Guidelines for the management of



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Principles of diagnosis 

1.  Understanding the clinical features of hemophilia 

and the appropriateness of the clinical diagnosis. 

2.  Using screening tests to identify the potential 

cause of bleeding, for example, platelet count, 

bleeding time (BT; in select situations), or other 

platelet function screening tests, prothrombin 

time (PT), and activated partial thromboplastin 

time (APTT).

3.  Confirmation of diagnosis by factor assays and 

other appropriate specific investigations.

Technical aspects 

Preparation of the patient prior to taking a blood 

sample 

1.  Fasting is not normally necessary before collec-



tion of blood for investigation of possible bleeding 

disorders, although a gross excess of lipids may 

affect some automated analysers. 

2.  Patients should avoid medications that can affect 

test results such as aspirin, which can severely 

affect platelet function and prolong the bleeding/

closure time. 

3.  Patients should avoid strenuous exercise imme-

diately prior to venipuncture.

3

LABORATORY 



DIAGNOSIS

GUIDELINES FOR THE MANAGEMENT OF HEMOPHILIA

30

4.  If a patient is particularly stressed by the sample 



collection procedure, the levels of FVIII and von 

Willebrand factor may be temporarily elevated. 

Sample collection 

1.  The sample should be collected as per standard 

guidelines [2]. 

2.  The sample should preferably be collected near 

the laboratory to ensure quick transport. 

3.  Samples should be tested within four hours of 

collection. 

4.  Results of tests can change according to the sample 

storage conditions. Higher temperatures (>25°C) 

lead to loss of FVIII activity over time, whereas 

sample storage in the cold (2-8°C) leads to cold 

activation. The sample should therefore be main-

tained at temperatures between 20°C and 25°C 

where possible, but for no more than four hours. 

5.  Venipuncture must be clean and the sample 

collected within one minute of tourniquet appli-

cation without prolonged venous stasis. 

6.  Blood should be withdrawn into a plastic syringe 

or an evacuated collection system. The needle 

should be 19-21 gauge for adults and 22-23 gauge 

for small children. Collection through periph-

eral venous catheters or non-heparinized central 

venous catheters can be successful for many tests 

of hemostasis. 

7.  Blood from an indwelling catheter should be 

avoided for coagulation tests. 

8.  Frothing of the blood sample should also be 

avoided. It is often useful to discard the first 2 ml 

of blood collected. 

9.  The sample should be collected in citrate tubes 

containing 0.105M–0.109M (c3.2%) aqueous 

trisodium citrate dihydrate, maintaining the 

proportion of blood to citrate as 9:1. If the tube 

contains less than 80% of the target volume, 

results may be adversely affected. The higher 

strength concentration of 3.8% trisodium citrate 

is no longer recommended.

10. Prompt and adequate mixing with citrate solu-

tion should be done by gentle inversion.

11. If the sample cannot be processed within four 

hours of collection, the platelet poor plasma can 

be frozen at -30°C and stored for a few weeks, or 

up to six months if stored at -70°C [3]. Storage 

at -20°C is usually inadequate. 

12. Frozen samples must be thawed rapidly for four 

to five minutes at 37°C to avoid formation of 

cryoprecipitate.

Preparation of platelet-poor plasma (PPP)

1.  PPP should be prepared as per standard guide-

lines [2].

2.  PPP is prepared by centrifugation of a sample at 

a minimum of 1700g for at least 10 minutes at 

room temperature (i.e. not refrigerated). 

3.  PPP may be kept at room temperature (20°C–

25°C) prior to testing.

4.  Plasma that has been hemolysed during collec-

tion and processing should not be analysed. 

End-point detection 

1.  Many laboratories now have some form of semi or 

fully automated coagulation analysers. Accurately 

detecting the clotting end-point using a manual 

technique requires considerable expertise, partic-

ularly if the clotting time is prolonged or if the 

fibrinogen concentration is low, and the clot is 

thin and wispy.

2.  For manual testing, the tube should be tilted 

three times every five seconds through an angle 

of approximately 90° during observation. The 

tube should be immersed in a water bath at 37°C

 

between tilting.



Screening tests 

1.  Platelet count, BT, PT, and APTT may be used to 

screen a patient suspected of having a bleeding 

disorder [4]. 

2.  Bleeding time lacks sensitivity and specificity 

and is also prone to performance-related errors. 

Therefore other tests of platelet function such as 

platelet aggregometry are preferred when avail-

able [5,6].


LABORATORY DIAGNOSIS

31

3.  Based on the results of these tests, the category 



of bleeding disorder may be partially charac-

terized to guide subsequent analysis (see Table 

3-1, above).

4.  These screening tests may not detect abnormal-

ities in patients with mild bleeding disorders 

including some defects of platelet function, 

FXIII deficiency, and those rare defects of fibri-

nolysis, which may be associated with a bleeding 

tendency.

Correction studies

1.  Correction or mixing studies using pooled 

normal plasma (PNP) will help to define whether 

prolonged coagulation times are due to factor 

deficiency or circulating anticoagulants of inhibi-

tors. Correction studies with FVIII/FIX-deficient 

plasma may be used to identify the particular defi-

ciency if a factor assay is not available.

Factor assays 

1.  Factor assay is required in the following situations:

 ■ To determine diagnosis 

 ■ To monitor treatment 

 ■

The laboratory monitoring of clotting factor 



concentrates is possible by measuring pre- 

and post-infusion clotting factor levels.

 ■

Lower than expected recovery and/or 



reduced half-life of infused clotting factor 

may be an early indicator of the presence 

of inhibitors.

 ■ To test the quality of cryoprecipitate 

 ■

It is useful to check the FVIII concentra-



tion present in cryoprecipitate as part of 

the quality control of this product. 

2.  Phenotypic tests lack sensitivity and specificity for 

the detection of carriers. Some obligate carriers 

may have a normal FVIII:C/VWF:Ag ratio. 

Genotypic testing is a more precise method of 

carrier detection and is therefore recommended.

3.  One-stage assays based on APTT are the most 

commonly used techniques. The following assay 

features are important:

 ■ FVIII- and FIX-deficient plasma must 

completely lack FVIII and FIX respectively, 

i.e. contain < 1 IU/dl, and have normal levels 

of other clotting factors.

 ■ The reference/calibration plasma, whether 

commercial or locally prepared, must be cali-

brated in international units (i.e. against an 

appropriate WHO international standard).

 ■ At least three different dilutions of the refer-

ence plasma and the test sample under analysis 

are needed for a valid assay.

 ■ Use of a single dilution of test sample substan-

tially reduces the precision of the test and may 

lead to completely inaccurate results in the 

presence of some inhibitors. 

 ■ When assaying test samples from subjects with 

moderate or severe hemophilia, an extended 

or separate calibration curve may be needed. It 

is not acceptable to simply extend the calibra-

tion curve by extrapolation without analysing 

additional dilutions of the calibration plasma.

 ■ Some cases of genetically confirmed mild 

hemophilia A have normal FVIII activity when 

the one-stage assay is used for diagnosis, but 

reduced activity in chromogenic and two-stage 

clotting assays. The reverse can also occur. This 

means that more than one type of FVIII assay 

is needed to detect all forms of mild hemo-

philia A [7,8]. 

TABLE 3-1: INTERPRETATION OF SCREENING TESTS

POSSIBLE DIAGNOSIS

PT

APTT*



BT

PLATELET COUNT

Normal

Normal


Normal

Normal


Normal

Hemophilia A or B**

Normal

Prolonged*



Normal

Normal


VWD

Normal


Normal or prolonged*

Normal or prolonged

Normal or reduced

Platelet defect

Normal

Normal


Normal or prolonged

Normal or reduced

* Results of APTT measurements are highly dependent on the laboratory method used for analysis. 

** The same pattern can occur in the presence of FXI, FXII, prekallikrein, or high molecular weight kininogen deficiencies.



GUIDELINES FOR THE MANAGEMENT OF HEMOPHILIA

32

Inhibitor testing 



1.  The presence of some form of inhibitor is 

suspected when there is a prolonged APTT that 

is not fully corrected by mixing patient plasma 

with PNP. 

2.  The most frequently encountered functional 

inhibitors of hemostasis are lupus anticoagu-

lants (LA), which are not directed against specific 

clotting factors and which should be excluded.

3.  Results of APTT testing on mixtures of test and 

normal plasma can be difficult to interpret, partic-

ularly since in acquired hemophilia there may 

initially be a full correction of APTT in the pres-

ence of a potent specific anti-FVIII antibody.

4.  Most FVIII inhibitors that occur secondary to 

replacement therapy in subjects with hemophilia 

A show a characteristic pattern: the APTT of a 

patient/PNP mixture is intermediate, i.e. between 

the APTTs of the two materials, and is further 

prolonged when the mixture is incubated at 37°C 

for 1-2 hours. 

5.  Confirmation that an inhibitor is directed against 

a specific clotting factor requires a specific inhib-

itor assay.

6.  The Nijmegen modification of the FVIII inhib-



itor assay offers improved specificity and 

sensitivity over the original Bethesda assay. 

(Level 1) [9,10] 

7.  It is performed as follows:

 ■ Buffered PNP (providing FVIII) is mixed with 

test plasma and incubated at 37°C.

 ■ After two hours, the residual FVIII is measured 

by comparison against the FVIII in a control 

mixture comprised of buffered PNP and FVIII-

deficient plasma, which has been incubated 

alongside the test mixture.

 ■ Residual FVIII is converted into inhibitor units 

using a semi-log plot of the residual FVIII 

against inhibitor convention, which has been 

constructed using the assumption that 100% 

residual = 0 BU/ml inhibitor, and 50% residual 

= 1.0 BU/ml (the latter being the internation-

ally agreed convention for defining inhibitor 

activity).

 ■ When residual FVIII activity is <25%, the 

patient plasma must be retested after dilu-

tion to avoid underestimation of the inhibitor 

potency.

 ■ An inhibitor titer of ≥ 0.6 BU/ml is to be taken 

as clinically significant [11].

Trained personnel

1.  Even the simplest coagulation screening tests are 

complex by nature. 

2.  A laboratory scientist/technologist with an 

interest in coagulation must have an in-depth 

understanding of the tests in order to achieve 

accurate results. 

3.  In some cases, it may be beneficial to have a labo-

ratory scientist/technologist who has had further 

training in a specialist centre.

3.2  Use of the correct equipment and reagents

1.  Equipment and reagents are the tools of the trade 

of any laboratory. The following requirements are 

necessary for accurate laboratory testing.



Equipment 

1.  A 37°C ± 0.5°C water bath.

2.  A good light source placed near the water bath 

to accurately observe clot formation. 

3.  Stopwatches.

4.  Automated pipettes (either fixed or variable 

volume) capable of delivering 0.1 ml and 0.2 ml 

accurately and precisely.

5.  Clean soda glass test tubes (7.5 cm × 1.2 cm) for 

clotting tests. Reuse of any glassware consumables 

should be avoided whenever possible, unless it 

can be demonstrated that test results are unaf-

fected by the process used. Plasticware used in 

coagulation analysers should not be re-used.



LABORATORY DIAGNOSIS

33

6.  An increasingly large number of semi-auto-



mated and fully automated coagulometers are 

now available. In many cases this equipment has 

the following advantages:

 ■ Accuracy of end-point reading.

 ■ Improved precision of test results.

 ■ Ability to perform multiple clot-based assays.

 ■ Reduction of observation errors (the end-point 

of the reaction is typically measured electro-

mechanically or photoelectrically).

 ■ Use of polystyrene (clear) cuvettes instead of 

glass tubes. 

7.  All equipment requires maintenance to be kept 

in good working order. 

 ■ When equipment is purchased consideration 

should be given to, and resources put aside for, 

regular maintenance by a product specialist.

 ■ Pipettes should be checked for accurate sample/

reagent delivery. 

 ■ Water baths, refrigerators, and freezers should 

undergo regular temperature checks.

8.  Good results can be obtained using basic 

equipment and technology provided that good 

laboratory practice is observed. These skills can 

then be adapted to more automated technology.

Selection of coagulometers 

1.  Many coagulation analysers are provided as a 

package of instrument and reagent, and both 

components can influence the results obtained. 

This needs to be taken into account when eval-

uating and selecting a system. Other important 

issues to consider are:

 ■ type of tests to be performed and the work-

load, as well as workflow, in the laboratory

 ■ operational requirements (power, space, 

humidity, temperature, etc)

 ■ service requirements and breakdown response

 ■ throughput and test repertoire

 ■ costs


 ■ ability to combine with reagents from other 

manufacturers 

 ■ user-programmable testing

 ■ comparability between results on primary anal-

yser and any back-up methods

 ■ compatibility with blood sample tubes and 

plasma storage containers in local use

 ■ safety assessment (mechanical, electrical, 

microbiological)

 ■ availability of suitable training

2.  Information is required in relation to the perfor-

mance characteristics of the system. This can be 

obtained from a variety of sources including the 

published literature and manufacturers’ data, but 

may also require some form of local assessment. 

Aspects to consider include:

 ■ precision of testing with a target of <3% of CV 

for screening tests and <5% for factor assays

 ■ carry-over

 ■ interfering substances

 ■ reagent stability on board analyser

 ■ comparability with other methods

 ■ sample identification

 ■ data handling, software, and quality control 

 ■ training required

 ■ reliability 

3.  A number of published guidelines and recom-

mendations describe the evaluation of coagulation 

analysers [12,13]. 

Reagents 

1.  It is good practice to ensure continuity of supply 

of a chosen reagent, with attention paid to conti-

nuity of batches and long shelf-life. This may be 

achieved by asking the supplier to batch hold for 

the laboratory, if possible. 

2.  Changing to a different source of material is not 

recommended unless there are supply prob-

lems or because of questionable results. Different 

brands may have completely different sensitivi-

ties and should not be run side by side. 

3.  Instructions supplied with the reagent should 

be followed. 

4.  Particular attention should be paid to reagent 

stability. Once a reagent is reconstituted or thawed 

for daily use, there is potential for deterioration 

over time depending on the conditions of storage 

and use.


5.  Once an appropriate test and reagents have been 

decided upon, normal/reference ranges should 

ideally be defined, and must take account of the 

conditions used locally.



GUIDELINES FOR THE MANAGEMENT OF HEMOPHILIA

34

3.3  Quality assurance 



1.  Quality assurance (QA) is an umbrella term used 

to describe all measures taken to ensure the reli-

ability of laboratory testing and reporting. 

2.  QA covers all aspects of the diagnosis process 

from sample-taking, separation and analysis, 

and internal quality control through to reporting 

of the result and ensuring that it reaches the 

clinician. 

3.  It is the responsibility of everyone involved to 

make sure that the procedures are followed in 

the correct manner.

Internal quality control (IQC)

1.  IQC is used to establish whether a series of 

techniques and procedures is being performed 

consistently over a period of time. 

2.  IQC measures are taken to ensure that the results 

of laboratory investigations are reliable enough to 

assist clinical decision making, monitor therapy, 

and diagnose hemostatic abnormalities.

3.  IQC is particularly useful to identify the degree 

of precision of a particular technique.

4.  For screening tests of hemostasis, normal and 

abnormal plasma samples should be included 

regularly. At least one level of IQC sample should 

be included with all batches of tests.



External quality assessment (EQA) 

1.  Laboratories are strongly advised to participate in 

an external quality assessment scheme (EQAS) to 

audit the effectiveness of the IQC systems in place. 

2.  EQAS helps to identify the degree of agreement 

between the laboratory results and those obtained 

by other laboratories. 

3.  Participation in such a scheme helps build confi-

dence between a laboratory and its users. 

4.  The WFH IEQAS is specifically designed to meet 

the needs of hemophilia treatment centres world-

wide. The scheme includes analyses relevant to the 

diagnosis and management of bleeding. Details 

of this scheme, which is operated in conjunc-

tion with the U.K. National External Quality 

Assessment Service for Blood Coagulation in 

Sheffield, U.K., can be obtained from the WFH 

[14]. 


5.  Other national and international quality assess-

ment schemes are also available.

6.  In order for a laboratory to attain a high level of 

testing reliability and to participate successfully in 

EQAS, it must have access to appropriate reagents 

and techniques and an appropriate number of 

adequately trained staff.

References

1.  Kitchen S, McCraw A, Echenagucia M. Diagnosis 

of Hemophilia and Other Bleeding Disorders: A 

Laboratory Manual, 2nd edition. Montreal: World 

Federation of Hemophilia, 2010. 

2.  Clinical and Laboratory Standards Institute. Collection, 

Transport, and Processing of Blood Specimens 

for Testing Plasma-Based Coagulation Assays and 

Molecular Hemostasis Assays: Approved Guideline–

Fifth edition. CLSI H21-A5, Wayne PA, Clinical and 

Laboratory Standards Institute 2008.

3.  Woodhams B, Girardot O, Blanco MJ, et al. Stability of 

coagulation proteins in frozen plasma. Blood Coagul 

Fibrinolysis 2001;12(4):229-36.

4.  Clinical and Laboratory Standards Institute. One 

Stage Prothrombin Time (PT) Test and Activated 

Partial Thromboplastin Time (APTT) Test: Approved 

Guideline–Second edition. CLSI H47-A2 Wayne PA, 

Clinical and Laboratory Standards Institute, 2008.

5.  Bick RL. Laboratory evaluation of platelet dysfunction. 

Clin Lab Med 1995 Mar;15(1):1-38.

6.  Rodgers RP, Levin J. Bleeding time revisited. Blood 1992 

May 1;79(9):2495-7.

7.  Duncan EM, Duncan BM, Tunbridge LJ, et al. Familial 

discrepancy between one stage and 2 stage factor 

VIII assay methods in a subgroup of patients with 

haemophilia A. Br J Haematol 1994:87(4);846-8.

8.  Oldenburg J, Pavlova A. Discrepancy between one-stage 

and chromogenic FVIII activity assay results can 

lead to misdiagnosis of haemophilia A phenotype. 

Haemostaseologie 2010:30(4);207-11.



LABORATORY DIAGNOSIS

35

9.  Meijer P, Verbruggen B. The between-laboratory 



variation of factor VIII inhibitor testing: the experience 

of the external quality assessment program of the ECAT 

foundation. Semin Thromb Hemost 2009;35(8):786-93.

10.  Verbruggen B, van Heerde WL, Laros-van Gorkom 

BA. Improvements in factor VIII inhibitor detection: 

From Bethesda to Nijmegen. Semin Thromb Hemost 

2009;35(8):752-9.

11.  Verbruggen B, Novakova I, Wessels H, Boezeman J, 

van den Berg M, Mauser-Bunschoten E. The Nijmegen 

modification of the Bethesda assay for factor VIII:C 

inhibitors: improved specificity and reliability. Thromb 

Haemos 1995; 73:247-251.

12.  Clinical and Laboratory Standards Institute. Protocol 

for the Evaluation, Validation, and Implementation of 

Coagulometers: Approved Guideline. CLSI document 

H57-A, Vol.28 No.4. Wayne PA, Clinical and Laboratory 

Standards Institute 2008c.

13.  Gardiner C, Kitchen S, Dauer RJ, et al. 

Recommendations for evaluation of coagulation 

analyzers. Lab Hematol 2006;12(1):32-8.

14.  Jennings I, Kitchen DP, Woods TA, et al. Laboratory 

Performance in the World Federation of Hemophilia 

EQA programme, 2003-2008. Haemophilia 

2009;15(1):571-7.



37

4.1  Clotting factor concentrates

1.  The WFH strongly recommends the use of viral-

inactivated plasma-derived or recombinant 

concentrates in preference to cryoprecipitate or 

fresh frozen plasma for the treatment of hemo-

philia and other inherited bleeding disorders. 

(Level 5) [1,2]

2.  The comprehensive WFH Guide for the Assess-

ment of Clotting Factor Concentrates reviews 

factors affecting the quality, safety, licensing, and 

assessment of plasma-derived products and the 

important principles involved in selecting suit-

able products for the treatment of hemophilia [2]. 

3.  The WFH also publishes and regularly updates 

a Registry of Clotting Factor Concentrates, which 

lists all currently available products and their 

manufacturing details [3]. 

4.  The WFH does not express a preference for 

recombinant over plasma-derived concentrates 

and the choice between these classes of product 

must be made according to local criteria.

5.  Currently manufactured plasma-derived concen-

trates produced to Good Manufacturing Practice 

(GMP) standards have an exemplary safety record 

with respect to lipid-coated viruses, such as HIV 

and HCV.


6.  Product safety is the result of efforts in several 

areas: 


 ■ improved donor selection (exclusion of at-risk 

donors)


 ■ improved screening tests of donations, 

including nucleic acid testing (NAT) 

 ■ type and number of in-process viral inactiva-

tion and/or removal steps 

7.  The risk of prion-mediated disease through 

plasma-derived products exists. In the absence 

of a reliable screening test for variant Creutzfeldt-

Jakob disease (vCJD), and with no established 

manufacturing steps to inactivate the vCJD 

prion, this problem is currently being handled 

by excluding plasma from all donors perceived 

to be at risk. As new information evolves in this 

field, constant awareness of current scientific 

recommendations is needed for those involved 

in making decisions regarding choice of clotting 

factor concentrate for people with hemophilia. 



Product selection

When selecting plasma-derived concentrates, consid-

eration needs to be given to both the plasma quality 

and the manufacturing process. Two issues deserve 

special consideration: 

 ■ Purity of product

 ■ Viral inactivation/elimination

4

HEMOSTATIC AGENTS



GUIDELINES FOR THE MANAGEMENT OF HEMOPHILIA

38

Purity



1.  Purity of concentrates refers to the percentage 

of the desired ingredient (e.g. FVIII), relative to 

other ingredients present. 

2.  There is no universally agreed classification of 

products based on purity.

3.  Concentrates on the market vary widely in their 

purity. 

4.  Some products have high or very high purity 

at one stage of the production process but are 

subsequently stabilized by albumin, which lowers 

their final purity. Generally speaking, products 

with higher purity tend to be associated with low 

manufacturing yields. These concentrates are, 

therefore, costlier. 

5.  Concentrates of lower purity may give rise to 

allergic reactions [4,5]. Patients who experience 

these repeatedly with a particular product may 

benefit from the administration of an antihista-

mine immediately prior to infusion or from use 

of a higher purity concentrate.

6.  Plasma-derived FVIII concentrates may contain 

variable amounts of von Willebrand factor 

(VWF). It is therefore important to ascertain a 

product’s VWF content (as measured by ristocetin 

cofactor activity) if it is used for the treatment 

of VWD [6]. 

7.  For treatment of FIX deficiency, a product 

containing only FIX is more appropriate than 

prothrombin complex concentrates, which also 

contain other clotting factors such as factors II, 

VII, and X, some of which may become acti-

vated during manufacture. Products containing 

activated clotting factors may predispose to 

thromboembolism. (Level 2) [7,8]

8.  The viral safety of products is not related to purity, 

as long as adequate viral elimination measures 

are in place. 

Viral inactivation/elimination

1.  In-process viral inactivation is the single largest 

contributor to the safety of plasma-derived 

concentrates [9]. 

2.  There is a growing tendency to incorporate two 

specific viral-reducing steps in the manufacturing 

process of concentrates. 

 ■ Heat treatment is generally effective against a 

broad range of viruses, both with and without 

a lipid envelope, including HIV, HAV, HBV, 

and HCV. 

 ■ Solvent/detergent treatment is effective against 

HBV, HCV, and HIV but does not inactivate 

non-enveloped viruses such as HAV. 

3.  Some viruses (such as human parvovirus B19) are 

relatively resistant to both types of process. None 

of the current methods can inactivate prions. 

4.  Nano (ultra) filtration can be used to remove 

small viruses such as parvovirus but filtration 

techniques currently in use do not eliminate the 

risk of transmission [10]. 

5.  A product created by a process that incorporates 

two viral reduction steps should not automati-

cally be considered better than one that only has 

one specific viral inactivation step.

6.  If only one step is used, this step should pref-

erably inactivate viruses with and without lipid 

envelopes.



FVIII concentrates

1.  FVIII concentrates are the treatment of choice 

for hemophilia A. 

2.  All plasma-derived products currently in the 

market are listed in the WFH Registry of Clotting 

Factor Concentrates [3]. Consult the product 

insert for specific details. 

Dosage/administration

1.  Vials of factor concentrates are available in 

dosages ranging from approximately 250 to 3000 

units each.

2.  In the absence of an inhibitor, each unit of 



FVIII per kilogram of body weight infused 

intravenously will raise the plasma FVIII level 

approximately 2 IU/dl. (Level 4) [11]

3.  The half-life of FVIII is approximately 8-12 hours.



HEMOSTATIC AGENTS

39

4.  The patient’s factor level should be measured 15 



minutes after the infusion to verify the calcu-

lated dose. (Level 4) [11]

5.  The dose is calculated by multiplying the patient’s 

weight in kilograms by the desired rise in factor 

level in IU/dl, multiplied by 0.5.



Example: 50 kg × 40 (IU/dl desired rise in level) 

× 0.5 = 1,000 units of FVIII. Refer to Tables 7-1 

and 7-2 for suggested factor level and duration of 

replacement required based on type of hemorrhage.

6.  FVIII should be infused by slow IV injection at 

a rate not to exceed 3 ml per minute in adults 

and 100 units per minute in young children, or 

as specified in the product information leaflet. 

(Level 5) [12]

7.  Subsequent doses should ideally be based on the 

half-life of FVIII and on the recovery in an indi-

vidual patient for a particular product.

8.  It is best to use the entire vial of FVIII once recon-

stituted, though many products have been shown 

to have extended stability after reconstitution. 

9.  Continuous infusion avoids peaks and troughs 



and is considered by some to be advantageous 

and more convenient. However, patients must 

be monitored frequently for pump failure. 

(Level 3) [13,14] 

10. Continuous infusion may lead to a reduction in 

the total quantity of clotting factor concentrates 

used and can be more cost-effective in patients 

with severe hemophilia [15]. However, this cost-

effectiveness comparison can depend on the doses 

used for continuous and intermittent bolus infu-

sions [16]. 

11. Dose for continuous infusion is adjusted based 

on frequent factor assays and calculation of clear-

ance. Since FVIII concentrates of very high purity 

are stable in IV solutions for at least 24-48 hours 

at room temperature with less than 10% loss of 

potency, continuous infusion for a similar number 

of hours is possible. 

FIX concentrates 

1.  FIX concentrates are the treatment of choice for 

hemophilia B. 

2.  All plasma-derived products currently in the 

market are listed in the WFH Registry of Clotting 

Factor Concentrates [3]. Consult the product 

information guide for specific details. 

3.  FIX concentrates fall into two classes:

 ■ Pure FIX concentrates, which may be plasma-

derived or recombinant. 

 ■ FIX concentrates that also contain factors II, 

VII, IX, and X, also known as prothrombin 

complex concentrates (PCCs), are only rarely 

used.


4.  Whenever possible, the use of pure FIX 

concentrates is preferable for the treatment of 

hemophilia B as opposed to PCC (Level 2) [7,8], 

particularly in the following instances: 

 ■ Surgery

 ■ Liver disease

 ■ Prolonged therapy at high doses

 ■ Previous thrombosis or known thrombotic 

tendency

 ■ Concomitant use of drugs known to have 

thrombogenic potential, including antifibri-

nolytic agents

5.  Pure FIX products are free of the risks of throm-

bosis or disseminated intravascular coagulation 

(DIC), which may occur with large doses of PCCs.

Dosage/administration

1.  Vials of FIX concentrates are available in doses 

ranging from approximately 250 to 2000 units 

each. 

2.  In absence of an inhibitor, each unit of FIX per 



kilogram of body weight infused intravenously 

will raise the plasma FIX level approximately 

1 IU/dl. (Level 4) [11] 

3.  The half-life is approximately 18–24 hours. 

4.  The patient’s FIX level should be measured 

approximately 15 minutes after infusion to 

verify calculated doses. (Level 4) [11]


GUIDELINES FOR THE MANAGEMENT OF HEMOPHILIA

40

5.  Recombinant FIX (rFIX) has a lower recovery 



than plasma-derived products, such that each unit 

of FIX per kg body weight infused will raise the 

FIX activity by approximately 0.8 IU/dl in adults 

and 0.7 IU/dl in children under 15 years of age. 

The reason for the lower recovery of rFIX is not 

entirely clear [17].

6.  To calculate dosage, multiply the patient’s weight 

in kilograms by the desired rise in factor level 

in IU/dl.

Example: 50 kg × 40 (IU/dl desired rise in level) 

= 2000 units of plasma-derived FIX. For rFIX, 

the dosage will be 2000 ÷ 0.8 (or 2000 × 1.25) = 

2500 units for adults, and 2000 ÷ 0.7 (or 2000 × 

1.43) = 2860 units for children. Refer to Tables 7-1 

and 7-2 for suggested factor level and duration of 

replacement therapy based on type of hemorrhage.

7.  FIX concentrates should be infused by slow 



IV injection at a rate not to exceed a volume 

of 3 ml per minute in adults and 100 units per 

minute in young children, or as recommended 

in the product information leaflet. (Level 5) [12] 

8.  If used, PCCs should generally be infused at 



half this rate. Consult the product information 

leaflet for instructions. (Level 2) [18]

9.  Purified FIX concentrates may also be admin-

istered by continuous infusion (as with FVIII 

concentrates). 

10. Allergic reactions may occur with infusions of 

FIX concentrates in patients with anti-FIX inhib-

itors. In such patients, infusions may need to be 

covered with hydrocortisone [19]. Changing the 

brand of clotting factor concentrate sometimes 

reduces symptoms.

4.2  Other plasma products

1.  The WFH supports the use of coagulation factor 



concentrates in preference to cryoprecipitate 

or fresh frozen plasma (FFP) due to concerns 

about their quality and safety. However, the 

WFH recognizes the reality that they are still 

widely used in countries around the world 

where it is the only available or affordable treat-

ment option. (Level 5) [1,2]

2.  Cryoprecipitate and FFP are not subjected to viral 

inactivation procedures (such as heat or solvent/

detergent treatment), leading to an increased 

risk of transmission of viral pathogens, which is 

significant with repeated infusions [1].

3.  Certain steps can be taken to minimize the risk 

of transmission of viral pathogens. These include:

 ■ Quarantining plasma until the donor has been 

tested or even retested for antibodies to HIV, 

hepatitis C, and HBsAg—a practice that is 

difficult to implement in countries where the 

proportion of repeat donors is low. 

 ■ Nucleic acid testing (NAT) to detect viruses—a 

technology that has a potentially much greater 

relevance for the production of cryoprecipi-

tate than for factor concentrates, as the latter 

are subjected to viral inactivation steps [20]. 

4.  Allergic reactions are more common following 

infusion of cryoprecipitate than concentrate [21]. 



Fresh frozen plasma (FFP)

1.  As FFP contains all the coagulation factors, it 

is sometimes used to treat coagulation factor 

deficiencies. 

2.  Cryoprecipitate is preferable to FFP for the 

treatment of hemophilia A. (Level 4) [22] 

3.  Due to concerns about the safety and quality of 



FFP, its use is not recommended, if avoidable 

(Level 4) [23]. However, as FFP and cryo-poor 

plasma contain FIX, they can be used for the 

treatment of hemophilia B in countries unable 

to afford plasma-derived FIX concentrates.

4.  It is possible to apply some forms of virucidal 

treatment to packs of FFP (including solvent/

detergent treatment) and the use of treated packs 

is recommended. However, virucidal treatment 

may have some impact on coagulation factors. 

The large scale preparation of pooled solvent/

detergent-treated plasma has also been shown to 

reduce the proportion of the largest multimers 

of VWF [24,25]. 


HEMOSTATIC AGENTS

41

Dosage/administration



1.  One ml of fresh frozen plasma contains 1 unit 

of factor activity. 

2.  It is generally difficult to achieve FVIII levels 

higher than 30 IU/dl with FFP alone. 

3.  FIX levels above 25 IU/dl are difficult to achieve. 

An acceptable starting dose is 15−20 ml/kg. 

(Level 4) [22]

Cryoprecipitate

1.  Cryoprecipitate is prepared by slow thawing of 

fresh frozen plasma (FFP) at 4°C for 10-24 hours. 

It appears as an insoluble precipitate and is sepa-

rated by centrifugation.

2.  Cryoprecipitate contains significant quantities of 

FVIII (about 3-5 IU/ml), VWF, fibrinogen, and 

FXIII but not FIX or FXI. The resultant super-

natant is called cryo-poor plasma and contains 

other coagulation factors such as factors VII, IX, 

X, and XI. 

3.  Due to concerns about the safety and quality 



of cryoprecipitate, its use in the treatment of 

congenital bleeding disorders is not recom-

mended and can only be justified in situations 

where clotting factor concentrates are not avail-

able. (Level 4) [1,22,26]

4.  Although the manufacture of small pool, viral-

inactivated cryoprecipitate has been described, it 

is uncertain whether it offers any advantage with 

respect to overall viral safety or cost benefit over 

conventionally manufactured large pool concen-

trates [27]. 

Dosage/administration

1.  A bag of cryoprecipitate made from one unit of 

FFP (200-250ml) may contain 70–80 units of 

FVIII in a volume of 30–40 ml. 

4.3  Other pharmacological options 

1.  In addition to conventional coagulation factor 

concentrates, other agents can be of great value 

in a significant proportion of cases. These include:

 ■ desmopressin

 ■ tranexamic acid

 ■ epsilon aminocaproic acid



Desmopressin (DDAVP)

1.  Desmopressin (1-deamino-8-D-arginine vaso-

pressin, also known as DDAVP) is a synthetic 

analogue of vasopressin that boosts plasma levels 

of FVIII and VWF [28]. 

2.  DDAVP may be the treatment of choice for 



patients with mild or moderate hemophilia 

A when FVIII can be raised to an appropriate 

therapeutic level because it avoids the expense 

and potential hazards of using a clotting factor 

concentrate. (Level 3) [28,29]

3.  Desmopressin does not affect FIX levels and is of 

no value in hemophilia B. 

4.  Each patient’s response should be tested prior to 



therapeutic use, as there are significant differ-

ences between individuals. The response to 

intranasal desmopressin is more variable and 

therefore less predictable. (Level 3) [28,29]

5.  DDAVP is particularly useful in the treatment 



or prevention of bleeding in carriers of hemo-

philia. (Level 3) [30]

6.  Although DDAVP is not licensed for use in 



pregnancy, there is evidence that it can be safely 

used during delivery and in the post-partum 

period in an otherwise normal pregnancy. Its 

use should be avoided in pre-eclampsia and 

eclampsia because of the already high levels 

of VWF. (Level 3) [31,32]

7.  Obvious advantages of DDAVP over plasma prod-

ucts are the much lower cost and the absence of 

any risk of transmission of viral infections. 

8.  DDAVP may also be useful to control bleeding 

and reduce the prolongation of bleeding time 

associated with disorders of hemostasis, including 

some congenital platelet disorders.



GUIDELINES FOR THE MANAGEMENT OF HEMOPHILIA

42

9.  The decision to use DDAVP must be based on 



both the baseline concentration of FVIII, the 

increment achieved, and the duration of treat-

ment required. 

Dosage/administration

1.  Though desmopressin is given subcutaneously 

in most patients, it can also be administered 

by intravenous infusion or by nasal spray. It is 

important to choose the correct preparation of 

desmopressin because some lower-dose prepara-

tions are used for other medical purposes. 

2.  Appropriate preparations include:

 ■ 4 µg/ml for intravenous use

 ■ 15 µg /ml for intravenous and subcutaneous 

use


 ■ 150 µg per metered dose as nasal spray

3.  A single dose of 0.3 µg /kg body weight, either 



by intravenous or subcutaneous route, can be 

expected to boost the level of FVIII three- to 

six-fold. (Level 4) [28,33]

4.  For intravenous use, DDAVP is usually diluted 

in at least 50–100 ml of physiological saline and 

given by slow intravenous infusion over 20–30 

minutes. 

5.  The peak response is seen approximately 60 

minutes after administration either intravenously 

or subcutaneously.

6.  Closely spaced repetitive use of DDAVP over 

several days may result in decreased response 

(tachyphylaxis). Factor concentrates may be 

needed when higher factor levels are required 

for a prolonged period. (Level 3) [34]

7.  Rapid infusion may result in tachycardia, flushing, 

tremor, and abdominal discomfort. 

8.  A single metered intranasal spray of 1.5 mg/ml 



in each nostril is appropriate for an adult. For 

an individual with a bodyweight of less than 

40 kg, a single dose in one nostril is sufficient. 

(Level 4) [35,36]

9.  Though the intranasal preparation is available, 

some patients find it difficult to use and it may be 

less efficacious than when given subcutaneously. 

10. As a result of its antidiuretic activity, water 

retention and hyponatremia can be a problem. 

When repeated doses are given, the plasma 

osmolality or sodium concentration should be 

measured. (Level 4) [28,37]

11. In most adults hyponatremia is uncommon. 

12. Due to water retention, DDVAP should be used 

with caution in young children and is contrain-

dicated in children under two years of age who 

are at particular risk of seizures secondary to 

cerebral edema due to water retention. (Level 4) 

[38,39]

13. There are case reports of thrombosis (including 



myocardial infarction) after infusion of DDAVP. 

It should be used with caution in patients with 

a history, or who are at risk, of cardiovascular 

disease(Level 4) [33]

Tranexamic acid

1.  Tranexamic acid is an antifibrinolytic agent that 

competitively inhibits the activation of plasmin-

ogen to plasmin. 

2.  It promotes clot stability and is useful as adjunc-

tive therapy in hemophilia and some other 

bleeding disorders [40].

3.  Regular treatment with tranexamic acid alone 



is of no value in the prevention of hemarthroses 

in hemophilia. (Level 4) [40]

4.  It is valuable, however, in controlling bleeding 



from skin and mucosal surfaces (e.g. oral 

bleeding, epistaxis, menorrhagia). (Level 2) 

[41-43]

5.  Tranexamic acid is particularly valuable in the 



setting of dental surgery and may be used to 

control oral bleeding associated with eruption 

or shedding of teeth. (Level 4) [42,44]

Dosage/administration

1.  Tranexamic acid is usually given as an oral tablet 

three to four times daily. It can also be given by 

intravenous infusion two to three times daily, 

and is also available as a mouthwash. 



HEMOSTATIC AGENTS

43

2.  Gastrointestinal upset (nausea, vomiting, or diar-



rhea) may rarely occur as a side effect, but these 

symptoms usually resolve if the dosage is reduced. 

When administered intravenously, it must be 

infused slowly as rapid injection may result in 

dizziness and hypotension. 

3.  A syrup formulation is also available for pedi-

atric use. If this is not available, a tablet can be 

crushed and dissolved in clean water for topical 

use on bleeding mucosal lesions.

4.  Tranexamic acid is commonly prescribed for 

seven days following dental extractions to prevent 

post-operative bleeding.

5.  Tranexamic acid is excreted by the kidneys and 

the dose must be reduced if there is renal impair-

ment in order to avoid toxic accumulation.

6.  The use of tranexamic acid is contraindicated for 

the treatment of hematuria as its use may prevent 

dissolution of clots in the ureters, leading to 

serious obstructive uropathy and potential perma-

nent loss of renal function. 

7.  Similarly, the drug is contraindicated in the 

setting of thoracic surgery, where it may result 

in the development of insoluble hematomas. 

8.  Tranexamic acid may be given alone or together 



with standard doses of coagulation factor 

concentrates. (Level 4) [45]

9.  Tranexamic acid should not be given to patients 



with FIX deficiency receiving prothrombin 

complex concentrates, as this will exacerbate 

the risk of thromboembolism. (Level 5) [46]

10. If treatment with both agents is deemed neces-



sary, it is recommended that at least 12 hours 

elapse between the last dose of APCC and the 

administration of tranexamic acid. (Level 5) [46]

11. In contrast, thromboembolism is less likely when 



tranexamic acid is used in combination with 

rFVIIa to enhance hemostasis. (Level 4) [47]

Epsilon aminocaproic acid

1.  Epsilon aminocaproic acid (EACA) is similar to 

tranexamic acid but is less widely used as it has 

a shorter plasma half-life, is less potent, and is 

more toxic [40]. 

Dosage/administration

1.  EACA is typically administered to adults orally 

or intravenously every four to six hours up to a 

maximum of 24 g/day in an adult. 

2.  A 250 mg/ml syrup formulation is also available.

3.  Gastrointestinal upset is a common complica-

tion; reducing the dose often helps. 

4.  Myopathy is a rare adverse reaction specifically 

reported in association with aminocaproic acid 

therapy (but not tranexamic acid), typically 

occurring after administration of high doses for 

several weeks. 

5.  The myopathy is often painful and associated 

with elevated levels of creatine kinase and even 

myoglobinuria. 

6.  Full resolution may be expected once drug treat-

ment is stopped.

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haemophilia A. Haemophilia 2001;7(3):258-66. 

31.  Mannucci PM. Use of desmopressin (DDAVP) during 

early pregnancy in factor VIII-deficient women. Blood 

2005;105(8):3382.

32.  Trigg DE, Stergiotou I, Peitsidis P, Kadir RA. A 

Systematic Review: The use of desmopressin for 

treatment and prophylaxis of bleeding disorders in 

pregnancy. Haemophilia 2012;18(1):25-33. 



HEMOSTATIC AGENTS

45

33.  Castaman G. Desmopressin for the treatment of 



haemophilia. Haemophilia 2008;14(Suppl 1):15-20.

34.  Mannucci PM, Bettega D, Cattaneo M. Patterns 

of development of tachyphylaxis in patients with 

haemophilia and von Willebrand disease after repeated 

doses of desmopressin (DDAVP). Br J Haematol 

1992;82(1):87-93.

35.  Khair K, Baker K, Mathias M, et al. Intranasal 

desmopressin (Octim): a safe and efficacious 

treatment option for children with bleeding disorders. 

Haemophilia 2007;13(5):548-51.

36.  Rose EH, Aledort LM. Nasal spray desmopressin 

(DDAVP) for mild hemophilia A and von Willebrand 

disease. Ann Intern Med 1991;114(7):563-8.

37.  Sica DA, Gehr TWG. Desmopressin: safety 

considerations in patients with chronic renal disease. 

Drug Safety 2006;29:553–556.

38.  Das P, Carcao M, Hitzler J. DDAVP-induced 

hyponatremia in young children. J Pediatr Hematol 

Oncol 2005;27(6):330-2.

39.  Smith TJ, Gill JC, Ambruso DR, Hathaway WE. 

Hyponatremia and seizures in young children given 

DDAVP. Am J Hematol 1989;31(3):199-202.

40.  Mannucci PM. Hemostatic drugs. N Engl J Med 1998 Jul 

23;339(4):245-53.

41.  Coetzee MJ. The use of topical crushed tranexamic 

acid tablets to control bleeding after dental surgery 

and from skin ulcers in haemophilia. Haemophilia 

2007;13(4):443-4.

42.  Frachon X, Pommereuil M, Berthier AM, et al. 

Management options for dental extraction in 

hemophiliacs: a study of 55 extractions (2000-2002). 

Oral Surg Oral Med Oral Pathol Oral Radiol Endod 

2005;99(3):270-5.

43.  Kouides PA, Byams VR, Philipp CS, et al. Multisite 

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laboratory haemostasis: a prospective crossover study of 

intranasal desmopressin and oral tranexamic acid. Br J 

Haematol 2009;145(2):212-20. 

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desmopressin in mild hemophilia A. Blood Coagul 

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Tranexamic acid combined with recombinant 

factor VIII increases clot resistance to accelerated 

fibrinolysis in severe hemophilia A. J Thromb Haemost 

2007;5(12):2408-14. 

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Haemophilia 2004 Sep;10 (Suppl 2):10-6.

47.  Giangrande PL, Wilde JT, Madan B, et al. Consensus 

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with inhibitors. Haemophilia 2009;15(2):501-8.


47

1.  Bleeding in patients with hemophilia can occur at 

different sites (see Table 1-2 and Table 1-3), each 

of which requires specific management. 

2.  As a general principle in case of large internal 

hemorrhage, hemoglobin should be checked 

and corrected while other measures are being 

planned. Measures of hemodynamic stability, 

such as pulse and blood pressure, should be moni-

tored as indicated. 

5.1  Joint hemorrhage (hemarthrosis)

1.  A joint bleed is defined as an episode character-

ized by rapid loss of range of motion as compared 

with baseline that is associated with any combina-

tion of the following: pain or an unusual sensation 

in the joint, palpable swelling, and warmth of the 

skin over the joint [1].

2.  The onset of bleeding in joints is frequently 

described by patients as a tingling sensation and 

tightness within the joint. This “aura” precedes 

the appearance of clinical signs. 

3.  The earliest clinical signs of a joint bleed are 

increased warmth over the area and discomfort 

with movement, particularly at the ends of range.

4.  Later symptoms and signs include pain at rest, 

swelling, tenderness, and extreme loss of motion. 

5.  A re-bleed is defined as worsening of the condi-

tion either on treatment or within 72 hours after 

stopping treatment [1]. 

6.  A target joint is a joint in which 3 or more sponta-

neous bleeds have occurred within a consecutive 

6-month period. 

7.  Following a joint bleed, flexion is usually the most 

comfortable position, and any attempt to change 

this position causes more pain. 

8.  Secondary muscle spasm follows as the patient tries 

to prevent motion and the joint appears “frozen”.

9.  The goal of treatment of acute hemarthrosis is to 

stop the bleeding as soon as possible. This should 

ideally occur as soon as the patient recognizes 

the “aura”, rather than after the onset of overt 

swelling and pain.

10. Evaluate the patient clinically. Usually, X-rays 

and ultrasound are not indicated.

11. Administer the appropriate dose of factor 

concentrate to raise the patient’s factor level 

suitably (refer to Tables 7-1 and 7-2). (Level 2) 

[2-5]

5

TREATMENT OF SPECIFIC 



HEMORRHAGES

GUIDELINES FOR THE MANAGEMENT OF HEMOPHILIA

48

12. The definitions listed in Table 5-1 are recom-



mended for the assessment of response to 

treatment of an acute hemarthrosis [1].

13. Instruct the patient to avoid weight-bearing, 

apply compression, and elevate the affected 

joint. (Level 3) [4]

14. Consider immobilizing the joint with a splint 

until pain resolves. 

15. Ice/cold packs may be applied around the joint 

for 15-20 minutes every four to six hours for 

pain relief, if found beneficial. Do not apply ice 

in direct contact with skin [39].

16. If bleeding does not stop, a second infusion 



may be required. If so, repeat half the initial 

loading dose in 12 hours (hemophilia A) or 24 

hours (hemophilia B). (Level 3) [4]

17. Further evaluation is necessary if the patient’s 

symptoms continue longer than three days. The 

presence of inhibitors, septic arthritis, or fracture 

should be considered if symptoms and findings 

persist.


18. Rehabilitation must be stressed as an active 


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