Von Willebrand Disease - College of American Pathologists

1

1

Von Willebrand Disease

Tim Hayes, DVM, MDMaine Medical Center

Portland, Maine

© College of American Pathologists 2004. Materials are used with the permission of

Timothy Hayes, DVM, MD, FCAP.

2

Overview• Brief review of physiology of vWF.

• Review classification systems for vWD.

• Focus on difficulties in making a Dx of mild Type 1 vWD.

• Discuss new concepts in “diagnosing” vWD.

2

3

The Beginning• In the 1920’s, Eric von Willebrand, a Finnish internist,

investigated a family living in the Aland Islands.

• The proband was a 5 year old girl with a severe bleeding tendency.– Four of her affected sisters died of hemorrhage before the age of

4 years.– The proband died at the age of 13 during her fourth menstrual

period.

• The parents and several other relatives (both genders) had mild bleeding symptoms.– The most common sites of bleeding were skin and mucous

membranes.– The severity of the bleeding was variable throughout this large

pedigree.– Some obligate heterozygotes were asymptomatic.

4Structure and Function of von Willebrand Factor, in Hemostasis and Thrombosis, 4th ed, 2001

3

5

Physiology of vWF• Multimers range in size – up to 20 million Da. The smaller molecules are

secreted, while the larger multimers are stored in Weibel-Palade bodies/alpha granules- actively secreted in response to epinephrine, histamine, thrombin, vasopressin analogue (dDAVP).

• These unusually large (highly hemostatically functional) forms are rapidly proteolyzed to “normal” size distribution when released into the circulation.

• vWF plays an important role in primary hemostasis by forming an adhesive bridge between platelets and sites of injured endothelium (subendothelialcomponents).

• The larger (longer) multimers are critical for this function.

• vWF plays an important role in secondary hemostasis by acting as a carrier protein for FVIII, protecting it from inactivation and clearance.

6Mannucci. NEJM 351;7:683, 2004

4

7

Classification Systems for vWD1970’s to 1994

• System originally distinguished between qualitative and quantitative abnormalities.

• Evolved to the occasional use of multimer patterns alone as the primary criterion to separate Type I from Type II – Type I: normal distribution (>14 varieties)– Type II: absence of HMW multimers (>13 varieties).– Type III: virtual absence of vWF.

• A system based on multimer patterns alone:– obscurred the distinction between quantitative and qualitative

abnormalities, – does not correlate well with clinical behavior or type of genetic lesion,– limits precision and clinical utility.

– Type I New York has normal multimers, but the clinical and lab features are otherwise similar to type IIB.

8

Classification Systems for vWD1994 to present

• The ideal classification system should be correlated to:– Pathophysiology– Type of genetic lesion– Clinical behavior– Response to therapy– Genetic counselling

• Classification should be independent of specific lab tests…should be based on biologic properties of vWF, and answer the question “why does the patient bleed?”

• Bleeding may be caused by – abnormal vWF-dependent platelet function, or– abnormal vWF-FVIII interactions.

• These may be due to quantitative or qualitative defects.

5

9


All vWD is caused by mutations at the vWFlocus.

Others should be referred to as:“pseudo-vWD” (platelet-type pseudo

vWD), or “acquired von Willebrand syndrome”

Sadler. Thromb Haem. 71:520, 1994

10

Acquired vWD• Malignancy

– *Lymphoproliferative (NHL, CLL, MM, Waldentrom’s, MGUS)– Myeloproliferative (ET, PV, CML)– Wilms tumor, carcinomas

• *Autoimmune disorders (SLE)• Drugs – Valproic acid, Ciprofloxacin, Griseofulvin• Other

– VSD Hypothyroidism– Aortic stenosis Uremia– Mitral valve prolapse Hemoglobinopathies– GI angiodysplasia

* = most common Veyradier. Thromb Haem. 84:346, 2000

6

11


(note the switch from Roman to Arabic numerals)

Type 1 vWD refers to partial quantitative deficiency of vWF.

Type 2 vWD refers to qualitative deficiency of vWF.

Type 3 refers to virtually complete deficiency of vWF


12


Subcategories of Type 2 vWD

• Type 2A refers to qualitative variants with decreased platelet-dependent function that is associated with the absence of HMW vWFmultimers.

• Type 2B refers to all qualitative variants with increased affinity for platelet glycoprotein Ib.

• Type 2M refers to qualitative variants with decreased platelet-dependent function that is not caused by the absence of HMW vWF multimers.

• Type 2N refers to qualitative variants with markedly decreased affinity for factor VIII.


7

13

14Structure and Function of von Willebrand Factor, in Hemostasis and Thrombosis, 4th ed, 2001

8

15

vWD Type 2• 2A

– 10-15% of all vWD Usually autosomal dominant– Moderate to moderately severe bleeding– Mutations mostly in the A2 domain.

• defective intracellular assembly of multimers• Defective cleavage – increased proteolysis

• 2B– 5% of all vWD Autosomal dominant– Moderate to moderately severe bleeding– Most mutations in the A1 domain – increased binding to GP Ib

• 2M– Rare Autosomal dominant– Most mutations in the A1 domain – decreased binding to GP Ib– Significant bleeding symptoms

• 2N– Uncommon Autosomal recessive– Most mutations in the N-terminus – binding site for FVIII– FVIII levels typically 5-15% of normal– Bleeding symptoms more characteristic of defect in secondary hemostasis

16

Rick. Classification and pathophysiology of vWD. UpToDate. 2004

9

17

vWD Type 3

• Rare (one per million).• A homozygous or compound heterozygous

disorder.• Multiple potential genetic defects.• Severe bleeding disorder, manifesting as both

primary and secondary hemostasis defects.

18

vWD Type 1• Accounts for 75% of all vWD.• Some cases are easy to Dx:

– very low levels of normal vWF (<15%),– repeated and serious bleeding,– appear to have autosomal dominant inheritance.– Definitive Dx requires all 3…without all 3, the Dx is merely

“possible”

• Most patients alleged to have vWD Type 1 have:– modestly decreased levels of vWF (15-50%),– mild bleeding (occurs in some family members, but not in

others).– The majority of those felt to have vWD Type 1 present a

significant diagnostic and therapeutic challenge.– The bleeding symptoms are not specific and heterozygotes may

be “normal”.

10

19

vWD: Status of DNA Testing• No current genotypic classification of vWD.

• > 250 mutations have been identified– Large and small deletions– Out-of-frame insertions– Splicing abnormalities– Nonsense mutations– Missense mutations

• ISTH SCC VWF Database: www.sheffield.ac.uk/vwf• Ginsburg database: http://mmg2.im.med.umich.edu

• Nice review: Clin Lab Haematol 2001;23:209-30.

20

Difficulties in Diagnosing vWD Type 1

• Difficult to distinguish vWD Type 1 from normal– Broad distribution of normal vWF levels.– High prevalence of mild bleeding symptoms.– Most diagnoses of vWD Type 1 are false

positives.– Weak relationship between vWF level and

bleeding.

Sadler. Blood. 101:2089, 2003

11

21




bleeding.

Sadler. Blood. 101:2089, 2003

22


Broad distribution of normal vWF levels.• Normal range is 50 – 200%.• Much of this variation is unexplained.

– Genetic components – 30-60% of variation.• ABO blood type: accounts for about 30% of genetic variation

– Mean vWF level for Type O (75%) is 25-35% below that for Types A (106%), B (117%), or AB (123%)

• Polymorphisms in the vWF promoter – correlate with small changes in mean vWF level.

– Non-genetic• Most of the variation is not heritable

• Considerable overlap between heterozygotes and normal– Obligate carriers of vWD Type 3 had a mean vWF level of 46% (11-

116%) – vWF level does not reliably distinguish between carrier and normal

Sadler. Blood. 101:2089, 2003

12

23

Difficulties in Diagnosing vWD Type 1Broad distribution of normal vWF levels.

NormalsMean = 0.75

+2SD = 0.36-1.57

Blood Type O alonemay cause vWF levelslow enough to suggest

a Dx of vWD

Broad overlap between“normal” and a

hypotheticalpopulation of

heterozygous carriers

24




bleeding.

Sadler. Blood. 101:2089, 2003

13

25


High prevalence of mild bleeding symptoms.

• Bleeding has many causes, is common, and no symptom is specific for vWD.

• Surveys of healthy controls report excessive:– Nosebleeds 5-39% Bleeding from trivial wounds 0.2-2%– Gum bleeding 7-51% Bleeding after tooth extraction 1-13%– Bruising 12-24% Bleeding after tonsillectomy 2-11%– Menorrhagia 23-44% Postoperative bleeding 6-23%

• Usually these symptoms are not medically significant, but form the basis for a Dx of a bleeding disorder consistent with vWD.

• Using the lowest value reported in any study, 25% of males and 46% of females have at least one bleeding symptom!

Sadler. Blood. 101:2089, 2003

26


• Difficult to distinguish vWD Type 1 from normal– Broad distribution of normal vWF levels.– High prevalence of mild bleeding symptoms.– Most diagnoses of vWD Type 1 are false positives.– Weak relationship between vWF level and bleeding.

Sadler. Blood. 101:2089, 2003

14

27


Most diagnoses of vWD Type 1 are false positives.

• Reported prevalence of vWD Type 1:– 1.3% US (600 healthy children) - 0.8% Italy (1218 children)

• Most reference ranges are established using the central 95% - leaving 2.5% of “normals” outside of either end of the range.

• If the prevalence of bleeding in a normal population is 25%, then 0.6% (25% of 2.5%) of the population will have both bleeding and low vWF by CHANCE = FALSE POSITIVE Dx of vWD TYPE 1

• Even if a positive family history of bleeding is required for a Dx, this relationship is only reduced to 0.4%.

• So, the published prevalence of vWD Type 1 is comparable to the required prevalence of false positive diagnoses.

• 9 of the 10 children “diagnosed” with vWD in the above Italian study had no medically significant bleeding in 13 years of followup….majority represented a coincidental association of bleeding and low vWF.)

• In summary, many patients diagnosed with vWD Type 1 do not have a specific hemorrhagic disease at all, which limits the utility of the diagnosis.

Sadler. Blood. 101:2089, 2003

28




bleeding.

Sadler. Blood. 101:2089, 2003

15

29


Weak relationship between vWF level and bleeding.

• While patients with undetectable vWF (Type 3) usually do have serious bleeding, modest decreases in vWF (Type 1) confers, at most, a modest risk for bleeding.

• 191 obligate heterozygous carriers of vWD Type 3:– Mean vWF level = 45% (range of <5% to 130%)– The risk of bleeding was not quite significantly different between 117

subjects with vWF < 50% and 74 subjects with vWF > 50% (P < 0.051, relative risk 2.0 for low vWF).

– In general, any bleeding was mild – bruising, epistaxis, bleeding after tooth extraction, or subjectively excessive menstrual bleeding.

– Significant post-op bleeding was reported in only one patient, whose vWF level was > 50%.

Sadler. Blood. 101:2089, 2003

30



• The Italian study of 1218 children, found that the pedigrees showed a striking lack of concordance between low vWF level and the occurrence of mild bleeding symptoms.

• Bleeding symptoms and vWF level are inherited independently.

• A low vWF level did not predict surgical bleeding in 832 consecutive patients.

• FVIII is the most important determinant of surgical and soft-tissue bleeding.

• It is unclear which measurement is the most important determinant of mucosal bleeding, or what levels are critical for control of mucosal bleeding.

Sadler Blood. 101:2089, 2003

16

31



• Relative risk of menorrhagia with a low vWF is 3.9.

• Athough a low vWF level appears to be a modest risk factor for menorrhagia at the population level, a causal relationship between low vWF and menorrhagia usually cannot be established for a specific individual patient.

• About 25,000 per million women have low vWF, among whom 11,000 may be predicted to have menorrhagia.

• It does not seem useful to diagnose a specific hemorrhagic disease in so many women when most of these with a low vWF level do not bleed, and a quarter of those who bleed have a low vWF merely by chance.

Sadler. Blood. 101:2089, 2003

32

Mis-diagnosing vWD Type 1

• Consequences of vWD misdiagnosis:

– Patients subjected to risky, expensive and ineffective treatments, while a legitimate cause of symptoms is overlooked and untreated.

– Dx may change a patient’s self-image and cause them to limit activities for fear of bleeding or transmitting a genetic disease.

– Denial of insurance coverage.Sadler. Blood. 101:2089, 2003

17

33

Mis-diagnosing vWD Type 1

• A Dx of vWD Type 1 is often difficult to confirm and may be more confusing rather than helpful.

• The current criteria for diagnosing vWD Type 1 exaggerates the significance of a modestly low vWF level and trivializes the true diagnoses.

Sadler. Blood. 101:2089, 2003

34


SummaryThe:

– High prevalence of mild bleeding symptoms, and– Broad distribution and overlap of vWF levels in both normal and mild vWD Type 1,

• Result in bleeding and low vWF levels often associating by chance (false positives).• The prevalence of false positive vWD Type 1 is comparable to the published

prevalence of the disease.

Also, a modestly low vWF level is a weak risk factor for bleeding.

Therefore, many patients diagnosed with vWD Type 1 do not have a specific hemorrhagic

disease, and are difficult to distinguish from normal - which limits the utility of the Dx.

This is a consequence of trying to force patients into binary categories of “diseased” or “healthy” – is incompatible with the continuous biologic context in which vWF functions.

“vWD Type 1: A diagnosis in search of a disease.”

Sadler. Blood. 101:2089, 2003

18

35

New Concepts in “Diagnosing” Type 1 vWD: An Epidemiologic Approach to vWF Level and Bleeding Risk.

• Instead of a “yes/no” diagnosis of vWD Type 1, use an approach often applied to other risk factors for disease….such as moderate increases in BP or total cholesterol: 2- to 4-fold increased risk for death from cardiovascular events.

• The increase in risk varies directly with the increase in either parameter.

• The decision to Tx balances the risks and benefits of treatment, and the threshold for intervention is influenced by the presence of other risk factors such as diabetes.

• Such an epidemiologic approach is appropriate for risk factors that are not, by themselves, managed as qualitative disease categories.

Sadler. Blood. 101:2089, 2003

36


• Reserve a Dx of “vWD Type 1” for:– Exceptionally low vWF levels…< 15%?– Frequent bleeding.– Dominant inheritance.

• Most of these patients appear to have vWF mutations – the Dxis useful in determining appropriate lifestyle changes and prophylactic interventions.

• This narrow use of the Dx avoids misdiagnosing an excessive number of healthy individuals as having an inherited hemorrhagic disease.

Sadler. Blood. 101:2089, 2003

19

37


• Manage “low vWF” (15 – 50%) as an epidemiologic risk factor for bleeding – not a disease.

• Most patients with bleeding and low vWF level could be told they have “low vWF” – a neutral term that reflects what we know and does not imply more.

• These same patients may have normal vWF levels with stress, age, pregnancy, etc. This variation is difficult to incorporateinto criteria for a disease Dx, but easier to handle in the context of risk management.

Sadler. Blood. 101:2089, 2003

38


Treat or prevent bleeding empirically by raising the vWF level if it is low.

• Similar to the management of high cholesterol and BP: reducing these levels will reduce the risk of cardiovascular disease.

Sadler. Blood. 101:2089, 2003

20

39


• Goal: – Deliver good care to bleeding patients,– Give advice on risk management to the many

with moderately low vWF.– Offer genetic counseling to the few with

significant inherited hemorrhagic disease.

Sadler. Blood. 101:2089, 2003

40

The Future

• To be most effective, we need more info about the likelihood of adverse events at various levels of vWF, and the efficacy of Tx – similar to the evolving approach to cardiovascular disease.

• The boundary between “vWD Type 1” and “low vWD” needs better definition.

• Current studies:– European (www.shef.ac.uk/euvwd) and Canadian studies of

vWD Type 1.– Italian study of carriers of vWD Type 3.

Sadler. Blood. 101:2089, 2003

21

41

Summary on vWD Diagnosis

• vWD types 2 and 3 are increasingly easy to Dx.• vWD Type 1 is common, but frequently difficult

to Dx – and is most likely overdiagnosed.• Using an approach that is based on vWF level

as a risk factor for bleeding has advantages over a binary (+/-) diagnostic method, for most of those currently carrying a diagnosis of vWDType 1.

Von Willebrand Disease - College of American Pathologists

Documents

Transcript of Von Willebrand Disease - College of American Pathologists