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.
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 Blood should be withdrawn into a plastic syringe or an evacuated collection system.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].
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].
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.
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-
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
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
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.
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
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.
= 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
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.
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
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
11. In most adults hyponatremia is uncommon. 12. Due to water retention, DDVAP should be used
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. References 1. Evatt BL, Austin H, Leon G, Ruiz-Sáez A, de Bosch N. Haemophilia therapy: assessing the cumulative risk of HIV exposure by cryoprecipitate. Haemophilia 1999;5(5):295-300. 2. Farrugia A. Guide for the assessment of clotting factor concentrates, 2 nd ed. Montreal: World Federation of Hemophilia, 2008. 3. Brooker M. Registry of Clotting Factor Concentrates, 9th edition. Facts and Figures monograph no 6. Montreal: World Federation of Hemophilia, 2012. 4. Brettler DB, Forsberg AD, Levine PH, Petillo J, Lamon K, Sullivan JL. Factor VIII:C concentrate purified from plasma using monoclonal antibodies: human studies. Blood 1989 May 15;73(7):1859-63. 5. Recht M, Pollmann H, Tagliaferri A, Musso R, Janco R, Neuman WR. A retrospective study to describe the incidence of moderate to severe allergic reactions to factor IX in subjects with haemophilia B. Haemophilia 2011 May;17(3):494-9.
GUIDELINES FOR THE MANAGEMENT OF HEMOPHILIA 44 6. Federici AB, Mannucci PM. Management of inherited von Willebrand disease in 2007. Ann Med 2007;39(5):346-58. 7. Kim HC, McMillan CW, White GC, et al. Purified factor IX using monoclonal immunoaffinity technique: clinical trials in hemophilia B and comparison to prothrombin complex concentrates. Blood 1992;79(3):568-75. 8. Lippi G, Franchini M. Pathogenesis of venous thromboembolism: when the cup runneth over. Semin Thromb Hemost 2008;34(8):747-61. 9. Giangrande PL. Blood products for hemophilia: past, present and future. BioDrugs 2004;18(4):225-34. 10. Burnouf T, Radosevich M. Nanofiltration of plasma- derived biopharmaceutical products. Haemophilia 2003 Jan;9(1):24-37. 11. Björkman S, Berntorp E. Pharmacokinetics of coagulation factors: clinical relevance for patients with haemophilia. Clin Pharmacokinet 2001;40(11):815-32. 12. Hemophilia of Georgia. Protocols for the treatment of hemophilia and von willebrand disease. Hemophilia of Georgia, 2012. http://www.hog.org/publications/page/ protocols-for-the-treatment-of-hemophilia-and-von- willebrand-disease-2 (Accessed June 6 2012). 13. Batorova A, Martinowitz U. Intermittent injections vs. continuous infusion of factor VIII in haemophilia patients undergoing major surgery. Br J Haematol 2000;110(3):715–20. 14. Martinowitz U, Luboshitz J, Bashari D, et al. Stability, efficacy, and safety of continuously infused sucrose- formulated recombinant factor VIII (rFVIII-FS) during surgery in patients with severe haemophilia. Haemophilia 2009;15(3):676-85. 15. Martinowitz U, Schulman S, Gitel S, et al. Adjusted dose continuous infusion of factor VIII in patients with haemophilia A. Br J Haematol 1992;82(4):729-34. 16. Mathews V, Viswabandya A, Baidya S, George B, Nair S, Chandy M, Srivastava A. Surgery for hemophilia in developing countries. Semin Thromb Hemost 2005 Nov;31(5):538-43. 17. Poon MC, Lillicrap D, Hensman C, Card R, Scully MF. Recombinant FIX recovery and inhibitor safety: A Canadian post-licensure surveillance study. Thromb Hemost 2002;87:431-5. 18. Ruiz-Sáez A, Hong A, Arguello A, Echenagucia M, Boadas A, Fabbrizzi F, Minichilli F, Bosch NB. Pharmacokinetics, thrombogenicity and safety of a double viral inactivated factor IX concentrate compared with a prothrombin complex concentrate. Haemophilia 2005;11(6):583-8. 19. Shibata M, Shima M, Misu H, et al. Management of haemophilia B inhibitor patients with anaphylactic reactions to FIX concentrates. Haemophilia 2003;9(3):269-71. 20. Chamberland ME. Surveillance for transfusion- transmitted viral infections in the United States. Biologicals 1998 Jun;26(2):85-8. 21. O’Shaughnesy DF, Atterbury C, Bolton Maggs P, et al. Guideline for the use of fresh frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 2004;126(1):11-28. 22. Stanworth SJ. The evidence-based use of FFP and cryoprecipitate for abnormalities of coagulation tests and clinical coagulopathy. Hematology Am Soc Hematol Educ Program 2007:179-86. 23. Kasper CK. Products for clotting factor replacement in developing countries. Semin Thromb Hemost 2005 Nov;31(5):507-12. 24. Budde U, Drewke E. Von Willebrand factor multimers in virus-inactivated plasmas and F VIII concentrates. Beitr Infusionsther Transfusionsmed 1994;32:408-14. 25. Chin S, Williams B, Gottlieb P, Margolis-Nunno H, Ben-Hur E, Hamman J, Jin R, Dubovi E, Horowitz B. Virucidal short wavelength ultraviolet light treatment of plasma and factor VIII concentrate: protection of proteins by antioxidants. Blood 1995 Dec 1;86(11):4331-6. 26. Chuansumrit A, Isarangkura P, Chantanakajornfung A, et al. The efficacy and safety of lyophilized cryoprecipitate in hemophilia A. J Med Assoc Thai 1999;82(Suppl 1):S69-73. 27. El-Ekiaby M, Sayed MA, Caron C, et al. Solvent- detergent filtered (S/D-F) fresh frozen plasma and cryoprecipitate minipools prepared in a newly designed integral disposable processing bag system. Transfus Med 2010;20:48-61. 28. Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 1997;90(7):2515-21. 29. Franchini M, Rossetti G, Tagliaferri A, et al. Dental procedures in adult patients with hereditary bleeding disorders: 10 years experience in three Italian Hemophilia Centers. Haemophilia 2005;11:504–9. 30. Leissinger C, Becton D, Cornell C Jr, Cox Gill J. High-dose DDAVP intranasal spray (Stimate) for the prevention and treatment of bleeding in patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease and symptomatic carriers of 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 management study of menorrhagia with abnormal laboratory haemostasis: a prospective crossover study of intranasal desmopressin and oral tranexamic acid. Br J Haematol 2009;145(2):212-20. 44. Franchini M, Zaffanello M, Lippi G. The use of desmopressin in mild hemophilia A. Blood Coagul Fibrinolysis 2010;21(7):615-9. 45. Hvas AM, Sorensen HT, Norengaard L, et al. 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. 46. Luu H, Ewenstein B. FEIBA safety profile in multiple modes of clinical and home-therapy application. Haemophilia 2004 Sep;10 (Suppl 2):10-6. 47. Giangrande PL, Wilde JT, Madan B, et al. Consensus protocol for the use of recombinant activated factor VII in elective orthopaedic surgery in haemophilic patients 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
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,
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.
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