CASE REPORT Non - Infection Unit VON WILLEBRAND DISEASE

Presentator

: Nur Farhanim Shuhaimi Nor Azila Muhd Aris

Supervisor Day/ date of presentation

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

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

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

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 Xlinked 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)

Coagulation cascade

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 (Ca2+), 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.

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

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 plateletbinding 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)

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 hemostatic challenges 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

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 Inheritance Factor deficiency Bleeding sites X-linked Factor VIII Muscle, joint, surgical Hemophilia B X-linked Factor IX Muscle, joint, surgical von Willebrand Disease Autosomal dominant von Willebrand factor Mucous membrane, skin,

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Prothrombin time aPTT Bleeding time Factor VIII coagulant activity vWF: Ag vWF activity Factor IX Ristocetin-induced platelet aggregation Treatment

Normal Prolonged Normal Low Normal Normal Normal Normal DDAVP or recombinant VIII

Normal Prolonged Normal Normal Normal Normal Low Normal Recombinant IX

surgical, menstrual Normal Prolonged or normal Prolonged or normal Low or normal Low Low Normal Normal, low, or increased at low dose ristocetin DDAVP or vWF concentrate

Treatment 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 antidiuretic 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 therapy Desmopressin (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 irondefeciency 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 1st 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 Thorax

: Lymph node enlargement (-) : Symmetrical fusiform, no retraction, HR= 128 bpm, regular, murmur (-), RR= 24 rpm, regular, ronchi (-).

Abdominal Extremities

: Distention (+), soepel, peristaltic (+) : 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 106/mm3 4.10 x 103/mm3 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 HEMOSTASIS PT + INR PROTHROMBIN TIME INR APTT Control Patient Control Patient Control Patient

160 x 103/mm3 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

12.90 s 12.80 s 1.00 29.8 28.8 12.0 11.4

THROMBIN TIME

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 Test Prothrombin time INR aPTT Thrombin time Factor VIII Factor IX Follow Up July 2nd 2010 S : Gingival bleeding (+), fever (-) O: Sens: CM, T: 36.7 0C, BW = 29 kg Head Neck Thoraks : Eyes: Light reflexes (+/+), isochoric pupil, pale inferior conj. palpebra (-/-). Edema palpebra (-/-). Ear/ Nose:within normal limit, mouth:pale mucosa (+) : Lymph nodes enlargement (-) : 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:

Result 12.7 sec 0.94 57.0 sec 13.4 sec 1.24% 47%

Normal value 12.9

30-40 13.1 50-150 50-150

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 mg PRC 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% Furosemide injection 29 mg 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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 Furosemide injection 29 mg Dexamethasone injection 12 mg PRC 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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Follow Up July 3rd 2010 S : Gum bleeding (-), fever (-) O: Sens: CM, T: 36.5 0C, BW = 29 kg Head Neck Thoraks : Eyes: Light reflexes (+/+), isochoric pupil, pale inferior conj. palpebra (-/-). Edema palpebra (+/+). Ear/ Nose: within normal limit, mouth:pale mucosa (+) : Lymph nodes enlargement (-) : Symmetrical fusiform, retraction (-) HR = 120 bpm, regular, murmur (-) RR = 20 tpm, regular, rales (-) Abdominal : Soepel, normal peristaltic Extremities : Pulse = 120 tpm, regular, adequate pressure/volume, BP = 100/70 mmHg A : von Willebrand disease P:

FFP transfusion 10cc / kg BW (300 cc) PRC washed transfusion follow demand Transamine Acid injection 250mg / 8 hr / IV Normal diet meal 1680 kkal with 60 g protein

PRC transfusion procedure III 50 cc of NaCl 0.9% Furosemide injection 29 mg Dexamethasone injection 12 mg 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% Furosemide injection 29 mg Dexamethasone injection 12 mg 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 4th 2010 S : Gingival bleeding (-), fever (-) O: Sens: CM, T: 36.5 0C, BW = 29 kg Head (+) Neck Thoraks : Lymph nodes enlargement (-) : Symmetrical fusiformic, retraction (-) HR = 72 bpm, regular, murmur (-) RR = 20 tpm, regular, rales (-) Abdominal : Soepel, normal peristaltic. Extremities : Pulse = 72 tpm, regular, adequate pressure/volume, BP = 110/60mmHg A : von Willebrand disease P:

: Eyes: Light reflexes (+/+), isochoric pupil, pale inferior conj. palpebra (-/-). Edema palpebra (-/-). Ear/ Nose: within normal limit, mouth:pale mucosa

FFP transfusion 10cc / kg BW (300 cc) PRC washed transfusion follow demand Transamine Acid injection 250mg / 8 hr / IV Normal diet meal 1680 kkal with 60 g protein PRC washed transfusion procedure IV Bag no. : 69-5127737 Blood type : O (+) PRC 175 cc Start : 12.05 End : 03.45

R: PRC washed transfusion procedure V FFP transfusion procedure III

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Follow Up July 5th 2010 S : Gingival bleeding (-), fever (-) O: Sens: CM, T: 36.3 0C, BW = 29 kg Head Neck Thoraks : Eyes: Light reflexes (+/+), isochoric pupil, pale inferior conj. palpebra (-/-). Edema palpebra (-/-). Ear/Nose:within normal limit, mouth:pale mucosa (+) : Lymph nodes enlargement (-) : Symmetrical fusiform, retraction (-) HR = 80 bpm, regular, murmur (-) RR = 24 tpm, regular, rales (-) Abdominal : Soepel, normal peristaltic Extremities : Pulse = 80 tpm, regular, adequate pressure/volume, BP = 100/60 mmHg A : von Willebrand disease

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P:

FFP transfusion 10cc / kg BW (300 cc) PRC washed transfusion follow demand Transamine Acid injection 250mg / 8 hr / IV Normal diet meal 1680 kkal with 60 g protein PRC washed transfusion procedure V Bag no. : 97 5125346 Blood type : O (+) PRC 175 cc Start : 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

Follow Up July 6th 2010 S : Gingival bleeding (-), fever (-)

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O: Sens: CM, T: 36.4 0C, BW = 30 kg Head Neck Thoraks : Eyes: Light reflexes (+/+), isochoric pupil, pale inferior conj. palpebra (-/-). Edema palpebra (-/-). Ear/ Nose/ Mouth: within normal limit : Lymph nodes enlargement (-) : Symmetrical fusiform, retraction (-) HR = 88 bpm, regular, murmur (-) RR = 20 tpm, regular, rales (-) Abdominal : Soepel, normal peristaltic Extremities : Pulse = 88 tpm, regular, adequate pressure/volume, BP = 100/50 mmHg A : 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: Test Result Normal value

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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 63.70 % 22.00 % 11.00 % 3.10 % 0.20 % 37-80 20-40 2-8 1-6 0-1 9.10 g% 4.00 x 106/mm3 6.46 x 103/mm3 30.40 % 146 x 103/mm3 63.70 fL 22.80 pg 29.90 g% 22.30 % 86 mm/hour 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

Follow Up July 7th 2010 S : Gingival bleeding (-), fever (-)

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O: Sens: CM, T: 36.8 0C, BW = 30kg Head Neck Thoraks : Eyes: Light reflexes (+/+), isochoric pupil, pale inferior conj. palpebra (-/-). Edema palpebra (-/-). Ear/ Nose/ Mouth: within normal limit : Lymph nodes enlargement (-) : Symmetrical fusiform, retraction (-) HR = 80 bpm, regular, murmur (-) RR = 20 tpm, regular, rales (-) Abdominal : Soepel, normal peristaltic. Extremities : Pulse = 80 tpm, regular, adequate pressure/volume, BP = 100/60 mmHg A : von Willebrand disease P:

Transamine tablet 3 x 250 mg Normal diet meal 1680 kkal with 60 g protein Patient discharged from the hospital

IV. DISCUSSION

29

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 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. This patient had been given FFP (Fresh Frozen Plasma) as replacement therapy to increase vWF that cannot be achieved using desmopressin. V. SUMMARY

30

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, 245249. 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., Longo D.L., Braunwald E, Hauser S.L., Jameson J.L. et al. Harrisons 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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