendations from Lippi et al. (2012) and Adcock Funk et al. (2012) as the best standardized methodology for collecting and processing samples for coagulation testing. The International Society on Thrombosis and Haemostasis (Lee et al., 2001) provides standard timepoints for consistent implementation of the pharmacokinetic study.

Language

English

Standards

Standard	Name	ID	Source

Derived Variables

The results of this protocol can be combined with the results of Emicizumab Therapy: Determination of Factor VIII Inhibitors Using the Bethesda Assay with Nijmegen Modification: Chromogenic Substrate Assay with Bovine Reagents to document:

Presence of an Inhibitor

The presence of an inhibitor is indicated by one or more of the following:

lack of clinical response (cessation of bleeding) to Factor infusion for treatment of bleeding;
less than expected (< 66%) recovery of Factor VIII level immediately after infusion (Response to Factor VIII Infusion in the Presence of Emicizumab - Individual Pharmacokinetic Study);
positive inhibitor titer (Quantitative Measure of Factor VIII Inhibitor Activity in the Presence of Emicizumab);
Reduced FVIII half-life below 6 hours.

Evolution of an Inhibitor

Inhibitor evolution is indicated by:

change in inhibitor titer over time (Quantitative Measure of Factor VIII Inhibitor Activity in the Presence of Emicizumab), with or without immune tolerance induction;
change in clinical response (i.e., bleeding) to FVIII infusion;
change in FVIII activity after Factor infusion (Response to Factor VIII Infusion in the Presence of Emicizumab - Individual Pharmacokinetic Study.

Resolution of an Inhibitor

Inhibitor resolution is indicated by the following:

for patients receiving immune tolerance therapy for eradication of an FVIII inhibitor, success is defined as a negative inhibitor titer (Quantitative Measure of Factor VIII Inhibitor Activity in the Presence of Emicizumab) and a normal recovery (>= 66% of expected) and half-life >=6 hours of infused FVIII concentrate (Response to Factor VIII Infusion in the Presence of Emicizumab - Individual Pharmacokinetic Study).

Persistence of an Inhibitor

A persistent inhibitor is indicated by a decreased response to FVIII concentrate infusion (Response to Factor VIII Infusion in the Presence of Emicizumab - Individual Pharmacokinetic Study) with or without a persistently positive inhibitor titer (Quantitative Measure of Factor VIII Inhibitor Activity in the Presence of Emicizumab).

Blanchette, V. S., Key, N. S., Ljung, L. R., Manco-Johnson, M. J., van den Berg, H. M., & Srivastava, A.; Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. (2014). Definitions in hemophilia: Communication from the SSC of the ISTH. Journal of Thrombosis and Haemostasis, 12(11), 1935-1939.

Process and Review

Not applicable.

Protocol Name from Source

Medical and Scientific Advisory Committee (MASAC) of the National Hemophilia Foundation (NHF), 2017

Source

Adcock Funk, D. M., Lippi, G., & Favaloro, E. J. (2012). Quality standards for sample processing, transportation, and storage in hemostasis testing. Seminars in Thrombosis and Hemostasis, 38(6), 576-585.

Lee, M., Morfini, M., Schulman, S., & Ingerslev, J.; Factor VIII/Factor VIII Scientific and Standardization Committee of the International Society for Thrombosis and Haemostasis. (2001). Scientific and Standardization Committee communication. The design and analysis of pharmacokinetic studies of coagulation factors. https://www.isth.org/members/group_content_view.asp?group=100348&id=159244. Retrieved August 30, 2018.

Lippi, G., Salvagno, G. L., Montagnana, M., Lima-Oliveira, G., Guidi, G. C., & Favaloro, E. J. (2012). Quality standards for sample collection in coagulation testing. Seminars in Thrombosis and Hemostasis, 38(6), 565-575.

Medical and Scientific Advisory Committee (MASAC) of the National Hemophilia Foundation (NHF). (2017). MASAC update on the approval and availability of the new treatment: Emicizumab (Hemlibra), for persons with hemophilia A with inhibitors to factor VIII: Interim guidance on acute bleed management and use of laboratory assays. https://www.hemophilia.org/sites/default/files/MASAC-Update-on-the-Approval-and-Availability-of-the-New-Treatment.pdf

General References

Blanchette, V. S., Key, N. S., Ljung, L. R., Manco-Johnson, M. J., van den Berg, H. M., & Srivastava, A.; Subcommittee on Factor VIII, Factor VIII and Rare Coagulation Disorders of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. (2014). Definitions in hemophilia: Communication from the SSC of the ISTH. Journal of Thrombosis and Haemostasis, 12(11), 1935-1939.

Hay, C. R., & DiMichele, D. M.; International Immune Tolerance Study. (2012). The principal results of the International Immune Tolerance Study: A randomized dose comparison. Blood, 119(6), 1335-1344.

Iorio, A., Edginton, A.N., Blanchette, V., Blatny, J., Boban, A., Cnossen, M., Collins, P., Croteau, S.E., Fischer, K., Hart, D.P., Ito, S., Korth-Bradley, J., Lethagen, S., Lillicrap, D., Makris, M., Matht, R., Morfini, M., Neufeld, E.J., Spears, J. (2018). Performing and interpreting individual pharmacokinetic profiles in patients with Hemophilia A or B: Rationale and general considerations. Research and Practice in Thrombosis and Haemostasis, 2(3), 535-548.

Kitchen, S., Kershaw, G., & Tiefenbacher, S. (2016). Recombinant to modified factor VIII and factor VIII Chromogenic and one-stage assays issues. Haemophilia, 22(Suppl. 5), 72-77.

Mahlangu, J., Oldenburg, J., Paz-Priel, I., Negrier, C., Niggli, M., Mancuso, M. E., Schmitt, C., Jimnez-Yuste, V., Kempton, C., Dhalluin, C., Callaghan, M.U., Bujan, W., Shima, M., Adamkewicz, J. I., Asikanius, E., Levy, G. G., & Kruse-Jarres, R. (2018). Emicizumab prophylaxis in patients who have hemophilia A without Inhibitors. New England Journal of Medicine, 379(9), 811-822.

Morfini, M., Lee, M., Messori, A. and the Factor VIII/Factor IX Scientific and Standardization Committee of the International Society for Thrombosis and Haemostasis. (1991). The design and analysis of half-life and recovery studies for factor VIII and factor IX. Thrombosis and Haemostasis, 66(3), 384-386.

Oldenburg, J., Mahlangu, J. N., Kim, B., Schmitt, C., Callaghan, M. U., Young, G., Santagostino, E., Kruse-Jarres, R., Negrier, C., Kessler, C., Valente, N., Asikanius, E., Levy, G. G., Windyga, J., & Shima, M. (2017). Emicizumab prophylaxis in hemophilia A with inhibitors. The New England Journal of Medicine, 377(9), 809-818.

Peyvandi, F., Oldenburg, J., & Friedman, K. D. (2006). A critical appraisal of one-stage and chromogenic assays of factor VIII activity. Journal of Thrombosis and Haemostasis, 14(2), 248-261.

Shima, M., Hanabusa, H., Taki, M., Matsushita, T., Sato, T., Fukutake, K., Fukazawa, N., Yoneyama, K., Yoshida, H., & Nogami, K. (2016). Factor VIII-mimetic function of humanized bispecific antibody in hemophilia A. New England Journal of Medicine, 374(21), 2044-2053.

Protocol ID

911401

Variables

Export Variables

Variable Name	Variable ID	Variable Description	dbGaP Mapping
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Pharmacokinetic_Study_After_Infusion_Hours_1
	PX911401040400	Was Factor VIII activity tested 1 hour after more infusion? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Pharmacokinetic_Study_After_Infusion_Hours_24
	PX911401040800	Was Factor VIII activity tested 24 hours more after infusion? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Pharmacokinetic_Study_After_Infusion_Hours_28
	PX911401040900	Was Factor VIII activity tested 28 hours more after infusion? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Pharmacokinetic_Study_After_Infusion_Hours_3
	PX911401040500	Was Factor VIII activity tested 3 hours more after infusion? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Pharmacokinetic_Study_After_Infusion_Hours_32
	PX911401041000	Was Factor VIII activity tested 32 hours more after infusion? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Pharmacokinetic_Study_After_Infusion_Hours_48
	PX911401041100	Was Factor VIII activity tested 48 hours more after infusion? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Pharmacokinetic_Study_After_Infusion_Hours_6
	PX911401040600	Was Factor VIII activity tested 6 hours more after infusion? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Pharmacokinetic_Study_After_Infusion_Hours_9
	PX911401040700	Was Factor VIII activity tested 9 hours more after infusion? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Pharmacokinetic_Study_After_Infusion_Minutes_10
	PX911401040200	Was Factor VIII activity tested 10-15 more minutes after infusion? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Pharmacokinetic_Study_After_Infusion_Minutes_30
	PX911401040300	Was Factor VIII activity tested 30 minutes more after infusion? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Pharmacokinetic_Study_Infusion_Baseline
	PX911401040100	Was Factor VIII activity tested before more infusion (baseline)? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Pharmacokinetic_Study_Interpretation_Results
	PX911401050000	Was the Factor VIII half-life (t) less than more 6 hours? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Collection
	PX911401010100	Were the sample collection procedures more outlined in Lippi et al. (2012) followed? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Collection_Blood_Draw
	PX911401010400	Was the order of blood draw recorded?	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Collection_Nonhemolyzed
	PX911401010300	Were nonhemolyzed samples collected?	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Collection_Tubes
	PX911401010500	Were collection tubes filled and mixed as more outlined in Lippi et al. (2012)? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Collection_Tubes_Discard
	PX911401011000	Was a discard tube drawn?	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Collection_Tubes_Filled
	PX911401010700	Were the tubes filled within 11% of the fill line?	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Collection_Tubes_Second
	PX911401010800	Was a second tube collected?	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Collection_Tubes_Winged
	PX911401010900	Was a winged butterfly collection system used?	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Collection_Venipuncture
	PX911401010600	Was blood collected by direct venipuncture more into 3.2% sodium citrate tubes? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Collection_Venous_Statsis
	PX911401010200	Were steps taken to prevent prolonged venous more stasis? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Processing
	PX911401020100	Were the sample collection and processing more procedures outlined in Adcock Funk et al. (2012) followed? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Processing_Agitation
	PX911401020500	Were samples agitated during transportation?	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Processing_Assayed
	PX911401021000	Were samples assayed within 4 hours of collection?	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Processing_Centrifuge_Validated
	PX911401021100	Was the centrifuge validated so that process more results in less than 10,000 platelets/microliter show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Processing_Deep_Freeze
	PX911401021300	Was the sample transferred to <= -70 C, more including shipment? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Processing_Frozen
	PX911401021200	Was the sample frozen immediately and stored more at -20 C for at most 2 weeks? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Processing_Platelet_Poor_Plasma
	PX911401020900	Were samples processed to platelet poor more plasma (PPP) within 1 hour of collection? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Processing_Refrigerated
	PX911401020300	Were samples refrigerated or stored on ice more or in an ice bath? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Processing_Sodium_Citrate
	PX911401020200	Did unprocessed or processed sodium citrate more samples remain capped and at room temperature until testing? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Processing_Storage_Plasma
	PX911401020800	Were samples stored as plasma processed by more centrifugation and aliquoting into a second tube? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Processing_Storage_Unprocessed
	PX911401020600	Were samples stored as unprocessed sodium more citrate whole blood samples? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Processing_Storage_Whole_Blood
	PX911401020700	Were samples stored as whole blood samples more centrifuged and maintained in sodium citrate tubes? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Sample_Processing_Transportation
	PX911401020400	Were samples transported vertically?	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Therapy_Bethesda_Assay_Nijmegen_Modification_Chromogenic_Substrate_Assay
	PX911401030100	Were any changes made in the protocol over more the course of the study? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Therapy_Bethesda_Assay_Nijmegen_Modification_Chromogenic_Substrate_Assay_Clinical_Trial
	PX911401030202	Is this study a part of multi-center more clinical trials? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Therapy_Bethesda_Assay_Nijmegen_Modification_Chromogenic_Substrate_Assay_Clinical_Trial_Laboratory
	PX911401030300	Is a central laboratory being used?	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Therapy_Bethesda_Assay_Nijmegen_Modification_Chromogenic_Substrate_Assay_Guidelines
	PX911401030400	Were the parameters outlined by the more Subcommittee on Factor VIII and Factor VIII of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (Lee et al., 2001) followed? show less	N/A
PX911401_Factor_Eight_Emicizumab_Individual_Standard_Therapy_Bethesda_Assay_Nijmegen_Modification_Chromogenic_Substrate_Assay_Record
	PX911401030201	Were the make and manufacturer of equipment, more repeatability and coefficients of variation for the assay, and the reagents used recorded? show less	N/A

Hemophilia Inhibitor

Measure Name

Response to Factor VIII Infusion in the Presence of Emicizumab - Individual Pharmacokinetic Study

Release Date

May 7, 2019

Definition

A series of plasma Factor VIII activity determinations in blood samples are obtained immediately prior to, and at timepoints after, infusion of FVIII concentrate.

Purpose

The results of an individual pharmacokinetic study (i.e., initial recovery and half-life) of infused Factor VIII concentrate can characterize an individual?s response to a new drug or can confirm the success of immune tolerance induction (ITI).

Keywords

Hemophilia inhibitors, Factor VIII, FVIII, hemophilia A, inhibitors, pharmacokinetic study, immune tolerance induction, prophylaxis, recovery, half-life

Measure Protocols

Protocol ID	Protocol Name
911401	Emicizumab Therapy: Individual Pharmacokinetic Study of Standard Half-life Factor VIII Products: Chromogenic Substrate Assay with Bovine Reagents
911402	Emicizumab Therapy: Individual Pharmacokinetic Study of Extended Half-life Factor VIII Products: Chromogenic Substrate Assay with Bovine Reagents

Publications

There are no publications listed for this protocol.