vwb disease case report

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CASE REPORT

Non - Infection Unit

VON WILLEBRAND DISEASE

Presentator : Nur Farhanim Shuhaimi

Nor Azila Muhd Aris

Supervisor : Prof. Dr. Hj. Bidasari Lubis,SpA(K)

Day/ date of presentation : Thursday/ 12 August 2010

I. INTRODUCTION

Definition

von Willebrand disease is due to an abnormality, either quantitative or

qualitative, of the von Willebrand factor, which is a large multimeric glycoprotein

that function as the carrier protein for factor VIII (FVIII). von Willebrand Factor

(vWF) is also required for normal platelet adhesion. It was first described by Erik

Adolf von Willebrand in 1926, von Willebrand disease is a congenital bleeding

disorder characterized by a lifelong tendency toward easy bruising, frequentepistaxis, and menorrhagia. (4)

Epidemiology

von Willebrand disease is estimated to affect about 1% of the population.

Prevalence worldwide is estimated at 0.9-1.3%. It is the most common inherited

bleeding disorder, with a prevalence of 66 to 100 cases per million in the general

population, taking patients referred for clinical manifestation of bleeding as a

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basis of the estimate. (2) Approximately 54% of patients with von Willebrand

disease have classic (type 1) disease (i.e., a mild to moderate deficiency of vWF).(7)

von Willebrand disease affects males and females in equal numbers. No

influence of ethnicity on the prevalence of von Willebrand disease has been

reported and can be diagnosed at any age. (4)

Etiology

von Willebrand disease is caused by either decreased quantity or abnormal

function of a large multimeric protein, vWF. The protein range in size from

450kDa to over 10,000 kDa and is located at chromosome 12p13.2. vWF is made

in the endothelium and by megakaryocytes. This protein has two roles: the

binding of platelets to exposed collagen at sites of vascular injury, and the binding

and stabilization of FVIII. (6)

von Willebrand disease usually is inherited as an autosomal dominant trait

and rarely as an autosomal recessive trait. von Willebrand factor may be either

quantitatively deficient or qualitatively abnormal. (7) Type 1 von Willebrand

disease is typically transmitted in an autosomal dominant manner. The genetic

mutations seen include nonsense mutations, deletions and frameshifts. Type 2

occurs primarily as an autosomal dominant disorder, but may also show recessive

inheritance. The primarily missence mutations seen in type 2 occur within the

various functional domains of the vWF gene, resulting in the four clinical

phenotypes (type 2A, B, M and N). Type 3 occurs in patients who are either

homozygous for the type 1 mutations. (6)

Classification

von Willebrand disease can be classified into 3 main types: type 1, type 2,

and type 3. Type 2 is further subdivided into type 2A, 2B, 2M, and 2N. Type 1

which accounts for 70-80% of cases, is characterized by a partial quantitative

decreased of qualitatively normal vWF and FVIII. An individual with type 1 von

Willebrand disease generally has mild clinical symptoms, and this type is usually

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inherited as an autosomal dominant trait; however, penetrance may widely vary in

a single family. In addition, clinical and laboratory findings may vary in the same

patient on different occasions. Typically, a proportional reduction in vWF

activity, vWF antigen, and FVIII is observed in type 1 von Willebrand disease. (3,

4)

Type 2 disease accounts for 15-20% of von Willebrabd disease cases.

Type 2 is a variant of the disease with primarily qualitative defects on vWF. Type

2 can be either autosomal dominant or autosomal recessive. Of the 4 described

type 2 von Willebrand disease subtypes, type 2A is by far the most common. (4)

Type 2A is inherited as an autosomal dominant trait and is characterized

by normal-to-reduced plasma levels of factor VIIIc (FVIIIc) and vWF. Analysis

of vWF multimers reveals a relative reduction in intermediate and high molecular

weight multimer complexes. The multimeric abnormalities are commonly the

result of in vivo proteolytic degradation of the vWF. The ristocetin cofactor

activity is greatly reduced, and the platelet vWF reveals multimeric abnormalities

similar to those found in plasma. (2,3,4)

Type 2B von Willebrand disease is also an autosomal dominant trait. This

type is characterized by a reduction in the proportion of high molecular weight

vWF multimers, whereas the proportion of low-molecular weight fragments are

increased. Patients with type 2B have a hemostatic defect caused by a

qualitatively abnormal vWF and intermittent thrombocytopenia. The abnormal

vWF has an increased affinity for platelet glycoprotein Ib. The platelet count may

fall further during pregnancy, in association with surgical procedures, or after the

administration of desmopressin acetate (DDAVP). Although some investigators

found DDAVP to be clinically useful in persons with type 2B, studies directed at

excluding the 2B variant should be completed before DDAVP is used.

Measurements of FVIIIc and vWF in plasma vary; however, studies involving the

use of titered doses of ristocetin reveal that aggregation of normal platelets is

enhanced and induced by unusually small amounts of the drugs. (4)

In patients with the rare type 2M von Willebrand disease, laboratory

results are similar to those of certain patients with type 2A. Type 2M is

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characterized by a decreased platelet-directed function that is not due to a

decrease of high-molecular weight multimers. Laboratory findings show

decreased vWF activity, but not vWF antigen, FVIII, and multimer analysis are

found to be within reference range. (2,4)

Type 2N is also rare and is characterized by a markedly decrease affinity

of vWF for FVIII, resulting in FVIII levels reduced to usually around 5% of the

reference range. Other vWF laboratory parameters (i.e. vWF antigen[vWF:Ag],

ristocetin cofactor activity) are usually normal. The FVIII-binding defect in these

patients is inherited in an autosomal recessive manner. Evaluate patients with

FVIII deficiency and a bleeding disorder that is not clearly transmitted as an X-

linked disorder or those who respond incompletely to hemophilia A therapy for

type 2N von Willwbrand disease. Unfortunately, the confirmatory test for type 2N

is not routinely available, likely resulting in an underestimate of the true

frequency of this subtype. (4)

Type 3 is the most severe form of von Willebrand disease. In the

homozygous patient, type 3 is characterized by marked deficiencies of both vWF

and FVIIIc in the plasma, the absence of vWF from both platelets and endothelial

cells, and a lack of response to DDAVP. Type 3 is characterized by severe clinical

bleeding and is inherited as an autosomal recessive trait. Consanguinity is

common in kidneys with this variant. Less severe clinical abnormalities and

laboratory abnormalities may be identified in occasional heterozygotes; however,

such cases are difficult to identify. Multimeric analysis of the small amount of

vWF present yields variable results, in some cases revealing only small

multimers. (3,4)

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Coagulation cascade

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In response to rupture of the vessel or damage to the blood itself, a

complex cascade of chemical reactions occurs in the blood involving more than a

dozen blood coagulation factors. The net result is formation of a complex of

activated substances collectively called prothrombin activator. The extrinsic

pathway for initiating the formation of prothrombin activator begins with a

traumatized vascular wall or traumatized extravascular tissues that come in

contact with the blood. It starts with the release of tissue factor. Traumatized

tissue releases a complex of several factors called tissue factor or tissue

thromboplastin. This factor is composed especially of phospholipids from the

membranes of the tissue plus a lipoprotein complex that functions mainly as a

proteolytic enzyme. Next, is the activation of Factor X which is the role of Factor

VII and tissue factor. The lipoprotein complex of tissue factor further complexes

with blood coagulation Factor VII and, in the presence of calcium ions, acts

enzymatically on Factor X to form activated Factor X (Xa). Effect of activated

Factor X (Xa) to form prothrombin activator is the role of Factor V. The activated

Factor X combines immediately with tissue phospholipids that are part of tissue

factor or with additional phospholipids released from platelets as well as with

Factor V to form the complex called prothrombin activator.Within a few seconds,

in the presence of calcium ions (Ca 2+), this splits prothrombin to form thrombin,

and the clotting process proceeds as already explained. At first, the Factor V in the

prothrombin activator complex is inactive, but once clotting begins and thrombin

begins to form, the proteolytic action of thrombin activates Factor V. This then

becomes an additional strong accelerator of prothrombin activation. Thus, in the

final prothrombin activator complex, activated Factor X is the actual protease that

causes splitting of prothrombin to form thrombin; activated Factor V greatly

accelerates this protease activity, and platelet phospholipids act as a vehicle that

further accelerates the process. (5)

The second mechanism for initiating formation of prothrombin activator,

and therefore for initiating clotting, begins with trauma to the blood itself or

exposure of the blood to collagen from a traumatized blood vessel wall. Blood

trauma causes activation of Factor XII and release of platelet phospholipids.

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Trauma to the blood or exposure of the blood to vascular wall collagen alters two

important clotting factors in the blood: Factor XII and the platelets.When Factor

XII is disturbed, such as by coming into contact with collagen or with a wettable

surface such as glass, it takes on a new molecular configuration that converts it

into a proteolytic enzyme called activated Factor XII. Simultaneously, the blood

trauma also damages the platelets because of adherence to either collagen or a

wettable surface (or by damage in other ways), and this releases platelet

phospholipids that contain the lipoprotein called platelet factor 3, which also plays

a role in subsequent clotting reactions. Next, is the activation of Factor XI. The

activated Factor XII acts enzymatically on Factor XI to activate this factor as well,

which is the second step in the intrinsic pathway. This reaction also requires

HMW (high-molecular-weight) kininogen and is accelerated by prekallikrein.

Followed by the activation of Factor IX by activated Factor XI. The activated

Factor XI then acts enzymatically on Factor IX to activate this factor also.

Activation of Factor Xrole of Factor VIII. The activated Factor IX, acting in

concert with activated Factor VIII and with the platelet phospholipids and factor 3

from the traumatized platelets, activates Factor X. It is clear that when either

Factor VIII or platelets are in short supply, this step is deficient. Factor VIII is the

factor that is missing in a person who has classic hemophilia, for which reason it

is called antihemophilic factor. Platelets are the clotting factor that is lacking in

the bleeding disease called thrombocytopenia. Action of activated Factor X to

form prothrombin activatorrole of Factor V. This step in the intrinsic pathway

is the same as the last step in the extrinsic pathway. That is, activated Factor X

combines with Factor V and platelet or tissue phospholipids to form the complex

called prothrombin activator. The net result is formation of a complex of activated

substances collectively called prothrombin activator. The prothrombin activator

catalyzes conversion of prothrombin into thrombin. The thrombin acts as an

enzyme to convert fibrinogen into fibrin fibers that enmesh platelets, blood cells,

and plasma to form the clot. (5)

It is clear that the intrinsic and extrinsic systems after blood vessels

rupture, clotting occurs by both pathways simultaneously. Tissue factor initiates

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the extrinsic pathway, whereas contact of Factor XII and platelets with collagen in

the vascular wall initiates the intrinsic pathway. An especially important

difference between the extrinsic and intrinsic pathways is that the extrinsic

pathway can be explosive; once initiated, its speed of completion to the final clot

is limited only by the amount of tissue factor released from the traumatized tissues

and by the quantities of Factors X, VII, and V in the blood. With severe tissue

trauma, clotting can occur in as little as 15 seconds. The intrinsic pathway is much

slower to proceed, usually requiring 1 to 6 minutes to cause clotting. (5)

Pathophysiology of von Willebrand Disease

von Willebrand disease is due to an abnormality, either quantitative or

qualitative, of the von Willebrand factor, which is a large multimeric glycoprotein

that functions as the carrier protein for factor VIII (FVIII). von Willebrand factor

is also required for normal platelet adhesion. As such, von Willebrand factor

functions in both primary (involving platelet adhesion) and secondary (involving

FVIII) hemostasis. In primary hemostasis, von Willebrand factor attaches to platelets by its specific receptor to glycoprotein Ib on the platelet surface and acts

as an adhesive bridge between the platelets and damaged subendothelium at the

site of vascular injury. In secondary hemostasis, von Willebrand factor protects

FVIII from degradation and delivers it to the site of injury. (4)

von Willebrand factor is composed of dimeric subunits that are linked by

disulfide bonds to form complex multimers of low, intermediate, and high

molecular weights. The small multimers function mainly as carriers for FVIII. (4)

Highmolecular weight multimers have higher numbers of platelet-

binding sites and greater adhesive properties. Each multimeric subunit has binding

sites for the receptor glycoprotein Ib on nonactivated platelets and the receptor

glycoprotein IIb/IIIa on activated platelets. This facilitates both platelet adhesion

and platelet aggregation, making high molecular weight multimers most important

for normal platelet function. (4)

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Clinical Manifestations

Patients have predominantly mucosal bleeding symptom, although

postoperative bleeding can also be seen. Bleeding symptoms are very uncommon

in infancy and usually manifest later in childhood with excessive bruising and

epistaxis. Since these symptoms occur commonly in childhood, the clinician

should particularly note bruising at sites unlikely to be traumatized and/or

prolonged epistaxis requiring medical attention. Menorrhagia is a common

manifestation of von Willebrand disease. Menstrual bleeding resulting in anemia

should warrant and evaluation for von Willebrand disease and, if negative,

functional platelet disorder. Frequently, mild type 1 von Willebrand disease first

manifests with dental extractions, particularly wisdom tooth extraction, or

tonsillectomy. (8)

Not all patients with low vWF levels have bleeding symptoms. Whether

patient bleed or not will depend on the overall hemostatic balance they have

inherited, along with environmental influences and the type of hemostaticchallenges they experience. Although the inheritence of von Willebrand disease is

autosomal, many factors influence both vWF levels and bleeding symptoms.

These have not all been defined but include blood type, thyroid hormone status,

race, stress, exercise, and hormonal (both endogenous and exogenous) influences.

Patients with type O blood have vWF protein levels about one-half those of

patients with AB blood type; in fact, the normal range for patients with type O

blood overlaps that usually considered diagnostic for von Willebrand disease.Therefore, people with blood group O have significantly lower levels of both

vWF:Ag and vWF:Rco than people with non-O blood type. A mildly decreased

vWF level should perhaps be viewed more as a risk factor for bleeding than as an

actual disease. (8)

Diagnosis

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A definite diagnosis requires a significant bleeding history, a family

history of bleeding and abnormal laboratory findings. Patients with abnormal

laboratory findings, combined with either a personal or a family history of

bleeding should be labelled as having probable von Willebrand disease, although

the distinction between definitive and probable von Willebrand disease does not

alter the clinical management of the disease. A positive bleeding history since

childhood may be suggestive of von Willebrand disease. In particular, bleeding is

prominent and/or easy bruising is seen in one or more of the five following

indicators that are frequent or prolonged nosebleeds, heavy menstrual bleeding,

prolonged bleeding (>5 minutes) or recurrent bleeding during or following

childbirth or surgery, prolonged/excessive bleeding or mucous membrane

bleeding during dental work and family history of an autosomal dominant or

recessive inherited bleeding disorder or easy bruising with indurations, which may

also indicate the presence of von Willebrand disease. (6)

Unfortunately, there are no reliable screening tests available for von

Willebrand disease. Commonly used tests include the activated partial

thromboplastin time (PTT), bleeding time (BT) and, more recently, the platelet

function analyzer (PFA-100 [Dade Behring Inc, USA]). The PTT may be

abnormal if the level of factor VIII is sufficiently decreased in conjunction with a

low quantity of vWF, but a normal PTT does not exclude von Willebrand disease.

The BT can be prolonged in severe von Willebrand disease, but has very poor

sensitivity. (6)

Due to the various problems with screening tests, any patient with

symptoms suggestive of von Willebrand disease or a family history of von

Willebrand disease should immediately have vWF antigen (vWF:Ag) and vWF

ristocetin cofactor (vWF:Rco) testing done. (6)

The laboratory diagnosis of von Willebrand disease depends on the

measurement of both the amount and activity of vWF. The vWF:Ag assay is a

measure of the quantity of the factor. vWF function is determined in most

laboratories by measuring the vWF:Rco by using a platelet aggregometer or by

ELISA. Ristocetin is an antibiotic that promotes the binding of vWF to platelets.

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Adding to the difficulty of making a diagnosis, vWF levels can increase in

response to a variety of stressors and in certain chronic illnesses. It is, therefore,

important to repeat tests to confirm or rule out von Willebrand disease. (3,6)

Other useful tests include factor VIII coagulation activity (FVIII:C), vWF

multimer levels and ristocetin induced platelet aggregation. Factor VIII is

dependent on vWF for stabilization in the circulation and, therefore, the quantity

is reduced when the vWF:Ag level is below normal. In type 3 von Willebrand

disease, the FVIII:C levels are usually less than 10% of normal, and the patient

can present with symptoms similar to those of a moderate hemophiliac. In type 2N

von Willebrand disease, in which vWF has decreased affinity for factor VIII, a

low FVIII:C level may be the only detectable abnormality and, therefore, the von

Willebrand disease can easily be misdiagnosed as hemophilia A. vWF factor VIII

collagen binding assay or DNA sequencing of the binding region of vWF to factor

VIII is required to confirm the diagnosis. vWF multimer analysis provides the

multimeric pattern of the vWF and is essential for determining the type of von

Willebrand disease. There is a uniform decrease in the multimer pattern in type 1

von Willebrand disease, whereas there is a selective loss of high molecular weight

multimers in types 2A and 2B. Ristocetin-induced platelet aggregation (RIPA) is

used primarily to distinguish type 2A from type 2B. RIPA is virtually absent in

type 2A, but platelet aggregation occurs even at low concentrations of ristocetin in

type 2B. (3,6)

Differential Diagnosis

Table 2: Comparison of Hemophilia A, Hemophilia B and von Willebrand

Disease (7)

Hemophilia A Hemophilia B von WillebrandDisease

Inheritance X-linked X-linked Autosomaldominant

Factor deficiency Factor VIII Factor IX von Willebrandfactor

Bleeding sites Muscle, joint,

surgical

Muscle, joint,

surgical

Mucous

membrane, skin,

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surgical,menstrual

Prothrombin time Normal Normal NormalaPTT Prolonged Prolonged Prolonged or

normalBleeding time Normal Normal Prolonged or

normalFactor VIIIcoagulant activity

Low Normal Low or normal

vWF: Ag Normal Normal LowvWF activity Normal Normal LowFactor IX Normal Low Normal

Ristocetin-induced plateletaggregation

Normal Normal Normal, low, or increased at lowdose ristocetin

Treatment DDAVP or recombinant VIII

Recombinant IX DDAVP or vWFconcentrate

Treatment

Treatment of von Willebrand brand is focused on increasing the

availability of vWF (and subsequently FVIII) to correct platelet function throughadhesion, aggregation, and hemostatic plug formation. Currently, NHLBI

recommends three approaches for managing von Willebrand disease. The first one

is non-replacement therapy that enables the release of endogenous vWF by

stimulating the endothelial cell with desmopressin, a synthetic derivate of the anti-

diuretic hormone vasopressin. Replacement therapy replaces missing vWF by

delivering safe concentrates of human plasma-derived, viral-inactivated

vWF/FVIII. Adjunctive therapy such as antifibrinolytics and oral contraceptives,act to promote hemostasis without altering the vWF concentration at all. (1)

The treatment of von Willebrand disease depends on the severity of the

bleeding. Desmopressin is the treatment of choice for most bleeding episodes in

patients with type 1 disease and some patients with type 2 disease. When high

levels of vWF are needed but cannot be achieved satisfactorily with desmopressin,

treatment with a virally attenuated, vWF-containing concentrate may be

appropriate. (1) The dosage can be calculated as for factor VIII in hemophilia.

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Cryoprecipitate should not be used because it is not virally attenuated. Hepatitis B

vaccine should be given before the patient is exposed to plasma-derived-products.

As in all bleeding disorders, aspirin should be avoided for patients with von

Willebrand disease. (7)

Non-replacement therapyDesmopressin (DDAVP)

Desmopressin (1-deamino-8-d-arginine vasopressin) is a synthetic

analogue of vasopressin originally designed for the treatment of diabetes

insipidus. It acts by inducing release of vWF into plasma by binding to the

vasopressin V2 receptor and thereby activating cyclic adenosine monophosphate

mediated signalling in vascular endothelial cells. DDAVP increases the plasma

concentrations of vWF and FVIII (and tissue plasminogen activator) when

administered to patients with mild haemophilia A and vWD. The obvious

advantages of DDAVP are that it is inexpensive and carries no risk of transmitting

blood-borne viruses. DDAVP (Emosint, Minirin) is usually administered

intravenously at a dose of 0.3 g/kg diluted in 50 mL saline infused over 30 min.

This treatment increases plasma vWF-FVIII 2-4 times above the basal levels

within 30 min. In general, high vWF-FVIII concentrations last in plasma for 6-8

h. Infusions can be repeated every 12-24 hours depending on the type and severity

of the bleeding episode. The drug is also available in concentrated forms for

subcutaneous and intranasal administration, which can be particularly convenient

for home treatment. Because responses in a given patient are consistent on

different occasions, a test infusion of DDAVP at the time of diagnosis helps to

establish the individual response patterns. Response to DDAVP is assessed at 1

hour (peak) after the infusion and is defined as an increase of at least 3-fold over

baseline levels of FVIII activity (FVIII:C) and vWF:RCo, reaching plasma levels

of at least 30 U/dL. It is also important to measure FVIII:C and vWF:RCo plasma

levels at 4 hours post-DDAVP infusion, in order to determine the pattern of

clearance of these moieties. DDAVP is usually effective in patients with type 1

von Willebrand disease and baseline vWF and FVIII levels higher than 10 U/dL.(9,10)

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Replacement therapy

For those von Willebrand disease patients in whom DDAVP is either

ineffective (inadequate response or prediction of prolonged treatments with

likelihood of tachyphylaxis) or contraindicated (type 2B), vWF and FVIII levels

can be restored by the infusion of virally-inactivated plasma-derived concentrates

containing both these proteins. Four products containing vWF/FVIII are licensed

in Italy for the treatment of von Willebrand disease only three of them (Haemate

P, Alphanate and Fandhi) have been evaluated in prospective studies in

terms of pharmacokinetics and efficacy. (9)

VWF/FVIII concentrates

In patients with type 3 von Willebrand disease, the half-life of FVIII:C

was approximately twice that of vWF:Ag (23.8 hours versus 12.9 hours) because

of the endogenous production of FVIII. A good clinical response with this

vWF/FVIII concentrate was observed in 86% of the spontaneous bleeding

episodes and in 71% of surgical or invasive procedures. A smaller prospective

study has also been performed using Fandhi, a concentrate manufactured using a

process very similar to that for Alphanate. Dosages given once daily or every

other day and spanning from 20 to 60 IU/kg of vWF:RCo/FVIII:C (depending on

the risk and severity of bleeding) are haemostatically effective in the treatment of

spontaneous bleeding episodes or for preventing bleeding during surgical or

invasive procedures in von Willebrand disease patients with severely reduced

factor levels (less than 10 U/dL). The accumulation of FVIII that is exogenously

infused together with that endogenously synthesised and stabilised by the infused

vWF may lead to very high FVIII:C concentrations in plasma (> 150 U/dL) when

repeated and closely spaced infusions are given for severe bleeding episodes or to

cover major surgery. (9)

Secondary long-term prophylaxis

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Patients with severe forms of von Willebrand disease (i.e., FVIII:C levels

< 5 U/dL) sometime have frequent haemarthroses and may, therefore, benefit

from secondary long-term prophylaxis, which should also be considered in

patients with recurrent gastrointestinal bleeding and children with frequent

epistaxis. The largest experience on secondary prophylaxis in von Willebrand

disease was gained in Sweden in 35 patients with severe von Willebrand disease.

Secondary prophylaxis was retrospectively evaluated also in a cohort of 12 Italian

von Willebrand disease patients, who underwent 17 longterm secondary

prophylaxis periods to prevent recurrent gastrointestinal or joint bleeding, with

clinical responses rated as excellent or good in 100% of cases. However, more

prospective trials are needed for a better evaluation of the cost-effectiveness of

this approach versus on demand therapy. (1,9)

vWF concentrate devoid of FVIII

Because von Willebrand disease patients have an intact endogenous

production of FVIII and in order avoid excessive post-infusion FVIII:C levels, a

highly purified plasma vWF concentrate containing very little FVIII has been

developed for exclusive use in von Willebrand disease (Wilfactin). However, as

post-infusion levels of FVIII:C rise slowly reaching a peak between 6 and 8 hours,

co-administration of a priming dose of FVIII is necessary if prompt haemostasis is

required in patients with baseline FVIII:C levels of 30 U/dL or lower. (9)

Adjunctive and adjuvant therapies

When mucosal tract haemorrhages are not controlled despite adequate

vWF/FVIII replacement therapy, platelet concentrates (1 unit from random donors

every 10 kg of body weight or 1 unit obtained by apheresis) are an adjunctive

weapon that often helps to control bleeding. Transfused normal platelets are

thought to be haemostatically effective because they contain vWF that is

transported and localised from the flowing blood at sites of vascular

injury. Antifibrinolytic amino acids . (i.e., tranexamic acid and epsilon

aminocaproic acid), given orally, intravenously or topically, are useful alone or as

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adjuncts to replacement therapy (DDAVP or vWF/FVIII concentrates) for the

prevention or treatment of bleeding in mucosal tracts, characterized by a rich

fibrinolytic activity. Thus, they may be sufficient when given alone for the

management of less severe forms of mucosal bleeding, such as epistaxis and

menorrhagia, or for dental procedures. (9,10)

Furthermore, these agents are useful in association with replacement

therapy during minor or major surgery involving mucosal surfaces. Tranexamic

acid should be administered at a dose of 10-15 mg/kg every 8-12 hours and

aminocaproic acid at a dose of 50-60 mg/kg every 4-6 hours. These drugs are

contraindicated in the management of urinary tract bleeding. (9)

Complications

Women who experience heavy menstrual bleeding can develop iron-

defeciency anemia. If abnormal bleeding occurs in the joints or soft tissue,

swelling and severe pain can result. Bleeding into knees, elbow, shoulder, ankle,

and hips can lead to chronic swelling and joint deformity. Many people with

severe von Willebrand disease can suffer from painful, debilitating, joints bleeds

and associated mobility issues that severely impede their quality of life. When

abnormal bleeding cannot be control, it can become life threatening and needs

emergency medical attention. (8)

Hepatitis virus were also transmitted in blood product used by persons

with bleeding disorder. There are six main hepatitis viruses which cause problems

ranging from mild chronic infections to liver failure. Almost 95% of all hepatitis

cases are hepatitis A, B , or C. Some hepatitis viruses can be asymptomatic for

many years and may never become chronic. Others can progress to liver cancer,

end-stage liver disease and other life threatening conditions. Symptoms may

include fatigue, nausea, vomiting, joint aches, liver tenderness and enlargement

and weight loss. (8)

Prognosis

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The prognosis for VWD disease is generally fairly good and most

individuals have a normal lifespan. The prognosis can depend, however on

accurate diagnosis and appropriate medical treatment. This disease is passed down

through families. Therefore, genetic counseling may help prospective parents

understand the risk to their children. (7)

II. OBJECTIVE

The aim of doing this paper is to report a case of von Willebrand disease

in an 11 years 8 months old girl.

III.CASE

MN, 11 years-8-month old girl, weight 29 Kg, height 145 cm, was

admitted to Haji Adam Malik Hospital at the Non-Infection Unit Pediatric

Department on July 1 st 2010 with the main complaint of gingival bleeding . It

started 3 days ago and become worse yesterday. Fever was not found . Patient had

vomitted once with volume 10-20 ml. Patient looked pale starting 2 days ago.

Patient had no micturation difficulties. Defecation is normal. Family history of similar disease is positive. Two of her sister had been diagnosed with hemophilia

A because of menorrhagia and gingival bleeding. Unfortunately her parents are

normal. She was first diagnosed with hemophilia A because of gingival bleeding

episode at 5 years old. A history of easy bruising is positive. Now, she is routinely

admitted to RSUP for blood tranfusion and Koate injection once every 2 to 3

months.

History of previous disease: patient of hemato-oncology unit with a

diagnosis of Hemophilia A.

History of medication: Koate injection

Physical Examination:

Sensorium : Compos mentis, BW= 29 Kg, BL= 145 cm, BW/BL= 112% ,

Temp. = 37 0C

Anemic (+), edema (-), cyanosis (-), icteric (-), dyspnoe (-)

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Head : Eye: Light reflexes (+/+), isochoric pupil, pale inferior conj.

palpebra(+/+).

Edema palpebra (-/-). Ear/Nose:within normal limit, mouth:pale

mucosa (+)

Neck : Lymph node enlargement (-)

Thorax : Symmetrical fusiform, no retraction,

HR= 128 bpm, regular, murmur (-),

RR= 24 rpm, regular, ronchi (-).

Abdominal : Distention (+), soepel, peristaltic (+)

Extremities : Pulse =124 tpm, regular, adequate pressure/volume,

BP=110/50 mmHg.

Working Diagnose: Hemophilia A

Differential Diagnose: -

Management:

Koate injection

Investigation Planning:

Complete blood count

Blood glucose test

Hemostasis test

Test Result Normal value

COMPLETE BLOOD COUNT

Hemoglobin (Hb)

Erytrocyes (RBC)

Leucocytes (WBC)

Hematocrit

2.03 g%

1.01 x 10 6/mm 3

4.10 x 10 3/mm 3

6.73 %

12.0-14.4

4.75-4.85

4.5-11.0

36-42

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Thrombocyte (PLT)

MCV

MCH

MCHC

RDW

MPV

PCT

PDW

Cell count:

Neutrophil

Lymphocyte

Monocyte

Eosinophil

Basophil

160 x 10 3/mm 3

66.90 fL

20.10 pg

30.10 g%

20.70 %

16.20 fL

0.260 %

20.5

69.30 %

14.80 %

8.74 %

5.73 %

1.49 %

150-450

75-87

25-31

33-35

11.6-14.8

7.0-10.2

37-80

20-40

2-8

1-6

0-1

HEMOSTASIS

PT + INR PROTHROMBIN TIME

Control

Patient

INR

APTT

Control

Patient

THROMBIN TIME

Control

Patient

12.90 s

12.80 s

1.00

29.8

28.8

12.0

11.4

CARBOHYDRATE METABOLISM

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Glucose ad random

Blood glucose

110.0 mg/dL < 200

R/: Pemeriksaan vWF:Ag dan vWF:Rco

Test that has been done on July 2006


Prothrombin time 12.7 sec 12.9

INR 0.94

aPTT 57.0 sec 30-40

Thrombin time 13.4 sec 13.1

Factor VIII 1.24% 50-150

Factor IX 47% 50-150

Follow Up July 2 nd 2010

S : Gingival bleeding (+), fever (-)

O: Sens: CM, T: 36.7 0C, BW = 29 kg

Head : Eyes: Light reflexes (+/+), isochoric pupil, pale inferior conj. palpebra (-/-).

Edema palpebra (-/-). Ear/ Nose:within normal limit, mouth:pale mucosa (+)

Neck : Lymph nodes enlargement (-)

Thoraks : Symmetrical fusiform, retraction (-) HR = 120 bpm, regular, murmur (-)

RR = 34 tpm, regular, rales (-)

Abdominal : Soepel, normal peristaltic.

Extremities : Pulse = 116 tpm, regular, adequate pressure/volume, BP = 110/70 mmHg

A : von Willebrand disease

P :

FFP transfusion 10cc / kg BW (300 cc)

PRC washed transfusion follow demand

Transamine Acid injection 10 - 15mg / kgBW / 8 hr ( 250mg / 8 hr / IV )

Normal diet meal 1680 kkal with 60 g protein

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PRC demand = ( 10 - 2.03) x 29 x 4

= 925 cc ( 5 bag )

PRC ability = 3 x 29

= 87 cc ( 1 bag)

PRC washed transfusion procedure I

50 cc of NaCl 0.9%

Furosemide injection 29 mg

Dexamethasone injection 12 mgPRC washed transfusion 175 cc

50 cc of NaCl 0.9%

Blood type : O (+)

Bag no. :5138192

Start : 00.36

End : 04.36

FFP transfusion procedure I

50 cc of NaCl 0.9%


Dexamethasone injection 12 mg

FFP transfusion 1 bag

50 cc of NaCl 0.9%Blood type : O (+)

Bag no. : 3893236

Start : 13.00

End : 14.00

PRC washed transfusion procedure II

50 cc of NaCl 0.9%

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Dexamethasone injection 12 mgPRC washed transfusion 175 cc

50 cc of NaCl 0.9%

Blood type : O (+)

Bag no. : 3894069

Start : 16.30

End : 20.00

vWF:Ag : < 30 U/dL (+)R/:

PRC transfusion procedure III

FFP transfusion procedure II

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23

Follow Up July 3 rd 2010

S : Gum bleeding (-), fever (-)

O: Sens: CM, T: 36.5 0C, BW = 29 kg


Edema palpebra (+/+). Ear/ Nose: within normal limit, mouth:pale mucosa (+)




Abdominal : Soepel, normal peristaltic

Extremities : Pulse = 120 tpm, regular, adequate pressure/volume, BP = 100/70 mmHgA : von Willebrand diseaseP :



Transamine Acid injection 250mg / 8 hr / IV


PRC transfusion procedure III

50 cc of NaCl 0.9%



PRC transfusion 1 bag

50 cc of NaCl 0.9%

Blood type : O (+)

Bag no. : 1052-5138118

Start : 23.30

End : 03.45

FFP transfusion procedure II

50 cc of NaCl 0.9%



FFP transfusion 1 bag

50 cc of NaCl 0.9%Blood type : O (+)

Bag no. : 3893009

Start : 09.00

End : 10.00


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Follow Up July 4 th 2010

S : Gingival bleeding (-), fever (-)

O: Sens: CM, T: 36.5 0C, BW = 29 kg


Edema palpebra (-/-). Ear/ Nose: within normal limit, mouth:pale mucosa

(+)


Thoraks : Symmetrical fusiformic, retraction (-) HR = 72 bpm, regular, murmur (-)



Extremities : Pulse = 72 tpm, regular, adequate pressure/volume, BP = 110/60mmHg

A : von Willebrand diseaseP :





PRC washed transfusion procedure IV

Bag no. : 69-5127737

Blood type : O (+) PRC 175 cc

Start : 12.05

End : 03.45R :

PRC washed transfusion procedure V

FFP transfusion procedure III

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O: Sens: CM, T: 36.3 0C, BW = 29 kg


Edema palpebra (-/-). Ear/Nose:within normal limit, mouth:pale mucosa (+)







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P :

FFP transfusion 10cc / kg BW (300 cc) PRC washed transfusion follow demand



PRC washed transfusion procedure V

Bag no. : 97 5125346

Blood type : O (+) PRC 175 ccStart : 19.00

End : 23.00

FFP transfusion procedure III

Bag no. : 3893303

Blood type : O (+)

Start : 11.00

End : 12.00

R :

Routine blood test post transfusion

Discharge if the result of routine blood test is good



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O: Sens: CM, T: 36.4 0C, BW = 30 kg


Edema palpebra (-/-). Ear/ Nose/ Mouth: within normal limit





Extremities : Pulse = 88 tpm, regular, adequate pressure/volume, BP = 100/50 mmHgA : von Willebrand disease

P :

Transamine Acid injection 250mg / 8 hr / IV (replace with Transamine tablet

3 x 250 mg)

Normal diet meal 1680 kkal with 60 gr protein

Blood test result:


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COMPLETE BLOOD COUNT

Hemoglobin (Hb)

Erytrocyes (RBC)

Leucocytes (WBC)

Hematocrit (Ht)

Thrombocyte (PLT)

MCV

MCH

MCHC

RDW

LED

Cell count:

Neutrophil

Lymphocyte

Monocyte

Eosinophil

Basophil

9.10 g%

4.00 x 10 6/mm 3

6.46 x 10 3/mm 3

30.40 %

146 x 10 3/mm 3

63.70 fL

22.80 pg

29.90 g%

22.30 %

86 mm/hour

63.70 %

22.00 %

11.00 %

3.10 %

0.20 %

12.0-14.4

4.75-4.85

4.5-11.0

36-42

150-450

75-87

25-31

33-35

11.6-14.8

< 20

37-80

20-40

2-8

1-6

0-1



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O: Sens: CM, T: 36.8 0C, BW = 30kg


Edema palpebra (-/-). Ear/ Nose/ Mouth: within normal limit







P :

Transamine tablet 3 x 250 mg


Patient discharged from the hospital

IV. DISCUSSION

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Patients with von Willebrand disease typically present with

mucocutaneous bleeding, most commonly bruising with minimal or no apparent

trauma, recurrent spontaneous epistaxis and oral cavity bleeding events. Other

bleeding symptoms include prolonged bleeding following skin laceration or oral

surgery, and spontaneous gastrointestinal bleeding. Thirteen percent of women

presenting with menorrhagia have von Willebrand disease. This patient presents

with gingival bleeding and a history of easy bruising with minimal or apparent

trauma, whereas her sisters each present with gingival bleeding and menorrhagia.

Due to the various problems with screening tests, any patient with

symptoms suggestive of von Willebrand disease or a family history of von

Willebrand disease should immediately have vWF antigen (vWF:Ag) and vWF

ristocetin cofactor (vWF:Rco) testing done. vWF antigen (vWF:Ag) and vWF

ristocetin cofactor (vWF:Rco) test had been done to this patient prior to symptoms

that suggest von Willebrand disease.

In mild cases of von Willebrand disease, it is usually misdiagnose with

hemophilia A. This is because decreased in number of factor VIII in both von

Willebrand disease and hemophilia A.

Treatment of von Willebrand brand is focused on increasing the

availability of vWF (and subsequently FVIII) to correct platelet function through

adhesion, aggregation, and hemostatic plug formation. Currently, NHLBI

recommends three approaches for managing von Willebrand disease. The first one

is non-replacement therapy that enables the release of endogenous vWF by

stimulating the endothelial cell with desmopressin, a synthetic derivate of the anti

-diuretic hormone vasopressin. Replacement therapy replaces missing vWF bydelivering safe concentrates of human plasma-derived, viral-inactivated

vWF/FVIII. Adjunctive therapy such as antifibrinolytics and oral contraceptives,

act to promote hemostasis without altering the vWF concentration at all. This

patient had been given FFP (Fresh Frozen Plasma) as replacement therapy to

increase vWF that cannot be achieved using desmopressin.

V. SUMMARY

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This report is about a case of an 11 years and 8 months old girl with von

Willebrand disease. The diagnosis was established based on history taking,

clinical manifestations and laboratory findings. This patient was given PRC

washed and Fresh Frozen Plasma (FFP) transfusion and transamine acid. After the

transfusion, gingival bleeding decreased. Treatment of von Willebrand disease

needs full support from family, doctors whom committed with their works and

patient itself whom willing to cooperate.

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REFERENCES

1. Dalzell M.D. 2010. Antihemophilic Factor/von Willebrand Factor

Complex (Human), Dried, Pasteurized. Product Profiler Humate-P. Vol

35 Issue 1, 1-21.

2. Federici A.B. 2008. Prophylaxis of Bleeding Episodes in Patients with von

Willebrand Disease. Blood Tranfuse 6(2), 26-32.

3. Gatot D. 2006. Penyakit von Willebrand. Permono H.B., Sutaryo,

Ugrasena, Windiastuti E, Abdulsalam M. Buku Ajar Hemato-Onkologi

Anak. Jakarta: Ikatan Dokter Anak Indonesia, 178-181.

4. Geil J.D. 2010. von Willebrand Disease. Division of Hematology/

Oncology, University of Kentucky College of Medicine.

5. Guyton A.C., Hall J.E. 2006. Hemostasis and Blood Coagulation.

Textbook of Medical Physiology Eleventh Edition. Philadelphia:

Saunders, 457-468.

6. Klaassen R.J., Halton J.M. 2002. The Diagnosis and Treatment of von

Willebrand Disease in Children. Paediatric Child Health Vol 7 No 4, 245-

249.

7. Kliegman R.M., Marcdante K.J., Jenson H.B., Behrman R.E. 2006.

Hemostatic Disorders. Nelson Essentials of Pediatrics Fifth Edition.

Philadelphia: Elsevier Saunders, 710-721.

8. Konkle B.A.2008. Disorders of Hemostasis. Fauci A.S., Kasper D.L.,

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Principles of Internal Medicine 17th Edition. United States of America:

The McGraw-Hill Companies, 723-725.

9. Manucci P.M., Franchini M, Castaman G, Federici A.B. 2009. Evidence-

based Recommendations on the Treatment of von Willebrand Disease in

Italy. Blood Transfus Vol 7, 117-126.

10. Ozgonenel B, Rajpurkar M, Lusher J.M. 2007. How do you Treat

Bleeding Disorders with Desmopressin?. Postgrad Med Vol 83, 159-163.

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vwb disease case report

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