von Willebrand's disease

TOC | HEME

von Willebrand's disease SX | DX | RX

Conduct a first-line screening work-up, including PT, PTT, CBC/platelets, and bleeding time (or PFA-100).
If first-line test results suggest VWD or exclude other bleeding disorders, perform a ristocetin cofactor assay.

Prolonged PTT, bleeding time, low vW protein/VIII complex
It is caused by a deficient or defective plasma von Willebrand factor.
Occurring with a prevalence of 8 per 1000 population, von Willebrand disease is the most commonly encountered inherited coagulopathy; it is usually transmitted in an autosomal-dominant pattern with variable expression.

SX:
easy bruising, mucosal bleeding (for example, epistaxis, menorrhagia, gastrointestinal bleeding), and potentially heavy bleeding after trauma or surgery. These clinical problems reflect the defective capacity of the vWF to mediate formation of the platelet plug by serving as a bridge between circulating platelets and components of the subendothelial matrix at the site of blood vessel injury.

DX:

Prolonged bleeding time and activated PTT time.
Decreased vWF antigen and activity (ristocetin cofactor); may be accompanied by decreased factor VIII coagulant protein activity
Family history of bleeding disorder, mucosa bleedings.

Three Main Types of von Willebrand's Disease

Type 1 or Classic type
is an autosomal dominant trait, usually is heterozygous, results from a quantitative deficiency (50% or less of normal) of vWF, which possesses a normal multimeric composition.It is characterized by lifelong history of mild to moderate bleeding, typically from mucosal surfaces, prolong bleeding time despite a platelet count > 100,000. The PTT may be slightly prolonged or normal.
Diagnosis is confirmed with the finding of low VIII:C, vWF, & ristocetin induced platelet agglutination with values of 5 - 40% of normal for each. The rare homozygous or doubly heterozygous form is marked by severe hemorrhage, a long PTT & VIII:C level of less than 5%.

Mild to moderate lowering of both quantitative (VWF:Ag) and functional levels of VWF (VWF:RCo);
usually has a normal multimer analysis
Most common variant (70% of all VWD)
Mostly autosomal dominant
Multimeric structure of the VWF protein is intact
Factor VIII level may or may not be low
Bleeding may be mild
Median age at first bleed of 10 years and median age at diagnosis of 13 years reported from females followed at hemophilia treatment centers

Type 2
is characterized by a decrease or absence in the larger, physiologically important multimers on crossed immunoelectrophoresis of vWF test.

Qualitative abnormalities of the VWF protein; qualitative level (VWF:RCo) is generally lower than quantitative level (VWF:Ag) Represents 20%-30% of VWD
Autosomal dominant or recessive
Bleeding may be mild or severe
Median age at first bleed of 4 years and median age at diagnosis of 7 years reported from females followed at hemophilia treatment centers (6)

Subtype 2A

Decreased production of intermediate and large multimers
Most common qualitative variant of VWD
Can lead to severe mucocutaneous bleeding
Selective loss of intermediate and large multimers
Low VWF:RCo with normal to reduced VWF:Ag

Subtype 2B
Intermittent thrombocytopenia may occur in patients with type IIB von Willebrand disease and may be exacerbated by the use of desmopressin, which increases the plasma concentration of abnormal vWF protein, leading to in vivo platelet agglutination and clearance. In type IIB von Willebrand disease, cryoprecipitate from a normal donor will not induce spontaneous agglutination of patient platelet-rich plasma .

Loss of large multimers due to spontaneous binding to platelets; increased platelet clearance and thrombocytopenia
Characterized by enhanced RIPA
Selective loss of large multimers
Features include mild thrombocytopenia and low to normal factor VIII

Subtype 2M

Qualitatively abnormal VWF protein with preservation of multimeric structure
Decreased platelet binding due to mutations that alter the VWF region responsible for platelet binding
Normal multimer analysis

Subtype 2N

Decreased affinity for factor VIII
May be associated with normal levels of VWF:Ag and VWF:RCo and normal multimer analysis
Low plasma factor VIII level
Consider in cases diagnosed as mild hemophilia A where the inheritance pattern is unknown or inconsistent with an X-linked disorder
Diagnosis confirmed by factor VIII binding assay

Type 3
is an unusually severe form of vWF deficiency with greatly reduced levels of factor VIII:C activity.
A rare pseudo- or platelet-type von Willebrand disease resembles the type IIB variant in its clinical features and in vWF multimeric pattern; however, the basic defect resides in an abnormal platelet GPIb, which has increased affinity for the highest molecular weight multimers of normal vWF. In platelet-type von Willebrand disease, the patient's platelet-rich plasma will agglutinate spontaneously with a source of normal donor vWF, found in cryoprecipitate.

Severe quantitative deficiency of the VWF protein; loss of all multimers
Least common variant (1%-3% of all VWD)
Autosomal recessive (may be homozygous or doubly heterozygous for VWF mutations)
Complete absence or profound deficiency of VWF and factor VIII
Median age at first bleed and median age at diagnosis of 1 year reported from females followed at hemophilia treatment centers

Acquired Type

Normal VWF is rapidly removed from plasma by the presence of antibodies or abnormal binding to tumor cells
Rare, not congenital
Suspect in a patient with acquired platelet type bleeding, no family history, and laboratory studies consistent with VWD
Underlying disorders include lymphoproliferative disease, myeloproliferative disease, cardiovascular disease, and neoplasia

Platelet-type/pseudo

A primary platelet disorder. No abnormality in the VWF protein
Rare; probable autosomal recessive inheritance pattern
Increased affinity of platelet GPIb/IX/V receptor complex for normal VWF
Laboratory and clinical similarity to type 2B

* RIPA = ristocetin-induced platelet aggregation; VWD = von Willebrand's disease; VWF = von Willebrand's factor; VWF:Ag = von Willebrand's factor:antigen; VWF:RCo = von Willebrand's factor:ristocetin cofactor.

American Society of Hematology 1996 Annual Meeting

Dr. Evan Sadler gave an outstanding overview of the diagnosis and present day classification of von Willebrand's disease, citing also the recent ISTH subcommittee formulation of the diagnosis of von Willebrand's disease:

a) definite von Willebrand's disease:

ristotocetin cofactor (and/or I assume vWF antigen) in the 2.5 percentile for that ABO type
documented family history with at least one member having a bleeding history with a documented low ristocetin cofactor (and/or I assume vWF antigen)

b) probable von Willebrand's disease:

ristotocetin cofactor (and/or I assume vWF antigen) in the 2.5 percentile for that ABO type
family member with significant bleeding history

c) possible von Willebrand's disease:

ristotocetin cofactor (and/or I assume vWF antigen) in the 2.5 percentile for that ABO type
no family history for bleeding

He also shared his own approach of screening for von Willebrand's disease in terms of:
CBC . Platelet count. PT/PTT. Ristocetin cofactor activity. Von Willebrand factor antigen.

Conspicuously absent was a bleeding time test. Beyond that initial screen, he would advise confirmatory/further screening with a Factor VIII level and ABO blood type and a ristocetin-induced platelet aggregation study with low activity or increased activity so suggesting one of the Type 2 subtypes.

He also stressed again the importance of ABO subtyping patients when one is seriously considering the diagnosis of von Willebrand's disease based on Dr. Gill and Montgomery, et al. study of blood donors where it was clearly and conclusively demonstrated that the blood group Type O vWF antigen range is on order 25% less than the non-O's.

Dr. Paul Foster reviewed subcutaneous and intranasal administration, the subcutaneous administration being studied extensively in Europe with a lower and later peak response while the intranasal administration available in the US is Stimate nasal spray 150 mcg (1.5 mg/ml in patients weighing < or = 50 kg with mild hemophilia A or mild to moderate von Willebrand's disease) with a peak effect at 60-90 minutes. There does not appear to be a dose response beyond the FDA-approved dose in adults whereas in children, half that dose is advised.

Question to Dr. Foster is whether there indeed is the same degree of tachyphylaxis occurring in vWD patients compared to the Factor VIII patients receiving DDAVP. It's been stated over the last few years that tachyphylaxis seems to be less of an issue in von Willebrand's disease. Indeed this has been studied by Mannucci who measured vWF and Factor VIII levels on four consecutive days of daily administration with indeed a 30% reduction on day two, but it did not reduce further on days three and four.

The side effects of DDAVP were reviewed by Dr. Foster including, of course, facial flushing, headache, hypotension, increased heart rate, hyponatremia particularly in children and in elderly patients. Dr. Foster also reviewed the potential risk of MI/CVA and that even though there have been some case reports, all of elderly patients with known vascular disease, there appears to be no causal association particularly in light of randomized studies done in using DDAVP during CABG in non-vWD patients with no apparent increase in post-operative MI or CVA.

For type 2B disease, the concern for worsening thrombocytopenia after DDAVP may be related in part to an artifact and there have been no adverse outcomes reported to date though the number of patients have been small and finally, there are some reports of DDAVP being effective in type 2N. The use of estrogen therapy for type 3 patients with menorrhagia was stressed.

Von Willebrand's Disease DX | Diff-Dx | RX
REF: PIER ACP 2007

Specific recommendation for Screening for VWD in women with menorrhagia and no gynecologic reason for heavy bleeding and in patients with unexplained procedural bleeding.:

Assess for clinically significant menorrhagia:

Use a validated instrument patient questionnaire, such as the Pictorial Blood Loss Assessment Chart, to determine clinically significant menorrhagia
Note that chronic iron deficiency or chronic iron replacement therapy due to menstrual blood loss may be indicative of abnormal bleeding

Screen for bleeding disorders in women with clinically significant menorrhagia and with a negative gynecologic evaluation.
Screen patients requiring repacking after dental procedures or patients with postsurgical hematomas for VWD.
Conduct a first-line screening work-up, including PT, PTT, CBC/platelets, and bleeding time (or PFA-100).
If first-line test results suggest VWD or exclude other bleeding disorders, perform a ristocetin cofactor assay.

Diagnosis for VWD

Base the diagnosis of VWD on history of bleeding, family history of a bleeding disorder, and low levels of VWF.

History and Physical Examination

* Obtain a thorough history with particular emphasis on personal history of bleeding and family history of a bleeding disorder.
* Look for signs of a bleeding disorder and anemia secondary to blood loss or iron deficiency on physical exam.

Specific recommendation for History & Physical Examination:

* Ask about this history:

Mucocutaneous bleeding: + Increased tendency for frequent or prolonged nosebleeds + Prolonged bleeding from lips, tongue, or frenulum after trauma + Bleeding with secondary dentition + Excessive bleeding with tooth extraction + Excessive bleeding with tonsillectomy + Menorrhagia + Easy bruisability, especially “spontaneous” or truncal bruising, and large or deeply colored bruises resulting from mild trauma + Excessive postoperative bleeding + Excessive GI or GU bleeding
“Deep” bleeding associated with low factor VIII levels that may accompany severe types of VWD: + Hemarthrosis + Muscle hematomas + Abdominal or retroperitoneal bleeding + Intracranial bleeding
Anemia symptoms related to blood loss or iron deficiency: + History of chronic iron deficiency anemia or need for chronic iron supplementation due to heavy menses + Weakness + Malaise + Decreased exercise tolerance + Shortness of breath + Dizziness
Family history of clinically significant bleeding or diagnosis of VWD; if positive, obtain records to determine subtype
Drugs that may provoke bleeding (e.g., aspirin, NSAIDs)
* See table History and Physical Examination Elements for von Willebrand's Disease.

* Look for these physical signs:

o Multiple bruises in various stages of healing
o Large or deeply colored purpura in response to mild trauma
o Truncal bruising
o Unprovoked bruising
o Gum bleeding
o Pallor of skin, mucus membranes, and conjunctiva
o Tachycardia
o Signs of CHF
* Physical exam may be unremarkable.

Laboratory Tests

* Use laboratory testing to evaluate patients with suspected VWD or other bleeding disorders. B
* Perform confirmatory laboratory work-up in patients with screening test results suggesting VWD; include testing for quantitative and functional levels of VWF as well as factor VIII levels. B
* Perform additional laboratory testing to characterize the type or subtype in patients who have confirmatory laboratory evidence of VWD.

Specific recommendation for Laboratory Tests:

* Obtain a panel of initial tests to detect abnormal hemostasis:

PT o PTT o CBC/platelet count o Bleeding time or PFA-100

* Obtain LFTs, renal function tests, or DIC panel if clinically indicated.
* If PTT, bleeding time, or PFA-100 is prolonged, suspect VWD and obtain ristocetin cofactor activity level.
* Obtain VWF:RCo:

If all screening test results are normal and the patient has clinical findings suggesting a bleeding disorder, especially if there is a family history of bleeding
If the platelet count is low without an apparent cause and the patient has other personal or family findings suggesting VWD

* Consider repeating the VWF:RCo if all initial test results including ristocetin cofactor are normal and the patient has clear evidence of a bleeding disorder.
* Do not obtain a VWF:RCo if another bleeding disorder is diagnosed from the initial screening tests.
* Note that a normal PTT does not necessarily exclude the diagnosis of VWD.

Perform confirmatory laboratory work-up in patients with screening test results suggesting VWD;
include testing for quantitative and functional levels of VWF as well as factor VIII levels.

Obtain baseline laboratory studies:

VWF:RCo (functional VWF level)
VWF:Ag (quantitative VWF level)
Factor VIII activity assay

For the most accurate assessment of the patient's true baseline levels:

Perform laboratory studies under basal conditions, not during periods of stress or while using hormones (e.g., postoperatively, during pregnancy, or while on oral contraceptives or hormone replacement therapy)
Perform tests during days 1 to 4 of the menstrual cycle in premenopausal women
Perform tests at least 1 to 2 weeks following transfusion of blood or blood products

Ensure that laboratory studies are performed by a specialty coagulation laboratory whenever possible and that blood is collected and handled by specially trained technicians.

Perform additional laboratory testing to characterize the type or subtype in patients who have confirmatory laboratory evidence of VWD. B

Diagnose type 3 VWD when levels of VWF:RCo, VWF:Ag, and factor VIII are less than 5% to 10%.
For all others, obtain the following laboratory tests to determine VWD type and subtype:

Electrophoresis for multimer analysis (useful in diagnosing some type 2 subtypes)
Ristocetin-induced platelet aggregation (diagnostic for type 2B but has poor sensitivity in other types of VWD)
Factor VIII binding assay (diagnostic for type 2N)

Laboratory and Other Studies for von Willebrand's Disease

Bleeding time - Use when a bleeding disorder is suspected. This is the most available screening test
PT/PTT - PT normal, PTT may be prolonged in all types if factor VIII level is low
PFA-100 - May not be available
Platelet count/CBC - If acutely bleeding, may recognize need for transfusion; platelet count may be low in type 2B
VWF:Ag - May be normal in type 2 disease. Will be proportionate to VWF:RCo in type 1. Will be very low in type 3. May be falsely elevated by stress, surgery, pregnancy, exercise, and exogenous estrogens
VWF:RCo - Proportionate to VWF:Ag in type 1; will be low or undetectable in type 3. Low in type 2 disease. May be falsely elevated by stress, surgery, pregnancy, exercise, and exogenous estrogens
Factor VIII - May be normal to low. Low levels contribute to bleeding diathesis
Multimer analysis - Proportionate decrease in all multimers in type 1 and 2M; absence of high-molecular-weight multimers in 2A, 2B; and absence of all multimers in type 3
RIPA - Type 2B shows increased agglutination with low-dose ristocetin; all other types show decreased agglutination with all doses of ristocetin
Factor VIII binding assay - Decreased in type 2N

CBC = complete blood cell (count); PFA-100 = platelet function analyzer; PT = prothrombin time; PTT = partial thromboplastin time; RIPA = ristocetin-induced platelet aggregation; VWF = von Willebrand's factor; VWF:Ag = von Willebrand's factor:antigen; VWF:RCo = von Willebrand's factor:ristocetin cofactor.

Differential Diagnosis of von Willebrand's Disease

Differential Diagnosis of von Willebrand's Disease
Disease	Characteristics	Notes
Platelet function disorder	Signs and symptoms include mucocutaneous bleeding, bruising, or postoperative bleeding. Laboratory studies show prolonged bleeding time, abnormal PFA-100, or both and abnormal findings on platelet aggregation studies. Normal PT, PTT, and VWF:RCo. Platelet count is usually normal	Congenital causes include Glanzmann's thrombasthenia, Bernard-Soulier syndrome, and platelet storage pool disorders. Acquired disorders may be due to chronic renal failure and drugs that inhibit platelet function
Thrombocytopenia	Signs and symptoms of mucocutaneous-type bleeding. Laboratory findings include low platelet count with a normal PT, PTT, and VWF:RCo. Elevations in bleeding time, PFA-100 are usually inversely proportional to platelet count and are not indicated	Congenital disorders include Fanconi's anemia, Wiskott-Aldrich syndrome, Alport syndrome, and thrombocytopenia with absent radii syndrome. Thrombocytopenia is more common due to an acquired disorder such as ITP, DIC, liver disease, or hypersplenism
Hemophilias	Signs and symptoms include trauma-related or spontaneous bleeding, especially into joints and soft tissue. Laboratory findings include a normal bleeding time, normal PT, prolonged PTT, and deficient factor VIII or factor IX level (<30%)	Inheritance is X-linked. Type 2N VWD should be considered when there is a low factor VIII level, normal von Willebrand's studies, and an inheritance pattern not consistent with hemophilia A. Specific testing is done with a factor VIII binding assay. See information on additional laboratory testing
Symptomatic carriers of hemophilia	Signs, symptoms, and laboratory values same as for mild hemophilia	Female carriers of hemophilia A or hemophilia B may have factor levels less than 50% with mild to moderate bleeding symptoms
Other clotting factor deficiency states such as factor XI, factor VII (and rarely factor X, factor V, or fibrinogen)	Easy bruising and easy bleeding. Laboratory findings include normal bleeding time and platelet count.	Abnormal PT or PTT, depending on which factor is deficient Autosomal inheritance; heterozygotes may be symptomatic when clotting factor levels are less than 20% to 30%
Circulating inhibitors to clotting factor VIII	Easy bruising and easy bleeding. Most commonly due to autoantibodies against factor VIII, resulting in a prolonged PTT that does not correct in a mixing study; PT, bleeding time, and platelet count are normal	Acquired. Rare disorder due to development of IgG autoantibodies against factor VIII. May be spontaneous in the elderly or associated with pregnancy, malignancy, or autoimmune disorders
Circulating inhibitors to prothrombin	Easy bruising and bleeding. Laboratory findings include a lupus anticoagulant associated with a prolonged PT	Acquired. Rare complication of lupus anticoagulants in which the antibodies have activity against prothrombin, leading to a bleeding diathesis
Low VWF levels due to extreme thrombocytosis	Spontaneous bleeding or risk of bleeding with trauma or surgeries. Laboratory studies show markedly elevated platelet count	Acquired. Rare complication of extreme thrombocytosis. Reduction of the platelet count can restore normal levels of circulating VWF

DIC = disseminated intravascular coagulation; ITP = idiopathic thrombocytopenic purpura; IgG = immunoglobulin G; PFA-100 = platelet function analyzer; PT = prothrombin time; PTT = partial thromboplastin time; VWD = von Willebrand's disease; VWF = von Willebrand's factor; VWF:RCo = von Willebrand's factor:ristocetin cofactor.

Consult a hematologist or a coagulation specialist, if the diagnosis of VWD is suspected, for the performance and interpretation of laboratory tests and confirmation of type or subtype.

Management

Reserve non-drug therapy for selected patients.

* Consider non-drug therapy for the rare patient with acquired VWD due to autoantibodies against VWF or for those with congenital VWD who develop antibodies or inhibitors to VWF.
* Consider plasma exchange and extracorporeal immunoadsorption to remove circulating IgG inhibitors of VWF.

Drug Therapy

Use therapies aimed at increasing functional VWF levels in treatment of significant bleeding events or for prevention of bleeds during invasive procedures or surgeries.
Use therapeutic modalities that augment hemostasis through means other than by correcting or replacing VWF and factor VIII levels in special circumstances.
Use dosing guidelines to achieve adequate circulating VWF and factor VIII in commonly encountered bleeding situations.

Use therapies aimed at increasing functional VWF levels in treatment of significant bleeding events or for prevention of bleeds during invasive procedures or surgeries.

Use desmopressin to treat mild to moderate bleeding episodes or in preparation for minor invasive procedures or dental work:

Treat most mild to moderate forms of VWD with desmopressin to achieve hemostatic levels of VWF:RCo and factor VIII
Note that desmopressin generally is not useful for repetitive dosing because it acts by releasing stores that require several days to replete
Do not use desmopressin for type 2B or type 3 VWD

Use plasma-derived concentrates of VWF and factor VIII to:

Raise and maintain levels of both VWF:RCo and factor VIII in the hemostatic range to treat mild to moderate bleeds in patients with type 2B and 3 VWD, or those with other types who do not respond to desmopressin
Treat patients who will require prolonged periods of normal hemostatic levels of VWF:RCo and factor VIII

In patients receiving intra- and postoperative concentrates to prevent bleeding, monitor VWF:RCo and factor VIII levels whenever possible in order to adjust dosing and frequency of dosing.
Keep in mind that the half-life of both VWF:RCo and factor VIII is approximately 12 hours so that redosing is necessary every 12 to 24 hours in patients with ongoing bleeding risks.

Use therapeutic modalities that augment hemostasis through means other than by correcting or replacing VWF and factor VIII levels in special circumstances.

* Use antifibrinolytic agents, such as epsilon-aminocaproic acid or tranexamic acid:

o To treat less severe forms of mucosal bleeding
o In conjunction with desmopressin- and VWF-containing concentrates for minor and major surgery

* Use fibrin glue to promote local hemostasis.
* Consider estrogen-containing oral contraceptive pills in women with severe menorrhagia.

Use dosing guidelines to achieve adequate circulating VWF and factor VIII in commonly encountered bleeding situations.

For minor bleed: o Raise plasma VWF:RCo and factor VIII levels above 30% to 50%
For major bleed: o Raise plasma VWF:RCo and factor VIII level above 50%
For life-threatening bleed or major head trauma: o Raise plasma VWF:RCo and factor VIII to 100%
For minor surgery: o Raise and maintain plasma levels of VWF:RCo and factor VIII levels above 50% until the procedure is complete; with minor procedures a single treatment of desmopressin or factor concentrate may be sufficient
For major surgery: o Raise and maintain plasma levels of VWF:RCo and factor VIII above 50% until initial healing is complete, followed by gradual tapering of the concentrate dose, depending on postoperative activity levels
For dental work especially those requiring deep nerve blocks:
o Raise plasma level of VWF:RCo and factor VIII levels to more than 30% to 50% for at least 12 hours, followed by daily oral antifibrinolytic agents for 7 to 10 days
For significant menorrhagia, choose among several options to achieve clinical benefit:

o Desmopressin at beginning of menses
o Antifibrinolytic therapy at the beginning or throughout menses
o Hormonal therapy for persistent menorrhagia

For severe VWD patients with frequent bleeding episodes, particularly in patients with severe type 3 VWD, regular prophylactic dosing of VWF-containing concentrates may be used to prevent bleeds.

Drug Treatment for von Willebrand's Disease

Agent	Mechanism of Action	Dosage	Benefits	Side Effects	Notes
Desmopressin - DDAVP, synthetic vasopressin	Vasoconstrictor that causes release of VWF from endothelial stores	0.3 µg/kg iv desmopressin or 10 µg dose of intranasal desmopressin	No risk of transfusion-transmitted disease. Easily self-administered (especially intranasal Stimate®). Useful for mild to moderate bleeds, menorrhagia, prophylaxis for minor invasive procedures, and dental work	Flushing, headache, nausea, water intoxication, hyponatremia	Can be used iv over 30 min, subcutaneously or intranasally. Response to desmopressin should be determined at the time of diagnosis of VWD, before its use. Tachyphylaxis occurs with desmopressin, and use is typically limited to 1 or 2 days. Monitor sodium level and do not administer unnecessary fluids
Antihemophilic factor (human) (VWF-containing factor VIII concentrates [intermediate purity factor VIII concentrates])	Increases blood levels of VWF and factor VIII	Varies by treatment needed; 20-50 IU/kg every 12 to 24 hours to achieve and maintain hemostatic levels of VWF and factor VIII	Low risk of transfusion-transmitted pathogens due to purification and specific viral inactivation steps. Rich in VWF. Contents listed by VWF:RCo	Rare development of alloantibodies in type 3 disease . High cost	Intermediate-purity factor VIII concentrates rich in VWF, with ratio of VWF:RCo:factor VIII includes Humate-P®, 2.5:1; Koate-DVI®, 1.2:1; and Alphanate®, 0.5:1
Cryoprecipitate	Increases blood levels of VWF and factor VIII	Varies by treatment needed. Give q 12-24 h	Available in most settings if concentrates are not available for emergency treatment	Risk of blood-borne transmissions	Rarely used secondary to other choices. Each bag contains 80-100 units of VWF
Aminocaproic acid (Amicar®)	Inhibits fibrinolysis	Initial loading dose of 5000 mg given before a procedure; then 50 mg/kg qid either po or iv for bleeding or surgical prophylaxis	No transfusion-transmission risk. Particularly useful in controlling mucocutaneous or oral bleeding	Contraindicated in bleeding of upper urinary tract because of risk of obstructive uropathy from clotting	Add with dental extractions, tonsillectomy, menorrhagia, mucosal hemorrhage (Amicar®, tranexamic acid) Adjunct to agents that increase VWF
Tranexamic acid (Cyklokapron®)	Inhibits fibrinolysis	20-25 mg/kg q 8-12 h po, iv, or topical	More potent than aminocaproic acid	Contraindicated in bleeding of upper urinary tract because of secondary risk of obstructive uropathy from clotting	Add with dental extractions, tonsillectomy, menorrhagia, mucosal hemorrhage (Amicar®, tranexamic acid) Adjunct to agents that increase VWF
Estrogenic compounds	Mechanism unknown, but increases serum level of VWF and factor VIII	Variable, depending on type of preparation	May reduce menorrhagia	Headache, hypertension	Not able to predict response. May also have favorable effect on endometrium
Fibrin sealant (Tisseel®)	A concentrate of fibrinogen combined with thrombin and calcium to form gelatinous fibrin-rich glue	Forms a gel for topical use	May control local bleeding. Useful in some surgeries	Risk of blood-borne disease when cryoprecipitates are used as a source of fibrinogen	May be an adjunct to other therapies in controlling bleeding
VWF concentrate	Raises VWF levels	Dose by VWF:RCo units	Highly purified plasma-derived VWF concentrate. Viral inactivation	Rare instance of development of VWF antibodies in type 3 VWD	Start 12-24 hours before needed, level secondary to de novo synthesis of factor VIII. Must use in conjunction with factor VIII concentrate in an acute bleed. Not available in U.S.

iv = intravenous; IU = international units; po = orally; qid = four times daily; VWD = von Willebrand's disease; VWF = von Willebrand's factor; VWF:RCo = von Willebrand's factor:ristocetin cofactor.

Patient Education

Educate patients and their families about VWD and the management of bleeding.

* Inform patients with known VWD of their increased risk of bleeding, basing risk assessment on disease type and severity.
* Educate patients about different treatment options appropriate for their type of VWD and review possible side effects and risks.
* Discuss with patients the signs and symptoms of bleeding and instruct them to seek medical care if uncontrolled bleeding occurs.
* Discuss the management of minor bleeds or menorrhagia at home using therapeutic options such as desmopressin, antifibrinolytic drugs, or factor concentrates.
* Inform patients about high-risk situations for which prophylaxis may be recommended, such as invasive procedures, dental work, and trauma.
* Advise patients about risks associated with trauma and precautions for head trauma:

o For severe forms of VWD, concentrate therapy and CT scanning may be recommended for head trauma
o For less severe forms of VWD, evaluation with CT scanning along with therapy with desmopressin or concentrates may be recommended

* Reassure patients that although they are at an increased risk of bleeding, there is no evidence that life expectancy is shortened.
* Advise patients with VWD to inform all of their treating physicians about their underlying condition.
* Counsel patients with VWD that family members should be screened for the disease when medically indicated.
* Instruct patients with severe forms of VWD and frequent bleeding episodes about home infusion of factor concentrates.

Therapy:

Avoid aspirin or NSAID med.
IV DDAVP 0.3 ug/kg in 50 mL of normal saline over 30 min IV or subc. is effective, may be repeated prn in several hours.
The rise in vWF achieved has a half life of about 8 hours. It is best monitored the Rx response by following the changes in VIII:C, vWF, & the bleeding time. DDAVP should not be used in type IIb (there are small & intermediate sized multimers, but the very largest multimers are defective Y probably reduced in number due to their excessive binding to platelets.) because it causes thrombocytopenia.
Following administration of desmopressin, care must be taken to minimize its antidiuretic effects by restricting intake of water to avoid severe hyponatremia, which could result in seizures. Desmopressin has also been reported to precipitate angina pectoris in elderly individuals with atherosclerotic heart disease. Tachyphylaxis occurs after repeated administration.

Stimate (desmopressin - DDAVP, synthetic vasopressin) nasal spray 1.5 mg/ml
1 spray in each nostril about 2 hours prior to scheduled surgery.
Replacement therapy with IV cryoprecipitate infusion of 10 units over 30 min just prior to the procedure, may repeat q 12 h prn; or intermediate-purity factor VIII concentrates containing functional vWF ( Humate-P, Armour).
These therapies are reserved for individuals with type IIB von Willebrand disease and severe type I, III, and IIA disease unresponsive to desmopressin.
Fresh frozen plasma
The concomitant use of antifibrinolytic agents (e-aminocaproic acid 4 gm q4h or 24g/day or tranexamic acid) is recommended to inhibit fibrinolysis (- because DDAVP seems to enhance fibrinolysis), particularly for dental extraction or oral surgery and for the treatment of mucosal bleeding (epistaxis, menorrhagia, and gastrointestinal bleeding).

2008