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Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e

Chapter 235: Chapter 235: Hemophilias and von Willebrand's DiseaseHemophilias and von Willebrand's Disease Robin R. Hemphill

INTRODUCTIONINTRODUCTION

Hemophilias are bleeding disorders due to deficiency in one of the factors present in the clotting cascade.1,2

The most common factor abnormalities are of factor VIII (hemophilia Ahemophilia A) or factor IX (hemophilia Bhemophilia B). vonvon

Willebrand's diseaseWillebrand's disease is a related defect of the von Willebrand factor.3

These hereditary bleeding disorders typically appear early in life, and adult patients will usually be able torelate a history of a bleeding problem. However, patients with mild forms of inherited disease may beunaware of a bleeding disorder until stressed by significant trauma or development of another hemostaticproblem.

Systemic bleeding disorders should be suspected in patients with severe bleeding related to trivial trauma orminor surgery, or spontaneous bleeding, particularly when the bleeding occurs in joints or muscle. Unusualbleeding or bruising at multiple areas should also raise concern about a coagulopathy. Medications can beresponsible for unmasking a mild bleeding diathesis.

The pattern of bleeding can suggest a likely cause. Patients with easy bruising, gingival bleeding, epistaxis,hematuria, GI bleeding, or heavy menses are more likely to have a deficiency or dysfunction of the platelets.Conversely, patients with spontaneous deep bruises, hemarthrosis, retroperitoneal bleeding, or intracranialbleeding are more likely to have a coagulation factor deficiency. In factor-deficient patients, bleedingassociated with trauma may be delayed, due to inadequate fibrin clot formation that inadequately stabilizesthe initial platelet thrombus. Patients with von Willebrand's disease may present with features of bothplatelet and clotting factor problems.

HEMOPHILIAHEMOPHILIA

EPIDEMIOLOGYEPIDEMIOLOGY

The genes that encode factors VIII and IX are located on the long arm of the X chromosome. A geneticmutation in the factor VIII gene produces hemophilia A, occurring in about 1 in 5000 male births in the UnitedStates. A mutation in the factor IX gene causes hemophilia B, a�ecting approximately 1 in 25,000 male birthsin the United States. Together, these two forms of hemophilia make up about 99% of patients with inherited

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coagulation factor deficiencies. Hemophilia A and B are clinically indistinguishable from each other, andspecific factor testing is required to identify the type.

Because hemophilia A and B are X-linked disorders, hemophilia is overwhelmingly a disease of men, withwomen typically being asymptomatic carriers. Only rarely do women have severe disease. While thesedisorders are genetic and usually inherited, a family history of bleeding may be absent becauseapproximately one third of new cases of hemophilia arise from a spontaneous gene mutation.

PATHOPHYSIOLOGYPATHOPHYSIOLOGY

Bleeding manifestations in patients with all forms of hemophilia are directly attribuTable to the decreasedplasma activity levels of either factor VIII or IX (Table 235-1Table 235-1). Those with factor activity levels of 0.3 to 0.4IU/mL (30% to 40% of normal) may never be aware that they have hemophilia, or they might manifestunusual bleeding only a�er major surgery or severe trauma. Unless there is another underlying disease,patients with hemophilia do not have problems with minor cuts and abrasions, as hemostasis from theseinjuries is achieved by platelet activation and the formation of the primary hemostatic plug (see chapter 232,"Tests of Hemostasis").

TABLE 235-1

Hemophilia SeverityHemophilia Severity

DiseaseDisease

SeveritySeverity

Percentage of Factor VIII or IX Activity (%Percentage of Factor VIII or IX Activity (%

of Normal)of Normal)Clinical FeaturesClinical Features

Severe <0.01 IU/mL (<1%) Severe spontaneous bleeding, di�icult to

control if trauma

Moderate 0.01–0.05 IU/mL (1%–5%) Usually bleeding from trauma; may bleed

spontaneously

Mild 0.06–0.40 IU/mL (6%–40%) Bleeding a�er trauma

Bleeding is the major complication of hemophilia, but as a result of frequent exposure to blood products,many hemophiliacs in the past were infected with viral hepatitis or human immunodeficiency virus, and had,in addition, complications related to these chronic infections; currently available factor replacementproducts have essentially eliminated the risk of seroconversion.

CLINICAL FEATURESCLINICAL FEATURES

Depending on the severity of the disease, both hemophilia A and B are characterized by easy bruising and

spontaneous recurrent bleeding into the joints and muscles.1,2 Although the joints and muscles are the most

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common areas into which bleeding occurs, hemorrhage may also occur in other areas (Table 235-2Table 235-2). Traumaor a surgical procedure can result in prolonged and di�icult-to-control bleeding.

TABLE 235-2

Hemophilia Bleeding ManifestationsHemophilia Bleeding Manifestations

SiteSite CommentsComments

Hemarthroses Most common site, more frequent in hinged joints (elbows, knees, ankles) than in

multiaxial joints.

So� tissue Bleeding into so� tissues or muscle; bleeding can dissect along fascial planes; most

dangerous in the neck (airway compromise), limbs (compartment syndromes), eye (retro-

orbital hematoma), spine (epidural hematoma), and retroperitoneum (circulatory shock).

Mucocutaneous

bleeding

Delayed bleeding a�er dental extractions; spontaneous bleeding from the nose, pharynx,

GI tract, or lungs is uncommon.

CNS Intracranial bleeding is the most common cause of hemorrhagic death in hemophiliacs of

all age groups; subdural hematomas occur spontaneously or with minimal trauma.

Hematuria Common, usually not serious, and a specific bleeding site is rarely found.

Hemophilic

pseudotumor

Unresolved or undertreated hematomas erode into adjacent bones resembling bone cysts

or malignancy; may compress adjacent nerves and vessels.

Although adults o�en know that they have hemophilia, young children may not have been diagnosed beforethey present to the ED with a bleeding episode. Family history may reveal a bleeding disorder on themother's side. Hemophilia should be suspected in an infant or child who presents with excessive bruising orwith bleeding into the joints, muscles, or CNS that is spontaneous or out of proportion to the history oftrauma. Because factor level determines the severity of disease, those with mild hemophilia may come tomedical attention only when they have a significant surgical procedure or trauma or have started amedication with antihemostatic e�ects.

Congenital hemophilia in neonates can be manifest as excess bleeding a�er circumcision or as intracranial

hemorrhage, usually associated with traumatic delivery.4,5 In infants and mobile children, nonpatternedbruising can suggest hemophilia. An irriTable infant with hemophilia can be di�icult to evaluate; if no othersource is found, there should be a presumption of occult bleeding.

DIAGNOSISDIAGNOSIS

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Hemophilia is diagnosed starting with the clinical suspicion of a bleeding disorder. Screening tests, such asthe prothrombin timeprothrombin time, which measures the extrinsic coagulation cascade, will be normal, whereas theactivated partial thromboplastin timeactivated partial thromboplastin time, which measures the intrinsic coagulation cascade, is usuallyabnormal. However, patients with mild hemophilia and factor levels above 0.3 to 0.4 IU/mL (30% to 40% ofnormal) may have an activated thromboplastin time within the test reference range. Bleeding time in bothBleeding time in bothforms of hemophilia will be normal and therefore not helpfulforms of hemophilia will be normal and therefore not helpful. The diagnosis is confirmed by quantitativemeasurement of factor VIII or IX levels below 0.50 IU/mL (<50% normal). If mild hemophilia A is suspected, avariant of von Willebrand's disease characterized by abnormal binding of factor VIII and von Willebrand factorshould be excluded by special binding tests or genetic analysis.

For patients with established hemophilia, hemostatic testing (e.g., prothrombin time, activated partialthromboplastin time) is unlikely to yield new information and is not routinely indicated. Female carriers of ahemophilic gene can be suspected by family history and confirmed by DNA mutation analysis performed atspecialized centers. Prenatal diagnosis is possible using chorionic villus sampling performed between 9 and14 weeks of gestation or amniocentesis done at 15 to 17 weeks to detect the genetic mutation.

HEMOPHILIA TREATMENTHEMOPHILIA TREATMENT

General Principles Treatment of patients with hemophilia relies on either the early replacement of missingfactors or, for those who have mild factor VIII deficiency, stimulating the body to secrete clotting factor fromintracellular stores. Begin replacement before or at the same time as other resuscitative and diagnosticBegin replacement before or at the same time as other resuscitative and diagnosticmaneuvers for intracranial, intrathoracic, intra-abdominal, retroperitoneal, ocular, or airway bleeding, asmaneuvers for intracranial, intrathoracic, intra-abdominal, retroperitoneal, ocular, or airway bleeding, assustained bleeding raises the risk for morbidity and death (sustained bleeding raises the risk for morbidity and death (Table 235-2Table 235-2)). Bleeding into the neck, tongue, orretropharynx can compromise the airway. Suspected intracranial hemorrhage, either spontaneous with anacute severe headache or following blunt head injury, should receive immediate factor replacement therapyfollowed by noncontrast head CT. Complaints of back, thigh, groin, or abdominal pain may be symptoms ofretroperitoneal bleeding. Hemorrhage into the iliopsoas muscle is a common form of retroperitonealbleeding seen in hemophiliacs, and patients may describe hip pain and have di�iculty straightening their leg,preferring to keep it in a flexed, externally rotated position. An iliopsoas muscle bleediliopsoas muscle bleed can compress anddamage the femoral nerve, cause anemia of blood loss, or produce circulatory shock.

The initial manifestations of bleeding can be subtle. Simple injuries, such as ankle and wrist sprains, may atfirst appear benign, and several hours may pass before hemarthrosis is apparent. So, while there may not beSo, while there may not bephysical signs of bleeding into a joint, patients reliably report when bleeding is occurringphysical signs of bleeding into a joint, patients reliably report when bleeding is occurring. Prompt treatmentof hemarthroses can prevent or reduce the long-term sequelae of hemophilic arthropathy. If a largehemarthrosis is already present, consultation with an orthopedist for appropriate splinting and rehabilitation

may improve the outcome once the bleeding has been controlled.6

Compartment syndromesCompartment syndromes can result from bleeds within the fascial compartments of the extremities.Compartment pressures can be safely measured a�era�er the patient has received factor replacement.

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Many patients and their families administer factor concentrate therapy at home. Patients are taught to self-treat or seek care at the first symptom before little outward evidence develops. Take patient concernsseriously. Many patients will have an established management plan for acute bleeding episodes in themedical record. Regional hemophilia foundations, associations, and centers o�en maintain a database thatcan be contacted for patient-specific information.

Bleeding episodes are terribly painful, so provide adequate pain control whether or not there is a history ofopiate abuse.

When treating patients with hemophilia for other reasons, some general principles apply. Do not placecentral venous access or arterial lines without factor replacement. Similar rules apply to arterial blood gases,lumbar puncture, and other invasive procedures. Do not give IM injections unless factor replacement is givenand maintained for several days. As a general rule, do not give compounds that contain aspirin ornonsteroidal anti-inflammatory drugs for pain relief. If a hemophiliac patient requires interhospital transfer,initiate factor replacement beforebefore transfer, and do not delay factor replacement with attempts to obtainimaging. Most hemophilia centers prefer to be consulted anytimeanytime a patient with hemophilia presents to theED, especially if there is an uncertainty about the need for factor replacement.

Hemophilia Factor Replacement TherapyHemophilia Factor Replacement Therapy

For patients with hemophilia, there are two sources for factor replacement therapy: recombinant technology

from hamster cell lines and purification from human plasma (Table 235-3Table 235-3).1,2,7,8 The highest level of purityand the lowest risk for human viral contamination are found with the recombinant factor concentrates: notransmission of human immunodeficiency virus, hepatitis B virus, or hepatitis C virus has been reported withthe current products available in the United States. However, recombinant products may have a higher risk

for the development of inhibitor antibodies than plasma-derived products.9,10,11 It remains possible for eventhe highly treated and purified plasma-derived products to potentially transmit viruses such as hepatitis A

and the highly heat-resistant parvovirus B19.1,2,7,8 Opinions vary as to the preferred product,12,13 and

current World Federation of Hemophilia guidelines do not express a preference.2 In the United States, theNational Hemophilia Foundation position is that recombinant factor concentrates are the preferred

treatment for hemophilia despite a cost higher than plasma-derived products.14 Where possible, the treatingWhere possible, the treatingphysician should use the product that the patient uses at homephysician should use the product that the patient uses at home.

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*Commercial trade names provided for ease of specific identification.

TABLE 235-3

Hemophilia Replacement Factor ProductsHemophilia Replacement Factor Products

Hemophilia TypeHemophilia Type Available ProductsAvailable Products** (Manufacturer/Distributor) (Manufacturer/Distributor)

Hemophilia A Recombinant Factor VIII Concentrates

Advate® (Baxter)

Helixate FS® (Bayer/CSL Behring)

Kogenate FS® (Bayer)

Recombinate® (Baxter)

Xyntha® (Pfizer)

Human Plasma-Derived Factor VIII Concentrates

Hemofil M® (Baxter)

Monoclate-P® (CSL Behring)

Human Plasma-Derived Factor VIII Concentrates That Contain von Willebrand Factor

Alphanate® (Grifols)

Humate-P® (CSL Behring GmbH)

Koate-DVI® (Grifols/Kedrion Biopharma)

Hemophilia B Recombinant Factor IX Concentrate

BeneFIX® (Pfizer)

Human Plasma-Derived Factor IX Concentrates

AlphaNine SD® (Grifols)

Mononine® (CSL Behring)

The dosing regimen used in the hemophilic patient is empiric based on the clotting factor volume ofdistribution, the half-life of the factor, and the hemostatic level of factor required to control the bleeding

(Table 235-4Table 235-4).15,16 Clotting factor is dosed in units of activity; 1 IU of factor represents the amount present in1 mL of normal plasma. In hemophilia A, 1 IU of factor VIII per kilogram of body weight raises the plasma levelby approximately 0.02 IU/mL (2%). The half-life of factor VIII is approximately 8 to 12 hours. For hemophilia B,1 IU of factor IX per kilogram of body weight will raise the plasma level by approximately 0.01 IU/mL (1%).The half-life of factor IX is approximately 16 to 24 hours.

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TABLE 235-4

Initial Factor Replacement Guidelines in Moderate and Severe HemophiliaInitial Factor Replacement Guidelines in Moderate and Severe Hemophilia

Severity and SiteSeverity and Site

DesiredDesired

FactorFactor

Level toLevel to

ControlControl

BleedingBleeding

HemophiliaHemophilia

A InitialA Initial

DoseDose

(IU/kg)(IU/kg)

HemophiliaHemophilia

B InitialB Initial

DoseDose

(IU/kg)(IU/kg)

CommentsComments

Minor: skin (deep

laceration)

— — — Abrasions and superficial

lacerations usually do not require

factor replacement. Treat with

pressure and topical thrombin.

Minor: early hemarthrosis,

mild muscle bleeding,

mild oral bleeding

0.2–0.4

IU/mL

(20%–

40%)

10–20 20–30 Repeat dose every 12–24 h for 1–

3 d until bleeding episode is

resolved. Typical duration of

replacement is 1–3 d.

Moderate: definite

hemarthrosis, moderate

muscle bleeding,

moderate oral bleeding

0.3–0.6

IU/mL

(30%–

60%)

15–30 25–50 Orthopedic consult may be

required for splinting, physical

therapy, and follow-up. Typical

duration of replacement is 3–5 d.

Major: retropharyngeal,

GI, intra-abdominal,

intrathoracic,

retroperitoneal

0.6–1.0

IU/mL

(60%–

100%)

30–50 30–50 Repeat dose every 8–24 h until

resolution of bleeding episode.

May require replacement for up

to 10 d.

CNS 1.0 IU/mL

(100%)

50 50–100 Treat before CT. Early

neurosurgical consultation.

Factor concentrates are supplied as lyophilized powder in single-use glass vials containing a range ofamounts, from 250 to 4000 IU per vial. Calculation of the amount of factor is done using the patient's weight,baseline factor level, the desired factor level, and, to avoid wasting factor, rounding up doses to the next vial.For patients with moderate and severe hemophilia and baseline factor levels below 0.05 IU/mL (5%), thepresence of such low levels can be discounted when calculating initial dosing guided by these formulae:

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For major bleeding, high levels of factor replacement are required and continued until bleeding stops (TableTable235-4235-4). Repeat doses are usually given as intermittent bolus therapy every 8 to 24 hours, or 6 to 12 hours inpatients under 6 years of age.

For less severe bleeding in so� tissue, muscle, or joints, a lesser amount of factor replacement is necessary;usually three doses over 1 to 2 days are su�icient to control bleeding. In addition to factor replacement,

extremity and joint bleeding may benefit from splinting followed by physical therapy.6 Cryotherapy has no

proven benefit in hemarthroses.17

There may be rare instances in which a patient presents with what appears to be a previously undiagnosedbleeding disorder. In these cases, treatment with fresh frozen plasmafresh frozen plasma is appropriate to control bleeding untildefinitive studies can be done. Fresh frozen plasma contains all of the plasma clotting factors, with anaverage concentration of 1 IU/mL. However, one bag (about 200 mL) of fresh frozen plasma will only raise thefactor levels by 3% to 5% in an average adult, so volume overload can complicate extensive factorreplacement using this product.

Special ConsiderationsSpecial Considerations

Oral and Mucosal BleedingOral and Mucosal Bleeding Oral bleeding from hemophilia is more common in children than in adults. For anoral bleed, the area should be identified, cleaned of inadequate clot, and solution of topical bovine topical bovine thrombinthrombinsprayed on to the site or applied in conjunction with a saturated absorbable gelatin sponge. Repeat dosesshould be limited because repetitive application of topical bovine thrombin can induce antibodies to factorV, resulting in a syndrome of severe bleeding and thrombosis, which can rarely be fatal. Factor replacementmay be required, dosed according to the severity of bleeding. Antifibrinolytic agents, such as aminocaproicaminocaproic

acidacid and tranexamic acidtranexamic acid, are useful adjunctive therapies with a low rate of adverse e�ects.2 For verysuperficial mucosal injuries, it may be possible to manage the bleeding with antifibrinolytic therapy alone.The dose of aminocaproic acid is 75 to 100 milligrams/kg every 6 hours for children, and 6 grams every 6hours for adults, given PO or IV. The dose of tranexamic acid is 10 milligrams/kg IV three times per day for 1 to7 days. Tranexamic acid should be used with caution if hematuria is present because ureteral obstruction

due to clot formation has been reported.7

Mild HemophiliaMild Hemophilia A Patients with mild hemophilia Amild hemophilia A (factor levels of 5% of normal or greater) who have mild

bleeding may not always require factor replacement.1,2,18 Rather, they may be treated with desmopressin,which stimulates the release of von Willebrand factor from endothelial storage sites promoting an increase of

factor VIII in the plasma (Table 235-5Table 235-5).19,20 A concentrated intranasal preparation is available and can be used

at home.21 IV or intranasal desmopressin will increase the factor VIII level by two to four times. Desmopressintreatment can be repeated in 24 hours, but with repetitive use, the patient's stores of factor VIII will becomedepleted, and subsequently, the e�ect will be less. Desmopressin is an antidiuretic agent, and fluid

restriction may be needed during use.19

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TABLE 235-5

Desmopressin Treatment of Mild Hemophilia A and von Willebrand DiseaseDesmopressin Treatment of Mild Hemophilia A and von Willebrand Disease

PatientPatient IV PreparationIV Preparation Nasal PreparationNasal Preparation

<2 y Not recommended Not recommended

<50 kg

weight

0.3 micrograms/kg IV over 30 min Single spray 150 micrograms in one nostril

>50 kg

weight

0.3 micrograms/kg IV over 30 min; maximum

dose, 20 micrograms

One spray 150 micrograms in each nostril (total

dose, 300 micrograms)

HematuriaHematuria Hematuria Hematuria is common in hemophilia but is typically not severe.22 Rest and hydration areimportant to ameliorate the degree of bleeding. Factor replacement is indicated for gross hematuria. There isevidence that hemophiliacs are at increased risk for nephrolithiasis, suggesting that renal imaging is

indicated for patients with symptoms of renal colic or new-onset hematuria.23

Factor InhibitorsFactor Inhibitors Factor inhibitors Factor inhibitors, antibodies against replacement factors, tend to occur most commonly in

severe hemophiliacs.2 Inhibitors not only interfere with the e�ectiveness of factor replacement therapy, but

also can cause anaphylaxis during factor administration in patients with hemophilia B.24 The use of factorreplacement in hemophilic patients with inhibitors is guided by the concentration of inhibitor (measured inBethesda inhibitor assay units) and the type of response the patient has to factor concentrates. ED physiciansshould query hemophiliacs about whether they have known inhibitors.

The overriding principle in treating patients with inhibitors is close consultation with a hematologistThe overriding principle in treating patients with inhibitors is close consultation with a hematologist. Inpatients with an inhibitor titer <5 Bethesda inhibitor assay units and who are not vigorous antibodyresponders, some hematologists may recommend giving an increased dose of factor in an attempt tooverwhelm the existing antibody. Alternative therapies include human plasma-derived activated

prothrombin complex concentrates and recombinant activated factor VII (Table 235-6Table 235-6).25,26,27 Activatedprothrombin complex concentrate contains factors II, IX, and X, mostly nonactivated, and factor VII, primarilyin the activated form. Activated factor VII, either from human plasma or recombinant, when complexed withtissue factor, activates factor X. Factor Xa, in concert with factor Va, calcium, and phospholipid, promotes theconversion of prothrombin to thrombin, which ultimately leads to the formation of a hemostatic plugcomposed of cross-linked fibrin. Even without tissue factor, activated factor VII can bind to the surface ofactivated platelets stimulating the conversion of factor X to factor Xa.

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*Commercial trade names provided for ease of specific identification.

TABLE 235-6

Replacement Therapy for Hemophilia A and B in Patients With InhibitorsReplacement Therapy for Hemophilia A and B in Patients With Inhibitors

Type of ProductType of Product** Initial DoseInitial DoseDosingDosing

IntervalIntervalCommentsComments

Human plasma-derived activated

prothrombin complex concentrate

FEIBA NF® (Baxter)

50–100

units/kg

6–12 h Total daily doses should not

normally exceed 200 units/kg

Recombinant activated factor VII

NovoSeven RT® (Novo Nordisk)

90

micrograms/kg

2 h Repeat until hemostasis achieved

or therapy judged ine�ective

Acquired HemophiliaAcquired Hemophilia Acquired hemophilia Acquired hemophilia occurs when autoantibodies are created against factor VIII,

resulting in inactivation of this factor and a hemorrhagic tendency.28,29 This rare disorder is associated otherconditions in about 40% of reported cases, such as autoimmune diseases, cancer, drugs (e.g., penicillin,sulfonamides, ciprofloxacin, phenytoin, clopidogrel), or the postpartum period. Acquired hemophilia occursequally in both genders with a median age of 60 to 70 years. The bleeding pattern in acquired hemophilia isusually widespread cutaneous purpura and internal bleeding, with hemarthroses being less common, adi�erence from congenital hemophilia.

The autoantibodies are typically polyclonal IgG4 antibodies that form complexes with factor VIII in a mannerthat enables some residual factor VIII activity, causing a poor correlation between measured factor activityand bleeding severity. The laboratory findings include a prolonged activated partial thromboplastin time and

a low factor VII level.30 The autoantibody of acquired hemophilia has di�erent kinetics of interaction withfactor VII, enabling a di�erentiation between the inhibitor antibody sometimes seen in congenitalhemophilia and antiphospholipid antibodies by mixing studies (see chapter 232).

Treatment of acute bleeding is with activated prothrombin complex concentrates or recombinant activated

factor VII (Table 235-6Table 235-6).30,31 Suppression of antibody formation is initiated with prednisone plus eithercyclophosphamide or azathioprine. Most patients respond and maintain remission a�er the

immunosuppressives are tapered and discontinued; relapse occurs in about 20%.32

Postpartum Acquired HemophiliaPostpartum Acquired Hemophilia Postpartum acquired hemophilia Postpartum acquired hemophilia is a rare condition with severe

hemorrhagic potential.33 The risk is highest with the first pregnancy, and presentation is typically 2 monthsa�er delivery with persistent vaginal bleeding being the most common presenting symptom. Treatment forhemorrhage is with activated prothrombin complex concentrates or recombinant activated factor VII (TableTable

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235-6235-6). Production of the autoantibodies will spontaneously cease over many months, achieving completeremission. Immunosuppressants will reduce time to remission. Recurrence with subsequent pregnancies isuncommon.

DISPOSITION AND FOLLOW-UPDISPOSITION AND FOLLOW-UP

Many hemophilic patients are able to judge the severity of bleeding, self-administer replacement therapy,

and monitor the response at home.1,2 Such patients may likely be discharged a�er initial treatment in the EDfor typical joint, so� tissue, or nasal hemorrhage. Relative indications for hospital admission includetreatment requiring multiple factor replacement doses or necessity for parenteral pain management.Patients with bleeding in the CNS, neck, pharynx, retropharynx, or retroperitoneum, or those with a potentialcompartment syndrome should be admitted. Given the complexity of treatment, consultation or transfer to ahemophilia treatment center is recommended.

VON WILLEBRAND'S DISEASEVON WILLEBRAND'S DISEASE

EPIDEMIOLOGYEPIDEMIOLOGY

von Willebrand's disease is the most common inherited bleeding disorder, present in 1% of the population.27

However, most patients have a mild defect, and clinically significant bleeding occurs in only about 1% ofthose with the disease. Congenital von Willebrand's disease is heterogeneously inherited and variablyexpressed, and although there are multiple variants, it can be classified into three major groups (Table 235-Table 235-

77).34,35 An acquired form of von Willebrand's disease occurs when autoantibodies develop against vonWillebrand factor, resulting in rapid clearance of the antibody–von Willebrand factor complex from thecirculation.

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Abbreviation: vWF = von Willebrand factor.

TABLE 235-7

von Willebrand Disease Classification and Treatmentvon Willebrand Disease Classification and Treatment

TypeType FrequencyFrequency DefectDefect TreatmentTreatment

1 70%–80%

of cases

Normal vWF is present, but in

decreased quantity (approximately

20%–50% normal levels)

Desmopressin and, if no response,

consider the measures below

2 10%–15%

of cases

The vWF is abnormal and dysfunctional vWF-containing concentrate or

cryoprecipitate if vWF-containing

product is not available

3 <10% of

cases

Almost no vWF is present vWF-containing concentrate or

cryoprecipitate if vWF-containing

concentrate is not available

PATHOPHYSIOLOGYPATHOPHYSIOLOGY

von Willebrand factor is a glycoprotein that, unlike most other coagulation factors, is synthesized, stored, andthen secreted by the vascular endothelial cells. von Willebrand factor serves two key roles in normal

hemostasis: as a cofactor for platelet adhesion and as the carrier protein for factor VIII.3,36 Circulating vonWillebrand factor does not bind directly to platelets, but, when exposed to the subendothelial matrix, vonWillebrand factor undergoes a structural change, allowing it to bind to platelet glycoprotein Ib. Thisinteraction between von Willebrand factor and platelet glycoprotein Ib leads to platelet activation andadhesion to other platelets, as well as to the damaged endothelium. As a carrier protein, von Willebrandfactor protects factor VIII from proteolytic degradation within the plasma. A defect in von Willebrand factorthat diminishes factor VIII binding can produce a clinical presentation similar to mild hemophilia A.

CLINICAL FEATURESCLINICAL FEATURES

Skin and mucosal bleeding is common in people with von Willebrand's disease, particularly in children and

adolescents.35 Examples of bleeding include recurrent epistaxis, gingival bleeding, unusual bruising, GIbleeding, and menorrhagia in young women. Hemarthrosis is not typical unless severe disease is present. Inmild cases of von Willebrand's disease, the patient may be unaware of the disease until a�er a surgicalprocedure or injury when unexpected bleeding occurs.

DIAGNOSISDIAGNOSIS

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Tests used to diagnose von Willebrand's disease include bleeding time, activated partial thromboplastintime, factor VIII coagulant activity, von Willebrand factor antigen level, and von Willebrand factor

activity.37,38 The common abnormalities seen in von Willebrand's disease include prolonged bleeding time,low or normal von Willebrand factor antigen, and low von Willebrand factor activity. The prothrombin timeshould be normal, and about half of patients have a mildly prolonged activated partial thromboplastin time.Diagnostic testing can be complicated, and misdiagnosis can occur from errors in specimen handling,storage, processing, and laboratory testing proficiency. Also, variability in von Willebrand factor levels cansometimes make von Willebrand's disease di�icult to di�erentiate from mild hemophilia A.

TREATMENTTREATMENT

Desmopressin: Nontransfusional TherapyDesmopressin: Nontransfusional Therapy

DesmopressinDesmopressin has become the primary therapy for many patients with type 1 von Willebrand's

disease.20,21,39,40 For other types of von Willebrand's disease, desmopressin may still work in conjunctionwith plasma products that contain von Willebrand factor, but hematologists tend to recommend either oneor the other. Desmopressin induces the release of von Willebrand factor from storage sites within theendothelium. In responsive individuals, it causes a transient two- to four-fold increase in von Willebrandfactor. Desmopressin also has an e�ect on the endothelium that promotes hemostasis. IV and concentrated

nasal spray preparations of desmopressin are available (Table 235-5Table 235-5).21 Desmopressin may be repeated in 24hours, but the response to subsequent doses diminishes as vWF stores become depleted. Fluid restriction for

24 hours a�er desmopressin administration is important to prevent hyponatremia.39 Medications withknown antiplatelet e�ects should be avoided, including aspirin, nonsteroidal anti-inflammatory drugs,antiplatelet agents, heparin, and some antibiotics.

Transfusional TherapiesTransfusional Therapies

Plasma derivatives that contain von Willebrand factor are used for those type I patients who do not (or no

longer) respond to desmopressin or have type II or III von Willebrand's disease.14,40,41 Because of the risk ofviral contamination, factor VIII concentrates that contain multimeric von Willebrand factor and haveundergone viral inactivation processes are preferred at a dose of 30 to 50 IU/kg (Table 235-3Table 235-3). Cryoprecipitatealso contains von Willebrand factor, but because it does not undergo viral inactivation, cryoprecipitateshould only be used in life-threatening emergencies when appropriate factor VIII concentrates are not

available.14 Platelet transfusions may benefit patients with certain types of von Willebrand's disease (type III)

who do not respond to von Willebrand factor–containing plasma products.42

Additional TherapyAdditional Therapy

Patients with von Willebrand's disease with significant epistaxis should be treated with desmopressin ortransfusion therapy as needed to control bleeding. If unsuccessful, intranasal topical therapy or cauterizationmay be necessary (see chapter 244, "Nose and Sinuses") in some cases. Menorrhagia is a common complaint

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1. 

2. 

3. 

4. 

5. 

6. 

7. 

in young women with von Willebrand's disease. Oral contraceptives can help raise von Willebrand factorlevels and limit the degree of menstrual bleeding. For dental injury or planned procedures in the oral cavity,an antifibrinolytic agent can be used. Aminocaproic acidAminocaproic acid can be taken orally and tranexamic acidtranexamic acid can bemade into a mouthwash, to be used for 5 to 10 days a�er the injury or surgical procedure.

DISPOSITION AND FOLLOW-UPDISPOSITION AND FOLLOW-UP

In most patients with von Willebrand's disease, the acute bleeding episodes can be controlled with localmeasures and desmopressin; such patients can usually be discharged. The unusual von Willebrand's diseasepatient with almost no von Willebrand factor activity is typically handled like a patient with hemophilia.Relative indications for hospital admission include treatment requiring multiple factor replacement doses ornecessity for parenteral pain management. Patients with bleeding in the CNS, neck, pharynx, retropharynx,or retroperitoneum or those with a potential compartment syndrome should be admitted.

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USEFUL WEB RESOURCESUSEFUL WEB RESOURCES

American Society of Hematology Clinical Guidelines—http://www.hematology.org/Practice/Guidelines/2934.aspx

British Committee for Standards in Haematology Guidelines (subcommittee of the British Society forHaematology)—http://www.bcshguidelines.com/

National Heart, Lung, and Blood Institute—http://www.nhlbi.nih.gov/health/indexpro.htm

National Hemophilia Foundation—http://www.hemophilia.org

World Federation of Hemophilia—http://www.wfh.org

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