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26THE USE OF RECOMBINANT FACTOR VIIa
S. Sobieszczyk and G. H. Brfborowicz
INTRODUCTION
As described in detail in other chapters of thisvolume, conditions with excessive bleeding, asare seen with uterine rupture, placenta accreta,abruption and uterine atony, often requireintensive resuscitation with blood componentsand coagulation factors. In such circumstances,blood transfusion may be life-saving, but onoccasion involves exposing the patient to addi-tional risks. Over the years, numerous effortshave been put forward to reduce these risks.One of the most spectacular is discussed in thischapter.
Recombinant activated factor VII (rFVIIa)(NovoSeven®; Novo Nordisk A/S, Bagsvaerd,Denmark) was developed for the treatment ofspontaneous and/or surgical bleeding episodesin patients with hemophilia A or B with forma-tion of allo-antibodies to FVIII or FIX afterreplacement therapy1–3. rFVIIa is currentlylicensed for this indication in most countriesworld-wide. The US Food and Drug Adminis-tration (FDA) licensed rFVIIa on March 25,1999 for bleeding episodes in patients withhemophilia A or B and inhibitors to FVIII orFIX. The FDA approved use of rFVIIa in 2005for additional indications such as surgical proce-dures in patients with hemophilia A or B andinhibitors, and treatment of bleeding episodesin patients with factor VII deficiency4. InEurope, it is also approved for use in bleedingepisodes in patients with acquired hemophiliadue to auto-antibodies against endogenousFVIII or FIX, surgical procedures in this groupof patients, and Glanzmann’s thrombasthenia.
Beyond its currently recognized indications,rFVIIa has been effectively used ‘off label’ on anempirical basis as a general hemostatic agent ina wide range of conditions associated with
acute, uncontrolled, or otherwise profoundbleeding, and in other clinical circumstancesassociated with excessive bleeding in patientswithout pre-existent coagulation defects5,6.Indeed, the early descriptions of the benefits ofrFVIIa in trauma patients7–9 were bolstered by acompassionate use study, which suggested thatrFVIIa administration could reverse massivebleeding, and thus significantly decrease trans-fusion requirements observed in critically ill,multi-transfused trauma patients10,11. Recently,rFVIIa was approved for the treatment ofhemorrhage associated with congenitalfactor VII deficiency12,13 and Glanzmann’sthrombasthenia14,15.
PECULIARITIES OF OBSTETRICHEMORRHAGE
Patients who develop massive, life-threateningpostpartum hemorrhage often have a combina-tion of ‘coagulopathic’ diffuse bleeding in addi-tion to ‘surgical bleeding’. Whereas bleedingfrom larger vessels may be controlled bysurgeons using a variety of operations (seeChapters 30–32), the ability to control diffusebleeding is limited and, in many cases, not feasi-ble. Thus administration of hemostatic drugsthat can control the coagulopathic componentof blood loss may reduce mortality and morbid-ity in such patients. Clinical experience pres-ently suggests that rFVIIa is a safe and effectivehemostatic measure in severe obstetric hemor-rhage, both as a adjunctive treatment to surgicalhemostasis as well as a ‘salvage’ or ‘rescue’ ther-apy where postpartum hemorrhage is refractoryto current pharmaceutical and ‘uterus sparing’surgical techniques. The ‘evidence’ behind thepreceding statement comes from three sources:
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(1) Studies on its mechanism of action;
(2) Accumulating reports in the literature; and
(3) Data from clinical studies.
All suggest that rFVIIa has the potential to func-tion as a ‘universal hemostatic agent’16 across arange of indications characterized by impairedthrombin generation in non-hemophilic patients,many of whom are critically ill and refractory toother hemostatic treatment options.
The usual manner for treating postpartumhemorrhage includes, first, non-invasive/non-surgical methods, including administration ofcrystalloid solutions and/or red blood cells,uterine massage, uterotonic medications(oxytocin, ergotamine, prostaglandins), and,second, invasive/surgical methods, e.g. ligationof uterine vessels, ligation of iliac arteries, angio-graphic embolism of uterine/iliac arteries, or theB-Lynch method. Unfortunately, the overalleffectiveness of such procedures to arrest hem-orrhage and prevent the need for emergencyhysterectomy is estimated to be only about50%17,18. Moreover, comparatively few centersworld-wide have access to the physical equip-ment or surgical manpower resources necessaryto conduct all the aforementioned procedures
COAGULATION FACTOR VII:THE HUMAN PROTEIN ANDRECOMBINANT PRODUCT
Structure of the human FVII (hFVII)
Human factor VII (eptacog alpha) is a serineprotease (molecular weight 50 kDa) composedof 406 amino acid residues, belonging to thegroup of vitamin K-dependent coagulationglycoproteins. The primary site of FVIIsynthesis in humans is the liver. Factor VIIis composed of four discrete domains:a γ-carboxyglutamic acid (Gla)-containingdomain, two epidermal growth factor (EGF)-like domains, and a serine protease domain. Allappear to be involved, to different extents, in anoptimal interaction with tissue factor (TF). TheGla domain of factor VII is also essential foractivation of factor X and other macromolecularsubstrates. The activation of factor VII to factorVIIa involves the hydrolysis of a single peptidebond between Arg152 and Ile153. The result is
a two-chain molecule consisting of a light chainof 152 amino acid residues and a heavy chainof 254 amino acid residues held together by asingle disulfide bond19,20 (Figures 1 and 2).
Production of rFVIIa using recombinantDNA technique
The development of rFVIIa was undertaken toalleviate the problems associated with the use ofplasma-derived factor VIIa, such as limited sup-ply and possible viral contamination. Multiplesteps were involved in the development of thisrecombinant protein. First, the human gene forfactor VII, located on chromosome 13, com-prising eight exons (coding regions), was iso-lated from the liver gene library. After standardamplification procedures used to generate mul-tiple copies of the hFVII gene, it was transfectedinto a baby hamster kidney cell line. A mastercell bank of the transfected cell line that secretesfactor VII in a single-chain form into the culturemedium was then established. During the laststeps, proteolytic conversion by autocatalysis tothe active two-chain form (rFVIIa) takes placein a chromatographic purification process,which was shown to remove exogenous viruses.No human serum or other proteins are used inthe production of rFVIIa (see Chapter 15). Theprotein backbone is identical with human puri-fied factor VIIa. The final product (rFVIIa),despite minor differences in carbohydratecomposition, is structurally similar to plasma-derived factor VIIa. The activity of rFVIIa issimilar to that of natural factor VIIa present inthe body21,22 (see Table 1).
Human activated factor VII (hFVIIa) orrecombinant activated factor VII (rFVIIa) is anaturally occurring initiator of hemostasis thatis vital to the coagulation process, as it combineswith tissue factor (TF) at the site of blood vesseldamage in a natural way, stimulates thrombingeneration, permits stable fibrin clot formation,and thereby the cessation of bleeding.
PHARMACOKINETIC STUDIES OFrFVIIa IN HUMANS
The pharmacokinetics of single-bolus dosesof rFVIIa have been studied in various adultpopulations: patients with hemophilia, patients
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with cirrhosis, and healthy volunteers. Thepharmacokinetic parameter values of rFVIIaafter bolus administration were similar. Theelimination half-life (t1/2) ranged from 2.45 to2.72 h and clearance (CL) ranged from 32.8to 34.9 ml/h.kg23. Lindley and colleaguesinvestigated the single-dose pharmacokineticsof rFVIIa, evaluated in three dose levels (17.5,35.0, 70 µg/kg) in hemophilic A/B patients withinhibitors. The results of these investigationsdemonstrate that the mean t1/2 of recombinantfactor VIIa is independent of dose level24.
Pharmacokinetic evaluations suggest theelimination of rFVIIa follows linear kineticswith a faster clearance rate and shorter t1/2 whenrFVIIa is administered for bleeding episodes(medians: 2.70 and 2.41 h, respectively) com-pared to non-bleeding indications (medians:3.44 and 2.89 h, respectively). Therefore, theduration of action may by shorter when rFVIIais used to control bleeding episodes. The
average percentage of the preparation found inplasma was significantly lower after administra-tion of rFVIIa in a dose of 70 µg/kg (42.7%)compared to doses of 17.5 µg/kg (50.1%)or 35 µg/kg (49.0%) (p = 0.0067). Additionaldoses for specific patient populations are war-ranted however23,24. An increased eliminationrate and lower recovery of rFVIIa during bleed-ing may be related to consumption throughcomplex formation with TF exposed at the siteof vessel damage and on the phospholipidsexposed on the activated platelet surface. Thevolume of distribution at steady state (Vss), istwo to three times that of plasma and similar tothe half-life of recombinant factor VIIa24.
MECHANISM OF HEMOSTATICACTION OF rFVIIa (see Figure 3)
Recombinant factor VIIa induces hemostasis atthe site of injury. The mechanism of action
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The use of recombinant factor VIIa
Figure 1 Three-dimensional molecular structure of factor VII. Reproduced with permission from NovoNordisk
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includes the binding of factor VIIa to theexposed tissue factor-dependent pathway and,independently of tissue factor, activation offactor X directly on the surface of activatedplatelets localized to the site of injury25,26.
The formation of the TF/FVIIa or TF/rFVIIa complex at the site of injury is necessaryto initiate hemostasis. TF is a membrane-boundglycoprotein, which normally is expressed oncells in the subendothelium and is only exposed
following injury. Tissue injury disrupts theendothelial cell barrier that normally separatesTF-bearing cells from the circulating blood.Once exposed to the blood, TF serves as ahigh-affinity receptor for FVIIa. FVIIa is foundin the circulation, comprising about 1% of thetotal circulating FVII protein mass in theplasma. It is endowed with very weak enzymaticactivity, which only becomes fully realized uponbinding to its cofactor, TF, at a site of vascularinjury25,26. Factor VIIa alone shows very littleproteolytic activity, only attaining its fullenzymatic potential when complexed to TF.
In studies using TF incorporated into lipidvesicles, van’t Veer and colleagues demon-strated that zymogen FVII acts as an inhibitorof FVIIa:TF-initiated thrombin generation.The addition of FVIIa at a concentration of10 nmol/l in hemophilic conditions overcomesthis inhibition and results in a thrombin genera-tion equivalent to normal. These data suggestthat the therapeutic effect of rFVIIa is due inpart to its ability to overcome the inhibitoryeffect of physiologic FVII on FVIIa:TF-initiatedthrombin generation27.
However, if TF is no longer available orexposed to the clotting factors in the blood-stream, e.g. when a platelet plug covers the TF-containing subendothelial space, or when TFactivity is inhibited by TFPI (tissue factor path-way inhibitor), then rFVIIa-mediated large-scale thrombin generation could take place onthe activated platelet surface independently ofTF28.
The initial formation of a TF/FVIIa or TF/rFVIIa complex allows activation of FIX andFX, and is crucial in generating the initial con-version of small amounts of prothrombin intothrombin (on the TF-bearing cells), which isessential to the amplification and propagationphase of coagulation. FXa cannot move to theplatelet surface because of the presence of
236
POSTPARTUM HEMORRHAGE
Figure 2 The active two-chain enzyme factorVIIa, is generated by specific cleavage AT Arg 152.Reproduced with permission from Novo Nordisk
Amino acid sequenceAmino acid compositionGamma-carboxylationPeptide mapBiological activityCarbohydrate composition
identicalidenticalidenticalidenticalidenticalsimilar
Table 1 Recombinant vs. plasma-derived FVIIa21
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normal plasma inhibitors, but instead remainson the TF-bearing cell and activates a smallamount of thrombin. Thrombin leads to theactivation of platelets and FV and FVIII at thesite of injury.
This small amount of thrombin is not suffi-cient for fibrinogen cleavage, but is critical forhemostasis, as it can activate platelets, activateand release FVIII from von Willebrand factor(vWF) or activate platelet and plasma FV, andFXI. FIXa moves to the platelet surface, whereit forms a complex with FVIIIa and activatesFX on the platelet surface. The activated
platelets provide for further thrombin genera-tion. Platelet-surface FXa is relatively protectedfrom normal plasma inhibitors and can complexwith platelet-surface FVa, where it activatesthrombin in quantities sufficient to provide forfibrinogen cleavage.
FIXa, FVIIIa and FVa bind efficiently to thesurface of the activated platelet and further acti-vation of FX into FXa occurs via the complexbetween FIXa and FVIIIa. During amplifica-tion, FXa complexes with FVa to generatethrombin and subsequently activate FV, FVIIIand platelets.
237
The use of recombinant factor VIIa
Figure 3 Mode of action of Eptacog alfa (activated) (with permission Novo Nordisk). (1) Tissue factor(TF)/FVIIa, or TF/rFVIIa interaction, is necessary to initiatiate hemostasis. (2) At pharmacologicalconcentrations, rFVIIa directly activates FX on the surface of locally activated platelets.This activation willinitiate the ‘thrombin burst’ independently of FVIII and FIX. This step is independent of TF. (3) Thethrombin burst leads to the formation of a stable clot
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At pharmacological concentrations (supra-physiological doses), rFVIIa also directlyactivates FX on the surface of locally activatedplatelets, helping to generate thrombin andfibrin (platelet-dependent TF-independentpathways). rFVIIa does not bind to restingplatelets. Instead, the effect of high-dose rFVIIa(which only activates FX on activated platelets)is localized to the sites of vessel injury where TFis exposed and platelets are activated29,30. Thisresults in the conversion of prothrombin intolarge amounts of thrombin. The full thrombinburst mediated by FXa in complex with FVa isnecessary for the formation of a fully stabilizedand solid fibrin hemostatic plug.
rFVIIa works by producing a stable fibrinclot directly at the site of vascular injury, bothdependently and independently of TF. Thisreaction provides an extremely strong activationof thrombin at the site of tissue damage, leadingto the formation of a stable fibrin network.Administration of rFVIIa might result in forma-tion of a more stable hemostatic plug by avariety of mechanisms, including enhancementof activation of thrombin activatable fibrinolysisinhibitor31, improvement of the physical prop-erties of the fibrin clot, enhancement of plateletactivation32, and possibly enhancement ofFXIII activation.
Lisman and colleagues observed that theenhanced thrombin generation from FVIIa notonly accelerates clot formation, but also inhibitsfibrinolysis by activation of thrombin activatablefibrinolytic inhibitor (TAFI) in factor VIII-deficient plasma28. rFVIIa binding to thrombin-activated platelets provides extra thrombin andthus ensures both full activation of TAFI andFXIII, and the formation of a dense fibrin struc-ture. The full thrombin burst generated con-verts fibrinogen into a firm plug that is resistantto premature lysis, thereby facilitating fullhemostasis.
MONITORING THE CLINICAL EFFECTOF rFVIIa
Currently, there is no good and/or satisfactorylaboratory method for monitoring the clinicaleffectiveness of rFVIIa. Administration ofrFVIIa results in shortening of the prothrombin
time (PT) and the activated partial thrombo-plastin time (APTT). The PT generally short-ens to around 7–8 s except in FV- orFX-deficient plasma, suggesting that patientscompletely deficient in FV and/or FX will notbenefit from therapy with this product33. PTmay not adequately reflect coagulation func-tion. The APTT shortening is due to the directactivation of FX by circulating FVIIa on thephospholipids used in the partial thrombo-plastin time test. Data indicate that clinicalimprovement during rFVIIa treatment is associ-ated with a shortening of APTT of 15–20 s33.Post-rFVIIa coagulation parameters normalizeas early as 20 min after infusion. Thus, theshortening of these two screening tests ofcoagulation does not necessarily reflect clinicaleffectiveness, which is judged subjectively.
Coagulopathy is usually easy to recognizeby the clinical assessment of ongoing bleeding,physical examination and observation of oozingfrom cut surfaces, intravascular catheter sitesor mucus membranes. The initial evaluationduring hemorrhage includes the PT, APTT,thrombin time (TT) and fibrinogen concentra-tion, antithrombin and platelet count. In theinterpretation of these tests, it is important toknow the normal range and to be aware of thesensitivity of the screening tests for each coagu-lation factor, as these vary from laboratoryto laboratory. In addition, assays of clottingparameters may provide different results withdifferent reagents, although these parameters donot show a direct correlation to the level ofhemostasis achieved. Finally, it is important toremember that laboratory coagulation para-meters may be used as an adjunct to theclinical evaluation of hemostasis for monitoringthe effectiveness and treatment schedule ofrFVIIa34.
Clotting parameters obtained prior to rFVIIaadministration are often outside the normalrange, perhaps indicating the developmentof dilutional or consumption coagulopathy inthese patients. Post rFVIIa, clotting parametersimprove, but do not normalize, and thus cannotbe used as predictors of rFVIIa efficacy.
Laboratory monitoring of the efficacy ofrFVIIa treatment is helpful. The effect on PTis particularly marked, but this does notalways translate to clinically improved blood
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coagulation. Similarly, measurement of the levelof FVII in plasma does not correlate with clini-cal efficacy. Study of the effects of rFVIIa onmonitoring plasma FVIIa levels demonstrates alinear relationship between the concentration ofFVIIa and FVII:C (functional clotting ability),but the therapeutic concentration range forFVIIa has not yet been established. The use ofplasma VIIa levels is controversial, and is not anassay that is widely available.
Levels of functional fibrinogen andantithrombin do not change during repeatedinjections of rFVIIa for the treatment of hemor-rhage. The minimal changes that occur post-operatively are not greater than those seen withpatients who do not have coagulation disorders.Nonetheless, it is still advisable to monitorpatients at risk of systemic activation.
Telgt and colleagues showed that lowconcentration of rFVIIa, in the absence of TF,can activate FX as assayed by the PT33,35.Higher concentration of rFVIIa had no addi-tional effect on the PT. At rFVIIa doses wellbelow the clinically therapeutic dose, a maxi-mum shortening of the PT occurs. Thus, atdoses in the clinically therapeutic range, no fur-ther effect on the PT is observed. This suggeststhat, at concentrations typical for clinical use,tests based on the PT are not useful formonitoring the effect of rFVIIa. Telgt andcolleagues, in an experimental study, observedthat rFVIIa effectively reduced PT and APTTin normal and deficient (FVIII, FIX, FXI,FXII) plasma. This reduction of both para-meters (PT and APTT) has been attributed tothe ability of rFVIIa to directly activate FX,even in the absence of TF34,35.
The best available indicator of rFVIIaefficacy is the arrest of hemorrhage judgedby visual evidence, hemodynamic stabilizationand reduced demand for blood components36.There is currently no satisfactory laboratory testto monitor the clinical effectiveness of rFVIIa.
SAFETY OF rFVIIa
The complex coagulopathy and high complica-tion rates seen in patients with intractablepostpartum hemorrhage, together with theunderstanding of the localized mechanismof action of rFVIIa, and the low risk
of thromboembolic complications followingadministration of the drug both in animal mod-els and in clinical use, all suggest that rFVIIa is auseful adjunctive therapy for control of severepostpartum hemorrhage. Recombinant FVIIa isa manufactured product, does not contain anyhuman plasma components, and therefore isfree from viral contamination. Neither albuminnor any other human protein is used in its man-ufacturing process. This means that there is norisk of transmission of human viruses or prions.Strict quality control standards are applied tothe fermentation process as well as the subse-quent extensive purification measures. Geneticrecombination eliminates the dependency ondonors and allows for the production ofunlimited amounts of the medication20.
Safety analyses demonstrate that rFVIIais associated with very few treatment-relatedadverse events and is very well tolerated. Thus,experience with recombinant factor VIIa inseveral thousand patients has shown that theincidence of non-serious adverse events is 13%and serious adverse events are less than 1%37.
Aledort calculated that the risk of rFVIIa-related thrombosis is 25 per 105 infusions38.Despite the mechanism of action, use of rFVIIain DIC and sepsis remains controversial. Sev-eral reports suggest that rFVIIa may be usedsafely in such situations, without induction ofthrombotic complications or when conventionalreplacement therapy with fresh frozen plasmaand red blood cell concentrates fails to provide ahemostatic response. Non-serious side-effectsare rarely seen during treatment with recombi-nant factor VIIa; the most common being painat the infusion site, fever, headache, vomiting,changes in the blood pressure and skin-relatedhypersensitivity reactions. Adverse events havenot been related to dose.
OUR EXPERIENCE
Between 2000 and 2006 in the Departmentof Gynecology and Obstetrics, University ofMedical Sciences, Poznan we used rFVIIa inalmost 45 cases of postpartum hemorrhage39–46.According to data gathered from other areas ofPoland, we estimate that it has been usedin approximately 100 cases of postpartumhemorrhage.
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The use of recombinant factor VIIa
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The data presented below concern our first18 patients in whom rFVIIa was used. Detailedinformation is presented in Tables 2–5. Ourpatient data were obtained when we were usinga study protocol and were prepared to use thedrug. This was not always the case in othercenters (see Table 6).
Recombinant FVIIa was administered intra-venously at doses of 16.6–48 µg/kg. In mostcases, single administration of rFVIIa was suffi-cient. However, in severe coagulopathy coexist-ing with postpartum hemorrhage or prolongedperiods of treatment (transfusions, complica-tions of shock) and recurrent bleeding, a seconddose similar to the initial dose was necessary tocontrol the bleeding.
Conclusions
The analysis of our data clearly shows thatrFVIIa was an effective hemostatic drug, whichsignificantly decreased bleeding and led to therapid stabilization of our patients’ conditions.Clearly, the early use of this agent decreases theamount of transfused preparations. An impor-tant secondary observation was the contractionof the uterus after the drug application inpatients who had qualified for hysterectomyshortly before the drug was administered. Wesuggest that rFVIIa should be administered inevery case in which embolization of uterinearteries is being considered. Coagulationparameters showed typical shortening of PTand APTT; however, the clinical effect – controlof bleeding – was the most important overalleffect of the drug. There were no complicationsof rFVIIa administration. The dose, timing ofadministration after the diagnosis of postpartumhemorrhage, and the apparent ability toenhance uterine contractility will need furtherstudy in the future.
WORLD-WIDE EXPERIENCE
Tables 6–8 present the world-wide experiencewith rFVIIa in obstetric hemorrhage. Theresults reported in the literature support thebenefit of rFVIIa therapy in obstetric cases withmajor/life-threatening hemorrhage, even inthe presence of disseminated intravascularcoagulopathy (DIC)-like ‘coagulopathy’. Theydemonstrate that rFVIIa is highly effective andsafe in allowing quick arrest of life-threateningpostpartum hemorrhage unresponsive to con-ventional treatments. Treatment with rFVIIaled to a reduction in the use of blood productsin this relatively large group of patients, decreas-ing blood product exposure for patients and
240
POSTPARTUM HEMORRHAGE
Numberof patients
Number of postpartum hemorrhages 18
Cause of bleeding/complicationsUterine atonyGenital tract traumaDisseminated intravascular coagulationShock
818
18
Reoperations before rFVIIa administrationObstetric hysterectomy*
72
*In six cases, hysterectomy was not performed.rFVIIa was administered after the decision to oper-ate was made due to uncontrolled, life-threateningbleeding. After its administration, the bleedingstopped and the operation was not necessary. Intwo women, hysterectomy was performed in anotherhospital, before the patients were transported to ourdepartment
Table 2 Clinical details of patients with severe,recurring and uncontrollable bleeding post-delivery
Blood loss Median (range) (ml)
Before rFVIIaAfter rFVIIa
3000 (1800–6800)0.00 (0–350)
Table 3 Blood loss before and after rFVIIaadministration
Before rFVIIa After rFVIIa
Median(range) U/P
Median(range) U/P
Red bloodcell (IU)
Fresh frozenplasma (IU)
6 (3–13)
4 (1–8)
6
4
4 (0–9)
2 (0–9)
3
2
U/P, units per patient
Table 4 Transfusion needed before and afterrFVIIa administration
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sparing an expensive and limited resource.Administration of rFVIIa should be also con-sidered before hysterectomy and as an adjunctto invasive/surgical procedures, before they areundertaken. This is particularly true in patientswho wish to preserve fertility
Conclusions
Randomized controlled studies are required todetermine the optimal dose and dose scheduleof rFVIIa for intractable postpartum hemorrhageand to investigate whether the need for hyster-ectomy/surgical procedures and overall morbid-ity rates can be reduced by earlier treatmentwith higher doses of rFVIIa. In the meanwhile,clinicians caring for acutely bleeding obstetricpatients should be aware of the potential ofrFVIIa to arrest life-threatening postpartumhemorrhage. Although an expensive product,a trial of one to four doses of rFVIIa can bejustified in cases of uncontrolled bleeding whichpersists despite maximal medical and surgicaltreatment to achieve hemostasis.
Although the limitations of anecdotal casedata are recognized, in the absence of efficacyand safety data from randomized trials, volun-tary registry submissions are being used to pro-vide a preliminary insight into the scope of thelow incidence of clinical problems, as well as theusefulness and adverse effects of this medicationwhen it is used ‘off-label’.
rFVIIa dose
When a rationale for using rFVIIa was stated, itwas most commonly ‘last-resort’ therapy, after
other clinical measures had failed. There wasno clear correlation between the severity ofbleeding and the dose of rFVII administered.Possibly the ‘timing’ determined the level of thedosing.
Efficacy
Bleeding either stopped, markedly decreasedor decreased following rFVIIa administration in54 of the cases. In one patient, there was noresponse to therapy with rFVIIa. Also only inone patient after an early significant reductionof bleeding, recurrence was observed. In gen-eral, however, the rapid onset of action meansthat rFVIIa can be used in the perioperativeperiod. There was no clear correlation betweenthe speed of response and either the type of pro-cedure performed, the severity of the bleedingcondition, or the dose of rFVIIa given.
Most patients continued to require someform of blood product replacement therapyduring the 24 h following rFVIIa administra-tion, but the need was greatly reducedcompared with the 24 h prior to rFVIIa admin-istration. No correlation existed betweenbaseline and post-rFVIIa administration inlaboratory measurements and the predictabilityof response to rFVIIa (data obtained fromreferences but not presented in tables). Further-more, of great importance, the results observedin these tables of cases of postpartum hemor-rhage suggest that rFVIIa may be administeredeven in the presence of DIC-like ‘coagulo-pathy’. In the patients shown in Tables 6–8,major conditions reported to be associatedwith postpartum hemorrhage included some
241
The use of recombinant factor VIIa
ParameterNormal
rangeBeforerFVIIa
2 hoursafter rFVIIa
4 hoursafter rFVIIa
12 hoursafter rFVIIa
PT (s)
APTT (s)
PLT (Gpt/l)
11.5–13.5
25–37
140–440
17.35(11.9–26.7)
55.00(26–81)76.50
(21–223)
11.10(9.1–18.3)
35.00(26–76)70.00
(20–197)
11.25(9.1–17.6)
36.80(22–69)69.50
(19–186)
12.65(11.2–17.1)
39.10(24–60)70.50
(37–165)
PT, prothrombin time; APTT, activated partial thromboplastin time; PLT, platelets
Table 5 Selected laboratory tests before and after rFVIIa administration. Data are given as median (range)
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242
POSTPARTUM HEMORRHAGE
Yea
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Dos
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ts
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471
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ctio
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nal
failu
re;s
ever
ein
tra-
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ngaf
ter
CS
CS
HY
SN
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thy
ster
ecto
my;
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inte
rval
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afte
r2
sing
ledo
ses;
sign
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481
Con
geni
talF
VII
defic
ienc
y(1
%be
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appl
icat
ion
ofrF
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ence
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lata
tion
ofth
ece
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als
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ence
ofbl
eedi
ngT
hefi
rst
case
ofa
preg
nant
wom
anw
ith
FV
IIde
fici
ency
rece
ivin
grF
VII
ain
trap
artu
m
2002
491
Acq
uire
dhe
mop
hilia
(FV
III
0.5%
)
VD
HY
SR
BC
(65)
;FF
P(6
0);C
RY
O(6
0);
vWF
(3×
500)
;F
VII
I(3
0×
1068
);F
IX(2
6×
600)
;18
gsa
ndog
lobu
lin
NA
(mas
sive
)11
days
post
-del
iver
y;la
stre
sort
160
Ble
edin
gst
oppe
d(r
apid
ly)
2002
501
2-h
post
CS
mas
sive
vagi
nal
blee
ding
;sho
ck;
DIC
,HE
LL
P
CS
No
RB
C(1
2);F
FP
(10)
;PP
Ts
(8);
CR
YO
(950
)
NA
Las
tre
sort
90B
leed
ing
stop
ped
Nor
mal
izat
ion
ofco
agul
atio
nte
sts
2003
511
Ble
edin
gfr
omth
epl
acen
tabe
din
low
erut
erin
ese
gmen
tan
dce
rvic
alca
nal
CS
Und
er-r
unni
ngsu
ture
sin
the
plac
enta
bed;
appl
icat
ion
ofho
tpa
cks;
dire
ctm
anua
lta
mpo
nade
wit
hsu
rgic
alga
uze;
inse
rtio
nof
intr
a-ce
rvic
alF
oley
’sca
thet
erba
lloon
RB
C(1
.5);
FF
P(5
00m
l)>
3000
Las
tre
sort
90B
leed
ing
stop
ped
(15)
The
ballo
onw
asre
mov
edon
the
firs
tpo
stop
erat
ive
day
Tab
le6
Clin
ical
char
acte
rist
ics
ofpa
tien
tsw
ith
risk
ofse
vere
,rec
urri
ngan
dun
cont
rolla
ble
bloo
dlo
ssdu
ring
deliv
ery
and
post
part
um:l
iter
atur
ere
view
264Z:\Sapiens Publishing\A5211 - Postpartum Hemorrhage\Make-up\Postpartum Hemorrhage - Voucher Proofs #T.vp30 August 2006 14:21:30
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243
The use of recombinant factor VIIa
2003
522
(cas
e1)
uter
ine
rupt
ure,
shoc
k(c
ase
2)ut
erin
eat
ony
(cas
e1)
VD
(cas
e2)
eCS
(cas
e1)
subt
otal
HY
S(c
ase
1)R
BC
(10)
;F
FP
(4)
(cas
e2)
RB
C(5
)
NA
(cas
e1)
intr
aope
rati
ve(c
ase
2)be
fore
plan
ned
hyst
erec
tom
y
NA
Ble
edin
gst
oppe
d(f
ewm
inut
es)
(cas
e2)
Hys
tere
ctom
yw
asav
oide
d
2003
531
Ute
rine
aton
y;sh
ock
IVD
lapa
roto
my:
bila
tera
lart
ery
ligat
ion;
subt
otal
HY
S;p
acki
ngof
pelv
is
Bef
ore
1st
adm
inis
trat
ion
RB
C(4
2);F
FP
(31)
;P
PT
s(4
);(d
esm
opre
ssin
)be
fore
2nd
adm
inis
trat
ion
FF
P(3
);P
PT
s(2
)
NA
Pos
tla
paro
tom
y60
;120
2-h
inte
rval
,(2
ndfo
rco
nsol
idat
ion)
Ble
edin
gst
oppe
dC
ardi
acar
rest
,re
susc
itat
ion;
high
-pre
ssur
eve
ntila
tion
,pu
lmon
ary
edem
a,pn
eum
otho
rax,
AR
DS
2003
541
Ute
rine
aton
y,pr
e-ec
lam
psia
CS
HY
SR
BC
(3);
FF
P(2
);C
RY
O(6
)N
AIn
trao
pera
tive
(CS
)be
fore
hyst
erec
tom
y
12B
leed
ing
sign
ific
antl
yre
duce
d
Dur
ing
gene
ral
anes
thes
iain
duct
ion,
faile
din
tuba
tion
was
follo
wed
byca
rdia
car
rest
;po
stop
erat
ivel
yD
IC;A
RD
S;t
rans
iten
ceph
alop
athy
,an
dbr
achi
alve
nous
eth
rom
bosi
s(F
olck
man
nsy
ndro
me)
2003
552
(cas
e1)
cong
enit
alde
ficie
ncy
ofF
VII
(2%
befo
reap
plic
atio
nrF
VII
a)(c
ase
2)liv
erdy
sfun
ctio
n
(cas
e1)
VD
(cas
e2)
CS
No
No
No
evid
ence
ofbl
eedi
ng(c
ase
1)P
roph
ylac
tic
firs
tdo
seat
com
plet
edi
lata
tion
ofth
ece
rvix
(cas
e2)
prop
hyla
ctic
befo
reC
S
(cas
e1)
60;
30(5
)ev
ery
2h.
(cas
e2)
90
No
evid
ence
ofbl
eedi
ng(c
ase
2)N
oev
iden
ceof
FV
IIde
ficie
ncy
2003
561
AF
E,D
ICC
SH
YS
;pel
vic
pack
ing
RB
C(1
2);F
FP
(8);
(apr
otin
in)
NA
Las
tre
sort
60B
leed
ing
sign
ific
antl
yre
duce
d
MO
F,d
ied co
ntin
ued
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244
POSTPARTUM HEMORRHAGE
Yea
rR
ef.
nP
rovo
catio
nof
blee
dT
ype
ofde
liver
yS
urgi
calt
reat
men
t
Blo
odpr
oduc
tsgi
ven
pre-
rFV
IIa
(uni
ts)
(hem
osta
ticag
ents
)
Blo
odlo
ssbe
fore
rFV
IIa
(ml)
Tim
ing
(whe
nrF
VII
agi
ven)
Dos
eof
rFV
IIa
(µg/
kg)
(num
ber
ofdo
ses)
Ove
rall
blee
ding
resp
onse
torF
VII
a(m
in)
Com
men
ts
2004
571
Ute
rine
rupt
ure;
shoc
k;D
ICIV
D3
lapa
roto
my:
1st:
HY
S;2
nd:
pack
ing
ofpe
lvis
;3r
d:sm
alla
rter
ies
ligat
edin
the
broa
dlig
amen
ts
Bef
ore
1st
adm
inis
trat
ion:
RB
C(2
6);F
FP
(11)
;PP
Ts
(10)
;P
CC
(120
0).
Tot
al:R
BC
(27)
;F
FP
(27)
;PP
Ts
(10)
;22
plat
elet
pher
esis
;(t
rane
xam
icac
id)
4000
to2n
dla
paro
tom
y;be
fore
3rd
lapa
roto
my
sudd
enin
crea
seof
blee
ding
1350
lin
1h
Bef
ore,
intr
a-an
dpo
stop
erat
ive
peri
od;l
ast
reso
rt
120
(19)
,sta
rtbe
fore
2nd
lapa
roto
my,
repe
ated
follo
win
gne
xt2
days
.F
irst
two
dose
s(1
stla
paro
tom
y)at
1-h
inte
rval
s,ne
xtdo
ses
duri
ngth
e2n
dda
y3
dose
s;ne
xtda
ytw
odo
ses
at1-
hin
terv
als
follo
wed
furt
her
dose
sev
ery
3h
Ble
edin
gsi
gnif
ican
tly
redu
ced
orst
oppe
d;re
curr
ent
blee
ding
was
obse
rved
Car
diac
arre
st,
resu
scit
atio
nbe
fore
2nd
lapa
roto
my
(hyp
erka
lem
ia8.
5m
mol
/l,hy
poth
erm
ia32
°C);
MO
FR
ecur
rent
blee
ding
was
obse
rved
beca
use
pati
ent
deve
lope
dse
vere
hypo
ther
mia
,ac
idos
is,h
ypox
ia,
dilu
tion
coag
ulop
athy
,all
thes
ere
duce
dth
eef
fica
cyof
rFV
IIa
invi
vo.
2004
582
Ute
rine
aton
y,sh
ock;
seve
reco
agul
opat
hy
(cas
e1)
CS
(cas
e2)
CS
(cas
e1)
ligat
ion
ofhy
poga
stri
car
teri
es(c
ase
2)la
paro
tom
y;lig
atio
nof
hypo
gast
ric
arte
ries
(cas
e1)
RB
C(1
9);
FF
P(3
350
ml)
;P
PT
s(9
00m
l);
fibri
noge
n(3
g);
[apr
otyn
in]
(cas
e2)
RB
C(2
2);
FF
P(3
400
ml)
;P
PT
s(3
400
ml)
;P
PT
s(3
00m
l);
fibri
noge
n(2
g);
[apr
otyn
in]
(cas
e1)
200
ml/h
(cas
e2)
2000
ml,
hem
o-pe
rito
neum
Las
tre
sort
(cas
e1)
60(c
ase
2)60
Ble
edin
gst
oppe
d(r
apid
ly)
(cas
e1)
4w
eeks
late
rde
velo
ped
thro
mbo
sis
ofbo
thov
aria
nve
ins
2004
591
Pla
cent
apr
evia
;ac
cret
a;D
ICC
SN
oR
BC
(11)
;FF
P(4
);C
RY
O(6
)10
00(i
nth
edr
ain)
5h
afte
rC
S
12m
gB
leed
ing
stop
ped
(few
hour
s)
2004
601
Gla
nzm
ann’
sth
rom
bast
heni
aV
DN
oP
PT
s(4
)N
oev
iden
ceof
blee
ding
Pro
phyl
acti
c36
(2)
1st
duri
ngva
gina
lde
liver
y,2n
d2
haf
ter
deliv
ery
800
ml
(int
ra-
and
post
part
umbl
ood
loss
)
rFV
IIa
may
offe
ran
alte
rnat
ive
opti
onin
pati
ents
wit
hG
lanz
man
n’s
thro
mba
sthe
nia
duri
ngde
liver
y
Tab
le6
Con
tinue
d
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245
The use of recombinant factor VIIa
2004
611
AF
E;D
IC(d
evel
oped
2m
inaf
ter
deliv
ery)
CS
No
RB
C(6
);F
FP
(1);
PP
Ts
(2)
3000
90H
emos
tasi
sw
asse
cure
dw
ithi
n30
min
2004
623
(cas
e1)
Ecl
amps
ia;
HE
LL
P;
cons
umpt
ive
coag
ulop
athy
;su
bcap
sula
rliv
erhe
mat
oma
wit
hca
psul
eru
ptur
e(c
ase
2)pl
acen
tape
rcre
ta,
pre-
ecla
mps
ia;
HE
LL
P(c
ase
3)pr
e-ec
lam
psia
;H
EL
LP
;pla
cent
aac
cret
a;co
nsum
ptiv
eco
agul
opat
hy;
seve
reva
gina
lbl
eedi
ngan
dut
erin
ecr
ampi
ng
(cas
e1)
CS
(cas
e2)
CS
(cas
e3)
CS
No
(cas
e1)
RB
C(1
6);
FF
P(1
4);P
PT
s(1
8);C
RY
O(1
0);
(cas
e2)
RB
C(8
);F
FP
(4);
PP
Ts
(6)
(cas
e3)
RB
C(2
);F
FP
(4);
PP
Ts
(6);
CR
YO
(10)
(cas
e1)
2500
(cas
e2)
3000
(cas
e3)
1300
last
reso
rt(c
ase
1)90
(2)
(cas
e2)
120
(3);
90(2
)2-
hin
terv
als
(cas
e3)
90(2
)2-
hin
terv
al
Ble
edin
gco
ntro
lled
(cas
e1)
pati
ent
deve
lope
dan
uric
rena
lfai
lure
;car
diac
arre
st;p
atie
ntdi
ed;
noev
iden
ceof
syst
emic
thro
mbo
sis
iden
tifie
d(c
ase
2)no
futu
retr
ansf
usio
nre
quir
emen
t;co
agul
atio
npr
ofile
stab
ilize
d
2004
631
Pre
-ecl
amps
ia;
HE
LL
P;D
IC;
shoc
k
eCS
Lap
arot
omy
12h
afte
rC
S,b
ecau
sein
tra-
abdo
min
alhe
mor
rhag
e
RB
C(2
2);F
FP
(18)
;PP
Ts
(30)
;C
RY
O(2
0);
(apr
otyn
in)
3500
inab
dom
inal
cavi
tyan
d60
0po
stop
erat
ivel
yfr
omdr
ains
Pos
tla
paro
tom
y90
Ble
edin
gre
duce
d(3
0),
Ble
edin
gst
oppe
d(1
80)
2005
643
(cas
e1)
Ute
rine
aton
y,sh
ock
(cas
e2)
plac
enta
prev
ia,u
teri
neat
ony
(cas
e3)
lace
rati
onof
vagi
na,a
tony
,co
nsum
ptiv
eco
agul
opat
hy
(cas
e1)
CS
(cas
e2)
VD
(cas
e3)
IVD
(cas
e1)
rela
paro
tom
yw
ith
intr
acav
itar
yox
ytoc
inin
ject
edin
toth
eut
erus
;lig
atur
eof
both
uter
ine
arte
ries
;pl
acem
ent
ofB
-Lyn
chsu
ture
s
(cas
e1)
RB
C(7
);F
FP
(9);
(cas
e2)
RB
C(1
0);
FF
P(1
3);P
PT
s(2
)(c
ase
3)R
BC
(13)
;F
FP
(16)
;PP
Ts
(2)
NA
(cas
e1)
befo
rere
lapa
roto
my
(cas
es2,
3)la
st-r
esor
t
(cas
e1)
120
(2)
1-h
inte
rval
(cas
e2)
60(2
)w
ithi
n3
h(c
ase
3)12
0(2
)
(cas
e1)
Ble
edin
gst
oppe
d(c
ase
2)B
leed
ing
stop
ped
(cas
e3)
Ble
edin
gst
oppe
d
Impr
ove
coag
ulat
ion
para
met
ers co
ntin
ued
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246
POSTPARTUM HEMORRHAGE
Yea
rR
ef.
nP
rovo
catio
nof
blee
dT
ype
ofde
liver
yS
urgi
calt
reat
men
t
Blo
odpr
oduc
tsgi
ven
pre-
rFV
IIa
(uni
ts)
(hem
osta
ticag
ents
)
Blo
odlo
ssbe
fore
rFV
IIa
(ml)
Tim
ing
(whe
nrF
VII
agi
ven)
Dos
eof
rFV
IIa
(µg/
kg)
(num
ber
ofdo
ses)
Ove
rall
blee
ding
resp
onse
torF
VII
a(m
in)
Com
men
ts
2005
651
Ute
rine
aton
y;sh
ock;
DIC
CS
HY
S;p
acki
ngof
the
pelv
isN
AN
AB
efor
ere
lapa
roto
my
and
ligat
ion
hypo
gast
ric
arte
ry
2.4
mg
Ble
edin
gco
ntro
lled
(rap
idre
spon
se)
Res
olut
ion
ofth
eco
agul
opat
hy
2005
664
Ute
rine
aton
yV
DU
teru
san
dva
gina
tam
pona
deN
A(c
ase
1)16
00(c
ase
2)24
00(c
ase
3)11
00(c
ase
4)25
00
befo
rede
velo
ped
seve
reco
agul
opat
hy,
surg
ical
proc
edur
es;
avoi
ded
mas
sive
tran
sfus
ion
(cas
e1)
82(c
ase
2)73
(cas
e3)
61(c
ase
4)72
(cas
e1)
Ble
edin
gst
oppe
d(1
5)(c
ase
2)B
leed
ing
stop
ped
(25)
(cas
e3)
Ble
edin
gst
oppe
d(3
5)(c
ase
4)B
leed
ing
stop
ped
(40)
Low
erth
anst
anda
rddo
ses
may
beef
fect
ive
whe
nre
spec
tgo
odti
min
g,be
fore
com
plic
atio
nde
velo
ps
2005
673
(cas
e1)
dehi
scen
ceof
uter
ine
scar
(cas
e2i
)pl
acen
tape
rcre
ta,a
dher
ent;
dehi
scen
ceof
uter
ine
scar
(pre
viou
sC
S)
(cas
e3)
NA
(cas
e1)
eCS
(cas
e2)
VD
(cas
e3)
ieC
S
(cas
e1)
3la
paro
tom
y;bi
late
rali
nter
nal
iliac
ligat
ion
(cas
e2)
subt
otal
HY
S
(cas
e1)
WB
(12)
;F
FP
(17)
;PP
Ts
(2);
(cas
e2)
WB
(11)
;F
FP
(7)
(cas
e1)
225
ml/h
(cas
e2)
600
wit
hin
40m
in(c
ase
3)50
0he
mat
oma
(cas
e1)
90(c
ase
2)90
(cas
e3)
80
(cas
e1)
Ble
edin
gco
ntro
lled
(16)
(cas
e2)
Ble
edin
gst
oppe
d(1
4)(c
ase
3)B
leed
ing
stop
ped
RB
C,r
edbl
ood
cell
conc
entr
ates
;FF
P,f
resh
froz
enpl
asm
a;P
PT
s,pl
atel
ets;
CR
YO
,cry
opre
cipi
tate
s;W
B,w
hole
bloo
d;P
CC
,pro
thro
mbi
nco
mpl
exco
ncen
trat
e;vW
F,v
onW
illeb
rand
fact
or;C
S,C
esar
ean
sect
ion
(e,e
mer
genc
y);V
D,v
agin
alde
liver
y;IV
D,i
nstr
umen
talv
agin
alde
liver
y;D
IC,d
isse
mi-
nate
din
trav
ascu
lar
coag
ulat
ion;
MO
F,m
ulti
ple
orga
nfa
ilure
;NA
,not
avai
labl
e;H
YS
,hys
tere
ctom
y;la
cera
tion
–ut
erin
eor
vagi
nal;
AF
E,a
mni
otic
flui
dem
bolis
m;H
EL
LP
,hem
olys
is,e
leva
ted
liver
enzy
mes
,low
plat
elet
s;‘la
stre
sort
’,th
erap
y,af
ter
othe
rcl
inic
alm
easu
res
had
faile
d;n,
num
ber
ofca
ses
Tab
le6
Con
tinue
d
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247
The use of recombinant factor VIIa
Cas
eP
rovo
catio
nof
blee
dT
ype
ofde
liver
yA
dditi
onal
surg
erie
s(n
umbe
rof
surg
ery)
Blo
odpr
oduc
tsgi
ven
pre-
rFV
IIa
(uni
ts)
Blo
odlo
ssbe
fore
rFV
IIa
(l)
Tim
ing
(whe
nrF
VII
aad
min
iste
red)
Dos
eof
rFV
IIa
(µg/
kg)
(num
ber
ofdo
ses)
Ove
rall
blee
ding
resp
onse
torF
VII
a(m
in)
1P
lace
nta
accr
eta
VD
HY
SR
BC
(42)
;FF
P(2
5);
PP
Ts
(40)
25.0
Aft
erH
YS
44P
arti
al
2A
dher
ent
plac
enta
CS
HY
SR
BC
(35)
;FF
P(1
4);
PP
Ts
(24)
20.0
Aft
erH
YS
95G
ood
3U
teri
neat
ony,
LA
CV
DS
urge
ry(3
)R
BC
(19)
;FF
P(8
);P
PT
s(8
)11
.0B
efor
eH
YS
78G
ood
4L
acer
atio
nV
DS
urge
ry(2
),em
boliz
atio
nR
BC
(25)
;FF
P(1
6);
PP
Ts
(24)
14.0
NA
103
Par
tial
5L
acer
atio
nC
SH
YS
(3la
paro
tom
y)R
BC
(32)
;FF
P(2
0);
PP
Ts
(40)
19.0
Aft
erH
YS
90G
ood
6U
teri
neat
ony
CS
Sur
gery
,em
boliz
atio
nR
BC
(10)
;FF
P(8
);P
PT
s(1
6)5.
5N
A11
6P
arti
al
7P
lace
nta
accr
eta
VD
HY
SR
BC
(14)
;FF
P(6
);P
PT
s(4
)7.
5A
fter
HY
S42
Par
tial
8L
acer
atio
nC
SS
urge
ry(2
),ri
ght
uter
ine
arte
rylig
atio
nR
BC
(11)
;FF
P(4
);P
PT
s(8
)5.
3N
A12
0N
one
9P
lace
nta
perc
reta
CS
HY
S(2
)R
BC
(25)
;FF
P(1
4);
PP
Ts
(16)
14.0
Aft
erH
YS
77G
ood
10L
acer
atio
nIV
DS
urge
ry,e
mbo
lizat
ion
RB
C(1
2);F
FP
(10)
;P
PT
s(3
2)8.
8N
A74
Par
tial
11L
acer
atio
nV
DS
urge
ryR
BC
(11)
;FF
P(6
);P
PT
s(6
)5.
5N
A86
Goo
d
12L
acer
atio
nV
DS
urge
ry,e
mbo
lizat
ion
RB
C(1
0);F
FP
(8);
PP
Ts
(16)
5.8
NA
96P
arti
al
RB
C,r
edbl
ood
cell
conc
entr
ates
;FF
P,f
resh
froz
enpl
asm
a;P
PT
s,pl
atel
ets;
CS
,Ces
area
nse
ctio
n(e
,em
erge
ncy)
;VD
,vag
inal
deliv
ery;
IVD
,ins
trum
en-
talv
agin
alde
liver
y;D
IC,d
isse
min
ated
intr
avas
cula
rco
agul
atio
n;M
OF
,mul
tipl
eor
gan
failu
re;N
A,n
otav
aila
ble;
HY
S,h
yste
rect
omy;
lace
rati
on–
uter
ine
orva
gina
l;A
FE
,am
niot
icfl
uid
embo
lism
;HE
LL
P,h
emol
ysis
,ele
vate
dliv
eren
zym
es,l
owpl
atel
ets;
‘last
reso
rt’,
ther
apy,
afte
rot
her
clin
ical
mea
sure
sha
dfa
iled
Tab
le7
Pat
ient
sw
ith
seve
repo
stpa
rtum
hem
orrh
age,
pres
ente
dby
Aho
nen
and
colle
ague
s(2
005)
68.T
heau
thor
sco
nclu
ded
that
trea
tmen
tw
ith
rFV
IIa
may
beof
bene
fit
inlif
e-th
reat
enin
gpo
stpa
rtum
hem
orrh
age
ofup
to20
lof
bloo
din
5–8
h.F
orco
mm
ents
onth
isar
ticl
e,se
ere
fere
nce
69
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248
POSTPARTUM HEMORRHAGE
Cas
eP
rovo
catio
nof
blee
dT
ype
ofde
liver
yA
dditi
onal
surg
erie
sB
lood
prod
ucts
give
npr
e-rF
VII
a(u
nits
)
Blo
odlo
ssbe
fore
rFV
IIa
(l)
Tim
ing
(whe
nrF
VII
aad
min
iste
red)
Dos
eof
rFV
IIa
(µg/
kg)
(num
ber
ofdo
ses)
Ove
rall
blee
ding
resp
onse
torF
VII
a(m
in)
1P
lace
nta
accr
eta
CS
HY
S;l
igat
ion
ofin
tern
alili
acar
teri
es;p
acki
ngR
BC
(44)
;FF
P(2
4);
PP
Ts
(60)
;CR
YO
(54)
NA
NA
90(2
)B
leed
ing
stop
ped
2U
teri
neru
ptur
eV
DH
YS
;lig
atio
nof
inte
rnal
iliac
arte
ries
RB
C(2
0);F
FP
(16)
;P
PT
s(6
0);C
RY
O(6
0)N
AN
A10
0(2
)B
leed
ing
stop
ped
3U
teri
neat
ony
CS
CS
,pac
king
ofut
erus
;lap
arot
omy;
pack
ing
ofte
ars
onliv
erR
BC
(19)
;FF
P(8
);P
PT
s(8
)N
AN
A90
(2)
Ble
edin
gre
duce
d
4U
teri
neat
ony
NA
Sub
tota
lHY
S;l
igat
ion
ofin
tern
alili
acar
teri
esR
BC
(14)
;FF
P(1
2);
PP
Ts
(10)
;CR
YO
(10)
NA
NA
90(2
)B
leed
ing
stop
ped
5U
teri
neru
ptur
eN
AL
igat
ion
ofin
tern
alili
acar
teri
es;
subt
otal
HY
SR
BC
(26)
;FF
P(1
6);
PP
Ts
(30)
;CR
YO
(60)
NA
NA
90(2
)B
leed
ing
stop
ped
6P
lace
nta
accr
eta
NA
Art
eria
lem
boliz
atio
n;H
YS
;ilia
clig
atio
n;4
lapa
roto
mie
s;pa
ckin
gR
BC
(100
);F
FP
(50)
;P
PT
s(5
0);C
RY
O(5
0)N
AN
A90
(2)
Ble
edin
gco
ntro
lled
7U
teri
neru
ptur
eN
AH
YS
;lig
atio
nof
inte
rnal
iliac
arte
ries
;pac
king
RB
C(1
0);F
FP
(6);
CR
YO
(4)
NA
NA
90(2
)B
leed
ing
redu
ced
8U
teru
sm
yom
atos
us,
men
orrh
agia
NA
HY
SR
BC
(6);
FF
P(9
)N
AN
A60
(2)
No
blee
ding
9U
teri
neru
ptur
eN
AH
YS
RB
C(1
5);F
FP
(6);
PP
Ts
(15)
;CR
YO
(30)
NA
NA
90(2
)B
leed
ing
stop
ped
10P
lace
nta
accr
eta
NA
HY
S;l
igat
ion
ofin
tern
alili
acar
teri
es;a
orti
ccl
amp
RB
C(2
7);F
FP
(30)
;P
PT
s(1
0);C
RY
O(3
0)N
AN
A90
(2)
Ble
edin
gst
oppe
d
RB
C,r
edbl
ood
cell
conc
entr
ates
;FF
P,f
resh
froz
enpl
asm
a;P
PT
s,pl
atel
ets;
CR
YO
,cry
opre
cipi
tate
s;C
S,C
esar
ean
sect
ion;
VD
,vag
inal
deliv
ery;
NA
,not
avai
labl
e;H
YS
,hys
tere
ctom
y
Tab
le8
Pat
ient
sw
ith
seve
repo
stpa
rtum
hem
orrh
age
pres
ente
dby
Seg
alan
dco
lleag
ues70
,71
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individuals with HELLP syndrome and otherswith both laboratory and clinical signs of DICbefore rFVIIa was administered. However,none of these patients developed an objectivelyconfirmed, clinically manifest thrombo-embolism (deep vein thrombosis, pulmonaryembolism, myocardial infarction, cerebro-vascular embolism) after rFVIIa therapy, even ifsome patients had pre-existing signs of DIC(often severe).
Patients with HELLP syndrome who developDIC are recognized as being at particular riskfor life-threatening complications. The HELLPsyndrome is a form of severe pre-eclampsia, andmay be confused with the development of DIC.Data presented in Tables 6–8 suggest a highefficacy and safety profile of rFVIIa in the treat-ment of HELLP syndrome and/or DIC withmassive bleeding. These findings are supportedby clinical experiences about the therapeuticeffectivity of rFVIIa in three patients withmassive obstetric hemorrhage due to placentaprevia, accreta, rupture of the uterus andpre-eclampsia with HELLP recently publishedby an Israeli group71. As mentioned by Segaland colleagues, these results raise the possibilitythat rFVIIa may be administered in obstetriccases with life-threatening bleeding episodes,even in the presence of DIC-like coagulopathy.Injection of rFVIIa should be also consideredbefore hysterectomy in a young patient withsevere bleeding, or after internal iliac arteryligation, if bleeding continues.
The series of patients reported here providesdata on the safety and efficacy of rFVIIa inintractable early postpartum hemorrhage. How-ever, as with any case series, there are difficultiesin data analysis because data were collected ret-rospectively after the bleeding episode hadoccurred.
Safety
Adverse thromboembolic events were reportedin one case that was considered to be directlyrelated to the use of rFVIIa54. In general, rFVIIaadministration was associated with an excellentsafety profile.
PROPOSAL OF RECOMMENDATIONFOR THE USE OF rFVIIa IN SEVEREPOSTPARTUM HEMORRHAGE
Based on our own experience and data fromthe literature36,72–80, we have prepared guide-lines for treatment of postpartum hemorrhagethat include administration of rFVIIa.
Definitions of severe hemorrhage
(1) Loss of entire blood volume within 24 h;
(2) Loss of 50% of blood volume within 3 h;
(3) Blood loss at a rate of 150 ml/min (for20 min > 50% blood volume);
(4) Blood loss at a rate of 1.5 ml/kg/minfor ≥ 20 min;
(5) Sudden blood loss > 1500–2000 ml (uter-ine atony; 25–35% blood volume).
Definition of insufficient standardmanagement
The hemorrhage continues despite:
(1) All standard pharmacological and surgicaltreatment methods have been used;
(2) Replacement therapy was performed;
(3) Coagulopathy was confirmed by laboratorytesting
(a) PT or APTT > 1.5 × times the controlvalue
(b) Thrombocytopenia < 50 × 109/l
(c) Fibrinogen < 0.6–0.8 g/l.
Preconditions for rFVIIa administration
(1) Hematological parameters
Hemoglobin levels > 70 g/l (4.3 mmol/l)International normalized ratio (INR) < 1.5Fibrinogen levels ≥ 1 g/lPlatelets levels ≥ 50 × 109/l
(2) pH correction (≥ 7.2) (suggest usingNaHCO3)
249
The use of recombinant factor VIIa
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(3) Body temperature should be restored if pos-sible to physiological values: rFVIIa retainsits activity in the presence of hypothermia
Correction of the pH to ≥ 7.2 is recommendedbefore rFVIIa administration (efficacy of rFVIIadecreases at a pH ≤ 7.1). We also suggest usingbicarbonate to elevate the serum pH. It shouldbe noted that NaHCO3 has not been shown toprovide benefits to patients in hemorrhagic shock.
Recommended replacement therapy
(1) Fresh frozen plasma: 5–10 ml/kg (4–5 units);
(2) Cryoprecipitates: 1–1.5 units/10 kg (8–10units);
(3) Platelets: 1 units/10 kg (5–8 units);
(4) Correction of acidosis (defined as pH ≥ 7.2);
(5) Warming of hypothermic patients (recom-mended, but not mandatory for administra-tion of rFVIIa).
Dosing administration protocol proposal
(1) The recommended initial dose of rFVIIafor treatment of severe postpartumhemorrhage is ~40–60 µg/kg administeredintravenously.
(2) If bleeding still continuous beyond15–30 min, following the first dose ofrFVIIa, an additional dose of ~40–60 µg/kgshould be considered. Repeat 3–4 timesat 15–30-min intervals if clinical signs ofbleeding are still present (based on visualevidence).
(3) If the response remains inadequate follow-ing a total dose of > 200 µg/kg, the precon-ditions for rFVIIa administration shouldbe re-checked, and corrected as necessarybefore another dose is considered.
(4) Only after these corrective measures havebeen applied should the next dose of rFVIIa~100 µg/kg be administered.
Recommended timing of administration
Because our experience suggests that rFVIIapermits effective control of obstetric bleeding,
especially in situations of coexisting coagulo-pathy, we therefore recommend administrationof rFVIIa as soon as possible under the follow-ing circumstances:
(1) When no blood is available;
(2) Before metabolic complications develop;
(3) In women refusing transfusions (e.g.Jehovah Witnesses) (see Chapter 15);
(4) In acquired hemophilia (see Chapter 25);
(5) Before the symptoms of severe thrombo-cytopathies, hypoxia and organ injuryappear;
(6) If correction of INR (PT) is urgentlyneeded;
(7) Before packing of the uterus or pelvis;
(8) Before surgical procedures such ashysterectomy, laparotomy;
(9) Before medical procedures such asembolization, ligation of the uterine andinternal iliac arteries (see Chapter 32).
Information obtained from the literatureallows us to summarize the advantages anddisadvantages of rFVIIa as follows.
Advantages
(1) Recombinant product;
(2) Not subject to blood shortage;
(3) No viral transmission;
(4) No human protein;
(5) Localized hemostasis;
(6) Low risk of anaphylaxis;
(7) No anamnestic responses;
(8) Low thrombogenicity;
(9) Effective during and after surgery.
Disadvantages
(1) Short t1/2 requires frequent, repetitivedosing;
(2) Not 100% effective;
250
POSTPARTUM HEMORRHAGE
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(3) No measurable lab parameter for efficacy;
(4) Limited vial sizes;
(5) Venous access;
(6) Cost.
References
1. Luster JM, Roberts HR, Davignon G, et al.A randomized, double-blind comparison of twodoses of recombinant factor VIIa in the treat-ment of joint, muscle and mucocutaneous haem-orrhages in persons with haemophilia A and B,with and without inhibitors. rFVIIa StudyGroup. Haemophilia 1998;4:790–8
2. Shapiro AD, Gilchrist GS, Hoots WK, CooperHA, Gastineau DA. Prospective, randomizedtrial of two doses of rFVIIa (NovoSeven®)in haemophilia patients undergoing surgery.Thromb Haemost 1998;80:773–8
3. Abshire T, Kenet G. Recombinant factor VIIa:review of efficacy, dosing regimens and safetyin patients with congenital and acquired factorVIII or IX inhibitors. J Thromb Haemost 2004;2:899–909
4. O’Connell KA, Wood JJ, Wise RP, Lozier JN,Braun MM. Thromboembolic adverse eventsafter use of recombinant human coagulationfactor VIIa. JAMA 2006;295:293–8
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9. Martinowitz U, Kenet G, Segal E, et al.Recombinant activated factor VII for adjunctivehaemorrhage control in trauma. J Trauma 2001;51:431–9
10. Kenet G, Walde R, Eldad A, Martinowitz U.Treatment of traumatic bleeding with recombi-nant factor VIIa. Lancet 1999;354:1879
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12. Mariani G, Testa MG, Di Paolantonio T,Molskov Bech R, Hedner U. Use of recombi-nant, activated factor VII in the treatment ofcongenital factor VII deficiencies. Vox Sang1999;77:131-6
13. Hunault M, Bauer KA. Recombinant factorVIIa for the treatment of congenital factor VIIdeficiency. Semin Thromb Hemost 2000;26:401–5
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17. Dildy GA 3rd. Postpartum hemorrhage: newmanagement options. Clin Obstet Gynecol2002;45:330–44
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23. Erhardtsen E. Pharmacokinetics of recombinantactivated factor VII (rFVIIa). Semin ThrombHemost 2000;26:385–91
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recombinant factor VIIa. Clin Pharmacol Ther1994;55:638–48
25. Monroe DM, Hoffman M, Oliver JA, et al.Platelet activity of high-dose Factor VIIa isindependent of tissue factor. Br J Haematol1997;99:542–7
26. Hoffman M, Monroe DM, Roberts HR. Acti-vated Factor VII activates Factor IX and X onsurface of activated platelets: thoughts on themechanism of action of high-dose activatedFactor VII. Blood Coagul Fibrinolysis 1998;9:S61–5
27. van’t Veer C, Golden NJ, Mann KG. Inhibitionof thrombin generation by the zymogen factorVII: implications for the treatment of hemophiliaA by factor VIIa. Blood 2000;95:1330–5
28. Lisman T, De Groot PG. Mechanism of actionof recombinant factor VIIa. J Thromb Haemost2003;1:1138–9
29. Hoffman M, Monroe DM. A cell-based model ofhaemostasis. Thromb Haemost 2001;85:958–65
30. Hedner U. Recombinant factor VIIa(Novoseven) as a hemostatic agent. SeminHematol 2001;38:43–7
31. Friederich PW, Levi M, Bauer KA, et al. Abilityof recombinant factor VIIa to generate thrombinduring inhibition of tissue factor in humansubjects. Circulation 2001;103:2555–9
32. Monroe DM, Hoffman M, Allen GA, RobertsHR. The factor VII–platelet interplay: effective-ness of recombinant factor VIIa in the treatmentof bleeding in severe thrombocytopathia. SeminThromb Hemost 2000;26:373–7
33. Telgt DS, Macik BG, McCord DM, MonroeDM, Roberts HR. Mechanism by which recom-binant factor VIIa shortens the aPTT: activationof factor X in the absence of tissue factor. ThrombRes 1989;56:603–9
34. Kessler CM. Antidotes to haemorrhage: recom-binant Factor VIIa. Best Pract Res Clin Haematol2004;17:183–97
35. Gabriel DA, Carr M, Roberts HR. Monitoringcoagulation and the clinical effects of recombi-nant factor VIIa. Semin Hematol 2004;41:20–4
36. Martinowitz U, Michaelson M, on behalf of theIsraeli Multidisciplinary rFVIIa Task Force.Guidelines for the use of recombinant activatedfactor VII (rFVIIa) in uncontrolled bleeding:a report by the Israeli Multidisciplinary rFVIIaTask Force. J Thromb Haemost 2005;3:640–8
37. Roberts HR, Monroe DM III, Hoffman M.Safety profile of recombinant factor VIIa. SeminHematol 2004;41:101–8
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