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Case 2 and 3. Review of the Complications and Management of Non-DDAVP Responsive VWD

Case 2 and 3. Review of the Complications and Management of Non-DDAVP Responsive VWD

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von Willebrand Disease: Prevention of Complications and Management of the Disease



Questions/Controversies in VWD

Complications and Management



• Can lower doses of DDAVP be used?

• Is antifibrinolytic therapy as effective in

adolescent HMB as in adult patients

with VWD-related HMB?

• Should the peripartum VWF target level

be similar to that achieved physiologically in normal pregnancies in the 200 %

range as opposed to guidelines advising

50–100 % target level (Kouides 2015)?

• Is there clinical benefit in genotyping

type 2 patients (Federici et al. 2009) and

suspected type 1c patients (Castaman

et al. 2009) given emerging data for a

correlation between genotype and phenotypic expression in terms of DDAVP

response and PPH risk (Castaman et al.

2010)?

• Which is more important to target for

major surgery, the VWF:RCo level

>100 % or the FVIIIc level >100 %?

• Should type 3 patients be encouraged to

begin prophylaxis sooner than later akin

to what advised in the severe

hemophiliac?

• Could aggressive use of antifibrinolytic

therapy reduce the frequency and

amount of VWF/FVIII concentrate in

type 2 and 3 patients undergoing surgery or possibly spare its use in minor

invasive procedures such as dental

extraction or colonoscopic biopsies in

type 2 and 3 patients (Davis et al. 2013)?



Expert Perspective This patient illustrates the

lifelong challenges of living with type 3 VWD

due to a myriad of complications, both diseaserelated (arthropathy, epistaxis, and heavy menses (Metjian et al. 2009)) and treatment-related

(HCV infection). HCV infection is less prevalent in those with VWD than in those with

hemophilia but in one registry has been reported

in 40 % (Federici et al. 2006). Her iron deficiency may not only reflect nasal and menstrual

blood loss but also occult GI bleeding from vari-



307



ces and/or arteriovenous malformations (AVMs)

(Makris et al. 2015). AVMs may be associated

with VWD as intact VWF has antiangiogenic

properties and its absence can lead to vascular

proliferation (Starke et al. 2011). Regarding

total elbow replacement, reports are emerging

but it has not yet supplanted an arthroscopic

synovectomy (Kotela et al. 2014; Vochteloo

et al. 2015).

In an analysis of 150 type 3 VWD patients

enrolled in the US Center for Disease Control

registry, all but 3 patients had reported bleeding episodes (98 %) and 92 % required blood

and/or factor treatment. Oral bleeding was the

first site of bleeding (in 54 %) but subsequent

muscle bleeding (28 %) and joint bleeding

(45 %) were noted. Intracranial hemorrhage

was reported in 8 % (Metjian et al. 2009). The

development of arthropathy has prompted the

use of prophylaxis to reduce the morbidity of

joint disease. Prophylaxis has also been

reported to reduce the frequency or epistaxis,

HMB, and GI bleeding (Abshire et al. 2013,

2015). A recent retrospective study of 61 subjects with severe VWD showed a significant

reduction in annualized bleeding rates within

individuals (during prophylaxis – before prophylaxis) and were significant for the total

group (P < 0.0001) and for those with primary

indications of epistaxis (P = 0.0005), joint

bleeding (P = 0.002), and GI bleeding

(P = 0.001) (Abshire et al. 2013).

The patient recently underwent treatment of

her HCV with ledipasvir-sofosbuvir with prompt

clearing of the viremia in just 2 weeks. She states

she feels great. She is feeling so well she would

like to undergo elbow surgery.

Question 10. She is scheduled to undergo

radial resection of the ulna. All of the following preoperative tests should be drawn except:

A.

B.

C.

D.

E.



Protime

Fibrinogen

CBC

Inhibitor screen

Iron panel



P.A. Kouides



308



Expert Perspective Her HCV-related chronic

liver disease justifies preoperative coagulation

screening for CLD-related coagulopathy.

Assuming her various causes of bleeding are not

brisk and the Mirena IUD can control her HMB

(Chi et al. 2011), restoring her iron stores should

improve her hematocrit and in turn give her a

greater margin of safety for surgery as well as

improve platelet function given the inverse relationship of platelet function and circulating red

cell mass (Hellem et al. 1961). For this patient,

unlike those with hemophilia, the risk of an

inhibitor is quite low and does not necessitate

screening before surgery. Furthermore, there are

no available reliable tests to screen for an inhibitor as conventional mixing tests or ELISA-based

assays have not been validated. If an inhibitor is

suspected, an in vivo and recovery study should

be done (Laffan et al. 2014).

Answers

Question 1. D

Question 2. D

Question 3. A

Question 4. B

Question 5. False

Question 6. C

Question 7. C

Question 8. B

Question 9. D

Question 10. D

Acknowledgments The author thanks the staff of the

Mary M. Gooley Hemophilia Center that fosters a very

productive environment for the clinical care and research

of patents with von Willebrand disease and other inherited

bleeding disorders.



Financial Support and Sponsorship None



Conflicts of Interest Dr. Kouides receives an

honorarium for consulting from CSL Behring

Inc. that he donates to the Mary M. Gooley

Hemophilia Center. CSL Behring markets

intranasal

DDAVP

and

manufactures

Humate-P. He also receives an honorarium for



consulting from Baxter Inc. Baxter is developing a recombinant von Willebrand factor

product.



References

Abshire TC, Federici AB, Alv+Írez MT, Bowen J, Carcao

MD, Cox Gill J, Key NS, Kouides PA, Kurnik K, Lail

AE, Leebeek FWG, Makris M, Mannucci PM,

Winikoff R, Berntorp E, VWD,P.N. Prophylaxis in

severe forms of von Willebrand’s disease: results from

the von Willebrand Disease Prophylaxis Network

(VWD PN). Haemophilia. 2013;19:76–81.

Abshire T, Cox-Gill J, Kempton CL, Leebeek FW, Carcao

M, Kouides P, Donfield S, Berntorp E. Prophylaxis

escalation in severe von willebrand disease: a prospective study from the von Willebrand Disease

Prophylaxis Network. J Thromb Haemost. 2015;13:

1585–9.

Akin M. Response to low-dose desmopressin by a subcutaneous route in children with type 1 von Willebrand

disease. Hematology. 2013;18:115–8.

Amesse LS, Pfaff-Amesse T, Leonardi R, Uddin D,

French JA. Oral contraceptives and DDAVP nasal

spray: patterns of use in managing vWD-associated

menorrhagia: a single-institution study. J Pediatr

Hematol Oncol. 2005;27:357–63.

Azzam HA, Goneim HR, El-Saddik AM, Azmy E, Hassan

M, El-Sharawy S. The condensed MCMDM-1 VWD

bleeding questionnaire as a predictor of bleeding disorders in women with unexplained menorrhagia.

Blood Coagul Fibrinolysis. 2012;23:311–5.

Biggs R, Matthews JM. The treatment of hemorrhage in

von Willebrand’s disease and the blood levels of factor

VIII (AHG). Br J Haematol. 1963;9:203.

Bonnar J, Sheppard BL. Treatment of menorrhagia during

menstruation: randomised controlled trial of ethamsylate, mefenamic acid, and tranexamic acid [see comments]. BMJ. 1996;313:579–82.

Bowman M, James P, Godwin M, Rapson D, Lillicrap

D. The prevalence of von Willebrand disease in the

primary care setting. Blood. 2005;106:1780 (Abstract).

Casonato A, Sartori MT, de Marco L, Girolami A.

1-Desamino-8-D-arginine vasopressin (DDAVP) infusion in type IIB von Willebrand’s disease: shortening

of bleeding time and induction of a variable pseudothrombocytopenia.

Thromb

Haemost.

1990;64:117–20.

Castaman G, Tosetto A, Rodeghiero F. Reduced von

Willebrand factor survival in von Willebrand disease:

pathophysiologic and clinical relevance. J Thromb

Haemost. 2009;7 Suppl 1:71–4.

Castaman G, Tosetto A, Rodeghiero F. Pregnancy and

delivery in women with von Willebrand’s disease and

different von Willebrand factor mutations.

Haematologica. 2010;95:963–9.



von Willebrand Disease: Prevention of Complications and Management of the Disease

Chi C, Lee CA, England A, Hingorani J, Paintsil J, Kadir

RA. Obstetric analgesia and anaesthesia in women

with inherited bleeding disorders. Thromb Haemost.

2009;101:1104–11.

Chi C, Huq FY, Kadir RA. Levonorgestrel-releasing intrauterine system for the management of heavy menstrual

bleeding in women with inherited bleeding disorders:

long-term follow-up. Contraception. 2011;83:242–7.

Clark P, Brennand J, Conkie JA, McCall F, Greer IA,

Walker ID. Activated protein C sensitivity, protein C,

protein S and coagulation in normal pregnancy.

Thromb Haemost. 1998;79:1166–70.

Coppola A, Franchini M, Makris M, Santagostino E, Di

MG, Mannucci PM. Thrombotic adverse events to

coagulation factor concentrates for treatment of

patients with haemophilia and von Willebrand disease:

a systematic review of prospective studies.

Haemophilia. 2012;18:e173–87.

Davis A, Walsh M, McCarthy P, Brown G, Roberts S,

Tran H, Street A, Fong CY, Kemp W. Tranexamic acid

without prophylactic factor replacement for prevention of bleeding in hereditary bleeding disorder

patients undergoing endoscopy: a pilot study.

Haemophilia. 2013;19:583–9.

de Lafuente B, Kasper CK, Rickles FR, Hoyer

LW. Response of patients with mild and moderate

hemophilia A and von Willebrand’s disease to treatment with desmopressin. Ann Intern Med.

1985;103:6–14.

Diaz R, Dietrich JE, Mahoney Jr D, Yee DL, Srivaths

LV. Hemostatic abnormalities in young females with

heavy menstrual bleeding. J Pediatr Adolesc Gynecol.

2014;27:324–9.

Dunn AL, Cox GJ. Adenotonsillectomy in patients with

desmopressin responsive mild bleeding disorders: a

review of the literature. Haemophilia. 2010;16:711–6.

Dunn AL, Powers JR, Ribeiro MJ, Rickles FR, Abshire

TC. Adverse events during use of intranasal desmopressin acetate for haemophilia A and von Willebrand

disease: a case report and review of 40 patients.

Haemophilia. 2000;6:11–4.

Elbatarny M, Mollah S, Grabell J, Bae S, Deforest M,

Tuttle A, Hopman W, Clark DS, Mauer AC, Bowman

M, Riddel J, Christopherson PA, Montgomery RR,

Rand ML, Coller B, James PD. Normal range of

bleeding scores for the ISTH-BAT: adult and pediatric

data from the merging project. Haemophilia.

2014;20:831–5.

Federici AB, Mazurier C, Berntorp E, Lee CA, Scharrer I,

Goudemand J, Lethagen S, Nitu I, Ludwig G, Hilbert

L, Mannucci PM. Biologic response to desmopressin

in patients with severe type 1 and type 2 von

Willebrand disease: results of a multicenter European

study. Blood. 2004;103:2032–8.

Federici AB, Santagostino E, Rumi MG, Russo A,

Mancuso ME, Soffredini R, Mannucci PM, Colombo

M. The natural history of hepatitis C virus infection in

Italian patients with von Willebrand’s disease: a cohort

study. Haematologica. 2006;91:503–8.



309



Federici AB, Mannucci PM, Castaman G, Baronciani L,

Bucciarelli P, Canciani MT, Pecci A, Lenting PJ, De

Groot PG. Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von

Willebrand disease type 2B: a cohort study of 67

patients. Blood. 2009;113:526–34.

Gill JC, Endres-Brooks J, Bauer PJ, Marks Jr WJ,

Montgomery RR. The effect of ABO blood group on

the diagnosis of von Willebrand disease. Blood.

1987;69:1691–5.

Girolami A, Tasinato V, Sambado L, Peroni E, Casonato

A. Venous thrombosis in von Willebrand disease as

observed in one centre and as reported in the literature.

Blood Coagul Fibrinolysis. 2015;26:54–8.

Greer IA, Lowe GD, Walker JJ, Forbes CD. Haemorrhagic

problems in obstetrics and gynaecology in patients

with congenital coagulopathies. Br J Obstet Gynaecol.

1991;98:909–18.

Hellem AJ, Borchgrevink CF, Ame SB. The role of red

cells in haemostasis: the relation between haematocrit,

bleeding time and platelet adhesiveness. Br

J Haematol. 1961;7:42–50.

Huq FY, Al-Haderi M, Kadir RA. The outcome of endometrial ablation in women with inherited bleeding disorders. Haemophilia. 2012a;18:413–20.

Huq FY, Kulkarni A, Agbim EC, Riddell A, Tuddenham

E, Kadir RA. Changes in the levels of factor VIII and

von Willebrand factor in the puerperium. Haemophilia.

2012b;18:241–5.

James AH. More than menorrhagia: a review of the

obstetric and gynaecological manifestations of bleeding disorders. Haemophilia. 2005;11:295–307.

James AH. Von Willebrand disease in women: awareness

and diagnosis. Thromb Res. 2009;124 Suppl

1:S7–10.

James AH, Jamison MG. Bleeding events and other complications during pregnancy and childbirth in women

with von Willebrand disease. J Thromb Haemost.

2007;5:1165–9.

James AH, Myers ER, Cook C, Pietrobon R. Complications

of hysterectomy in women with von Willebrand disease. Haemophilia. 2009;15:926–31.

James AH, Konkle BA, Kouides P, Ragni MV, Thames B,

Gupta S, Sood S, Fletcher SK, Philipp CS. Postpartum

von Willebrand factor levels in women with and without von Willebrand disease and implications for prophylaxis. Haemophilia. 2015;21:81–7.

Jarvis RR, Olsen ME. Type I von Willebrand’s disease

presenting as recurrent corpus hemorrhagicum. Obstet

Gynecol. 2002;99:t-8.

Kadir RA, Economides DL, Sabin CA, Owens D, Lee

CA. Frequency of inherited bleeding disorders in

women with menorrhagia. Lancet. 1998a;351:485–9.

Kadir RA, Sabin CA, Pollard D, Lee CA, Economides

DL. Quality of life during menstruation in patients

with inherited bleeding disorders. Haemophilia.

1998b;4:836–41.

Kadir RA, Davies J, Winikoff R, Pollard D, Peyvand F,

Garagiola I, Pabinger I, Federici AB. Pregnancy



310

complications and obstetric care in women with inherited bleeding disorders. Haemophilia. 2013;19 Suppl

4:1–10. doi:10.1111/hae.12269.,1-10.

Kirtava A, Drews C, Lally C, Dilley A, Evatt B. Medical,

reproductive and psychosocial experiences of women

diagnosed with von Willebrand’s disease receiving

care in haemophilia treatment centres: a case-control

study. Haemophilia. 2003;9:292–7.

Kotela I, Zbikowski P, Ambroziak P, Buczma A,

Gwozdowska A, Kotela A, Windyga J. Total elbow

arthroplasty in patient with severe von Willebrand disease. Haemophilia. 2014;20:e441–3.

Kouides PA. Preventing postpartum haemorrhage-when

guidelines fall short. Haemophilia. 2015;21:502–4.

Kouides PA, Burkhart P, Phatak P, Porter J, Peacock L,

Braggins C, Cox C, Belling L, Michalovic D, Howard

F. Gynecological and obstetrical morbidity in women

with type I Von Willebrand disease: results of a patient

survey. Haemophilia. 2000;6:643–8.

Kouides PA, Byams VR, Philipp CS, Stein SF, Heit J,

Lukes AS, Skerette N, Dowling NF, Dowling NF,

Evatt BL, Miller CH, Owens S, Kulkarni R. A multisite management study of menorrhagia with abnormal

laboratory hemostasis: a prospective crossover study

of intranasal desmopressin and oral tranexamic acid.

Br J Haematol. 2009;145:212–20.

Laffan MA, Lester W, O’Donnell JS, Will A, Tait RC,

Goodeve A, Millar CM, Keeling DM. The diagnosis

and management of von Willebrand disease: a United

Kingdom Haemophilia Centre Doctors Organization

guideline approved by the British Committee for

Standards in Haematology. Br J Haematol.

2014;167:453–65.

Leissinger C, Carcao M, Gill JC, Journeycake J, Singleton

T, Valentino L. Desmopressin (DDAVP) in the management of patients with congenital bleeding disorders. Haemophilia. 2014;20:158–67.

Lethagen S, Harris AS, Sjorin E, Nilsson IM. Intranasal

and intravenous administration of desmopressin:

effect on F VIII/vWF, pharmacokinetics and reproducibility. Thromb Haemost. 1987;58:1033–6.

Lukes AS, Moore KA, Muse KN, Gersten JK, Hecht BR,

Edlund M, Richter HE, Eder SE, Attia GR, Patrick

DL, Rubin A, Shangold GA. Tranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trial. Obstet Gynecol. 2010;116:865–75.

Makris M, Federici AB, Mannucci PM, Bolton-Maggs

PH, Yee TT, Abshire T, Berntorp E. The natural history of occult or angiodysplastic gastrointestinal

bleeding in von Willebrand disease. Haemophilia.

2015;21:338–42.

Malec LM, Moore CG, Yabes J, Lie J, Ragni

MV. Postpartum hemorrhage in women with Von

Willebrand disease: an observational study of the

Pennsylvania Health Care Cost Containment Council

(PHC4) database. Haemophilia. 2015;21:e442–5.

Mannucci PM, Canciani MT, Rota L, Donovan

BS. Response of factor VIII/von Willebrand factor to

DDAVP in healthy subjects and patients with haemophilia A and von Willebrand’s disease. Br J Haematol.

1981;47:283–93.



P.A. Kouides

Mannucci PM, Kempton C, Millar C, Romond E, Shapiro

A, Birschmann I, Ragni MV, Gill JC, Yee TT,

Klamroth R, Wong WY, Chapman M, Engl W, Turecek

PL, Suiter TM, Ewenstein BM. Pharmacokinetics and

safety of a novel recombinant human von Willebrand

factor manufactured with a plasma-free method: a prospective clinical trial. Blood. 2013;122:648–57.

Mazurier C, Gaucher C, Jorieux S, Goudemand

M. Biological effect of desmopressin in eight patients

with type 2N (‘Normandy’) von Willebrand disease.

Collaborative Group. Br J Haematol. 1994;88:

849–54.

Metjian AD, Wang C, Sood SL, Cuker A, Peterson SM,

Soucie JM, Konkle BA. Bleeding symptoms and laboratory correlation in patients with severe von

Willebrand disease. Haemophilia. 2009;15:918–25.

Mikhail S, Varadarajan R, Kouides PA. The prevalence of

disorders of haemostasis in adolescents with menorrhagia referred to a haemophilia treatment centre.

Haemophilia. 2007;13:627–32.

Neff AT, Sidonio Jr RF. Management of VWD. Hematol

Am Soc Hematol EducProgram. 2014;2014:536–41.

Nichols WL, Hultin MB, James AH, Manco-Johnson MJ,

Montgomery RR, Ortel TL, Rick ME, Sadler JE,

Weinstein M, Yawn BP. von Willebrand disease

(VWD): evidence-based diagnosis and management

guidelines, the National Heart, Lung, and Blood

Institute (NHLBI) Expert Panel report (USA)1.

Haemophilia. 2008;14:171–232.

Rae C, Furlong W, Horsman J, Pullenayegum E, Demers

C, St-Louis J, Lillicrap D, Barr R. Bleeding disorders,

menorrhagia and iron deficiency: impacts on healthrelated quality of life. Haemophilia 2013;19(3):

385–91.

Shankar M, Lee CA, Sabin CA, Economides DL, Kadir

RA. von Willebrand disease in women with menorrhagia: a systematic review. Bjog. 2004;111:734–40.

Sharma R, Stein D. Hyponatremia after desmopressin

(DDAVP) use in pediatric patients with bleeding disorders undergoing surgeries. J Pediatr Hematol Oncol.

2014;36:e371–5.

Sidonio Jr RF, Smith KJ, Ragni MV. Cost-utility analysis

of von Willebrand disease screening in adolescents

with menorrhagia. J Pediatr. 2010;157(456–60):460.

Siew DA, Mangel J, Laudenbach L, Schembri S, Minuk

L. Desmopressin responsiveness at a capped dose of

15 mug in type 1 von Willebrand disease and mild

hemophilia A. Blood Coagul Fibrinolysis.

2014;25:820–3.

Silwer J. Von Willebrand’s disease in Sweden. Acta

Paediatr Scand. 1973;238:1–159.

Srivaths LV, Dietrich JE, Yee DL, Sangi-Haghpaykar H,

Mahoney Jr D. Oral tranexamic acid versus combined

oral contraceptives for adolescent heavy menstrual

bleeding- a pilot study. J Pediatr Adolesc Gynecol.

2015;28:254–7.

Starke RD, Ferraro F, Paschalaki KE, Dryden NH,

Mckinnon TA, Sutton RE, Payne EM, Haskard DO,

Hughes AD, Cutler DF, Laffan MA, Randi

AM. Endothelial von Willebrand factor regulates

angiogenesis. Blood. 2011;117:1071–80.



von Willebrand Disease: Prevention of Complications and Management of the Disease

Stoof SC, van Steenbergen HW, Zwagemaker A, Sanders

YV, Cannegieter SC, Duvekot JJ, Leebeck FWG, Peters

M, Kruip MJHA, Eikenboom J. Primary postpartum

haemorrhage in women with von Willebrand disease or

carriership of haemophilia despite specialised care: a

retrospective study. Haemophilia. 2015;21:505–12.

Svensson PJ, Bergqvist PB, Juul KV, Berntorp

E. Desmopressin in treatment of haematological disorders and in prevention of surgical bleeding. Blood

Rev. 2014;28:95–102.

Tengborn L, Blomback M, Berntorp E. Tranexamic acid –

an old drug still going strong and making a revival.

Thromb Res 2015;135(2):231–42.

Tosetto A, Rodeghiero F, Castaman G, Goodeve AC,

Federici A, Batlle J, Meyer D, Fressinaud E, Mazurier

C, Goudemand J, Eikenboom JC, Schneppenheim R,

Budde U, Ingerslev J, Vorlova Z, Habatt D, Holmberg

L, Lethagen S, Pasi J, Hill F, Peake I. A quantitative

analysis of bleeding symptoms in type 1 von



311



Willebrand disease: results from a multicenter

European study (MCMDM-1 VWD). J Thromb

Haemost. 2006;4(4):766–73.

Trigg DE, Stergiotou I, Peitsidis P, Kadir RA. A systematic review: the use of desmopressin for treatment and

prophylaxis of bleeding disorders in pregnancy.

Haemophilia. 2012;18:25–33.

Vessey MP, Villard-Mackintosh L, Mcpherson K, Coulter

A, Yeates D. The epidemiology of hysterectomy: findings in a large cohort study. Br J Obstet Gynaecol.

1992;99:402–7.

Vochteloo AJ, Roche SJ, Dachs RP, Vrettos BC. Total

elbow arthroplasty in bleeding disorders: an additional

series of 8 cases. J Shoulder Elbow Surg.

2015;24:773–8.

Von Mackensen S. Quality of life in women with bleeding

disorders. Haemophilia. 2011;17 Suppl 1:33–7.

von Willebrand EA. Hereditar pseudohemofili. Finska

Lakarsallskapets Handl. 1926;67:7–112.



Antifibrinolytics: Indications

and Precautions

Munjid Al Harthy and Peter Kouides



Introduction



M. Al Harthy

Department of Medicine, Rochester General Hospital,

Rochester, NY, USA

e-mail: munjid.alharthy@rochesterregional.org



the proteolytic enzyme plasmin from plasminogen. Plasmin cleaves the polymerized fibrin stands

into fibrin degradation products (FDP), whose carboxyterminal lysine residues prompt continued

clot lysis through binding and activation of tPA

and plasminogen (Silva et al. 2012). Multiple

feedback mechanisms exist to ensure this clot

elimination process is regulated to prevent excess

or insufficient clot lysis. One such pathway occurs

via activation of the thrombin activatable fibrinolysis inhibitor (TAFI) by the thrombin thrombomodulin complex. TAFI is a proenzyme form of

carboxypeptidase-B that cleaves carboxyterminal

lysine residues of fibrin, thereby reducing clot

lysis (Binette et al. 2007). Other inhibitors of fibrinolysis include plasminogen activator inhibitors

(PAIs) which inactivate plasmin through inhibition

of tPA and alpha-2 antiplasmin (Thelwell and

Longstaff 2007; Simpson et al. 2011).

Given the increasing recognition of complications of blood transfusion such as transfusion

reactions and infections (Moor et al. 1999;

Vamvakas and Blajchman 2009), there has been

an increasing demand for hemostatic agents to

reduce the need for allogeneic blood transfusions

during trauma and surgery. This review will focus

on the common antifibrinolytic agents and evidence supporting their efficacy, indications, dosing, and adverse effects.



P. Kouides (*)

Department of Hematology, Rochester General

Hospital, 1425 Portland Avenue,

Rochester, NY 14621, USA

e-mail: peter.kouides@rochesterregional.org



Question 1. A 63-year-old man presents to the

emergency room after a mechanical fall and complains of left hip pain. He is found to have a left



A very important regulator of hemostasis is the

fibrinolytic pathway, which is activated concurrently with platelet aggregation, with thrombin

production, and ultimately with fibrin generation.

Fibrinolysis is influenced by many factors including clot burden, the concentration of coagulation

factors, and the local environment. In certain

nonphysiological conditions, such as trauma and

surgery, there is an increased propensity toward

fibrinolysis related to the release of tissue plasminogen activator (tPA) at the site of injury

which may result in increased bleeding (Bluth

and Kashuk 2011; Cardenas et al. 2014). Patients

with hereditary bleeding disorders such as Von

Willebrand disease (VWD) and hemophilia also

have a tendency to bleed that is partly influenced

by increased activity of the fibrinolytic pathway

(Matsumoto et al. 2013).

Fibrinolysis is responsible for clot resorption

after fibrin formation results in the control of

bleeding. It is initiated by tPA that in turn generates



© Springer International Publishing Switzerland 2016

S.A. Abutalib et al. (eds.), Nonmalignant Hematology, DOI 10.1007/978-3-319-30352-9_28



313



M. Al Harthy and P. Kouides



314



intertrochanteric fracture and is scheduled to go

to the operating room for an open reduction and

internal fixation. His past medical history is significant for hypertension, stage 2 chronic kidney

disease, and a history of transfusion-related lung

injury. On admission, he is noted to have acute on

chronic kidney injury, with an increase in creatinine from a baseline of 1.3 to 1.8 mg/dl.

Which antifibrinolytic agent would be the

most appropriate to decrease surgery-related

blood loss?

A.

B.

C.

D.



Table 1 Intravenous dosing regimens of common

systemic antifibrinolytic agents based on clinical trials

investigating their use in patients undergoing major

surgery (primarily cardiac and orthopedic surgery)

Agent

ε-aminocaproic

acid



Tranexamic acid



Aprotinin

Tranexamic acid

ε-Aminocaproic acid (EACA)

Textilinin



The use of antifibrinolytic agents can be

divided into two broad categories based on clinical setting: surgical and nonsurgical. Surgeries

associated with large amounts of blood loss

arguably benefit the most from the use of systemic antifibrinolytic agents. Clinical trials supporting the efficacy of antifibrinolytic drugs in

surgery and trauma investigated these agents primarily in cardiac and orthopedic surgeries, as

well as in smaller trials of vascular, thoracic,

hepatic, gynecologic, and maxillofacial surgeries. Local hemostatic agents are also commonly

used for the control of bleeding at the site of

injury, such as during dental extractions in

patients on anticoagulation (Patatanian and

Fugate 2006).

Antifibrinolytic agents are divided into two

major categories: the lysine analogues and the

protease inhibitors. The lysine analogues,

ε-aminocaproic acid (EACA), and tranexamic

acid are negatively charged and work by reversibly binding to the positively charged lysine sites

on plasminogen, thereby preventing its incorporation into fibrin polymers and subsequent conversion to plasmin. EACA, discovered a decade

before tranexamic acid, is approximately tenfold

less potent, therefore requiring much higher

doses to achieve a similar effect (Mannucci

1998). The recommended dosages for the most

frequently used antifibrinolytic agents are shown

in Table 1.



Aprotinin



Dosage

Loading dose of 75–150 mg/kg/h

(commonly 5–10 g/h) followed by

an infusion of 10–15 mg/kg/h

(commonly 1–2 g/h, with an

optional 2–2.5 g/L added to the

priming solution) (Fergusson

et al. 2008)

Dosing regimens vary

significantly. A common

perioperative dosing is 15 mg/kg

IV over 30 min 1 h pre-op

followed by 10 mg/kg IV three

times daily post-op. Loading

doses of 2.5–100 mg/kg, followed

by maintenance doses of

0.25–4 mg/kg/h, have been

reported (Henry et al. 2011)

High dose (full Hammersmith

regimen): initial loading dose of

2 million kallikrein inactivator

units (KIU) intravenously at

induction of anesthesia, followed

by an infusion of 500,000 KIU/h

for the duration of the surgery

Low dose (half Hammersmith

regimen): initial loading dose of 1

million KIU at induction of

anesthesia, followed by an

infusion of 250 KIU/h for the

duration of the surgery, with an

additional optional priming dose

of 1 million KIU of aprotinin

added to the pump prime (Bayer

Health Care 2006)

Little difference in effect has been

show between the two dosing

regimens



The efficacy of EACA as a hemostatic agent

has been widely studied in patients undergoing

major surgery. In a 2011 Cochrane systematic

review, EACA was noted to reduce the need for

allogeneic blood transfusion by 19 % compared

to placebo (RR 0.81; 95 % CI 0.67–0.99) or an

absolute risk reduction of 10 %, with no increase

in mortality or increase in the risk of myocardial

infarction, stroke, deep vein thrombosis (DVT),

pulmonary embolism (PE), or renal failure

(Henry et al. 2011).



Antifibrinolytics: Indications and Precautions



Available in both intravenous (IV) and oral

formulations, the drug is eliminated unchanged

(65 %) through the kidneys, compared to 95 % for

tranexamic acid. Due to this reason, EACA

(Choice C) is preferred over TA (Choice B) for

the control of bleeding in patients with renal

insufficiency.

Contraindications to its use include active

thrombosis and disseminated intravascular coagulation (DIC) (Clover Pharmaceuticals Corp.

2012). Case reports of glomerular capillary

thrombosis in patients with hematuria have

prompted the recommendation that EACA be

avoided in patients with hematuria of an upper

urinary tract origin (Tubbs et al. 1979). Although

several cases of myopathy and rhabdomyolysis

due to EACA (brand name Amicar™) have also

been reported (Van Renterghem et al. 1984), the

drug is generally well tolerated. The most common side effects are nausea and gastrointestinal

intolerance.

Tranexamic acid (trans-4-aminomethyl cyclohexanecarboxylic acid, Cyklokapron™) is available in both IV and oral formulations. When

given intravenously, peak levels are typically

achieved within 1 h of administration, with a biologic half-life of 80 min. Since it is primarily

excreted by the kidneys, dose adjustment is

required in patients with a creatinine >1.4 mg/dl,

but no hepatic adjustment is necessary (Eriksson

et al. 1974).

In major surgery, tranexamic acid reduces the

need for allogeneic blood transfusion by 39 %

(RR 0.61; 95 % CI 0.53–0.70) and reduces intraoperative blood loss, but does not reduce the risk

of reoperation due to bleeding (Henry et al.

2011). A prospective randomized study by

Horrow et al. analyzed the effect of tranexamic

acid dose on the degree of operative bleeding in

cardiopulmonary bypass (CABG) surgery. They

assessed varying loading doses (2.5–40 mg/kg)

and maintenance doses at one-tenth of the dose

for 12 h and found a threshold loading dose of

10 mg/kg was required to produce a significant

reduction in bleeding. Higher doses did not provide additional benefit (Horrow et al. 1995).

The use of tranexamic acid has been especially useful in the control of spontaneous and



315



surgical-related bleeding in patients with hereditary bleeding disorders such as VWD, hemophilia, and thrombocytopathies such as

Bernard-Soulier syndrome and Glanzmann

thrombasthenia and as an adjunct to factor concentrates (Seligsohn 2012; Davis et al. 2013). It

can be reconstituted as an aqueous solution and

used as a mouthwash in those undergoing dental

procedures (Federici et al. 2000) or applied topically for the control of nosebleeds.

Aprotinin (Choice A) is a reversible serine

protease inhibitor that works by directly inhibiting plasmin as well as other important enzymes

including trypsin, chymotrypsin, and tissue and

plasma kallikrein (Mannucci 1998). In 2007,

aprotinin was withdrawn from the market after

preliminary data from the Blood Conservation

Using Antifibrinolytics Trial (BART) suggested

an increased risk of death in patients who received

the drug. The BART trial was a multicenter randomized blinded study that assigned 2331 highrisk cardiac surgical patients into groups using

aprotinin, tranexamic acid, and EACA. At

30 days postoperatively, all-cause mortality in

patients treated with aprotinin was 1.53 times

higher than those treated with tranexamic acid or

EACA (Fergusson et al. 2008). Additional observational studies have also suggested that patients

who receive aprotinin are at an increased risk of

renal failure requiring dialysis, stroke, encephalopathy, myocardial infarction, and heart failure

as compared with those receiving tranexamic

acid or EACA (Mangano et al. 2006). Following

these publications, several advisory panels

including Health Canada and the European

Medicines Agency independently reviewed the

data presented by the BART trial and the other

observational studies and concluded that there

were significant limitations related to sample

size, statistical analysis, and treatment allocation,

leading to a reversal of the ban in Canada (Health

Canada 2011).

Contrary to the studies presented above, a

recent mixed treatment meta-analysis (Howell

et al. 2013) and a Cochrane systematic review that

examined randomized controlled trials of aprotinin concluded that it was not associated with an

increased mortality or increased risk of myocar-



M. Al Harthy and P. Kouides



316



dial infarction, stroke, DVT, or pulmonary embolism. Despite a trend toward increased rates of

renal failure when used for cardiac surgery, the

use of aprotinin did not statistically increase the

rates of renal dysfunction (Fergusson et al. 2008).

Aprotinin (Trasylol™) is approved in the USA

only for investigational use in patients who are at an

increased of bleeding and adverse effects of transfusions undergoing CABG surgery, where alternative

agents are unacceptable. Due to their favorable

safety and efficacy profile, the lysine analogues

have essentially replaced protease inhibitors and

would be the appropriate choice in the above patient.

Textilinin (Choice D) is a serine protease inhibitor in the experimental stages of development that

is derived from the Australian snake venom

Pseudonaja textilis. Unlike aprotinin, it does not

inhibit tPA, urokinase, activated protein C, and

elastase (Millers et al. 2013). This narrower spectrum of inhibition could possibly decrease some of

the adverse effects associated with aprotinin, making textilinin a promising agent in need of further

investigation (Flight et al. 2005).

Question 2. A 23-year-old woman is evaluated

in the clinic for heavy menstrual bleeding. She

has menorrhagia since menarche and expresses

concern that her symptoms are significantly

impacting her quality of life. She has also been

trying to conceive for the past 2 months. Her past

medical history is significant for gastritis for

which she is on a proton pump inhibitor. Her family history is significant for a father with moderate

hemophilia. She has tried desmopressin and combination oral contraceptives without a significant

improvement in her menstrual bleeding.

What would be a reasonable next agent to

use in the management of her condition?

A.

B.

C.

D.



Tranexamic acid

Hysterectomy

Low-dose progestin-only oral contraceptive

Naproxen



Tranexamic acid has been proven effective in

the treatment of heavy menstrual bleeding, a significant cause of morbidity in conditions such as

VWD. A randomized control trial by Lukes et al.



in women with HMB examined the efficacy of a

sustained-release formulation of tranexamic acid

(Lysteda™) in reducing menstrual blood loss compared with placebo and analyzed quality-of-life

measures. Women who received tranexamic acid

had significantly greater reductions in blood loss

compared with placebo (40.4 % vs. 8.2 %, respectively) and experienced significant improvements

in their quality of life and self-perceived menstrual

blood loss (Lukes et al. 2010). It may also be more

effective than desmopressin (Kouides et al. 2009)

and controls heavy menstrual bleeding better than

medroxyprogesterone acetate (Kriplani et al.

2006). Lysteda, which is FDA approved for the

treatment of menorrhagia, is given at a dose of

3,900 mg/day in three divided doses for up to the

first 5 days of menses. The licensure study

excluded adolescents so data are needed to confirm its safety and efficacy in this age group.

Only high-dose progestin oral contraceptives

have been shown to be effective in reducing

abnormal uterine bleeding, and therefore (Choice

C), low-dose progestin-only oral contraceptive is

incorrect. Advantages of using tranexamic acid

over naproxen (Choice D) in this patient include

her history of gastric ulcers and her wish to conceive, for which the use of nonsteroidal antiinflammatory drugs (NSAIDs) is a relative

contraindication. While hysterectomy (Choice B)

is potentially curable, it is typically reserved for

patients who have failed medical management,

especially in women of child-bearing age.

Question 3. The patient described in Question 2

is prescribed tranexamic acid 1.3 g orally three

times daily for 5 days of bleeding during each

menstrual cycle. You review the side effects with

her prior to starting therapy.

Which of these most-likely and least-likely

combination answers is correct?



A.

B.

C.

D.



Most likely

Visual changes

Abdominal cramping

Venous

thromboembolism

Paresthesias



Least likely

Abdominal cramping

Venous

thromboembolism

Abdominal cramping

Conjunctivitis



317



Antifibrinolytics: Indications and Precautions



Tranexamic acid is generally well tolerated,

although common mild reactions may include

headache, sinus congestion, abdominal, back,

and muscle pains. Tranexamic acid does not

reduce mortality and does not increase the risk of

myocardial infarction, stroke, DVT, pulmonary

embolism, or renal failure (Berntorp et al. 2001).

Patients who receive tranexamic acid at doses

above 100 mg/kg are at risk for developing generalized convulsive seizures, which is thought to

be due to dose-dependent CNS hyperexcitability.

For this reason it is recommended the total dose

of tranexamic acid in patients >50 years of age

should not exceed 100 mg/kg over 24 h (Menkis

et al. 2012).

Contraindications to the use of tranexamic

acid include active thromboembolic disease, a

history of hypercoagulability including venous or

arterial thrombosis, concomitant oral contraceptive use, and subarachnoid hemorrhage. Caution

should also be taken in patients receiving other

treatments that may lead to an increased risk of

thrombosis, such as those on all-trans retinoic

acid for the treatment of leukemia, or patients

receiving factor IX or anti-inhibitor coagulant

concentrates (Ferring Pharmaceuticals 2013).

(See Table 2 for a summary of the safety profiles

of the most commonly used systemic antifibrinolytic agents.)

While robust evidence regarding the utility of

tranexamic acid in the management of postpartum hemorrhage is still lacking, a few randomized controlled trials suggest it may be useful in

the management of this highly morbid condition.



A randomized controlled trial by Gungorduk

et al. compared intravenous tranexamic acid vs.

placebo in 660 women prior to cesarean section.

Postoperative blood loss was significantly lower

in the cohort of women who received tranexamic

acid compared with placebo, and there was a

reduced use of additional uterotonic agents, but

no difference in maternal or neonatal outcomes

(Gungorduk et al. 2011). In a subsequent study,

adding tranexamic acid to standard management

in women undergoing vaginal delivery significantly reduced blood loss as compared to placebo. Thromboembolic events were not

increased in either trial (Gungorduk et al. 2013).

An international randomized double-blind,

placebo-controlled trial to reduce postpartum

bleeding, termed the World Maternal

Antifibrinolytic (WOMAN) study, is currently

underway with a target accrual of 15,000

patients. Such a large trial should be adequately

powered not only for efficacy but also to assess

severe maternal morbidity (hysterectomy and

VTE) and maternal death (Shakur et al. 2010a).

Another area of active investigation is the utility

of tranexamic acid to reduce blood loss in

trauma patients. The CRASH-2 trial showed a

significant reduction in all-cause mortality and

reduced mortality due to bleeding in trauma

patients who received tranexamic acid within

8 h of injury compared with placebo (RR 0.91;

95 % CI 0.85–0.97) (Shakur et al. 2010b). Other

trials including the PATCH trial will examine

TA in a modern trauma care setting (Mitra et al.

2014), and the CRASH-3 trial will examine the



Table 2 Safety profiles of the most commonly used systemic antifibrinolytic agents

Agent

ε-Aminocaproic acid

Tranexamic acid



Adverse effect

Gastrointestinal

++

+



Nephrotoxicity







Thrombosis







Aprotinin







+







Adapted from: Fraser et al. (2008)

Frequency of adverse effects: − indicates none, + indicates low, ++ indicates high



Other

Rhabdomyolysis (rare)

Changes in color vision

(rare); seizures at very

high doses

Possible increase in

mortality;

hypersensitivity

reactions



318



utility of TA in traumatic brain injury (Dewan

et al. 2012).

With the overwhelming evidence suggesting a

benefit of the lysine analogues in reducing clinically significant bleeding, coupled with their

favorable side-effect profile, the possibilities for

its use in various clinical conditions are promising. Larger patient pools are still needed to reliably ascertain any possible adverse effects and to

determine patient groups that will benefit the

most from its use. Nonetheless, these medications are likely to be used more frequently in the

coming years, and a basic understanding of its

indications and contraindications will become

more pertinent to the general physician.

Answers

Question 1. C

Question 2. A

Question 3. B



Bibliography

Bayer Health Care. Trasylol (aprotinin injection). US prescribing information. West Haven (CT): Bayer

Pharmaceuticals Corporation; 2006.

Berntorp E, Follrud C, Lethagen S. No increased risk of

venous thrombosis in women taking tranexamic acid.

Thromb Haemost. 2001;86(2):714–5.

Binette TM, Taylor FB, Peer G, Bajzar L. Thrombinthrombomodulin connects coagulation and fibrinolysis: more than an in vitro phenomenon. Blood.

2007;110(9):3168–75.

Bluth MH, Kashuk JL. Mechanistic links in traumainduced coagulopathy: a tale of two cities. Ann Surg.

2011;254(1):20–1.

Cardenas JC, Matijevic N, Baer LA, Holcomb JB, Cotton

BA, Wade CE. Elevated tissue plasminogen activator

and reduced plasminogen activator inhibitor promote

hyperfibrinolysis in trauma patients. Shock.

2014;41(6):514–21.

Gungorduk K, Yıldırım G, Asıcıoğlu O, Gungorduk OC,

Sudolmus S, Ark C. Efficacy of intravenous tranexamic

acid in reducing blood loss after elective cesarean

section: a prospective, randomized, double-blind,

placebo-controlled study. Am J Perinatol. 2011;

28(3):233–40.

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



M. Al Harthy and P. Kouides

management of the third stage of labor in vaginal

delivery? A randomized controlled study. Am J

Perinatol. 2013;30(5):407-13.

Clover Pharmaceuticals Corp. Amicar (aminocaproic

acid). Marietta, 2012.

Davis A, Walsh M, Mccarthy P, et al. Tranexamic acid

without prophylactic factor replacement for prevention of bleeding in hereditary bleeding disorder

patients undergoing endoscopy: a pilot study.

Haemophilia. 2013;19(4):583–9.

Dewan Y, Komolafe EO, Mejía-Mantilla JH, et al.

CRASH-3 – tranexamic acid for the treatment of significant traumatic brain injury: study protocol for an

international randomized, double-blind, placebocontrolled trial. Trials. 2012;13:87.

Dietrich W, Ebell A, Busley R, Boulesteix AL. Aprotinin

and anaphylaxis: analysis of 12,403 exposures to aprotinin in cardiac surgery. Ann Thorac Surg.

2007;84(4):1144–50.

Eriksson O, Kjellman H, Pilbrant A, Schannong

M. Pharmacokinetics of tranexamic acid after intravenous administration to normal volunteers. Eur J Clin

Pharmacol. 1974;7(5):375–80.

Federici AB, Sacco R, Stabile F, Carpenedo M, Zingaro

E, Mannucci PM. Optimising local therapy during oral

surgery in patients with von Willebrand disease: effective results from a retrospective analysis of 63 cases.

Haemophilia. 2000;6(2):71–7.

Fergusson DA, Hébert PC, Mazer CD, et al. A comparison of aprotinin and lysine analogues in high-risk

cardiac surgery. N Engl J Med. 2008;358(22):

2319–31.

Flight S, Johnson L, Trabi M, et al. Comparison of textilinin-1 with aprotinin as serine protease inhibitors and

as antifibrinolytic agents. Pathophysiol Haemost

Thromb. 2005;34(4–5):188–93.

Fraser IS, Porte RJ, Kouides PA, Lukes AS. A benefit-risk

review of systemic haemostatic agents: part 1: in

major surgery. Drug Saf. 2008;31(3):217–30.

Health Canada's response to the final report of expert

advisory panel on Trasylol® (aprotinin). (2011,

September 15). Retrieved 1 Apr 2015.

Henry DA, Carless PA, Moxey AJ, et al. Anti-fibrinolytic

use for minimising perioperative allogeneic blood

transfusion. Cochrane Database Syst Rev.

2011;3:CD001886.

Horrow JC, Van Riper DF, Strong MD, Grunewald KE,

Parmet JL. The dose-response relationship of

tranexamic acid. Anesthesiology. 1995;82(2):383–92.

Howell N, Senanayake E, Freemantle N, Pagano

D. Putting the record straight on aprotinin as safe and

effective: results from a mixed treatment meta-analysis

of trials of aprotinin. J Thorac Cardiovasc Surg.

2013;145(1):234–40.

Kouides PA, Byams VR, Philipp CS, et al. Multisite management study of menorrhagia with abnormal laboratory haemostasis: a prospective crossover study of

intranasal desmopressin and oral tranexamic acid. Br

J Haematol. 2009;145(2):212–20.



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