The use of prophylaxis in the treatment of rare bleeding …williams.medicine.wisc.edu/rare_bleeding_disorders...FX 1 40% 56% Strong 20-40h pd-FX and pd-FIX/FX

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Thrombosis Research

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Full Length Article

The use of prophylaxis in the treatment of rare bleeding disorders

Amy ShapiroIndiana Hemophilia & Thrombosis Center, 8326 Naab Rd., Indianapolis, IN 46260, USA

A R T I C L E I N F O

Keywords:Rare bleeding disordersProphylaxisSurgical prophylaxisObstetric prophylaxisGynecological prophylaxis

A B S T R A C T

Rare bleeding disorders (RBDs) are a heterogeneous group of coagulation factor deficiencies that include fi-brinogen, prothrombin, α2-antiplasmin, plasminogen activator inhibitor-1, and factors II, V, V/VIII, VII, X, XIand XIII. The incidence varies based upon the disorder and typically ranges from 1 in 500,000 to 1 per millionpopulation. Symptoms vary with the disorder and residual level of the clotting factor, and can range fromrelatively minor such as epistaxis, to life threatening, such as intracranial hemorrhage. Rapid treatment ofbleeding episodes in individuals with severe bleeding phenotypes is essential to preserve life or limb and toprevent long-term sequelae; therapeutic options depend on the deficiency and range from plasma-derived (eg,fresh frozen plasma, prothrombin complex concentrates, factor X concentrate) to highly purified and re-combinant single factor concentrates. The rarity of these disorders limits the feasibility of conventional pro-spective clinical trials; instead, clinicians rely upon registries, published case reports/series and experience toguide treatment. In some disorders, long-term prophylactic therapy is administered in response to the bleedingphenotype in an individual patient or based on the known natural history and severity of the deficiency.Intermittent prophylaxis, surrounding surgery, pregnancy, labor, and menstruation may be required to preventor control excessive bleeding. This review summarizes therapeutic options, guidelines, recommendations andobservations from the published literature for long-term, surgical, gynecological, and obstetric prophylaxis indeficiencies of fibrinogen; prothrombin; factors II, V, V/VIII, VII, X, XI and XIII; combined vitamin-K dependentfactors; α2-antiplasmin; and plasminogen activator inhibitor 1. Platelet disorders including Glanzmann'sthrombasthenia and Bernard-Soulier syndrome are also addressed.

1. Introduction

Rare diseases are disorders with a prevalence of< 1 per 2000 po-pulation (European Union) or affecting fewer than 200,000 in theUnited States. Hemophilia A and B with a prevalence of approximately1:5000 and 1:30,000 respectively therefore qualify as rare and com-prise approximately 95–97% of all individuals with RBDs [1]. The re-maining 3–5% include coagulation disorders caused by a quantitativeor qualitative abnormality of a clotting factor including but not limitedto fibrinogen; prothrombin; α2-antiplasmin; plasminogen activator in-hibitor-1; and factors II, V, V/VIII, VII, X, XI and XIII. The prevalence ofthese disorders range from 1:500,000 to 1:2,000,000 (Table 1). Specificplatelet disorders are also considered RBDs, such as Glanzmann'sthrombasthenia and Bernard-Soulier syndrome, etc.

RBDs present important challenges related to accurate diagnosis,optimal strategies for treatment and prevention of bleeding episodesand perioperative management. Hemophilia A and B have witnessedsignificant advances with the development of best practices and im-proved therapies. In contrast, advances in RBD treatments have laggeddue to their rarity; this has resulted in insufficient aggregate data to

elucidate the need for therapeutic regimens, such as prophylaxis or on-demand therapy, based upon the relationship between residual plasmalevels and bleeding phenotype. In addition, a potentially smaller com-mercial market has largely limited advances in replacement products.

Evidence-based guidelines are largely absent for RBDs; instead, in-dividual experience, bleeding severity, and product availability haveguided use of either on-demand versus prophylactic therapy in RBDs.For example, FXI-deficient individuals rarely utilize long-term pro-phylaxis as spontaneous bleeds are uncommon; whereas FXIII-deficientindividuals routinely utilize prophylaxis due to the high risk of life-threatening bleeds.

Many RBDs have historically been treated with whole blood or freshfrozen plasma (FFP) to replace the deficient procoagulant [1]; in spe-cific deficiencies (eg, FVII, FX, and FXIII) case studies/series with newproducts have formed the basis for improved therapies. Some productsused for treatment of RBDs may be associated with adverse events. FFPmay be associated with volume overload, allergic or infusion reactions,and viral transmission; and prothrombin complex concentrates (PCC)and FXI concentrates may be associated with thrombotic events. Theseadverse events may impact the risk-benefit assessment for use of

https://doi.org/10.1016/j.thromres.2019.07.014Received 8 February 2019; Received in revised form 2 July 2019; Accepted 16 July 2019

E-mail address: [email protected].

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specific agents for treatment.The understanding of RBDs has been advanced with retrospective

and prospective registries (eg, the Rare Bleeding Disorders Database[RBDD] and the Prospective Rare Bleeding Disorders Database [PRO-RBDD]) [2]. These registries have been instrumental to advance ourknowledge of diagnostic criteria (Table 1); elucidate severity categoriesbased upon phenotypic data, residual factor level and bleeding risk; anddetermine deficiencies where prophylaxis is warranted and deficienciesfor which no specific or adequate replacement therapy exists [2–7].Females with RBDs are particularly vulnerable due to gynecologic andobstetric burdens including menorrhagia, miscarriage, anemia andpregnancy-related bleeding [8]; their needs extend beyond the controlof recurrent bleeding as the RBD may place constraints on education,work and overall quality of life. These registries have highlighted thevariability of bleeding risk and phenotypic expression in RBDs, andreinforced the need for further clinical research in each disease state[2].

Based upon the RBDD and PRO-RBDD, data has emerged to guideseverity definitions and need for prophylactic treatment in some RBDs;however, further work remains. The rarity of these disorders often re-sults in delayed diagnosis; few clinicians possess the depth of experi-ence required to treat these patients and few biopharmaceutical com-panies risk development of new products in this arena. This review isfocused on the role of long-term, gynecological and obstetric, andsurgical prophylaxis in RBDs, and highlights reported therapeutic re-gimens and outcomes, complications and side-effects, and areas whereknowledge of prophylaxis remains limited and in need of critical re-search. The specific RBDs addressed include deficiencies of fibrinogen;prothrombin; factors II, FV, FV/FVIII, FVII, FX, FXI, and FXIII; com-bined vitamin-K dependent factors, α2-antiplasmin; and plasminogenactivator inhibitor 1. Platelet disorders such as Glanzmann's throm-basthenia and Bernard-Soulier syndrome are also discussed.

2. Fibrinogen deficiency

Plasma-derived fibrinogen concentrates are available in manycountries and are the preferred treatment option; where unavailable,cryoprecipitate or FFP can also provide a source of fibrinogen. Thepharmacokinetic profile of fibrinogen concentrates can vary widelyamong patients, and prophylactic dosing is individualized to maintaintrough activity levels> 0.5 g/L [3]. Individuals with afibrinogenemiaare the most likely to require prophylactic therapy; those with hypofi-brinogenemia may require prophylaxis depending on their fibrinogenlevels. Tranexamic acid may be suitable for use in minor procedures.

2.1. Long-term prophylaxis

Individuals with afibrinogenemia are often diagnosed at birth, withumbilical cord bleeding occurring in up to 85% of cases [9]. Dependingon the individual, bleeding may occur spontaneously or only in re-sponse to trauma or surgery; clinical symptoms range from minor suchas epistaxis, to recurrent life-threatening bleeds, including intracranialhemorrhage (ICH). Primary prophylaxis is not routinely utilized, al-though it has been proposed [4,10,11]; currently, it is recommendedthat prophylaxis with fibrinogen concentrate (50–100mg/kg qw tomaintain trough activity > 0.5 g/L) be considered based on a patient'shistory of severe bleeding or if fibrinogen activity is< 0.1 g/L [3].Long-term prophylaxis is suggested following ICH [11].

Negrier et al. followed 9 afibrinogenemia subjects on a prophylacticregimen (Clottafact®, LFB, France) for 1 year [12]. Doses were adjustedto maintain trough fibrinogen activity> 0.5 g/L and ranged from 60 to80mg/kg for children < 12 years and 20–60mg/kg for adults ad-ministered every 11.3 ± 5.7 days. No spontaneous bleeds were ob-served in this group which included 5 subjects with a history of CNSbleeds; 10 trauma-related bleeds occurred that were not consideredfailure of prophylaxis. The study was not designed to compare on-Ta

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A. Shapiro Thrombosis Research xxx (xxxx) xxx–xxx

2


demand to prophylaxis; however, 5 additional afibrinogenemia subjectsfollowed an on-demand regimen and experienced 49 bleeding eventsover the same 1-year period. Other case studies have shown a lack ofbleeding while on a prophylactic regimen [11]. Prophylaxis has alsobeen suggested for young children to avoid the complications of traumaas they learn to walk [12,13].

Individuals with afibrinogenemia may experience severe thromboticevents [14,15]. The risk factors are not clear and appear independent ofthe use of replacement concentrate; most cases reported also lack riskfactors traditionally associated with thrombosis such as advanced age.There is no standard antithrombotic therapy in this patient population,although the use of fibrinogen concentrate to balance the anticoagulanttreatment (eg, low molecular weight heparin, LMWH) is common [15].

2.2. Gynecological and obstetric prophylaxis

Menorrhagia and obstetric complications are common in womenwith afibrinogenemia. Menorrhagia may be managed with oral con-traceptives, replacement therapy and/or antifibrinolytics [9,16].

Prophylaxis is essential throughout pregnancy due to the high riskof miscarriage, placenta abruption and post-partum hemorrhage (PPH)[17,18]; without the use of prophylactic fibrinogen, spontaneousabortion occurs at 6–8weeks of gestation [19]. Kadir et al. noted thatonly 6/20 pregnancies resulted in successful live births; the successfulpregnancies were all achieved using a prophylactic fibrinogen regimen[17]. Currently, it is recommended to maintain fibrinogen trough le-vels > 1 g/L throughout pregnancy using a fibrinogen concentrate(50–100mg/kg twice a week); levels < 0.4 g/L are inadequate toprevent hemorrhage [3,18,20]. During labor, levels should be increasedto> 1.5 g/L for at least 3 days [3]; continuous infusion protocols tomaintain levels > 2.0 g/L and prevent placental abruption have beenproposed [19]. Due to the potential risk of thrombotic complications,thromboprophylaxis with LMWH may be necessary.

Females with hypofibrinogenemia may also experience obstetriccomplications including miscarriage; they may require prophylacticfibrinogen if they have a history of bleeding or their fibrinogen levelis< 1.5 g/L.

2.3. Surgical prophylaxis

Peyvandi et al. summarized 79 surgery-related bleeding events re-ported by centers in 10 countries; both fibrinogen concentrate andcryoprecipitate were utilized and had similar hemostatic efficaciesof> 90% [21]. Major procedures required prophylactic treatment for4-14d with peak fibrinogen levels of 1.5–2.0 g/L; for minor procedures,the duration of treatment was reduced (1–7 d) as was the peak level(1.0 g/L). The United Kingdom Doctors' Haemophilia Organisation(UKHCDO) recommends maintaining trough fibrinogen levels > 1.0 g/L for major procedures; fibrinogen concentrate (50–100mg/kg) ispreferred, with additional smaller doses administered every 2–4 d asrequired [3]. Tranexamic acid may be an option for minor procedures.

3. Prothrombin (FII) deficiency

No purified single factor concentrate is available; instead, PCC orFFP are utilized. Cryoprecipitate lacks prothrombin and should not beused. Antifibrinolytics may be used for minor bleeding or minor sur-gical procedures.


Prothrombin deficiency is an extremely rare condition; details oflong-term prophylactic regimens are limited to a few pediatric casereports utilizing PCC or FFP [22–24]. Both agents can be effective toreduce or prevent breakthrough bleeds. The literature reports largevariations in dose and interval: one patient received PCC (20 FII IU/kg)

every other week [25]; whereas an infant required weekly PCC (130 FIIIU/kg) following a second ICH which was later reduced to 70 FII IU/kgqw to maintain a trough of 6–11% [22].

ICH may be a common symptom in severe deficient patients, withone report noting an incidence of 20% in individuals with FII < 1%[26].

Prophylaxis is recommended for those with a history of severebleeding or FII < 1%; PCC (20–40 IU/kg) adjusted to maintain atrough>10% is recommended.


Menorrhagia is reported to be frequent [27,28]; when severe, it maybe controlled using a prophylactic PCC regimen [29]. A 13-year oldfemale (FII < 1%) received weekly PCC prophylaxis (25 FII IU/kg)with an additional administration of PCC (25 FII IU/kg) on day 1, andday 3 or 4 of menses [30]. Menstrual function was reported as normalwith this regimen, which was used instead of a hormonal therapy.

Girolami et al. reviewed data on 8 pregnancies in 4 prothrombin-deficient females (FII activity 1–10%) [31]; seven of the pregnanciesrequired replacement therapy during labor and/or the postpartumperiod. Catanzarite et al. reported 8 pregnancies in 1 woman (FII ac-tivity < 1%) [29]. All pregnancies were complicated with first trime-ster bleeding which resolved without intervention in 4 pregnancies andresulted in miscarriage in the others. Prophylactic FFP or PCC wasadministered prior to labor; PPH was observed with FFP but not PCC.Peyvandi and Mannucci reported no incidences of PPH in a group of 11Iranian females (FII levels, 4–10%); the use of replacement therapy wasnot reported [27].

It is recommended that females (FII < 20%) receive prophylacticPCC (20–40 IU/kg) during labor and additional PCC (10–20 IU/kg) at48 h to maintain FII > 20% for> 3 d [3]. There are insufficient data toconclude whether replacement prothrombin is routinely requiredduring pregnancy.


Few details of surgical procedures have been reported in this patientpopulation. Individuals with FII≤ 60% may bleed following hemo-static challenge [32]; those with FII≤ 10% may require prophylacticcoverage during a surgical procedure [33]. It is recommended thattranexamic acid (15–20mg/kg q6h or 1 g q6h) be considered for minorprocedures; PCC (20–40 FIX IU/kg) is preferred for major procedures,with additional doses every 48 h to maintain FII > 20% [3].

4. Factor V deficiency

Virally-inactivated FFP is the preferred source of FV as no com-mercial FV concentrate is available. Platelets provide an alternate op-tion as they contain approximately 20% of the normal circulatingsupply of FV; platelet transfusions may be considered for unresponsivebleeding and are recommended for patients with FV inhibitors [34].rFVIIa and aPCC have also been suggested for patients who develop FVinhibitors. Tranexamic acid is commonly used to treat menorrhagia[35]. Super-FVa, a recombinant variant with increased resistance toproteolytic inactivation is under preclinical investigation for hemo-philia; it may also have applicability to FV-deficient patients onceavailable [36].


Routine prophylaxis is uncommon in FV-deficient patients due tothe infrequency of severe bleeding symptoms in the majority of in-dividuals [23]; patients are most likely to present with skin and mu-cocutaneous bleeds. ICH and recurrent severe bleeds have been re-ported in severely deficient patients; in these cases, long-term FFP


3


prophylaxis has sometimes been administered every other day or twicea week [37–39]. A weak correlation exists between FV level and bleedseverity [6]; therefore, bleeding phenotype rather than baseline FVlevel may be used to determine the need for routine prophylaxis.


Menorrhagia is common and may be managed with oral contra-ceptives, antifibrinolytics, levonorgestrel intrauterine device and re-placement therapy [35,40]. Lak et al. noted menorrhagia in 5/10women of Iranian descent with a moderate or severe FV-deficiency[41], and Vijapurkar et al. reported menorrhagia in 3/3 FV-deficientwomen from the Indian subcontinent [42].

Literature reports of pregnancy and FV deficiency are limited;however, it is suggested that heterozygotes (FV activity ~ 50%) areunlikely to suffer miscarriage or bleeding complications during delivery[40]. Conversely, Naderi et al. described 8 moderate deficient FVwomen (3.5–8% FV) with a history of pregnancy, 6 of whom had ex-perienced at least one miscarriage [43]. The lack of other risk factorsincluding antiphospholipid syndrome suggested moderate FV defi-ciency as the causative effect. To reduce the likelihood of miscarriage,prophylactic FFP has been recommended: Younesi and Aligoudarzi re-ported on 5 homozygous women (FV activity≤ 1.5%) who receivedprophylactic FFP 3–4 times a week before and during pregnancy, andfollowing delivery [44]. All achieved successful outcomes, despite ahistory of miscarriage in 3 of the women; FV levels during delivery were18–25%. Similarly, Maeda et al. reported a case of a pregnant womanwith FV deficiency (4.8%) who received prophylactic FFP to increaseFV levels (approximately 20%) during cesarean delivery with no post-operative concerns noted; prophylactic FFP was not required prior tolabor in this case [45].

Rouzi et al. [46] and Iwase et al. [47] independently reportedcontrolled ovulation, insemination and delivery in 2 women (5% and0.7% FV activity) who previously avoided pregnancy due to ovulation-related hemoperitoneum. Rouzi et al. noted the antenatal period pro-ceeded smoothly, and the patient presented in labor at 36 weeks. Fol-lowing prophylactic FFP treatment and vaginal delivery she experi-enced PPH which could not be controlled with FFP and wassubsequently managed by gynecologic procedures. In the case reportedby Iwase et al., the pregnancy proceeded without complication untilweek 31, at which point an emergency cesarean was performed withprophylactic FFP without antifibrinolytics due to severe lower ab-dominal pain. Prophylactic FFP was continued once-daily for 4 dayspost-delivery.

Guidelines note that FV levels should be increased to≥15% at onsetof labor, with additional FFP administered to maintain this level untilrecovery following cesarean or vaginal delivery [48].


During surgical procedures, the goal is to maintain trough FV le-vels> 15% [49] or> 20% [50] in severe deficient individuals, or inthose with a history of spontaneous or perioperative bleeding. An initialpre-operative dose (FFP, 15–25mL/kg) is recommended for majorsurgery, with additional FFP (10mL/kg q12h) to maintain FV le-vels> 15–20% until wound healing [3]. Tranexamic acid (15–20mg/kg q6h or 1 g q6h) may be sufficient to achieve hemostasis in minorprocedures [3]. On-demand FFP can be administered in individualswith a non-severe deficiency who lack a history of bleeding if abnormalbleeding occurs [48]. It is often impossible to achieve adequate troughlevels in neonates and babies out to 48 h due to the volume of FFPrequired; in such cases, plasma exchange may be required [39,48].

5. Combined Factor V and Factor VIII deficiency

Patients with combined FV/FVIII deficiency require dual product

therapy to achieve hemostatic levels of FV and FVIII. FFP (15-25mL/kg) is the preferred source for FV as no specific FV replacement therapyis available. FFP contains insufficient FVIII for hemostasis so DDAVP orFVIII concentrate [51] is administered with the FFP to achieve hemo-static levels of both procoagulants.


Routine prophylaxis is rarely required in combined FV/FVIII defi-ciency as levels typically range from 5 to 20% and most patients ex-perience mild or moderate bleeding symptoms; bleeding symptoms arecomparable to those observed in individuals with a single factor defi-ciency meaning that the dual deficiency is not additive to the observedbleeding symptoms [52]. It has been suggested that prophylaxis can beconsidered in cases of recurrent severe hematoma or hemarthrosis [53].


Menorrhagia is common in affected females, with symptoms re-ported in 2/6, 7/12, 6/9 and 8/8 women [52,54–56]; a systematicreview by Spiliopoulos and Kadir encompassing 86 females notedsymptoms in 49% of affected women [57]. Symptomatic females whodesire to conceive may require hemostatic agents during ovulation.

FVIII levels typically increase during pregnancy, whereas FV levelsremain largely unchanged; therefore, the risk of bleeding during laborand the postpartum period is believed to be primarily dependent on FVlevels [48]. Few cases of pregnancy in women with combined FV/FVIIIdeficiency are reported. Spiliopoulos and Kadir reviewed 19 pregnan-cies; however, therapeutic details were incomplete – medications uti-lized included tranexamic acid, FVIII supplementation (FVIII con-centrate or DDAVP), and/or FV supplementation (FFP) [57].Postpartum hemorrhage was reported in 32% of pregnancies, withblood transfusions required in a third of cases.

FV and FVIII levels should be measured during the third trimester[53]. As in the case of FV deficiency, it is recommended that FV levelsbe maintained>15% during labor; FVIII levels should be>50%. It isrecommended that FFP (15–25mL/kg) be administered while in labor,with additional FFP (10mL/kg q12h) for ≥3 days [3]. In the case of acesarean delivery, replacement therapy should be continued untilwound healing.

The incidence of miscarriage in women with combined FV/FVIIIdeficiency is not established [58].


Guidance for surgical procedures in individuals with combined FV/FVIII deficiency is limited to case reports including procedures such astonsillectomy [59], mitral valve replacement [60], and percutaneouscoronary intervention [61]. In all cases, the surgery and post-operativeperiod were successfully managed using FFP and FVIII. In one mildly-deficient patient (FV, 9.6%; FVIII, 24.8%) an abdominal procedure fortreatment of hydrosalpinx and ovarian endometrioma was successfullycompleted without the need for hemostatic agents [62].

The UKHCDO recommends tranexamic acid (15-20mg/kg q6h or1 g q6h) for low-risk surgery; for high-risk surgery it is recommended tomaintain FV levels> 15% (FFP, 15-25 mL/kg) and FVIII levels> 50%(FVIII, 20–40 μg/kg) [3]. Desmopressin (0.3 μg/kg q12h) may be ad-ministered in some FV/FVIII deficient patients to increase FVIII levels iffluid status (water retention) is closely monitored.

6. Factor VII deficiency

Several therapeutic options are available to treat and preventbleeding episodes in patients with severe bleeding symptoms, includingFFP, PCC, aPCC, plasma-derived FVII and recombinant FVIIa (rFVIIa)[63]. Where available, rFVIIa is the preferred option due the low


4


likelihood of viral contamination and the low infusion volume; it iscommonly administered at a dose of 15-30 μg/kg to treat a bleed, orthree times a week prophylactically (with a cumulative weekly dose ofapproximately 90 μg/kg) [64]. Several new rFVIIa variants are inclinical development; however, these are targeted for hemophilia A andB with inhibitors [65].


FVII-deficient patients may be divided into 3 groups based on theirbleeding phenotype: asymptomatic; those with a non-severe phenotype(bleeding similar to individuals with a platelet-like deficiency); andthose with a severe deficiency (bleeding comparable to those with se-vere hemophilia). In general, patients with FVII < 2% are more likelyto experience severe bleeds [48]; however, there is a poor correlationbetween residual FVII level and hemorrhagic risk and so the need forprophylaxis is based upon clinical bleeding phenotype rather thanfactor level alone [23]. The use of routine prophylaxis is less common inFVII deficiency as compared to FVIII or FIX deficiency with similarlevels and the majority of patients utilize on-demand therapy [66].

Clinical guidance for the use of prophylaxis is derived primarilyfrom case studies and registries. Cohen et al. reported the first use ofprimary and secondary FVII prophylaxis in 3 children with ICH, all ofwhom responded well to treatment [67]. Results from the SevenTreatment Evaluation Registry (STER) confirmed this finding usingrFVIIa in children and adults with severe bleeding episodes, and ad-ditionally recommended that rFVIIa prophylaxis be adopted in childrenwith recurrent hemarthrosis or other severe bleeding episodes [64].Multiple additional case series concluded that rFVIIa prophylaxis wassafe and effective [68,69], and recommended that prophylaxis beconsidered in newborns based on their/their family's bleeding history,or that prophylaxis be initiated following the first major hemorrhage.Recommendations issued by the UKHCDO include long-term prophy-laxis for patients who have a history/family history of severe bleeding,or a FVII level < 1%; rFVIIa (20-40 μg/kg, three times a week) ad-justed for clinical response is recommended [3].

Inhibitors to FVII are a rare complication which occurred in ap-proximately 1–3% of patients in the STER study group [70].


An analysis of combined registry data from IRF7 (InternationalRegistry of Factor VII deficiency) and STER noted that menorrhagia wasthe most common bleeding symptom, occurring in 46% of FVII deficientfemales [71]. Gynecological bleeding was more commonly observed infemales with lower baseline FVII levels: specifically, females withFVII < 3% had a significantly increased risk of gynecological bleeding;furthermore, these women were more likely to be diagnosed at ayounger age. The use of rFVIIa or pdFVII on the first, and sometimessecond day of menses, controlled bleeding. The authors suggested thatlong-term rFVIIa prophylaxis should be the standard of care as it mayreduce the burden on the reproductive system, reduce iron loss andlower the long-term risk of hysterectomy [71].

Kulkarni et al. reported 14 pregnancies in 7 women with mild/moderate FVII deficiency (FVII level, 7–49%) [72]. PPH was rare, ob-served in only one of the 12 full-term deliveries and occurred despitethe use of prophylactic rFVIIa; PPH was not observed in the womenwho did not receive prophylaxis. This low incidence of PPH may be dueto the increase in FVII levels in mild or moderately FVII deficientwomen during pregnancy. Interestingly, two early terminations, neitherof which were covered with prophylactic rFVIIa, both resulted in ex-cessive hemorrhage, an observation consistent with maximal increasesin FVII occurring only near term [72,73].

This increase in FVII does not occur in severe deficient women [72];as such, some clinicians have recommended that all women withFVII < 10–20% receive prophylactic rFVIIa during delivery [17,74].

However, an extensive review by Baumann Kreuziger et al. concludedthat as hemorrhage rates during delivery were comparable in womenwith or without prophylaxis, prophylaxis should not be consideredmandatory but rather individualized to the patient, their bleeding his-tory and delivery method [75]. Current recommendations reflect this,noting that females (FVII < 20% in the third trimester) who have ahistory of bleeding or require cesarean delivery should be consideredcandidates for rFVIIa prophylaxis (15–30 μg/kg q4h) for at least 3 days[3].

There are no data to suggest that miscarriage is more likely inwomen with FVII deficiency [17].


The minimal FVII level required to prevent excess bleeding duringsurgery is not clearly defined; different reports have recommended FVIItrough levels of> 8%, 10–20% and>20%, reflecting both interpatientdifferences and the hemostatic requirements of each surgical procedure[17,48,76]. Case reports utilizing FFP and PCC are available; however,rFVIIa is the preferred therapeutic option where available [77]. Tra-nexamic acid (15-20mg/kg q6h or 1 g q6h) may be used in minorsurgery or in patients with a low bleeding risk [3].

An analysis of 41 surgical procedures in STER found that rFVIIa wassafe and effective across a range of minor and major procedures pro-vided a minimal dose of 13 μg/kg (administered at least 3 times) wasused [78]. Wiszniewski et al. reported 17 surgical procedures, 15 usingrFVIIa and 2 using PCC; venous thrombosis developed in one of thepatients receiving PCC, whereas no adverse events were reported withrFVIIa. The rFVIIa therapeutic regimen was selected based on the pa-tient's baseline FVII level: those with higher FVII levels received lowerinitial doses and treatment was discontinued earlier. The authors re-commended that the dosing regimen be adjusted based upon patientresponse. Mumford et al. recommended a more rigorous dosing regimenduring major surgery (rFVIIa, 15–30 μg/kg, q4-6h) [3].

Bolus infusion of rFVIIa is the most common route of administrationfor surgical procedures; continuous infusion has been rarely reported[78].

7. Factor X deficiency

The preferred option for the treatment and prevention of bleedingepisodes in FX deficient individuals is the high purity plasma-derivedFX (pdFX) concentrate which was approved in the US (2015) and theEU (2016), and indicated for use as an on-demand, prophylactic, andperioperative management agent in adults and children. Prior toavailability, PCC, FFP and intermediate purity FIX concentrates con-taining known quantities of FIX and FX were used.


A strong association exists between endogenous FX level and clin-ical bleeding severity [6]; those most severely affected have FX le-vels < 1% and are often diagnosed in the neonatal period due toumbilical stump bleeding [79]. Throughout life, affected individualsmay suffer severe bleeds comparable to those with severe hemophiliaincluding ICH, hemarthrosis and hematoma formation. Mild or mod-erately deficient individuals are more likely to experience easy bruising,menorrhagia and bleeding following surgery [80].

Long-term prophylaxis is recommended in individuals with severebleeding symptoms [3]; clinical guidance comes from case studies, re-gistries and clinical studies. A study in 11 children (< 12 years, 1–5%FX at diagnosis) examined the utility of pdFX prophylaxis; the re-commended dosing regimen (40–50 IU/kg, twice-weekly) was in-dividualized to maintain trough FX > 5% [81]. Overall prophylacticefficacy was rated as excellent and all patients experienced a reductionin bleeding frequency, with 8 children reporting no bleeding events.


5


During the 6-month study, 6 minor (cut/wound, epistaxis and menor-rhagia) and 3 major bleeds (epistaxis and menorrhagia) were reportedin 3 patients; on-demand therapy was not reported in all cases, butbleeds treated with pdFX (25-40 IU/kg) resolved with a single infusion.Tranexamic acid was co-administered in all cases of menorrhagia in thispatient group. No comparable adult prophylactic study is available;however, individual prophylactic regimens in adults have been re-ported [82,83]. The indicated prophylactic regimen for adults is 25 IU/kg twice weekly [84].

Prophylactic PCC and intermediate purity FIX/FX concentrates havebeen used. Karimi et al. reported 10 individuals receiving prophylaxiswith an intermediate purity FIX/FX concentrate (20 IU/kg qw) [85]. Nobleeding was observed in 9 subjects over a 1-year period; prior toprophylaxis, the subjects experienced 1–20 bleeds/month includingmultiple instances of ICH. One subject had an anaphylactic reaction tothe concentrate and was removed from the study. No instances ofthrombosis were reported in this study or the long-term Greifswaldregistry [86]. Commercial sources of FIX/FX concentrate contain aknown quantity of FX, supporting dosing calculations.

Prophylactic PCC use is reported to be successful: one individualexperienced a single bleed in 23months (reduced from 3 to 14 bleeds/year) while using PCC prophylaxis (30 FIX IU/kg, twice weekly) [87].Likewise, McMahon et al. reported 4 individuals who experienced largedecreases in the number of bleeding episodes with PCC prophylaxis (70FIX IU/kg, once or twice weekly) [88]. Despite these successes,thrombosis remains a concern with the use of PCC [86] and monitoringof FIX and FX levels is required during long-term treatment.

There are no published reports of FX inhibitor development in in-dividuals receiving a FX containing prophylactic agent.


Menorrhagia is common and affects individuals with FX levels≤36% [89]; 50–80% of females of childbearing potential with FX <5% experience menorrhagia [42,89–91]. Common treatments includetranexamic acid (15mg/kg or 1 g orally q6–8 h), oral contraceptivesand factor replacement products [91,92]. A post hoc analysis of femalesaged>12 years in the pdFX clinical trial noted that the majority ofinstances of menorrhagia were successfully treated with a single dose ofpdFX (24.3 IU/kg) following onset of bleeding symptoms; tranexamicacid was co-administered in<5% of treated cases in this adolescent/adult population [91]. Prophylactic use of pdFX prior to bleeding wasreported in 2 cases.

It is recommended that the use of hormonal contraceptives and/orhemostatic agents (eg, tranexamic acid) begin at menarche to reducemenstrual blood flow and reduce long-term reproductive complicationsincluding ovarian hemorrhage [93].

Severe FX deficient females can experience a number of pregnancy-related complications including miscarriage, placental abruption, pre-mature delivery and PPH. As FX levels increase naturally during preg-nancy, it is recommended that FX activity be determined during thefirst and third trimester; levels are unlikely to increase sufficiently insevere deficient women. The bleeding phenotype prior to pregnancymay not be predictive of the risk of bleeding during pregnancy; there-fore, the use of a prophylactic hemostatic regimen should be based onbleeding observed during pregnancy and/or prior medical history[91,93]. It is recommended that factor replacement therapy (pdFX, PCCor FFP) be available to females undergoing a cesarean section, and tothose with a history of bleeding and FX < 30% during vaginal de-livery. In such cases, FX levels should be increased to> 40% and mayneed to be maintained at> 30% for ≥3 days in the postpartum period[3]. Nance et al. reviewed 24 pregnancies in 15 women (0–41% FXactivity); fifteen of the pregnancies required substitution therapy (FFPor PCC) during the pregnancy and/or labor and 6 pregnancies requiredhemostatic treatment during the postpartum period [93]. Nine (38%) ofthe pregnancies resulted in premature births.

There is a lack of conclusive data supporting the use of substitutiontherapy throughout pregnancy; however, individual case studies sup-port its use in females who have experienced premature births, pla-cental abruption or miscarriage [17,92]. Kulkarni et al. reported on awoman (3% FX) who experienced 4 spontaneous abortions while re-ceiving prophylactic pdFX (23 IU/kg, twice weekly); during a fifthpregnancy, the prophylactic regimen was increased to three-times aweek and she delivered a baby at 39 weeks with no bleeding compli-cations [91]. A second subject (FX,< 1%) received no prophylactic FXtherapy during pregnancy until 2 days prior to full-term delivery. Noexcessive bleeding was reported during delivery during which FFP wasinfused; however, PPH occurred which was treated with pdFX (18.8 IU/kg).

Guidelines have been published for the management of pregnanciesin FX deficient females but these guidelines predate the availability ofthe commercial pdFX concentrate [93].


Escobar et al. reported the use of pdFX in 5 subjects (FX < 20%)undergoing 4 major and 3 minor surgical procedures including kneereplacement, coronary artery bypass and dental extraction [83]. FXlevels were increased to 70–90% 1–4 h prior to surgery, and post-operative doses to maintain FX≥ 50% were administered until re-covery. Minor procedures typically required a single perioperative in-fusion of pdFX. Overall, pdFX was considered safe and efficacious withno thrombotic events or adverse events related to its administration.

Case reports covering the use of FFP, PCC and intermediate purityFIX/FX during perioperative care are also available. Knight et al. re-ported the use of PCC to increase FX levels to 35% prior to evacuationof 800mL of blood from the abdomen and subsequent removal of alarge ovarian cyst [94]. FFP (twice daily for 6 d) was administered tomaintain FX levels of 10–20%. Mori et al. administered PCC duringsurgery to repair a broken femur; FX levels were raised to 100% duringthe procedure and then sustained at 10–20% for 3months [95]. Martin-Salces et al. also reported the surgical repair of a fractured femur; in-termediate purity FIX/FX (20 IU/kg) raised preoperative FX levels to82% with additional daily administrations (10 IU/kg) for 15 days tomaintain levels > 30% [96].

The use of tranexamic acid (15-20mg/kg q6h or 1 g q6h) for minorsurgery is also recommended [3].

8. Factor XI deficiency

Virally inactivated, purified FXI concentrates are available inEurope; however, they are not available in other countries, includingthe US. Where available, it is recommended that FXI concentrates beused sparingly due to the risk of serious thrombotic events (13 TEs werereported in 256 treatments) [97]. Thrombotic risk is elevated in in-dividuals with preexisting risk factors for thrombosis [97]. In the ab-sence of purified or recombinant concentrates, tranexamic acid,DDAVP, FFP and rFVIIa have been utilized.

Several reports of inhibitors exist; in one study 7/118 unrelatedIsraeli patients were affected [98]. Individuals with inhibitors do notusually bleed spontaneously; however, bleeding following surgery canbe severe.


FXI deficient individuals experience a variable bleeding phenotypewhich is not correlated to baseline FXI level [99]. Spontaneous bleedingother than menorrhagia is uncommon and usually resolves withouttherapeutic intervention [100]; routine prophylaxis is not indicated [7].


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Twenty-one percent (56/268) of FXI deficient females reportedmenorrhagia in an analysis by Wiewel-Verschueren et al. [101]. Tra-nexamic acid (15-20mg/kg q6h or 1 g q6h) is often sufficient to treatmenorrhagia; it should not be co-administered with a purified FXIconcentrate due to an elevated risk of thrombosis [3].

Salomon et al. reviewed the outcomes of 164 pregnancies in 62women with severe FXI deficiency (FXI < 17%); PPH was observed in30% of the women although the risk of bleeding was not correlatedwith genotype, FXI plasma level, or prior incidence of surgical bleeding[102]. The authors suggested that on-demand treatment was the ap-propriate therapy during and after vaginal delivery and that a similarstrategy might be employed for cesarean section, although few reportsof cesarean delivery exist. A subsequent retrospective analysis of 105pregnancies in 33 women with predominantly mild deficiency (medianFXI, 42%; range,< 1–65%) noted an increased incidence of PPH inwomen with a history of bleeding (relative risk, 7.7) [103]. This ob-servation was confirmed by Verghese et al. who also noted that thecause was obstetric in the majority of cases, recommending that thiscause be excluded prior to the administration of replacement factor[104].

The incidence of miscarriage is approximately the same as in thegeneral population [101].

It is recommended that FXI concentrate (10-15 IU/kg), or FFP (15-25mg/kg) and tranexamic acid (15-20 mg/kg) be considered in femaleswith FXI levels< 15% at established labor, or prior to cesarean section[3]. Females with higher FXI levels (15–70%) and a history of bleedingshould consider prophylactic tranexamic acid (15mg/kg q6h or 1 gq6h) for ≥3d.


Multiple studies have shown purified FXI concentrates to be effi-cacious in surgical procedures [105,106]; however, an elevated in-cidence of thrombosis has restricted its use to cases where the bleedingrisk is high and other therapies are unlikely to achieve satisfactory re-sults [3,106]. Reduced doses (10–15 IU/kg) are now recommended. Therestrictions placed on the use of FXI concentrates are not limiting, asFFP (15–20mL/kg) and/or tranexamic acid (15-20mg/kg q6h or 1 gq6h) are sufficient for the majority of procedures. FFP is not associatedwith thrombosis [107].

As there is a poor correlation between bleeding and FXI plasmalevel, the use of prophylactic therapy may be based on the individual'sbleeding history and the site of surgery. Major surgeries at sites of highfibrinolytic activity are likely to require prophylactic factor replace-ment or FFP; whereas, tranexamic acid for 5–7 days is often sufficientfor minor procedures [108]. As bleeding risk is greatly reduced at sitesof low fibrinolytic activity (eg, orthopedic procedures, circumcision orappendectomy) prophylactic therapy may not be required; instead, on-demand treatment may be considered [108]. Riddell et al. reported thesuccessful use of low dose rFVIIa (15–30 μg/kg q2-4h for 24-48 h) andtranexamic acid (1 g iv q6h for 5d) in 4 procedures including cesareansection, abdominoplasty and cholecystectomy [109]. The low dose re-gimen was determined using in vitro ROTEM spiking experiments,which predicted in vivo results.

rFVIIa may also be used in individuals who develop FXI inhibitors.Kenet et al. reported 4 minor procedures using a single rFVIIa dose(33–44 μg/kg) and 4 major procedures using a low initial dose(33–47 μg/kg) followed by a low dose continuous infusion protocol(3–10.5 μg/kg/h) to achieve hemostasis [110]. Livnat et al. reported 5major surgeries with prophylactic tranexamic acid and a single rFVIIadose (15–30 μg/kg) immediately following the surgery [111]. O'Connellet al. reported the use of rFVIIa (90 μg/kg) preoperatively and 4 hpostoperatively for minor procedures [112]. Major surgeries utilized90 μg/kg rFVIIa q2h for 24 h and then 90 μg/kg q4h for another 24 h

period (oral tranexamic acid was also administered following majorprocedures). Highlighting the risk of rFVIIa in individuals with pre-existing thrombotic risk factors, a 77-year old subject experienced acerebrovascular infarct following the 17th administration of rFVIIa anddied 3 days later. rFVIIa does not have a specific indication for use inFXI deficiency.

9. Factor XIII deficiency

Plasma-derived (pdFXIII) and recombinant (rFXIII) factor XIII arecommercially available in many countries. FXIII circulates as a tetramer(FXIII-A2B2) comprised of 2 catalytic subunits (FXIII-A2) and 2 non-catalytic subunits (FXIII-B2). Commercial pdFXIII may be used in in-dividuals with genetic defects in either of the subunits; rFXIII containsonly the A-subunit and is not indicated for use in individuals with B-subunit defects [113]. Over 95% of individuals with FXIII deficiencyhave defects in the FXIII-A2 subunit [114]; they tend to have a moresevere bleeding phenotype than those with FXIII-B2 defects. In locationswhere a FXIII concentrate is unavailable, FFP or cryoprecipitate may beused. Tranexamic acid may be used for minor bleeding or minor sur-geries.

Inhibitors to FXIII have been reported [115]; they do not appear tobe a consequence of long-term prophylaxis [116].


Primary prophylaxis is the standard of care for individuals withsevere FXIII deficiency or those with a personal or family history ofbleeding, due to the high risk of life-threatening bleeds, including ICH[3]. The presence of a severe deficiency is often determined shortlyfollowing birth as> 80% of cases present with umbilical cord bleedingand ~30% of newborns experience ICH [117]. The long half-life ofFXIII permits extended prophylactic dosing intervals of up to a month.

The long-term prophylactic efficacy of pdFXIII (1.6–15 IU/kg qw)was confirmed by Dreyfus et al. in a prospective study in individualswith FXIII≤6% [118]. A significant reduction in hemorrhage was ob-served, with 63% of subjects experiencing zero bleeds on-study. Ahigher incidence of bleeding was observed in subjects who re-ceived< 5 IU/kg/week, suggesting the minimum weekly dose shouldbe at least 5 IU/kg. A subsequent prospective study examined pdFXIII(40 IU/kg) dosed every 4 weeks; the dose was adjusted to maintain atrough level of 5–20% [119]. 14 bleeding events were observed, ofwhich 2 (1 trauma and 1 surgery) required additional pdFXIII treat-ment; the overall annualized bleed rate was reduced from 2.5 to 0.37.No clinical signs of thrombosis were observed.

Inbal et al. reported the long-term efficacy of rFXIII (35 IU/kg, oncemonthly) [115]. The mean annualized bleed rate decreased from 2.91to 0.14 and 90% of subjects experienced no bleeding on-study; all re-ported bleeds were traumatic and were treated with pdFXIII-containingproducts. Approximately 10% of subjects developed transient, non-neutralizing, low titer antibodies following the first or second infusionand most withdrew from the study for this reason; all had previouslyreceived long-term pdFXIII prophylaxis without inhibitor development.


Menorrhagia is common in FXIII deficient females. Lak et al. re-ported an incidence of 35% among 20 Iranian women of child-bearingpotential (FXIII < 5%) [120]; whereas two separate reviews havecalculated the incidence of menorrhagia at 26% and 64% [121,122].Intraperitoneal bleeding at the time of ovulation was reported in 20% ofwomen [120] and may be controlled with prophylaxis [121].

Miscarriage is very common and the use of prophylactic FXIIIduring pregnancy has a large impact on outcome. When prophylacticFXIII was administered throughout pregnancy 40/45 (89%) of preg-nancies resulted in a live birth, whereas only 12/136 (9%) of


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pregnancies were viable in the absence of prophylactic coverage [121].The risk of miscarriage was elevated (70%) for females with a defect inthe FXIII-A2 subunit; females with FXIII-B2 defects had a 15% risk ofmiscarriage. FXIII concentrate is the preferred therapeutic option, withcryoprecipitate and FFP being used less frequently or when a purifiedconcentrate is unavailable [121].

PPH has been reported in 25% of pregnancies [121]. The risk of PPHwas reported to be greater for females with FXIII-B2 defects (82% vs13%), possibly as prophylaxis is less common in females with FXIII-B2

defects.It is recommended that females receive prophylactic FXIII con-

centrate during pregnancy, with the dosing interval adjusted to every14–21 days to maintain a trough level≥ 20% [3]. Once in establishedlabor, or prior to cesarean section, additional FXIII (10–40 IU/kg) maybe administered depending on the interval since the last dose to preventPPH. An alternative weekly dosing regimen that administered 250 IUuntil the 22nd week and 500 IU from the 23rd week to maintain FXIIIlevels> 10%, and a 1000 IU dose at labor is also used [123]. Tra-nexamic acid has also been administered for 5–7 days following a ce-sarean section [124].


Prophylactic coverage during surgery is essential due to the highrisk of intraoperative bleeding. Non-severe FXIII deficient individualsmay bleed during invasive procedures, and so may also require pro-phylactic coverage. A purified FXIII concentrate is the preferredtherapy.

Naderi et al. reported on 164 minor and major surgeries in severelyFXIII deficient patients who received a monthly prophylactic regimen ofpdFXIII (10 IU/kg) [124]. Surgeries were scheduled 1–2 days prior tothe next regular prophylactic dose. Minor procedures required a single10 IU/kg dose prior to the procedure along with adjuvant tranexamicacid; a single 30 IU/kg dose and tranexamic acid provided prophylacticcoverage for circumcision. Major surgeries utilized a preoperativepdFXIII (30 IU/kg), followed by postoperative pdFXIII (30 IU/kg) onday 3; neurosurgery followed a similar schedule with two 50 IU/kgdoses. Two subjects experienced perioperative bleeding events: one wasundiagnosed prior to the procedure and the second bled from a suturesite; both responded well to an additional pdFXIII dose (30 and 20 IU/kg respectively).

Ashley et al. reported 4 surgeries that were scheduled the same day(or 1-week following) a scheduled monthly prophylactic dose of pdFXIII[119]. Three of the surgeries required no additional hemostatic agent;the fourth required an additional administration of pdFXIII followingwisdom tooth extraction. A subject requiring an emergency appen-dectomy received no additional perioperative administration ofpdFXIII; they received FFP following the surgery and experienced nopostoperative bleeding.

Twelve minor procedures in patients receiving prophylactic rFXIIIwere reported by Carcao et al. [125]. Procedures were performed up to21 days following the prior prophylactic dose; no additional factorproduct was required perioperatively. Antifibrinolytics were adminis-tered for dental extractions and colonoscopy.

pdFXIII is currently indicated for perioperative use; rFXIII is notspecifically indicated for surgical use.

10. Alpha-2-antiplasmin deficiency

Antifibrinolytic agents are the most commonly utilized medicationfor the treatment of bleeding events or to provide perioperative pro-phylactic coverage; FFP may also be utilized [126,127].


A severe deficiency may result in severe bleeding symptoms [128],

most commonly in response to trauma, dental extraction or surgery.Most heterozygotes are asymptomatic with no evidence of excessbleeding following substantial trauma or surgery [129]. All femalesreported with α2-antiplasmin deficiency may experience menorrhagia.No reports of long-term prophylaxis are available in the literature.


Menorrhagia has been reported in females with α2-antiplasmin de-ficiency; however, there are too few reports to determine prevalence orseverity. Likewise, very few reports of pregnancy are available; mis-carriage, vaginal bleeding, preterm delivery and PPH are reported, butit is not clear how common these symptoms are [127,130].


Tranexamic acid is used as the hemostatic agent for surgical pro-cedures. Takahashi et al. reported cases of orthopedic surgery to treatlesions caused intra-medullary hemorrhage into the diaphyses of thelong bones in 2 sisters (α2-antiplasmin < 5%) [131]. Oral or in-travenous tranexamic acid prophylaxis during surgery (10mg/kg/h)and postoperatively (20–40mg/kg/day) was successfully utilized.Morimoto et al. provided details on 10 dental extractions where tra-nexamic acid (7.5–10mg/kg) was administered orally 3 h prior to theprocedures and then every 6 h for 7–10 days [132].

11. Plasminogen activator inhibitor, Type 1 (PAI-1) deficiency

Antifibrinolytic agents are the mainstay of treatment and preventionof bleeding episodes in PAI-1 deficient individuals [133]. Tranexamicacid and aminocaproic acid (EACA) are widely utilized. Isolated reportsof FFP use are also available.


Severe deficiencies of PAI-1 are typically characterized by mild/moderate bleeding in response to trauma or surgery; occasionally, life-threatening bleeding may occur [134]. Spontaneous bleeding is rarelyobserved and routine prophylaxis is seldom utilized. Use of the cur-rently available PAI-1 activity assay reveals a high incidence of un-detectable or low PAI-1 activity in the healthy population who lack ableeding diathesis; therefore this assay alone should not be used toestablish the diagnosis [135].


Menorrhagia and pregnancy complications are reported to becommon [127]. Case reports indicate that menorrhagia may be suc-cessfully treated with prophylactic EACA (1 g orally; followed by500mg q6h) and optionally with a progesterone cream (3 g q4h)[136,137]; and tranexamic acid (25mg/kg three times a day for thefirst few days of each menstrual cycle; or 1.3 g three times a day for4 days) [129,136]. It is suggested to start low dose prophylactic EACA(100mg/kg qd) or tranexamic acid (25mg/kg qd) one week prior tomenses, with an increase to full dose EACA (100mg/kg q6h) or tra-nexamic acid (25mg/kg q6–8h) on day 1 for ≥5 days [136]. One casereport of prophylactic FFP use during pregnancy is available; however,the use of FFP is not recommended as it may be insufficient to control orprevent instances of massive bleeding following the 25th week of ge-station [138].

A review of 17 pregnancies by Saes et al. noted that only 24%reached term [127]; high instances of vaginal bleeding (54%), PPH(27%) and miscarriage (24%) were reported. Case reports indicatebleeding during pregnancy, or during or following labor may be con-trolled with prophylactic EACA or tranexamic acid [136].


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Delayed bleeding following a surgical procedure is a hallmark ofPAI-1 deficiency; the use of tranexamic acid for several days before andafter a procedure may be effective [129]. Hirose et al. described theprophylactic use of intravenous and oral tranexamic acid in total hiparthroplasty and total knee arthroplasty [139]. Postoperative adminis-tration of tranexamic acid for 4–5weeks to control delayed bleedingwas recommended.

Tranexamic acid (7.5–10mg/kg) may be administered 3 h prior to adental procedure, with additional tranexamic acid being administeredevery 6 h for 7 days to control bleeding [132].

FFP (10-15mL/kg) may be used to rapidly increase levels of PAI-1prior to achieving a therapeutic level of antifibrinolytic agents.

12. Combined vitamin K-dependent Factor deficiency

Vitamin K1 is the preferred therapy for routine prophylaxis; FFP andfour-factor PCC may be administered in individuals during obstetric orsurgical procedures.


A range of bleeding phenotypes are associated with a deficiency ofcombined vitamin K-dependent clotting factors including ICH andumbilical stump bleeding [140,141]. As spontaneous bleeds may occur,routine prophylaxis with oral vitamin K1 (5-20mg/day) or parenteralvitamin K1 (5-20mg/week) is the standard of care [3,142]. This ther-apeutic regimen is supported by case studies and typically results in animprovement in vitamin K-dependent clotting factor activity[141,143,144]; in rare cases, infusion reactions have been reportedwith parenteral administration [145]. Some severely deficient in-dividuals do not respond to vitamin K administration [146] and FFP orfour-factor PCC may be required; however, there are no reports of theprophylactic use of these hemostatic agents in this population.


Menorrhagia and pregnancy complications have been reported infemales with a congenital deficiency of combined vitamin K-dependentclotting factors [147]. McMahon et al. reported a pregnancy in a femalewho had received oral vitamin K since birth (15mg/day during preg-nancy) [142]. Following vaginal delivery she bled profusely at theepisiotomy site and required FFP (3 units) to achieve hemostasis. It isrecommended that females consider four-factor PCC (20–30 FIX IU/kg)or FFP (15-25mL/kg) during labor if they present with any of the vi-tamin K-dependent factors < 20 IU/mL in the 3rd trimester [3].

Prenatal diagnosis of the combined deficiency is not indicated; in-stead, administration of oral vitamin K1 during the 3rd trimester shouldbe considered if the child is at risk of inheriting the deficiency.


Minor surgical procedures may be performed using tranexamic acid(15–20mg/kg q6h or 1 g q6h) or intravenous vitamin K; it can take 24 hfor dependent factors to achieve maximal activity if vitamin K is ad-ministered [3,147]. In major procedures, four-factor PCC (20–30 FIXIU/kg) with vitamin K1 (5–20mg) is recommended; if four-factor PCCis unavailable, FFP (15–25mL/kg) may be utilized.

Lapecorella et al. reported the successful use of rFVIIa for a dentalextraction; however this therapeutic choice was based on the assump-tion that the patient was FVII-deficient [147].

13. Platelet function disorders

Multiple bleeding disorders result from defects in platelet function,

including Glanzmann's thrombasthenia (GT) and Bernard-Soulier syn-drome. It is beyond the scope of this review to cover all platelet dis-orders, instead Glanzmann's thrombasthenia, and Bernard-Soulier syn-drome are discussed below. The reader is directed to the RareCoagulation Disorders Resource Room (www.rarecoagulationdisorders.org) for further information on specific platelet disorders [148].

14. Glanzmann's thrombasthenia (GT)

Antifibrinolytic agents and rFVIIa are commonly utilized as pro-phylactic agents in GT patients. Platelet transfusion may be used insurgical procedures or unresponsive bleeding; however, transfusionscarry the risk of bacterial and viral infection, anaphylaxis, and trans-fusion-related acute lung injury. The use of human leukocyte antigen(HLA)-matched leukocyte-reduced platelets is preferred as the devel-opment of anti-αIIbβ3 integrin and anti-HLA antibodies has been re-ported in this population [149–151]. Prophylactic rFVIIa (90 μg/kgq2h) is indicated for perioperative use in individuals refractory toplatelet transfusions (with or without antibodies, depending on the li-censing agency); however, it is often used for surgical procedures in GTpatients regardless of platelet refractoriness and/or antibody status[152].


Individuals are often diagnosed at a young age with epistaxis andgingival bleeding being common; bleeding can be severe and may re-quire platelet transfusion for control. Spontaneous bleeding is un-common and routine prophylaxis is not reported.


Menorrhagia is common, with 3 case series/registries indicating anincidence of 74–100% in females of childbearing potential with GT;another report from an Iranian cohort suggested a lower incidence of13% [153]. Antifibrinolytic agents and/or oral contraceptives are theprimary treatment option [154]; unresponsive bleeding may require aplatelet transfusion or treatment with rFVIIa [149,155].

Siddiq et al. reviewed therapeutic options and outcomes in 40pregnancies [156]. Bleeding during and following delivery wascommon and often severe; intrapartum bleeding and primary or sec-ondary PPH were observed in 61%, 34% and 24% of cases respectively.Prophylaxis using platelet transfusion reduced the incidence of PPH to38% compared to 63% in those who did not receive prophylaxis. Pro-phylactic rFVIIa is reported to be ineffective in preventing PPH. It hasbeen suggested that fetal thrombocytopenia and hemorrhage may becaused by transplacental passage of maternal platelet alloantibodies tothe fetus; for this reason, it may be preferable to avoid platelet trans-fusions in females, especially those of child-bearing potential [156].


Reflecting the high risk of bleeding, Orsini et al. noted that 155/182procedures in individuals with GT utilized prophylaxis; platelet trans-fusion (with and without antifibrinolytics) was the most commonlyused therapy [157]. Separately, the observational Glanzmann Throm-basthenia Registry recorded hemostatic agent(s) and outcomes in 206surgical procedures [152]. Platelet transfusion is the standard hemo-static option for surgical procedures; however, rFVIIa alone or incombination with platelets and/or antifibrinolytics is commonly uti-lized (77% of procedures), including in patients without antibodiesand/or platelet refractoriness.

In patients lacking antibodies or refractoriness, rFVIIa alone, rFVIIawith antifibrinolytics, and platelets with antifibrinolytics were con-sidered to be effective in all minor/major procedures reported [152]. Inpatients with antibodies and/or refractoriness, the use of rFVIIa with or


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without antifibrinolytics was most effective for minor procedures;conclusions for major procedures were limited by the small numberreported and the observation that some patients responded to platelets,suggesting antibodies were no longer present or they were no longerrefractory. Registry data indicated rFVIIa was safe and efficacious;doses of 90–140 μg/kg q2h until hemostasis were considered optimalfor minor procedures and 90 μg/kg q2.5h (or more frequently) formajor procedures.

Antifibrinolytics alone were considered effective in minor (56%)and major (100%) procedures; however, it is not recommended thatantifibrinolytics be used without the availability of backup hemostaticagents [152].

15. Bernard-Soulier Syndrome (BSS)

Antifibrinolytic agents (eg, tranexamic acid, 15-25 mg/kg q8h),DDAVP (0.3 μg/kg), rFVIIa (90 μg/kg), platelet transfusions and hor-monal therapy (in females) have all been utilized for prophylaxis in BSSpatients [158,159]. Platelet transfusion is commonly used in surgicalprocedures and unresponsive bleeding; however, bacterial and viralinfection, anaphylaxis, transfusion-related acute lung injury and theemergence of platelet refractoriness are significant concerns; the use ofHLA-matched platelets is preferred.


Individuals with an autosomal recessive (bi-allelic, bBSS) in-heritance are often diagnosed at a young age; those with the lesscommon, milder autosomal dominant form of BSS (mono-allelic, mBSS)may not be diagnosed until adulthood [160]. The bleeding tendencymay vary from mild to severe between individuals and most bleedingoccurs in mucocutaneous tissues; spontaneous ICH or bleeding intojoints is rare and severe bleeding is most likely to be associated withtrauma or surgery [161]. As such, routine prophylaxis is not reported inthe literature; instead coverage may be provided for surgical proceduresand obstetric/gynecological considerations.


Menorrhagia is common and often moderate to severe [160]; re-ports indicate an incidence of 50–100% in females of childbearingpotential [161–163]. Antifibrinolytic agents are the first treatmentoption; if inadequate, hormone therapy is recommended [160]. Routinetreatment with oral contraceptives is an option if pregnancy is notdesired.

Severe bleeding may occur during childbirth in females with bBSSand prophylactic hemostatic coverage is common during and followingdelivery; there are no reports of prophylaxis during pregnancy prior tothe onset of labor. Peitsidis et al. reviewed the course and outcomes of30 pregnancies in 18 females with BSS [164]. The most common pro-phylactic agent employed during labor and delivery (vaginal and ce-sarean) was platelet transfusion (40%); prophylactic antifibrinolyticsand DDAVP were also utilized. Primary and secondary PPH were re-ported to be common (33% and 40% respectively), with 2 females re-quiring emergency obstetric hysterectomy. PPH was treated with bloodtransfusion (38% of cases), platelet transfusion (35%), tranexamic acid(18%) and DDAVP (10%). A subsequent retrospective study by Noriset al. noted a much lower incidence of excessive bleeding (14% of de-liveries) [167]; this difference was suggested to be attributed to a lesssevere bleeding tendency in this cohort of females, or reporting bias inthe earlier review.

Prophylactic rFVIIa (90 μg/kg q2h, 3–4 doses or until adequatehemostasis) in combination with tranexamic acid is recommended forvaginal deliveries with subsequent administration of tranexamic acidfor up to 6 weeks following delivery to prevent PPH [164,165]. Pro-phylactic rFVIIa (90 μg/kg)/fibrinogen (2 g iv) has been utilized to

prevent bleeding during vaginal delivery and PPH; this combination hasalso been reported to stop labor-associated bleeding in a female re-fractory to platelet transfusions [166]. Hemostatic coverage using HLA-matched platelets with tranexamic acid is recommended for a cesareansection [164,165]. Alloimmune neonatal thrombocytopenia has beenreported in 6 neonates with 2 deaths (ICH and severe fetal gastro-intestinal bleeding) [164].

Data suggest that pregnancy outcomes in females with mBSS (34deliveries with no excessive bleeding) is similar to that of the healthypopulation [167]. Guidelines for the management of pregnant femaleswith BSS have been published [160,164,165].


Perioperative prophylaxis is routinely administered in individualswith bBSS. Retrospective data on 36 procedures (19 major, 7 minor,and 10 dental) in 17 subjects with bBSS were reported by Orsini et al.[157]. The majority of procedures (97%) required prophylactic hemo-static coverage, 44% of which resulted in excessive bleeding. Prophy-lactic coverage was most commonly provided by platelet transfusion(77%) and platelet transfusion combined with antifibrinolytics (8.8%);other agents included antifibrinolytic agents alone (2.9%), DDAVP(2.9%) and combined DDAVP/antifibrinolytic (5.9%). Few mBSS sub-jects required prophylactic coverage (18%); the majority who did uti-lized platelet transfusion (54%) or antifibrinolytics (39%). The use ofrFVIIa was not reported in any procedures in this study.

Although platelet transfusion is the most common hemostatic optionutilized for perioperative care, rFVIIa use alone or in combination withantifibrinolytics or platelets has been successfully used as a first-linetherapy. Rodseth summarized 8 procedures (orchidopexy, open kneesurgery, arthroscopy, strabismus repair, exploratory laparotomy andmultiple dental extractions) that utilized prophylactic rFVIIa(90–104 μg/kg) as the primary hemostatic agent (ancillary therapiesincluded tranexamic acid or platelet transfusion depending on theprocedure) [168]. rFVIIa is not licensed for use in individuals with BSS.

16. Conclusions

RBDs are a disparate group of diseases that result from deficienciesof a variety of coagulation proteins and affect both males and females;the impact of RBDs in females may be more severe due to recurrentgynecological and obstetric manifestations. The use of prophylaxis inmany of these conditions is warranted based on the severity and fre-quency of bleeding symptoms. In some cases, prophylaxis may begin asa neonate and be lifelong; in other RBDs, prophylaxis may only be re-quired in a few patients with a more severe bleeding phenotype, or tocover hemostatic challenges, such as surgical or dental procedures. Theuse of clinical trials, case studies/series and international registrieshave provided critical data that define the disease state and offer in-sights into clinical symptoms and treatment regimens. Due to the rarityof these disorders, optimal prophylactic regimens in most RBDs remainunclear; it is only through the continued funding of prospective inter-national registries and clinical trials that clinicians may be able to ad-vance care in these disorders and address current knowledge gaps.

Declaration of Competing Interest

Dr. Shapiro has served on a speakers' bureau for Genentech; hasserved on advisory boards for Shire, Novo Nordisk, Kedrion Biopharma,HEMA Biologics, Bioverativ, and Genentech, has served on globalsteering committees for Shire and Bayer; has received consulting feesfrom Chugai Pharma USA, Prometic Life Sciences, and KedrionBiopharma; and has received research funding from BioMarin, CSLBehring, Bioverativ, Sangamo Biosciences, Daiichi Sankyo, Genentech,Kedrion, Novartis, Novo Nordisk, Octapharma, OPKO, Prometic LifeSciences, Agios Pharmaceuticals, and Shire. Dr. Shapiro received no


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funding (directly or indirectly) to support the writing of this review. Dr.Shapiro's employment contract with the IHTC requires all consultingfees and honoraria to be paid directly to the Indiana Hemophilia andThrombosis Center; Dr. Shapiro is not permitted to accept them per-sonally.

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