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Case 1. Review of the Complications and Management of Type 1 VWD

Case 1. Review of the Complications and Management of Type 1 VWD

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

Table 4 Specific treatment of VWD based on VWD

subtype

Type 1

Type 2A

Type 2B

Type 2M

Type 2N

Type 3

Platelet type



Desmopressina (VWF/FVIII

concentrate)

VWF/FVIII concentrate

(desmopressina)

VWF/FVIII concentrate

(desmopressina; may require platelets)

Desmopressina (VWF/FVIII

concentrate)

VWF/FVIII concentrate

(desmopressina)

VWF/FVIII concentrate

Platelets ± VWF/FVIII concentrate



Antifibrinolytic therapy (epsilon-aminocaproic acid or

tranexamic is used as adjunctive therapy for mucosalbased bleeding/surgery)

a

Desmopressin use should be based on trial dose; DDAVP

is theoretically contraindicated in type 2B due to risk of

worsening thrombocytopenia and risk of thrombosis, but

it has been used in select cases



PTT 31.5 s (29.0 s), closure times – ADPcollagen 13 s (60–110 s), epinephrine-collagen

200 s (88–160 s).

Question 1. What would be the next step in

management?

A. Trial of oral contraceptive

B. Tranexamic acid (Lysteda™) 1.3 g po tid

first 3 days of menses

C. Stop ASA and just observe

D. Further diagnostic testing

Expert Perspective As opposed to semiempiric

management in terms of choice a, b, or c, the next

step should be testing for VWD. By pattern recognition, heavy menstrual bleeding (HMB) at menarche should prompt testing for von Willebrand

disease, as both are very common clinical situations

(Fig. 1) (Gill et al. 1987; Vessey et al. 1992). An

argument against semiempiric management with

oral contraceptive is supported by a decision analysis model that showed testing for VWD in adolescents with HMB before the initiation of oral

contraceptives is cost effective (Sidonio et al. 2010).

The patient undergoes testing for VWD:

Ristocetin cofactor (measures VWF activity) = 26 %



297



(normal 40–120 %); VWF antigen (direct measurement of VWF) = 25 % (normal 50–150 %) and

FVIIIc level (indirect measurement of VWF as

VWF carries FVIII in the plasma) = 47 % (normal

50–150 %). VWF multimers are slightly reduced

but in normal pattern. A presumptive diagnosis of

type 1 VWD is made (definitive diagnosis when a

second set of levels return subnormal).



Question 2. All but which of the following are

clinical manifestations/complications of VWD

in females?

A. Iron deficiency anemia

B. Increased rate of gynecological surgical

interventions (dilatation and curettage,

hysterectomy)

C. Decreased quality of life

D. Anovulatory menstrual bleeding

E. Postpartum vulvar hematoma

Expert Perspective HMB and VWF deficiency

are two very common clinical situations that

invariably overlap (Table 6). Women with VWD

certainly have a very high relative risk of HMB

compared to the general population, and often

HMB will prompt the diagnosis of VWD. A systematic review by Shankar et al. (2004) summarized the overall prevalence of the laboratory

diagnosis of VWD in women presenting with

HMB to be 13 % (confidence intervals 11 % and

15.6 %) of a total of 988 women in 11 studies

(Fig. 1). In the adolescent population presenting

with HMB, the prevalence of VWD may be up to

33 % (Mikhail et al. 2007; Diaz et al. 2014).

Lastly, in this case, the bleeding occurred at menarche. Beyond menarche, the menstrual cycle is

usually ovulatory, i.e., regular as anovulatory

HMB intuitively occurs on a hormonal basis as

the cause. But, certainly, there can be overlap,

and further research is needed in order to define

the prevalence of underlying VWD in females

with anovulatory HMB.

VWD women in comparison to a control

group of non-VWD women show a higher prevalence of anemia and a much higher frequency of



Tonsillectomy and adenoidectomy



Major surgery



Minor procedures



Epistaxis



Clinical situation

Dental extractions



Advisement

Deciduous teeth: local measures like thrombin powder on gauze, EACA or TA syrup for 1–3 days if oozing

Molars and wisdom teeth:

1. EACA or TA syrup bolus 1 h pre-extraction then half dose 4 h post-extraction for 3–7 days depending on depth of

extraction and number of teeth extracted

2. IN-DDAVP 1 h pre-extraction if response is > 50 %, second dose POD #1 if oozing

3. Type 2 and 3 VWD – 40 u/kg VWF/FVIII for 1–3 days

1. Apply local pressure by pinching nasal soft tissue for 15 min

2. Adjunctive therapy: nosebleed QR, saline gel, Vaseline, frozen salt pork, Afrin, Neo-Synephrine, thrombin powder, saline

nose spray, nose clips, Surgicel, Gelfoam, short fingernails!

3. If local pressure and adjunctive therapy fails, DDAVP or VWF/FVIII concentrate may be required

4. Type 2 or type 3 VWD patients rarely require prophylaxis for severe recurrent epistaxis but has been done

5. EACA or TA for recurrent epistaxis

Vaccine administration: no prophylaxis (including types 2 and 3) for IM injections provided small-gauge needle is used and

firm pressure for 10–15 min on injection site post administration

Circumcision: no precautions in type 1; VWF/FVIII for 2–3 days in type 2 and 3 patients

1. In type 1 patients, DDAVP trial to document rise to ≥75–100 % with estimation of half-life sampling at 15′ and 4 h

2. In type 1 patients, even if DDAVP responders, use VWF/FVIII if major blood loss expected (e.g., scoliosis surgery or

arthroplasty) or if high risk of hyponatremia (e.g., CNS surgery)

3. In type 2 and 3 patients or type 1 poor DDAVP responders – VWF/FVIII at 40–60 u/kg; (if logistically possible stat level

1 h preoperatively to ensure level ≥75–100 %) with follow-up level 4–6 h post-op to decide on subsequent dosing q 12–24 h

and frequency for up to 5–14 days depending on type of surgery (e.g., shorter for cholecystectomy, longer for arthroplasty or

brain surgery)

1. DDAVP trial as above (if inadequate response or type 2 and 3 VWD then VWF/FVIII concentrate preop and post-op for

3–5 days as above)

2. In responders, IV DDAVP 30 min preop preceded by IV EACA or TA with subsequent IV EACA or TA around the clock

postoperatively

3. Restrict IV and oral free fluids postoperatively

4. Admit overnight with following AM on postoperative day (POD) #1 a stat serum Na, Hct, and VWF levels to decide on

second dose and possibly third dose on POD #2

5. Discharge on POD #1 or #2 on EACA or TA for 10–14 days if clinically stable with dry surgical field

6. DDAVP (either IV or IN) 7–10 days around time eschar expected to fall off



Table 5 Expert perspective: clinical management of specific clinical bleeding or high risk to bleed situations



298

P.A. Kouides



Advisement

1. Obtain third trimester VWF levels

2. If >50 % clear for epidural and delivery without prophylaxis

3. If <50 %, VWF/FVIII 40–60 u/kg q 12 h at time of active labor aiming for peak/trough levels 100–200 % for 3–7 days

(DDAVP deferred due to hyponatremia risk and possibility that it may not raise levels consistently high enough for several

days)

4. Postpartum TA or EACA for 7–14 days if EBL >500 cc or past history of PPH or if types 2 and 3 (EACA, TA safe if

breastfeeding)

Lacerations that require sutures: 1 dose DDAVP or FVIII/VWF concentrate; in those with low FVIII, 1 dose prior to suture

removal

Hematomas: 1 dose DDAVP or FVIII/VWF concentrate; may require additional doses if severe type 1, type 2, or type 3 VWD

Fractures: if simple fracture, 1 dose DDAVP or FVIII/VWF concentrate as for hematomas; for compound fractures or those

requiring surgical intervention, treat as for major or minor surgery depending on the severity; monitor cast tightness carefully



Courtesy in part from Dr. Joan Gill. See Fig. 2 for gynecological management



Sports injuries/lacerations



Clinical situation

Obstetrical



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

299



300



P.A. Kouides



Fig. 1 Prevalence of VWD

in adult females presenting

with HMB (Adapted from

Shankar et al. (2004))



European studies

Edlund (1996)

Kadir (1998)

Woo (2001)

Krause (2000)

Total



18 %



N. American studies

Kouides (2000)

Hambleton (2000)

G-Gruen (2001)

Dilley (2001)

Philip (2003)

Total

Other studies

Baindur (2000)

Ekiaby (2002)

Trasi (2005)



10 %



0



10



20



30



40



50



Prevalence(%) CI



Table 6 The overlap of VWD deficiency and heavy menstrual bleeding

VWF deficiency: scope

of the problem

~45 % population is

blood type O

Data for healthy blood

donors indicate that

VWF levels<50 % are

expected in 14 % of

type O subjects



Heavy menstrual bleeding:

scope of the problem

5 % of women seek medical

attention for menorrhagia

In 50 % of women with

menorrhagia, an underlying

cause is not found

Once referred to a

gynecologist, surgical

intervention is highly likely

In the UK, 20 % of women

will have a hysterectomy

before age 60

In at least half of those

undergoing hysterectomy,

menorrhagia is the main

presenting problem

In the USA, hysterectomy is

the second most common

surgical procedure in

women after cesarean

section



other mucocutaneous bleeding symptoms (Kadir

et al. 1998a; Kouides et al. 2000; Kirtava et al.

2003). Not surprisingly then, women with

unexplained HMB who test positive for VWD

have a higher bleeding score based on the condensed European Union VWD bleeding questionnaire (Azzam et al. 2012). A general outline

of the bleeding score is outlined in Table 7 with

the basic principle that the score is higher the

more the symptoms (rigorously defined) and the



greater the degree of intervention. A recent analysis established a bleeding score of 0–5 in women

of reproductive age (Elbatarny et al. 2014). This

patient’s score would be 5 (1 point for bruising, 3

points for epistaxis, 1 point for HMB changing

pads/tampons every 2 or fewer hours) with the

normal range in children being <2.

Regarding psychosocial aspects, several studies comprising over 300 patients with VWD

compared to non-VWD women have shown

unequivocally that these women do have

impaired quality of life (Kouides et al. 2000;

Kirtava et al. 2003; Rae et al. 2012; Von 2011).

Dysmenorrhea has been noted in approximately

half (Kouides et al. 2000; Kadir et al. 1998b; Von

Mackensen 2011). A high rate of mid-cycle pain,

termed “mittelschmerz,” has also been noted in

women with VWD (Kouides et al. 2000), and

these patients can develop an acute surgical

abdomen from hemoperitoneum due to bleeding

into the corpus luteum with subsequent rupture

(Jarvis and Olsen 2002). A report from Sweden

showed that nine of 136 women with VWD

(6.8 %) experienced hemorrhagic ovarian cysts

(Silwer 1973). There have also been reports of

bleeding into the broad ligament with the patient

presenting with a positive iliopsoas sign (Greer

et al. 1991).

The patient and her parents are informed that

there are numerous treatment options for managing her HMB.



301



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



Table 7 Summary of 12 key bleeding items adapted from the EU bleeding score assessment (Tosetto et al. 2006) in

terms of the varying significance of each symptom with the most significant symptom characteristic accorded a score of

4 points (pts)

Bleeding symptom

1. Epistaxis



2. Bruising

3. Bleeding with

trivial cuts

4. Oral cavity

bleeding

5. Gastrointestinal

bleeding



6. Dental extractionb



7. Surgical related

bleedingb

8. Menorrhagia



When it is significant More significant (2

(1 pt)

pts)

>5 events or >10′

Consultation only



>1 cm and

atraumatic

>5 events or >5′



Consultation only



Even more significant

(3 pts)

Packing or

antifibrinolytic

therapy (rx)





Consultation only



Surgical hemostasis



Referred at least

once

In presence of ulcer,

portal hypertension,

angiodysplasia, or

hemorrhoids

Referred in less than

a quarter of cases



Consultation only



Packing or

antifibrinolytic rx

Packing or

antifibrinolytic rx or

transfusion or

DDAVP

Re-suturing or

packing



Referred in less than

a quarter of all

surgeries

Consultation only



Consultation only



Referred in more

than a quarter of

cases

Referred in more

than a quarter of

procedures

Pill use or

antifibrinolytic rx



9. Post-partum

hemorrhageb



Consultation only



10. Muscle hematoma



Traumatic, no rx



Dilatation and

curettage or

antifibrinolytic rx or

iron rx

Spontaneous, no rx



11. Hemarthrosis



Traumatic, no rx



Spontaneous, no rx



12. Central nervous

bleeding











Most significant (4

pts)

Transfusiona or

DDAVP



Transfusiona or

DDAVP

Transfusiona or

DDAVP









Transfusiona or

DDAVP



Surgical hemostasis

or antifibrinolytic rx



Transfusiona or

DDAVP



Dilatation and

curettage or

antifibrinolytic rx

Transfusion* or

DDAVP



Transfusiona or

DDAVP



Replacement rx or

DDAVP (can be

traumatic)

Replacement or

DDAVP (can be

traumatic)

Subdural



Hysterectomy



Surgical

intervention or

blood transfusion

Surgical

intervention or

blood transfusion

Intracerebral



a



Transfusion unless specified refers to red blood cell (RBC) or plasma-derived replacement therapy

No bleeding with at least two dental extractions or two surgeries or two deliveries is accorded a minus one point



b



Question 3. What would you advise?

A. Trial

of

intranasal

desmopressin

(IN-DDAVP)

B. Tranexamic acid (Lysteda TM) 1.3 g po tid

first 3 days of menses

C. Mirena IUD

D. Estrogen-containing oral contraceptive (OC)

E. Plasma-derived VWF-containing FVIII

concentrate



Expert Perspective There is no one superior

option for HMB management, but before prescribing treatment, a newly diagnosed type 1

VWD patient should undergo a DDAVP trial,

particularly if non-DDAVP options are chosen

for HMB control. It should be documented

whether the patient responds adequately to

DDAVP, so this information is available prior to

any invasive procedure, e.g., wisdom tooth

extraction.



P.A. Kouides



302

Fig. 2 Treatment

approaches for VWDrelated HMB numbered in

order of potential

preference in relation to

stage of reproductive cycle



VWD-related heavy mesntrual bleeding



Intranasal DDAVP trial



Menarche



Reproductive years



Post-child bearing

years



1.



Intranasal DDAVP



1.



Oral contraceptive



1.



2.



Antifibrinolytics



2.



Intranasal DDAVP



2.



Antifibrinolytics



3.



Oral contraceptive



3.



Antifibrinolytics



3.



Levonorgestrel intrauterine

device



4.



Oral contraceptive



5.



Endometrial ablation



6.



Hysterectomy



Thereafter, if the patient is a DDAVP

responder, i.e., at least a doubling of the VWF

levels, then intranasal DDAVP (IN-DDAVP) is

an additional option to antifibrinolytic therapy

(tranexamic acid) or hormonal therapy (oral

contraceptives, OC) or surgical management

(endometrial ablation or hysterectomy).

Figure 2 illustrates the “best” choice in relation

to the patient’s stage in the reproductive lifespan: in the menarchal patient, nonhormonal

therapy is more likely prescribed than

IN-DDAVP or tranexamic acid, unless the

patient is sexually active. In the childbearing

years, endometrial ablation (Huq et al. 2012a)

or hysterectomy (James et al. 2009) may be

more likely prescribed.

Since HMB is characterized by increased

fibrinolysis of the menstrual fluid, tranexamic

acid (TA) has been a mainstay of treatment for

decades for the general HMB population (Bonnar

and Sheppard 1996). There is also a sustained

release formulation of TA available in the USA,

Lysteda™, approved for the general HMB population dosed at two tablets of 650 mg/tablet three

times a day for the first 5 days of menses.

Menstrual blood flow (MBL) was reduced 41 %

compared to 8 % in the placebo arm accompanied

by significant improvements in numerous quality

of life (QOL) parameters (Lukes et al. 2010). In

our patient, however, tranexamic acid may not

necessarily be the first choice since it is recommended for age >18 years of age. However, there



Intranasal DDAVP



is emerging data that it is safe and effective in the

adolescent population (Srivaths et al. 2015).

Regarding desmopressin (DDAVP), in nonrandomized cohort studies, DDAVP has been

reported by patient self-assessment as

“excellent”/“very effective” in approximately

three-quarters of patients with subcutaneous or

intranasal (IN) use (Leissinger et al. 2014).

However, more objective measurements of

efficacy have not shown as great a benefit of

IN- DDAVP for VWD-related HMB compared

to prior studies using subjective assessment as

the endpoint of efficacy. A relatively large multicenter US crossover trial of women with

abnormal laboratory hemostasis (including

VWD) comparing IN-DDAVP and TA using

the PBAC for assessment of MBL and four previously validated QOL measures was carried

out (Kouides et al. 2009). Both medications

reduced menstrual flow and improved QOL

among females with HMB and abnormal laboratory hemostasis, but TA proved to be more

effective than IN-DDAVP (Kouides et al.

2009).

Approximately 10–15 % of women with

VWD do not respond to DDAVP due to a mutation or the severity of their type 1 VWD or type 2

or type 3 VWD. In those patients, for severe

intractable HMB refractory to antifibrinolytic

therapy and/or hormonal therapy or for prophylaxis before surgery, a plasma-derived von

Willebrand factor-containing FVIII concentrate



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



(VWF/FVIII) can be administered (Abshire et al.

2013).

An intranasal DDAVP trial was administered

with adequate response observed



Preintranasal

DDAVP

Postintravenous

DDAVP

(90 min

after)



Ristocetin

cofactor (nl =

40–120 %)

20 %



93 %



VWF

antigen (nl =

50–150 %)

27 %



99 %



Factor 8

level (nl =

50–150 %)

52 %



115 %



The patient and parents were informed of the

positive DDAVP response. The parents opted for

IN-DDAVP over TA because of fewer treatment

days, 3 versus 5 days, and parenteral ethical concerns regarding OC at her age. The patient was

instructed to use one puff to each nostril for first

3 days of menses. Follow-up PBAC score

decreased from 320 to 60.

A year later, the pediatrician calls the hematologist for advisement, as the patient is now

pregnant.

Expert Perspective As noted above, there is not

one ideal agent for control of VWD-related

HMB. One has to individualize in terms of whether

the patient is soon planning pregnancy, wants to

defer pregnancy, or is post-childbearing. In this

case, the hematologist when offering the various

treatment options did not obtain the social history

that this adolescent was sexually active wherein OC

use would be preferable given its additional benefit

beyond HMB control. OC and IN-DDAVP appear

to have equivalent efficacy (Amesse et al. 2005) in

controlling adolescent VWD-related HMB.



Question 4. In your advisement regarding

pregnancy in this type 1 VWD patient, which

of the following statements is correct?

A. The bleeding score predicts the risk of

postpartum hemorrhage (PPH).



303



B. The VWF levels can begin to fall 3 days

postpartum placing the patient at risk of

postpartum hemorrhage.

C. DDAVP

use

in

peripartum

is

contraindicated

D. There is increased risk of miscarriage in

type 1 VWD.

Question 5. Patients with type 1 VWD usually

should not be cleared for epidural analgesia,

true or false?

Expert Perspective Recent studies have shown

that VWF levels fall by the third day postpartum

(Huq et al. 2012b; James et al. 2015), so the clinician must be vigilant of the risk of PPH beyond

day 3 postpartum (if the patient’s third trimester

VWF levels are <50 %). On the other hand, there

is no conclusive evidence that the rate of miscarriage is greater than the 12–13.5 % rate of miscarriage in the general population (James 2005).

Studies are still ongoing in type 1 VWD to

determine whether a high antepartum bleeding

score predicts higher risk of PPH. In general,

immediate PPH is rare in type 1 VWD as in this

patient near delivery, the VWF antigen and VWF

ristocetin cofactor activity peak in the 225–250 %

range (Clark et al. 1998). Incidentally, this data

reminds the clinician that almost all type 1 VWD

can be cleared for an epidural given the adequate

rise in VWF levels >50 % in the third trimester

(Chi et al. 2009).

Regarding PPH, in an analysis of the US

Nationwide Inpatient Sample (NIS) of 4,067

deliveries in women with VWD (1 in 4,000 deliveries), James and Jamison observed that women

with VWD were more likely to experience a

postpartum hemorrhage (OR, 1.5; 95 % CI: 1.1,

2.0) and require a transfusion (OR, 4.7; 95 % CI:

3.2, 7.0) (James and Jamison 2007). In a recent

analysis of the state of the Pennsylvania Health

Care Cost Containment Council database, a similar risk of PPH was observed (Malec et al. 2015).

Regarding the use of peripartum DDAVP, for

women whose VWF levels have not exceeded

50 %, there have been theoretical concerns that it

might decrease placental blood flow, induce



304



P.A. Kouides



premature labor, or cause neonatal hyponatremia.

However, a systematic review of 30 studies of the

use of DDAVP for treatment and prophylaxis of

bleeding disorders in pregnancy further confirmed its efficacy and safety (Trigg et al. 2012)

but confirming two cases of symptomatic hyponatremia postpartum in 172 pregnancies.

Expert Perspective Despite the systematic

review above, the risk of peripartum hyponatremia with aggressive fluid resuscitation, the risk of

DDAVP tachyphylaxis, and the relative “undertreatment” of women with VWD (James et al.

2015; Stoof et al. 2015), we advise VWF/FVIII

concentrate every 12–24 h peripartum for

3–7 days in those women with VWF levels <50 %

in the third trimester. The need for a higher target

than stipulated (Kouides 2015) is supported by

recent studies showing a higher rate of PPH

(OR = 2.7) in deliveries given no prophylactic

treatment (Stoof et al. 2015) and the degree of

PPH (615 mL vs. 448 mL) comparing nontreatment to treatment targeting 50–100 % (James

et al. 2015). Figure 3 depicts the options in preventing and managing PPH in the setting of

VWD.

This patient’s brother, who is 10 years of age,

is now scheduled for a T&A. This prompts testing

for VWD and his levels are subnormal on two

occasions in the same range as his sister’s. Also,



Fig. 3 General

management approach for

prophylaxis and treatment

of PPH in the VWD patient



he has an excellent response to DDAVP. DDAVP

is prescribed at a dose of 0.3 microgram/kilogram

(mcg/kg) IVSS in 50 cc normal saline (NS) over

15–30 min preoperatively (preceded also by

Amicar 1 g IVSS over 30 min.).



Question 6. Choose the typical mild/moderate

adverse reaction that is associated with a

related severe adverse reaction of DDAVP:



A.

B.

C.

D.

E.



Common mild to

moderate adverse

reaction

Abdominal pain and

cramping

Parathesias

Headache

Nausea

Flushing



Most likely severe adverse

reaction

Stroke

Myocardial infarction

Hyponatremia and seizure

Venous thrombosis

Renal failure



Expert Perspective Side effects of DDAVP

include flushing, tachycardia, nausea, headache,

and seizures secondary to hyponatremia (if fluids

not restricted) (Dunn et al. 2000; Leissinger et al.

2014). Rarely, thrombosis has been noted. We caution the patient that the headache may be a reason to

stop desmopressin (DDAVP) and that pretreating

with acetaminophen may help. We also caution

about the risk of hyponatremia (ten times greater



Clinical peripartum scenario



Prophylaxis of PPH



If 3rd trimester VWF level

< 50 %, replace to >100–200 %

peripartum then minimum4–

7 days post-partum

(if prior robust responder to

DDAVP, could use DDAVP In

lieu of replacement)



Consider peripartum IVTA

and post discharge oral TA or

EACA if high bleeding score



Treatment of PPH



1. Fundal massage

2. Crystalloid resuscitation and red

cells as indicated

3. Double uterotonics- e.g. oxytocin

and misoprotol

4. Continue VWF/FVIII replacement

and IVTAIVC

5. Continued obstetrical assesment

and possible intervention

6. Fibrinogen replacement for

superimposed DIC if falling fibrinogen

7. rVII a before hysterectomy



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

Table 8 Weight-based fluid restriction post-DDAVP

(courtesy of Ann Neff MD)

Weight

(kg)

Weight

(lbs)

22

44

66

88

110

132

154

176

198

220



10

20

30

40

50

60

70

80

90

100



Maximum fluid Maximum fluid

in first 12 h

in next 12 h

(ounces)

(ounces)

Hours 12–24

after DDAVP

11

16

16

24

19

28

21

32

24

36

27

40

29

44

32

48

35

52

37

56



with the IV than IN form (Leissinger et al. 2014))

and the need to limit free water intake (see Table 8)

particularly given that 47 % of T&A cases in a

review by Dunn and Gill of 144 cases developed

hyponatremia, 6 of whom developed hyponatremic

seizures (Dunn and Cox 2010). A more recent

report from Toledo Children’s Hospital in children

with bleeding disorders undergoing various surgeries observed hyponatremia <130 meq/l in 11 %

(11/107; 95 % CI 5 %,16 %) after a preoperative

dose (Sharma and Stein 2014). The lack of sufficient data in children under 2 years of age and concerns regarding controlling free water precludes use

of DDAVP in this group (Leissinger et al. 2014).

The risk of venous thrombosis is considered to

be exceedingly low, as thoroughly reviewed by

Girolami et al. (2015).

The T&A is scheduled.

Question 7. Prior to the surgery, all the following should be on the “checklist” except:

A. Arrange for overnight stay.

B. Arrange for CBC, VWF levels, and basic

metabolic panel for postoperative day 1.

C. Arrange for infusion of VWF/FVIII concentrate 1 h preoperatively.



305



D. Obtain insurance approval for postdischarge EACA for 10–14 days.



Expert Perspective There has been a trend

nationally to perform T&A on an outpatient basis

or at least a 23 h stay, but patients with VWD

should be admitted overnight for monitoring for

bleeding given an approximate 7.5 % risk of hemorrhage within 24 h and another 7.5 % risk beyond

24 h (Dunn and Cox 2010). Given the risk of hyponatremia as noted, a follow-up serum sodium the

next AM along with repeat VWF level should be

obtained to decide if additional dosing is needed.

This patient was an excellent responder to DDAVP

so we would not have used VWF/FVIII concentrate unless the procedure was associated with significant blood loss (e.g., spinal fusion surgery,

repair of cranial synostosis, arthroplasty) given the

risk of tachyphylaxis after three doses of daily

DDAVP and the risk of hyponatremia with fluid

resuscitation in major surgery. Regardless of the

VWD subtype, the use of antifibrinolytic therapy

should be used perioperatively and post-discharge

for 10–14 days as an effective adjunctive measure

(Dunn and Cox 2010). Around days 7–10, the

eschar usually sheds and a dose of DDAVP should

be given preemptively to this patient.

In preparing a VWD patient for T&A, as in

this case, the standard dose of DDAVP is

0.3 mcg/kg. In actuality, though, this specific

dose was established based on five healthy controls receiving varying doses from 0.1 to 0.4 mg/

kg. A dose-response relationship was observed

for FVIII:C up to 0.3 mg/kg and for VWF:Ag up

to 0.2 mcg/kg (Mannucci et al. 1981). Recently

this had led some to utilize lower dosing,

0.15 mcg/kg, which may reduce potential

adverse reactions like headache, hyponatremia,

or thrombosis while still achieving a three- to

fivefold rise in the VWF levels. A lower dose of

DDAVP may be worth considering in the patient

undergoing surgery who has additional prothrombotic risks like morbid obesity and undergoing, for example, abdominal-pelvic surgery

(Akin 2013; Siew et al. 2014).



P.A. Kouides



306



Case 2 and 3. Review

of the Complications

and Management of Non-DDAVP

Responsive VWD

A 42-year-old male with type 2B is undergoing a

laparoscopic cholecystectomy. He is a nonresponder to DDAVP. His baseline VWF levels are

VWF:RCo of 9 % (50–120 %) and VWF:Ag of

46 % (60–200 %); platelet count is 147,000/mcl.

Question 8. How would you dose the

VWF/FVIII concentrate?

A. VWF level to 50 % immediately preop and

then 25 % postoperatively for 5–7 days

B. VWF level to 100 % immediately preop

and then 75–100 % for 24–48 h postoperatively followed by 50 % for 5–7 days total

C. VWF level to 100 % immediately preop

and then 75–100 % for 24–48 h postoperatively followed by 50 % for 10–14 days total

D. VWF level to 200 % immediately preop

and then 100–200 % for 24–48 h postoperatively followed by 100 % for 5–7 days total

E. VWF level to 200 % immediately preop

and then 100–200 % for 24–48 h postoperatively followed by 100 % for 10–14 days

total



Expert Perspective In general for tooth extractions and injections, we advise a target of 50 %

(20–40 ristocetin units/kg dependent on baseline VWF level) for one dose (plus antifibrinolytics for oral cavity surgery, bleeds, and tooth

extractions). In general for minor surgery and

bleeds (e.g., joint bleed), we advise 50–75 %

and then maintain above 40–50 % for 1–3 days,

depending on the procedure. For major bleeds/

major surgery like this cholecystectomy, we

advise 100 % initial level (40–60 ristocetin

units/kg dependent on baseline VWF level) and

then maintain VWF levels for 7–14 days,

depending on the type of surgery (Nichols et al.

2008). This type of surgery is associated with

adequate healing in 7 days, so we would treat

not beyond that unless the case necessitated an



open incision and liver resection, for example.

The cost of factor and the potential risk of

thrombosis (Coppola et al. 2012) justify obtaining a peak FVIIIc level and VWF:RCo level

immediately post-infusion and then infuse additional factor if below the target. While hospitalized, we also obtain daily levels with the intent

of being cost effective and with the intent of

theoretically reducing the risk of thrombosis.

While guidelines advise a target of 100 % for

major surgery (Nichols et al. 2008; Laffan et al.

2014), its still not clear if specifically the

VWF:RCo level or the FVIIIc level is the most

important to target at 100 %. Intuitively, the

VWF:RCo level may be more important for

mucosal-based surgeries like a T&A and the

FVIIIc level more important for “deep tissue”

surgeries like arthroplasty (Biggs and Matthews

1963).



Case 3

A 28-year-old female has type 3 VWD. Both of

her older siblings are affected. Her oldest sibling

expired from HIV due to transmission from cryoprecipitate while she and her remaining sibling

are HIV negative but HCV positive. Her

FibroSure score is consistent with cirrhosis, and

her platelet count is in the 70,000/ml range consistent with hypersplenism from portal venous

hypertension. She did not tolerate a course of

interferon in the past. Her menstrual periods are

heavy. She has intermittent severe epistaxis lasting 20–30 min. She is anemic with a hemoglobin

of 10 g/dl (12–15 g/dl) with a ferritin of 2 ng/ml

(40–200 ng/mL). She also has severe right elbow

pain due to chronic arthropathy.

Question 9. This patient would benefit from

all but which of the following measures:

A.

B.

C.

D.

E.



VWF/FVIII concentrate prophylaxis TIW

Course of ledipasvir-sofosbuvir

Digital capsule endoscopy

Total elbow arthroplasty

Mirena IUD



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



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