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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.


• 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


• 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-


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:









Inhibitor screen

Iron panel

P.A. Kouides


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).


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





Humate-P. He also receives an honorarium for

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



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Antifibrinolytics: Indications

and Precautions

Munjid Al Harthy and Peter Kouides


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


M. Al Harthy and P. Kouides


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?





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)




Tranexamic acid


Tranexamic acid

ε-Aminocaproic acid (EACA)


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.



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


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


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


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


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


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?





Tranexamic acid


Low-dose progestin-only oral contraceptive


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?





Most likely

Visual changes

Abdominal cramping




Least likely

Abdominal cramping



Abdominal cramping



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


ε-Aminocaproic acid

Tranexamic acid

Adverse effect








Adapted from: Fraser et al. (2008)

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


Rhabdomyolysis (rare)

Changes in color vision

(rare); seizures at very

high doses

Possible increase in





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.


Question 1. C

Question 2. A

Question 3. B


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M. Al Harthy and P. Kouides

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

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