Local/topical hemostatic agents for treatment of postpartum hemorrhage Technology Opportunity Assessment

Prepared for the

Merck for Mothers Program

June 2014

MAILING ADDRESS PO Box 900922 Seattle, WA 98109 USA

ADDRESS 2201 Westlake Avenue Suite 200 Seattle, WA, USA

TEL: 206.285.3500

FAX: 206.285.6619

www.path.org

Copyright © 2014, PATH. All rights reserved.

Cover photo credit: PATH/Evelyn Hockstein.

The activities discussed in this publication were supported by funding from Merck through its Merck for

Mothers Program. The content of this publication is solely the responsibility of the author(s) and does not

represent the official views of Merck.

iii

Table of contents

Statement of need ............................................................................................................................. 1

Technology solutions landscape ...................................................................................................... 2

Mechanical agents .................................................................................................................... 9

Biologically active agents ........................................................................................................ 9

Flowable agents ..................................................................................................................... 10

Topical fibrin sealants ............................................................................................................ 10

Antifibrinolytic agents ........................................................................................................... 11

Nonfibrin sealants and tissue adhesives ................................................................................. 12

Novel local hemostatic agents ............................................................................................... 13

Scenarios for use of local hemostatic agents ................................................................................. 13

Gap analysis ................................................................................................................................... 15

Investment opportunities ................................................................................................................ 16

References ...................................................................................................................................... 20

1

Statement of need

Obstetric hemorrhage is estimated to cause 25 percent of all maternal deaths and is the leading direct

cause of maternal mortality worldwide.1 Immediate postpartum hemorrhage (PPH), defined as vaginal

bleeding in excess of 500 mL in the first 24 hours after delivery, accounts for most cases of obstetric

hemorrhage, occurs in over 10 percent of all births, and is associated with a 1 percent case-fatality rate.2

Additionally, if women do survive PPH, approximately 12 percent will have severe anemia.3 Also, if

women survive severe PPH (greater than 1,000 mL of blood loss) (“near misses”), they are significantly

more likely to die in the year following the PPH.4 The United Nations Millennium Development Goal 5,

to reduce 75 percent of maternal mortality by 2015, cannot be reached without significant improvements

in PPH-related mortality.5,6

There are four specific causes of immediate PPH that can be remembered with the well-known mnemonic

of the “Four Ts”:7

Tone: Uterine atony, or inadequate uterine contraction, is the most common cause of severe PPH in

the first 24 hours after childbirth. Contractions of the uterine muscle fibers help to compress maternal

blood vessels. Bleeding may continue from the placental site if contractions are inadequate.

Clinically, 70 to 90 percent of all immediate PPH is due to uterine atony.

Trauma: Lacerations, hematomas, uterine inversion, and uterine rupture are responsible for up to

20 percent of PPH. In countries where non-specialist physicians perform cesarean operations,

“trauma” caused by complications of cesareans may become increasingly common. For example, a

confidential enquiry into maternal deaths in South Africa for the period 2008–2010 found that

bleeding during and after cesarean accounted for 26.2 percent of deaths due to obstetric hemorrhage.8

Tissue: Retained placenta or placental fragments, or invasive placenta (accreta/increta/percreta) are

responsible for up to 10 percent of PPH. The rising cesarean birth rate may result in an increase in the

proportion of PPH caused by placenta praevia and placenta accreta, as they are associated with

cesarean operations.9

Thrombin: Although uncommon, clotting disorders are responsible for approximately 1 percent of

PPH cases. Coagulation defects may be acquired or congenital and may be associated with

thrombocytopenia and/or hemostatic defects. Acquired causes include disorders that are related to

conditions of pregnancy (e.g., severe preeclampsia, eclampsia, HELLP (hemolysis, elevated liver

enzymes, low platelet count) syndrome, abruptio placentae, fetal demise, amniotic fluid embolism,

massive hemorrhage, and sepsis), surgical site bleeding, or medications.

Outcomes from PPH depend on the timeliness of the response. When births occur in the home, outcomes

depend on initiating first aid as temporizing measures until definitive management can be provided. When

women have access to skilled birth attendants or surgery, access to conservative adjunct interventions to

control bleeding may be lifesaving and could prevent radical surgery when standard techniques (such as

uterotonic drugs, suturing, ligature, cautery, or pressure) are insufficient or impractical to implement.

2

Local (also known as “topical”) hemostatic agents* (LHAs) are applied directly to the affected area of the

body and can be used either as a “first aid” measure or as adjunct therapy for management of PPH. They

have potential for use at all points of care because they do not require injection, many do not require

storage in the cold chain, they have fewer adverse effects than systemic hemostatic agents, and their

application is relatively simple. An additional advantage is that LHAs have the potential to be used to

manage bleeding due to multiple causes: tone (bleeding at the placental implantation site due to uterine

atony), trauma (lacerations, bleeding at surgical incision sites, bleeding in hard to reach areas), or

thrombin (coagulopathies). While some novel technologies apply LHAs to gloves or gauze used to

manually remove a placenta (tissue), the LHAs induce hemostasis at the placental implantation site after

the placenta has been safely removed.

Factors affecting the selection of an appropriate LHA include potential use, severity of bleeding, site

(internal or external), cause of bleeding (lacerations, vascular, arterial, coagulopathy), and the personal

experience and preference of the provider. These are important and will affect the clinical outcome for the

patient.10 Use of LHAs for PPH in low-resource settings (LRS) will depend on these factors as well as

considerations of ease of use, cost, and storage requirements. Ideal qualities of LHAs for PPH use

include:11,12

• Ability to rapidly promote hemostasis and control bleeding.

• Safe to use with no risk of injury to tissues or transmission of infection.

• Affordability.

• Safety.

• Stability at room temperature (RT).

• No or minimal requirements for mixing or pre-application preparation.

• Simplicity of handling and application.

• Availability in multiple forms for versatility.

Technology solutions landscape

The US Food and Drug Administration (FDA) approved the introduction of the first widely accepted

tissue glue in 1998,13 and LHAs have been used successfully in neurosurgery, urology, orthopedics,

trauma medicine, and gynecology.14 LHAs come in a range of configurations15 (see Appendix A for an

overview of available LHAs):

Mechanical agents: These agents produce swelling and cause a mechanical barrier to bleeding and

oozing. They require an intact coagulation system. They can be used with saline or thrombin.

* Please note that this landscape only focuses on local (applied directly to the bleeding site) hemostatic agents and

does not address use of systemic (administered parenterally) hemostatic agents.

3

Biologically active agents: These are thrombin-containing products that require intact fibrinogen and

do not rely on the patient’s intrinsic clotting system. Thrombin converts fibrinogen to fibrin,

stimulating activity in the coagulation cascade.

Flowable agents: These LHAs have a thick, flowable consistency and combine both active

(thrombin) and mechanical hemostatic agents (collagen or gelatin).

Topical fibrin sealants: These LHAs combine high concentrations of human fibrinogen and

thrombin. May also contain antifibrinolytic (e.g., aprotinin) to stabilize the clot.

Antifibrinolytic agents: These agents prevent clot breakdown (fibrinolysis) in order to reduce

surgical blood loss.

Nonfibrin sealants and tissue adhesives: Tissue adhesives can be used to promote hemostasis, but

are predominantly used as an alternative to sutures for tissue approximation.

Novel LHAs: Several upstream LHAs are available that work primarily by exerting physical effects

or by enhancing existing hemostatic mechanisms.

Unfortunately high-quality data establishing the effectiveness of LHAs are lacking. There are some

published randomized controlled trials (RCTs) in which LHAs were used for minor intraoperative

bleeding sites, including (but not limited to):

Comparison of hemostatic sealants (Floseal®, Proceed™ [Baxter Healthcare],) and thrombin-

gelatin combination (Gelfoam® [Pharmacia & UpJohn]-thrombin): In three trials, hemostatic

sealants were found to have significantly higher rates of hemostasis (88 to 99 versus 57 to 93

percent) at ten minutes after application compared with thrombin-gelatin combination in cases

involving patients undergoing vascular, spinal, or cardiac surgery.16–18

Comparison of autologous fibrin sealant (Vivostat® [Vivostat A/S]-derived sealant) and oxidized

regenerated cellulose (Surgicel® [Ethicon]): In a prospective, randomized, multicenter clinical

study, use of an autologous fibrin sealant resulted in a significantly higher rate of hemostasis (94

versus 65 percent) at five minutes after application in 69 patients undergoing obstetric,

gynecologic, general, vascular, and cardiothoracic surgery.19

Comparison of fibrin sealant and a conventional LHA: In a multicenter trial, 333 patients were

randomly assigned to receive the fibrin sealant or a conventional topical hemostatic agent in

patients undergoing either reoperative cardiac surgery (redo) or emergency resternotomy.20 Fibrin

sealant controlled bleeding successfully within five minutes of application in significantly more

patients (93 versus 12 percent) compared with conventional LHAs.

To date, there have been no published reports on RCTs on use of LHAs in cases of PPH occurring in

LRS. There is an ongoing clinical trial21 to assess the safety and efficacy of HemCon GuardaCare®XR

(HemCon Medical Technologies [chitosan technology]) compared to standard bandaging in subjects with

PPH as a result of cervical and vaginal lacerations; as of April 2014, the study was still open and had no

published reports. However, there is now growing evidence, in the form of published case studies, to

4

support their use for PPH management in cases of uterine atony, placenta praevia, vaginal lacerations,

hemorrhage at the uterine incision site, arterial and venous bleeding, placenta accreta/increta/percreta, or

anticoagulation (see Appendix B). All of the configurations described above—except for biologically

active, topical use of antifibrinolytic agents, and nonfibrin sealants and tissue adhesives—have published

case studies about their use for PPH (see Table 1).

In addition to LHAs listed in Table 1, topical application of antifibrinolytic agents (most notably

tranexamic acid [TXA]), nonfibrin sealants/tissue adhesives, and biologically active LHAs are also

potential candidates for use for PPH in LRS, although there are no published case studies of their use in

PPH management (see Table 2).

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Table 1. Local hemostatic agents used successfully for management of postpartum hemorrhage.

Class Mechanical agents Flowable agent Topical fibrin sealants Novel

Chitosan-covered gauze

Kaolin-infused gauzes

Porcine gelatin sponge

Gelatin-thrombin

matrix

Human fibrinogen and thrombin

Thymus vulgaris, Glycyrrhiza glabra, Vitis vinifera, Alpinia officinarum, and Urtica dioica

Product names Arsenal foam

XStatTM

(RevMedx)

CeloxTM (Medtrade)

QuikClot®

(Z-Medica)

Gelfoam® (Pharmacia & UpJohn)

Floseal® (Baxter Healthcare)

TachoSil®

(Nycomed Pharma)

TISSEEL®

(Baxter Healthcare)

ABSa (Ankaferd Health Products)

Case studies of successful use for postpartum hemorrhage

Tone Uterine atony.

Bleeding at placental implantation site.

Bleeding at placental implantation site.

During uterine arterial embolization for uterine atony.22

Uterine atony.

Bleeding at placental implantation site.

Intractable lower uterine segment hemorrhage.

Trauma Hemorrhage at the uterine incision site.

Bleeding from multiple vaginal lacerations.

Complicated obstetric lacerations.

During episiotomy repair.

Thrombin Coagulopathy Disseminated intravascular coagulation.

Ability to rapidly promote hemostasis and control bleeding

Hemostasis typically achieved in 3 to 5 minutes. Hemostasis typically achieved in 2 to 10 minutes.

Hemostasis typically achieved in 3 to 5 minutes.

Hemostasis typically achieved between 30 seconds and 2 minutes.

Affordable Least expensive. More expensive than mechanical.

More expensive than mechanical or flowable.

More expensive than mechanical.

Stability at room temperature

Stored at room temperature (RT) or “non-extreme” temperatures (<5°C and >60°C).

Stored at controlled RT (2°C–25°C) or RT.

Freeze dried: stored at 2°C–25°C.

Frozen: store at ≤₋20°C; thaw 5–10

minutes.

Unknown

a Ankaferd blood stopper.

6

Class Mechanical agents Flowable agent Topical fibrin sealants Novel

Chitosan-covered gauze

Kaolin-infused gauzes

Porcine gelatin sponge

Gelatin-thrombin

matrix

Human fibrinogen and thrombin

Thymus vulgaris, Glycyrrhiza glabra, Vitis vinifera, Alpinia officinarum, and Urtica dioica

Safe to use with no risk of injury to tissues or transmission of infection

Risks:

Swelling

Infection

Risks:

Fever

Encapsulation

Risks:

Swelling

Viral/prion disease transmission.

Risks associated with particular standalone thrombin that is chosen.

Risks:

Viral/prion disease transmission.

Antibody formation.

Swelling.

May require intact coagulation.

Air/gas embolism if administered using pressurized gas.

TISSEEL® contains aprotinin (associated with anaphylactic reactions).

Risks:

Localized redness and minor swelling.

No or minimal requirements for mixing or pre-application preparation

Immediately available for use. Requires cutting to the desired size.

Requires mixing products.

Patch and sponge are immediately available for use.

Freeze-dried products require warming and mixing products.

Immediately available for use.

ABS solution is sprayed onto a sponge.

Simplicity of handling and application

Relatively easy. Relatively easy. Relatively more complex. Relatively easy.

Availability in multiple forms for versatility

Powder

Compression pads

Lyophilized/absorbable sponges

Sprayable liquid

Gelatin powder or paste

Powder

Sponges

Prefilled syringe TachoSil®: sponges, patches.

TISSEEL®: spray, prefilled syringe.

Spray

Pad/tampon

Sponge

7

Table 2. Promising local hemostatic agents for management of postpartum hemorrhage.

Class/Type of agent

Antifibrinolytic Nonfibrin sealant/tissue adhesive Biologically active agents

Topical TXAa Nonfibrin sealant/tissue adhesive Thrombin, topical (bovine)

Thrombin, topical (human)

Thrombin, topical (recombinant)

Case studies of successful use for postpartum hemorrhage

No case studies for management of postpartum hemorrhage available.

Ability to rapidly promote hemostasis and control bleeding

Hemostasis typically achieved in 3–5 minutes.

Bonds to tissue in 2–3 minutes after application.

Hemostasis typically achieved in less than 10 minutes.

Safe to use with no risk of injury to tissues or transmission of infection

Thromboembolic effect uncertain but must be considered.

Inflammatory effects on skin.

Some sealants must not be used internally; need area to be kept dry for healing to occur.

Excessive heat generation can occur during polymerization.

Labeling for topical thrombin specifically states that it is not for use in cases of infection or for postpartum hemorrhage or menorrhagia.

Bovine has received the strongest possible FDAb label warning, and can cause fatal severe bleeding or thrombosis.

Human has risks for plasma-derived infectious disease or anaphylactic or severe systemic reaction to human blood products.

Recombinant has risks of hypersensitivity to hamster or snake proteins.

Affordable Similar price range to mechanical agents.

More expensive than mechanical agents. More expensive than mechanical; less expensive than flowable or fibrin sealant.

Stability at room temperature Should be stored at room temperature (RT) away from direct heat and light.

Stable for up to 12 weeks at temperatures up to 50°C.

Stored at controlled RT(5°C–25°C).

Store away from moisture, direct heat, and direct light.

Frozen or stored unopened at controlled RT (5°C–25°C).

Stored at controlled RT

(5°C–25°C) or 2°C–8°C after reconstitution.

No or minimal requirements for mixing or pre-application preparation

Relatively easy.

Requires mixing with saline.

No preparation.

Adhesiveness makes application relatively difficult.

Some are available in prefilled syringes.

Others require reconstitution or assemblage of kits.

Simplicity of handling and application

Relatively easy. Adhesiveness makes application relatively difficult to handle.

Relatively easy.

Availability in multiple forms for versatility

Gel

Spray

Liquids and gels come in a vial/blister pouch with an applicator tip coated with an initiator that starts the chemical process.

Prefilled syringe

Spray kit

Pump spray kit

Vials

8

Class/Type of agent

Antifibrinolytic Nonfibrin sealant/tissue adhesive Biologically active agents

Topical TXAa Nonfibrin sealant/tissue adhesive Thrombin, topical (bovine)

Thrombin, topical (human)

Thrombin, topical (recombinant) a Tranexamic acid. b US Food and Drug Administration

9

Mechanical agents

Mechanical LHAs are applied to a bleeding site using direct pressure and are thought to be most effective

when there is minimal bleeding. There are four main categories of mechanical agents: porcine gelatin,

bovine collagen, oxidized cellulose, and polysaccharide spheres.12 They come in various forms: powder,

compression pads, lyophilized sponges, absorbable sponges, sprayable liquid, and gelatin powder or

paste. Mechanical LHAs can be used to control PPH after both vaginal and cesarean births.

Mechanical LHAs are generally low-cost, easy to use, biodegradable, and immediately available for use

(i.e., can be used immediately out of the package). Bovine collagen, porcine gelatin, and oxidized

regenerated cellulose may be stored at RT; polysaccharide spheres require storage in “non-extreme”

temperatures (<5°C and >60°C). Of the four types of mechanical agents available, bovine and

polysaccharide spheres are considered the most effective.23

Many of the mechanical agents use animal products, and their potential for causing allergic reactions is of

concern. Typically these agents act by expanding quite rapidly, which might compress and cause nerve

damage in an enclosed space, such as the uterus or the genital tract. Other potential adverse effects

reported have been granulomas at the bleeding sites, abscess formation, and neurological

complications.24–26

The following mechanical LHAs have been used to control bleeding due to various causes of PPH:

Chitosan-coated gauze (Arsenal foam, XStatTM [RevMedx], CeloxTM [Medtrade]): uterine atony,

placenta accreta/increta, anticoagulation.

Kaolin-infused gauzes (QuikClot® [Z-Medica]): bleeding from the placental implantation site.27

Porcine gelatin sponge (Gelfoam®): anticoagulation.28,29

Smectite-impregnated gauze or patches are currently being studied for use in PPH; their use for

obstetrics remains in the research phase.

The cost of these mechanical agents ranges from US$5 to US$200 per application. For example, one

packet of QuikClot® costs up to US$46 and a packet of Gelfoam® that includes two sterile packs of two

sponges each can cost up to US$90. Mechanical products are generally the least-expensive LHAs.

Biologically active agents

There are three origins of topical thrombins: bovine, pooled human plasma, and recombinant. They are

used in drip or spray format and are applied with a syringe (when the bleeding may be difficult to reach)

or sprayed. Topical thrombins will not work unless bleeding is present. Little is known about the use of

these agents for the management of PPH, and no case studies have been reported of use of biologically

active agents to manage PPH.

The storage and preparation of biologically active agents depends on the formulation. In general,

biologically active agents will need to be refrigerated, and some formulations require storage in a freezer.

10

Most of the formulations require some kind of reconstitution. All types of thrombins are equally effective

at controlling bleeding.

The major concerns with biologically active agents are the possible risks of blood-borne pathogen

transmission in pooled plasma thrombin: hypersensitivity to bovine, snake, or hamster thrombin;

anaphylactic or severe systemic reaction to human thrombin; antibody formation; and immune

coagulopathy.

The cost of these agents ranges from US$50 to US$150 per application. In general, biologically active

agents are only slightly more expensive than mechanical agents.

Flowable agents

The combination of active (thrombin) and mechanical hemostatic agents (collagen or gelatin) forms a

flowable paste that is used to control bleeding mechanically and by the conversion of fibrinogen to fibrin.

Most commonly, these flowable agents are injected by syringe into the bleeding site. The agent then

conforms to the shape of the area.

Flowable agents combine the strengths of both mechanical and biologically active LHAs, and

consequently have the advantages and disadvantages of both. Flowable LHAs have the same

risks/precautions as mechanical and biologically active agents: swelling and viral/prion disease

transmission. In addition, particular risks will be associated with the thrombin that is chosen.

Porcine gelatin agents, with or without thrombin, should be stored at controlled RT

(2°C to 25°C); bovine gelatin with pooled human thrombin may be stored at RT. All flowable agents

require preparation before application, but the ease of preparation varies from one product to another.

Gelatin-thrombin matrix (Floseal®) is a flowable LHA that has been used to control bleeding due to

various causes of PPH:30,31 atony of the lower uterine segment, bleeding from the placental implantation

site, uterine atony associated with disseminated intravascular coagulopathy, bleeding from vaginal cuff

and pelvic raw surfaces associated with coagulopathy of sepsis, or scattered arterial and venous bleeding

sites that were diffusely distributed over the length of the rectovaginal septum.

The price for flowable hemostatic agents ranges from US$50 to US$250, slightly higher than mechanical

and biologically active LHAs.

Topical fibrin sealants

These LHAs provide fibrinogen and thrombin at the site of bleeding in larger concentrations than those

ordinarily found in blood, which expedites conversion of fibrinogen to fibrin and clot formation. Some

preparations include an antifibrinolytic agent to prevent lysis of the clot. Fibrin sealants are effective for

managing both localized and diffuse bleeding and can be used in patients with coagulopathy who do not

have sufficient fibrinogen to form a clot. However, use of this product may require intact coagulation.

These LHAs have the greatest amount of trial data available. Comparative trials suggest that topical fibrin

sealants are superior to other LHAs.32

11

All formulations of topical fibrin sealants require either freezing or refrigeration. Most products contain

two components that require a complex process for coordinating their reconstitution and preparation. In

addition, providers must wait at least 15 minutes for frozen components to thaw. A ready-to-use,

absorbable patch was FDA approved for cardiovascular surgery in 2010.* Patches (e.g., TachoSil®

[Nycomed Pharma], Veriset™ [Covidien], Evarrest™ [Ethicon]) composed of fibrin sealant combined

with other hemostatic agents (e.g., polyglactin, oxidized regenerated cellulose) are in the early stages of

clinical investigation.33–35

There are a number of safety concerns with fibrin sealants. The biggest concern with fibrin sealants is the

potential risk of blood-borne infection from pooled plasma. This risk is reduced by screening donors and

testing donor blood and in commercial products through various purification and viral inactivation

processes. However, this would not be a feasible or practical option in LRS. Additional risks of use of

fibrin sealant with bovine thrombin include antibody formation and swelling. Adverse effects include

possible allergic reactions to milk or bovine by-products and higher concentrations of thrombin in the

sealant increasing the rate of thrombosis.36–39 TISSEEL® contains aprotinin, a protein associated with

anaphylactic reactions.

The following fibrin sealant LHAs have been used to control bleeding due to various causes of PPH:

Hemostatic collagen fleece (TachoSil®):* intractable lower uterine segment hemorrhage after

placenta praevia, hemorrhage at the uterine incision site.

Biologically active, fibrin sealant (TISSEEL®): complicated obstetric laceration, multiple vaginal

lacerations resulting from rotational forceps delivery.

Cost is another limitation of this category of local hemostatic agents. Prices of these agents range from

US$400 to US$800 per application. Although more expensive, fibrin sealants have significantly higher

rates of hemostatic control compared with gelatin-thrombin combinations.

Antifibrinolytic agents†

TXA, an antifibrinolytic agent, has been available for decades and has been used intravenously (IV) to

reduce blood loss in surgery by preventing clot breakdown (fibrinolysis). Although there have been no

RCTs on the use of TXA for the treatment of PPH following vaginal delivery that address the priority

outcomes, the World Health Organization (WHO)40 recommended the use of parenteral TXA for

treatment for PPH if: “(i) administration of oxytocin, followed by second-line treatment options and

prostaglandins, has failed to stop the bleeding; or (ii) it is thought that the bleeding may be partly due to

trauma.” There is also interesting new evidence showing successful use of IV TXA for prevention of

PPH.41

* TachoSil® package insert. Available at:

http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProducts

BLAs/FractionatedPlasmaProducts/UCM207483.pdf.

† The landscape is focused on LHAs and will not describe or discuss the research on systemic TXA.

12

However, concerns about possible thromboembolic events with parenteral administration of TXA have

stimulated increasing interest in its topical use. The direct application of TXA to the bleeding surface has

the potential to reduce bleeding with minimal systemic effects and has the additional advantage that it

could be used by providers not authorized to give injections. A systematic literature review of the use of

topical TXA for bleeding identified 28 trials that indicated that local application of TXA reduces bleeding

after surgery (cardiac, thoracic, spinal, knee, or head and neck surgery).42 In most of the trials, TXA was

administered in saline solution directly onto the bleeding site, either by pouring or spraying into the

surgical wound or in some cases as a gel.43 To date, local use of TXA has not been investigated for

obstetric complications and PPH.

Hemostasis is typically achieved in 3–5 minutes after administration. When used systemically, TXA has a

thromboembolic effect; it is not certain whether or by what degree this effect is limited by topical

application, but the risk must be considered when making a decision to use topical TXA. Preparation

requires mixing TXA with a saline solution, which is straightforward but requires injection skills. Both a

gel and spray are available for use topically, and application to the bleeding site is not complicated.

TXA does not require refrigeration, which is a big advantage. In general, it is recommended that TXA be

stored at RT away from direct heat and light. At additional advantage is that it is stable for up to 12 weeks

at temperatures up to 50ºC.

Generic TXA is manufactured by 65 companies.‡ The cost of the drug will depend on the manufacturer,

the country of purchase, and the presentation of the drug: tablet, capsule, syrup, cream, gel, ointment,

liquid, or injection. The CRASH-2 trial (Clinical Randomisation of an Antifibrinolytic in Significant

Haemorrhage) studied the cost-effectiveness of administering TXA to trauma patients and found that the

cost of giving TXA to 1,000 patients was Int$17,483 in Tanzania, Int$19,550 in India, and Int$30,830 in

the United Kingdom.44 Use of the product would, therefore, most likely be under Int$100.

Nonfibrin sealants and tissue adhesives

Tissue adhesives are mostly used as an alternative to sutures for tissue approximation but can be used to

promote hemostasis as well. An advantage of tissue adhesives is that they join tissues without need for an

intact clotting mechanism and polymerize within approximately 30 seconds. A Cochrane review provided

evidence that tissue adhesives are an option to sutures, staples, and adhesive strips for the management of

simple traumatic lacerations.45 Providers using them need to have a good understanding of preparation

time and application techniques. To date these agents have not been investigated for obstetric

complications and PPH.

Two examples of nonfibrin sealants/tissue adhesives are FocalSealTM (Genzyme Biosurgery) and

CoSeal® (Baxter Healthcare). These are both polyethylene glycol (PEG)-based agents. FocalSeal TM has

been used largely for sealing air leaks in thoracic surgery. It requires activation by a light source, and is,

therefore, probably not appropriate for use in LRS for PPH due to equipment cost. CoSeal® is a synthetic

‡ http://www.medindia.net/drug-price/tranexamic-acid.htm.

13

hydrogel that acts as a sealant. The hydrogel is formed at the time of administration when PEG powder,

liquid sodium phosphate buffer, and a desiccant are mixed together. At an approximate cost of US$150 to

US$200/ml,§ CoSeal® is also likely not appropriate for use in LRS.

More information about mechanism of action and efficacy is needed in this group of newer PEG

polymers.46–49

Novel local hemostatic agents

A polymeric hemostatic agent is a relatively newer category of LHA with little currently available trial

data. However, it offers additional options and might be lower in cost. The products available are

BioHemostat™ (Hemodyne), which is a mechanical LHA dressing that once inserted into the site of

bleeding absorbs fluid and expands, creating backpressure to stop bleeding; WoundSeal® (Biolife)** is

available over the counter and indicated for minor bleeding and small lacerations. A number of synthetic

polymeric sealants are currently under investigation.

Another novel LHA is a peptide-based nanohaemostat, which self-assembles into a sheet of nanofibers on

contact with ionic solutions.50 Its mechanism of action is not completely clear; it may be related to tight

conformation to the wound, followed by formation of a barrier stemming the flow of blood. Importantly,

it is not thought to involve the inherent clotting mechanisms and is nontoxic and nonimmunogenic. This

local agent, discovered by researchers at the Massachusetts Institute of Technology and the University of

Hong Kong, could be very promising and is undergoing clinical testing.

Ankaferd® blood stopper (ABS [Ankaferd Health Products]) is a new hemostatic agent that is designed

for external bleeding sites. ABS comprises a standard mixture of Thymus vulgaris, Glycyrrhiza glabra,

Vitis vinifera, Alpinia officinarum, and Urtica dioica. It has been approved in Turkey for the management

of maternal bleeding. This LHA would be dispensed as an ABS spray to control bleeding during

episiotomy repair.51

One other novel approach is a hemostatic intrauterine suction cup. It is an innovative medical device that

is still in the proof-of-concept stage. It is introduced in the uterus and depresses the uterine walls and

collapses them. The actuation of the suction cup leads to aspiration of all sides of the uterus to stop the

bleeding.52

Scenarios for use of local hemostatic agents

When a woman has PPH, there are a series of actions that must be taken to manage it prior to surgical

intervention. Management options include uterine massage, uterotonic drugs, internal bimanual uterine

compression, aortic compression, pressure from a uterine tamponade, suturing, compression sutures, or

IV hemostatic agents (e.g., TXA, and recombinant activated factor VIIa). In cases where bleeding

§http://webcache.googleusercontent.com/search?q=cache:vMSfaBiF4GwJ:eblast.devicepharm.net/10269/+&cd=3&hl=en&ct=clnk&gl=u

s. ** Formally known as Quick Relief (QR™).

14

continues in spite of management, it would be beneficial to have an intervention that could limit blood

loss and the possibility of disseminated intravascular coagulation and allow time for uterotonic drugs to

act. LHAs have a potential to serve this purpose and, if adequate evidence were available, could be

integrated into existing algorithms for management of PPH (see Appendix C).

An advantage of LHAs, when compared with other technologies to manage PPH, is that they can be used

in cases of uterine atony, lacerations, or anticoagulation rather than being confined to managing only one

cause of PPH (e.g., uterine atony). LHAs could be used in the following scenarios depending on the

primary causes of PPH deaths in any given country, province, district, or facility:

Tone (uterine atony):

Some case studies have found that bleeding resolves when LHAs are placed directly on the placental

implantation site when conventional treatments for uterine atony (uterotonic agents, uterine balloon

tamponade [UBT], vessel ligation, uterine compression sutures, over-sewing placental bed bleeding

sites) have failed. If the uterus does not contract adequately after delivery of the placenta, blood

vessels at the implantation site bleed freely and hemorrhage occurs. LHAs can cause hemostasis until

uterotonic drugs can begin to induce uterine contractions in both the upper and lower segments of the

uterus.

We assume that LHAs could be used for this purpose at all points of care but would require a

mechanism to transport the LHA to the placental site, training to apply it, and means to ensure

sterility during application. It is possible that application of an LHA could replace bimanual uterine

compression or UBT.

LHAs could also be used during interventional radiology procedures, including uterine arterial

embolization for uterine atony. This would, of course, require specialized physicians and equipment

to perform the procedure and would, therefore, be restricted to hospitals providing comprehensive

emergency obstetric care.

Trauma (lacerations, hematomas, uterine inversion, and uterine rupture):

LHAs could serve as a first aid measure for providers not skilled to suture or in cases of complicated

obstetric lacerations if they are safe, effective, affordable, can be safely applied by less-skilled

providers, are quickly and easily prepared and applied, and do not require special conditions for

storage. LHAs could theoretically be used in the community setting by community health workers

and traditional birth attendants for use in treating simple genital lacerations.

Nonfibrin/tissue sealants could be used for uncomplicated, first- or second-degree genital lacerations

and would theoretically obviate the need for suturing and induce hemostasis. LHAs that induce

hemostasis but do not seal the wound would still require that the woman be transferred to a facility

where the laceration could be sutured. It would be necessary to ensure that community-based

15

providers are able to distinguish between lacerations that require assessment and repair by a skilled

provider.

In cases of complicated genital lacerations, including third- or fourth-degree tears, where repair of

sphincters and muscle layers is necessary, LHAs could be applied to minimize bleeding until the

lacerations could be repaired by a skilled provider competent to repair them.

LHAs can be used for bleeding during or after cesarean operation. Bleeding during or after cesarean

may be due to uterine atony, lacerations and tears if the initial incision was not wide enough for the

baby to be lifted out, accidental nicking of large arteries and veins near the uterus, or inadequate

suturing. Ongoing bleeding despite routine treatment may also occur during cesarean for placenta

praevia/accreta/increta.

We assume that LHAs could be used for this purpose at all points of care but would require

guidelines on specific use by a cadre of providers, training to apply it, and means to ensure sterility

during application.

Thrombin (clotting disorders):

Diagnosis of a coagulopathy can be done using the bedside clotting test that does not require special

laboratory equipment or specialized training. Providers at all facility levels should, therefore, be able

to diagnose coagulopathy in cases of PPH or oozing not responding to conventional treatment. While

definitive management of a clotting disorder should occur at a comprehensive emergency obstetric

care facility, LHAs may be used to induce hemostasis until definitive treatment can be provided by a

specialist physician.

We assume that LHAs could be used for this purpose at all facilities providing maternity services

with staff able to perform the bedside clotting test but would require guidelines on use, training to

perform the bedside clotting test and apply LHAs for this purpose, and means to ensure sterility

during application.

Gap analysis

Many LHAs are available, and there has been an upsurge of interest in their use for PPH. Although the

use of LHAs for various surgical applications has generated a significant body of literature, there are few

rigorous randomized trials for their use in PPH or in LRS. It is, therefore, difficult to tell clinicians,

policymakers, or program managers whether any given LHA is more effective, safer, or more cost-

effective than another LHA or than products/interventions currently being used.

In addition, there is widespread variation in and no international guidelines for their use. Knowledge

deficits related to use of LHAs for management of PPH in LRS, include:

16

Lack of adequate clinical trial data to guide providers in managing their patients or develop clinical

guidelines for their use in cases of PPH.

Lack of uniform outcome measures to judge efficacy and few studies establishing the efficacy of

LHAs for PPH.

Lack of studies to compare efficacy of LHAs and conservative treatments for PPH (e.g., direct

pressure, UBT, and systemic hemostatic agents).

Insufficient studies comparing the various LHAs to guide choice of the most relevant LHAs for each

cause of PPH.

Limited safety data on use of LHAs for PPH, including safety when combined with other treatments

for PPH and coagulopathies.

Insufficient data on which LHAs have the least side effects when used by less-skilled providers.

Limited understanding of the biological effects of LHAs in women with PPH to help determine who

should receive it.

Lack of data on cost-effectiveness of LHAs for different scenarios of use.

Investment opportunities

There are good reasons to consider adding LHAs to PPH management programs: many LHAs are

currently available, LHAs are generally capable of effectively achieving hemostasis within 10 minutes or

less, some are relatively inexpensive and easy to prepare and apply, and there is experience with some in

managing PPH. They would have measurable impact if they could be introduced at points of care where

treatment options are currently limited because of lack of skilled providers or lack of infrastructure and/or

equipment. LHAs could be used:

As “first aid” to induce hemostasis until suturing can be performed at points of care where providers

are not competent to suture or are not competent/confident to suture complicated obstetric lacerations.

As first-line treatment for bleeding occurring in hard-to-reach areas.

As adjunct treatment to induce hemostasis:

o At the placental implantation site until uterine contractions are induced by uterotonic drugs.

o In cases of complicated lacerations when suturing is difficult.

o In cases of bleeding due to coagulopathy.

During interventional radiology procedures, including uterine arterial embolization for uterine atony.

Regrettably, there is widespread practice variation, guidelines are vague, LHAs are not matched to the

type of hemorrhage, and safety data are not fully recorded or recognized. Several investment

17

opportunities over a period of the next one to three years exist to support the use of LHAs for PPH in

LRS, including:

Investment opportunity #1: Gain consensus and build evidence

Convene a multidisciplinary panel of experts, preferably with experience using LHAs for PPH, to:

o Gain consensus around a rational approach to LHA use by: (1) identifying use scenarios of LHAs

for PPH and (2) gaining consensus on possible uses in LRS.

o Gain consensus on steps required for inclusion of LHAs in international clinical guidelines for

management of PPH, including key research questions and study designs to support gathering

evidence on use of LHAs for PPH in LRS.

The consultation would specifically aim to increase awareness of LHAs for PPH, propel LHAs to the

forefront of the global agenda on PPH management protocols, and guide the level and kind of

evidence that would be required.

Facilitate the development of a community of practice for LHAs to:

o Rationalize and strengthen research efforts.

o Track development of promising novel LHAs. A number of novel approaches and methods are

currently under investigation, but most of the work is either in early proof-of-concept stages or in

early trials. Special attention will be given to LHAs that are safe, easy to use, low cost, and address

the identified scenarios of use where LHAs for PPH would be most impactful.

Support comparative efficacy and safety trials for LHAs that have already been used for PPH:

Chitosan-covered gauze (Arsenal foam, XSTATTM), kaolin-infused gauze (QuikClot®), smectite-

impregnated gauze or patches, topical fibrin sealants (TachoSil®, TISSEEL®) and the novel ABS).

Studies should focus on the mechanical LHAs that when compared to other categories of LHAs seem

to be the safest, lowest cost, most heat stable, and easiest to prepare and use.

Investigate the efficacy, safety, and cost-effectiveness of:

o Nonfibrin sealant/tissue adhesives for use in cases of simple genital lacerations and to compare

their efficacy and safety with suturing.

o Local application of TXA for PPH.

These studies need to track bleeding and other patient outcomes and contribute to the refinement of

practice guidelines and choice of LHAs that can be safely and effectively used in different scenarios

of use in LRS.

Investment opportunity #2: Use expert consensus and/or evidence for guideline development

If there is either adequate evidence or consensus by experts on use:

18

o Initiate critical steps to advance policy and programmatic plans to accelerate market penetration

and uptake, ensure commercial sustainability, ensure LRS affordability, and ensure global access

to the technology.

o Advocate promoting inclusion in the WHO guidelines for PPH management and global and

in-country regulatory approvals.

o Develop and disseminate a simple decision-making tool to assist program managers and countries

in choosing a rational selection of LHAs by type of provider and point of care.

o Develop and disseminate algorithms for management of PPH that include use of LHAs (see

Appendix C).

o Develop and disseminate a simple decision-making tool to assist the provider in choosing the most

appropriate LHA by site and type of hemorrhage. For example, a decision tree could be developed,

similar to that developed by Shander et al. 32 (see Figure 1), to choose the type of LHA based on

severity of bleeding and whether bleeding is local or diffuse.

Figure 1. Selection of local hemostatic agent by extent of bleeding.

Once optimal LHAs have been identified and tested, conduct operations research to demonstrate

acceptability, feasibility, cost-effectiveness, and optimal scenarios of introducing them. This

information will assist ministries of health and donors to understand these products and their

advantages, disadvantages, complications, costs (financial and system costs), and optimal ways to

scale up their use.

19

Investment opportunity #3: Develop market for and expand use of existing products

Build a global constituency for LHAs by linking with established networks to support LHA

development, introduction, and scale-up. Achieving access to lifesaving technologies is best

supported by enlisting and organizing influential and invested champions of a new technology to

leverage resources, share information, and coordinate activities to ensure efficient and aligned

outcomes.

Characterize the potential market opportunity for LHAs to ensure that product development activities

and decisions are well informed by a robust understanding of key market drivers. Improving the

evidence base will ensure that the most effective technologies are adequately guided and accelerated

toward global and regional introduction.

Characterize readiness to sustainably introduce and integrate LHAs to proactively establish an

understanding of conditions that will be required and country-level activities necessary for country-

level introduction and transition to scale-up.

Where possible, promote technology transfer to manufacturers in LRS to facilitate access and reduce

cost.

Investment opportunity #4: Develop new products that are appropriate for LRS

Consider adaptation of existing LHAs to: (1) simplify preparation, (2) improve heat stability, or

(3) simplify application.

Consider development of LHAs that are designed for use in LRS.

20

References

1. Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PFA. WHO analysis of causes of maternal

death: a systematic review. The Lancet. 2006; 367(9516):1066–1074.

2. World Health Organization (WHO). MPS Technical Update: Prevention of Postpartum Haemorrhage

by Active Management of the Third Stage of Labour. Geneva: WHO; 2006.

3. Abou-Zahr C. The global burden of maternal death and disability. British Medical Bulletin. 2003;67:1–

11.

4. Immpact International. Pregnancy: A Holistic Approach to Maternal Health. Aberdeen, United

Kingdom: Immpact International; February 2007. Available at: www.prb.org/pdf07/Outcomes.pdf.

5. International Federation of Gynaecology and Obstetrics (FIGO), International Confederation of

Midwives (ICM). Prevention and Treatment of Post-partum Haemorrhage: New Advances for Low

Resource Settings. Joint Statement: International Confederation of Midwives (ICM), International

Federation of Gynaecology and Obstetrics (FIGO). The Hague: ICM; London: FIGO; 2006. Available at:

http://www.pphprevention.org/files/FIGO-ICM_Statement_November2006_Final.pdf.

6. United Nations. The Millennium Development Goals Report 2008. New York: United Nations; 2008.

7. Anderson JM, Etches D. Prevention and management of postpartum hemorrhage. American Family

Physician. 2007;75(6):875–882.

8. Department of Health (South Africa). Mothers 2008–2010: Fifth Report on the Confidential Enquiries

into Maternal Deaths in South Africa. Pretoria: National Department of Health; 2012.

9. Wohlmuth C, Dela Merced J. Topical hemostatic agents in obstetric hemorrhage: International case

reports. In: Arulkumaran S, Karoshi M, Keith LB, Lalonde AB, B-Lynch C, eds. A Comprehensive

Textbook of Postpartum Hemorrhage 2nd Edition: An Essential Clinical Reference for Effective

Management. London, UK: Sapiens Publishing Ltd; 2012:480–486.

10. Achneck HE, Sileshi B, Jamiolkowski RM, Albala DM, Shapiro ML, Lawson JH. A comprehensive

review of topical hemostatic agents: efficacy and recommendations for use. Annals of Surgery.

2010;251(2):217–228.

11. Pusateri AE, Holcomb JB, Kheirabadi BS, Alam HB, Wade CE, Ryan KL. Making sense of the

preclinical literature on advanced hemostatic products. Journal of Trauma. 2006;60(3):674-682.

12. American Society of Health-System Pharmacists (ASHP). Achieving Hemostasis in the Operating

Room and Critical-Care Setting: A Discussion Guide for Health-System Pharmacists on Local

Hemostatic Agents. Bethseda: ASHP; 2013. Available at:

http://ashpadvantagemedia.com/downloads/discussion_guide_hemostasis.pdf.

13. Spotnitz WD, Burks SG, Prabhu R. Fibrin-based adhesives and hemostatic agents. In: Quinn JV, ed.

Tissue Adhesives in Clinical Medicine. Hamilton, Ontario, Canada: BC Decker, Inc; 2005:77–112.

14. Mahmoud S, El Hamamy E. Use of fibrin sealants in obstetric hemorrhage. In: Arulkumaran S,

Karoshi M, Keith LB, Lalonde AB, B-Lynch C, eds. A Comprehensive Textbook of Postpartum

Hemorrhage 2nd Edition: An Essential Clinical Reference for Effective Management. London, UK:

Sapiens Publishing Ltd; 2012: 479–479.

15. Seyednejad H1, Imani M, Jamieson T, Seifalian AM. Topical haemostatic agents. British Journal of

Surgery. 2008;95(10):1197–1225.

21

16. Weaver FA, Hood DB, Zatina M, Messina L, Badduke B. Gelatin-thrombin-based hemostatic sealant

for intraoperative bleeding in vascular surgery. Annals of Vascular Surgery. 2002;16(3):286–293.

17. Oz MC, Cosgrove DM 3rd, Badduke BR, et al. Controlled clinical trial of a novel hemostatic agent in

cardiac surgery. The Fusion Matrix Study Group. Annals of Thoracic Surgery. 2000;69(5):1376–1382.

18. Renkens KL Jr, Payner TD, Leipzig TJ, et al. A multicenter, prospective, randomized trial evaluating

a new hemostatic agent for spinal surgery. Spine. 2001;26(15):1645–1650.

19. Hanks JB, Kjaergard HK, Hollingsbee DA. A comparison of the haemostatic effect of Vivostat®

patient-derived fibrin sealant with oxidised cellulose (Surgicel®) in multiple surgical procedures.

European Surgical Research. 2003;35(5):439–444.

20. Rousou J, Levitsky S, Gonzalez-Lavin L, et al. Randomized clinical trial of fibrin sealant in patients

undergoing resternotomy or reoperation after cardiac operations. A multicenter study. Journal of Thoracic

and Cardiovascular Surgery. 1989;97(2):194–203.

21. Page on Hemcon® bandage for postpartum bleeding due to the multiple vaginal lacerations.

ClinicalTrials.gov website. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01373801. Accessed

May 1, 2014.

22. Hong TM, Tseng HS, Lee RC, Wang JH, Chang CY. Uterine artery embolization: an effective

treatment for intractable obstetric haemorrhage. Clinical Radiology. 2004;59(1):96–101.

23. Spotnitz WD, Burks S. State-of-the-art review: Hemostats, sealants, and adhesives II: update as well

as how and when to use the components of the surgical toolbox. Clinical and Applied

Thrombosis/Hemostasis. 2010;16(5):497–514.

24. Sharma JB, Malhotra M. Successful management of uterine incision hemorrhage in caesarean section

with topical oxidized regenerated cellulose (Surgicel® Nu Knit): a case report. Archives of Gynecology

and Obstetrics. 2006;274(2):115–116.

25. Gao HW, Lin CK, Yu CP, Yu MS, Chen A. Oxidized cellulose (Surgicel®) granuloma mimicking a

primary ovarian tumor. International Journal of Gynecological Pathology. 2002;21(4):422–423.

26. Azmy AF. Oxidized cellulose haemostat mimicking a possible recurrence of neuroblastoma. BJU

International. 2001;88(3):295–296.

27. Schmid BC, Rezniczek GA, Rolf N, Saade G, Gebauer G, Maul H. Uterine packing with chitosan-

covered gauze for control of postpartum hemorrhage. American Journal of Obstetrics & Gynecology.

2013;209(3):225.e1–e5.

28. Horng HC, Hu WM, Tseng HS, Chang WH, Chao KC, Yang MJ. Uterine arterial embolization in the

management of severe post-partum hemorrhage: a successful rescue method to avoid peripartum

hysterectomy. Journal of the Chinese Medical Association. 2011;74(6):255–258.

29. Eriksson LG, Mulic-Lutvica A, Jangland L, Nyman R. Massive postpartum hemorrhage treated with

transcatheter arterial embolization: technical aspects and long-term effects on fertility and menstrual

cycle. Acta Radiologica. 2007;48(6):635–642.

30. Lemmer R, Albrech M, Bauer G. Use of Floseal® hemostatic matrix in a patient with severe

postpartum hemorrhage. Journal of Obstetrics & Gynaecology Research. 2012;38(2):435–437.

31. Wohlmuth C, Dela Merced J. Gelatin-thrombin hemostatic matrix in the management of placental site

postpartum hemorrhage, a case report. Journal of Reproductive Medicine. 2011;56(5–6):271–273.

32. Ferraris VA. Impact of topical hemostatic agents. Presented at: Society for the Advancement of Blood

Management Annual Meeting, September 19, 2013; Los Angeles, CA.

22

33. Lisy M, Kahlil M, Stock UA, Wildhirt SM. Fibrin sealant patch for repair of acute type-A aortic

dissection. Journal of Cardiac Surgery. 2013;28(6):736–741.

34. Öllinger R, Mihaljevic AL, Schuhmacher C, et al. A multicentre, randomized clinical trial comparing

the Veriset™ haemostatic patch with fibrin sealant for the management of bleeding during hepatic

surgery. HPB. 2013;15(7):548–558.

35. Fischer CP, Bochicchio G, Shen J, Patel B, Batiller J, Hart JC. A prospective, randomized, controlled

trial of the efficacy and safety of fibrin pad as an adjunct to control soft tissue bleeding during abdominal,

retroperitoneal, pelvic, and thoracic surgery. Journal of the American College of Surgeons.

2013;217(3):385–393.

36. Kaddoum RN, Chidiac EJ, Zestos MM, Rajan SD, Baraka A. An anaphylactic reaction after primary

exposure to an aprotinin test dose in a child with a severe milk allergy. Journal of Cardiothoracic and

Vascular Anesthesia. 2007;21(2):243–244.

37. Dietrich W, Ebell A, Busley R, Boulesteix A. Aprotinin and anaphylaxis: analysis of 12,403

exposures to aprotinin in cardiac surgery. Annals of Thoracic Surgery. 2007;84(4):1144–1150.

38. Drake DB, Faulkner BC, Amiss LR Jr, Spotnitz WD, Morgan RF. Thrombogenic effects of a

nonthrombin-based fibrin sealant compared with thrombin-based fibrin sealant on microvenous

anastomoses in a rat model. Annals of Plastic Surgery. 2000;45(5):520–524.

39. Frost-Arner U, Spotnitz WD, Rodeheaver GT, Drake DB. Comparison of the thrombogenicity of

internationally available fibrin sealants in an established microsurgical model. Plastic and Reconstructive

Surgery. 2001;108(6):1655–1660.

40. World Health Organization (WHO). Guidelines for the Management of Postpartum Haemorrhage and

Retained Placenta. WHO: Geneva, 2009.

41. Gungorduk K, Asıcıoğlu O, Yıldırım G, Ark C, Tekirdağ Aİ, Besımoglu B. Can intravenous injection

of tranexamic acid be used in routine practice with active management of the third stage of labor in

vaginal delivery? A randomized controlled study. American Journal of Perinatology. 2013;30(5):407–

413.

42. Krohn CD1, Sørensen R, Lange JE, Riise R, Bjørnsen S, Brosstad F. Tranexamic acid given into the

wound reduces postoperative blood loss by half in major orthopaedic surgery. The European Journal of

Surgery: Acta Chirurgica. Supplement. 2003;(588):57–61.

43. Ker K, Beecher D, Roberts I. Topical application of tranexamic acid for the reduction of bleeding.

Cochrane Database of Systematic Reviews. 2013;7:CD010562.

44. Guerriero C, Cairns J, Perel P, Shakur H, Roberts I; CRASH 2 trial collaborators. Cost-effectiveness

analysis of administering tranexamic acid to bleeding trauma patients using evidence from the CRASH-2

trial. PloS One. 2011;6(5):e18987.

45. Coulthard P, Esposito M, Worthington HV, van der Elst M, van Waes OJ, Darcey J. Tissue adhesives

for closure of surgical incisions. Cochrane Database of Systematic Reviews. 2010;(5):CD004287.

46. Torchiana DF. Polyethylene glycol based synthetic sealants: potential uses in cardiac surgery. Journal

of Cardiac Surgery. 2003;18(6):504–506.

47. Macchiarini P, Wain J, Almy S, Dartevelle P. Experimental and clinical evaluation of a new synthetic,

absorbable sealant to reduce air leaks in thoracic operations. Journal of Thoracic and Cardiovascular

Surgery. 1999;117(4):751–758.

48. Ranger WR, Halpin D, Sawhney AS, Lyman M, Locicero J. Pneumostasis of experimental air leaks

with a new photopolymerized synthetic tissue sealant. The American Surgeon. 1997;63(9):788–795.

23

49. Glickman M, Gheissari A, Money S, Martin J, Ballard JL, CoSeal Multicenter Vascular Surgery

Study Group. A polymeric sealant inhibits anastomotic suture hole bleeding more rapidly than

gelfoam/thrombin: results of a randomized controlled trial. Archives of Surgery. 2002;137(3):326–

331;discussion 332.

50. Hartgerink JD. Nanomedicine: New material stops bleeding in a hurry. Nature Nanotechnology.

2006;1(3):166–167.

51. Eyi EG, Engin-Ustün Y, Kaba M, Mollamahmutoğlu L. Ankaferd blood stopper in episiotomy repair.

Clinical and Experimental Obstetrics & Gynecology. 2013;40(1):141–143.

52. Page on vacuum device for hemostasis in obstetrics and gynecology: proof of concept study in the

post partum hemorrhage. ClinicalTrials.gov website. Available at:

http://clinicaltrials.gov/ct2/show/NCT01589744. Accessed March 27, 2014.