bleeding disorders march 2008

7/27/2019 Bleeding Disorders March 2008

1/8 The Royal College of Pathologists of Australasia The Royal College of Pathologists of Australasia

MARCH 200

A JOINT INITIATIVE OF

CSPCommon Sense Pathology The importance

of assessing thebleeding history

Collection of samplesand laboratory testing

Case studies

CONTENTS

A REGULAR CASE-BASED SERIES ON PRACTICAL PATHOLOGY FOR GPs


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Dr Huyen A M Tran,

staff haematologist, clinical haematology unit,

Monash Medical Centre, Clayton, Victoria.

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IntroductionWe know it is important to determine a patients risk of bleeding, but clinically it can be a difficult

thing to do. Current evidence does not support the indiscriminate use of coagulation screening tests to

predict bleeding in unselected patients. Patients may present with a history of spontaneous bleeding

or unexpectedly heavy bleeding after a minor trauma or procedure. Investigation to assess bleeding

risk may be required before a procedure in the presence of a personal or family history of bleeding

or the finding of an abnormal coagulation test. Inherited and acquired bleeding disorders can be

associated with significant morbidity and mortality, so it is important to have a standardised diag-

nostic approach to assess for possible haemostatic defects.

Bleeding disorders - does this patienthave an increased risk of bleeding?

Cover: Roger Harris/Science Photo Library.


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Bleeding disorders are divided into impairedprimary or secondary haemostasis. Primary

haemostatic disorders are most common and

include von Willebrand disease (see box below),

thrombocytopenia and platelet function disorders

(See CSP Thrombophilia November 2004).

Disorders of secondary haemostasis involve

disorders of fibrin formation, the haemophilias

(deficiencies of factors VIII and IX) and also

deficiencies of factors V, VII and XI.

There can be some overlap in bleeding sympto-

matology between primary and secondary haemo-

static disorders, but spontaneous haemarthroses areusually indicative of coagulation factor deficiencies

and are not seen in disorders of primary haemosta-

sis. Figure 1 illustrates the process involved in

normal coagulation and the causes of abnormal

bleeding are listed in Table 1 (page 4).

The bleeding historyA detailed personal and family history using stan-

dardised criteria is an essential tool for correctly

diagnosing a bleeding disorder. Table 2 (page 4) sum-

marises the most important symptoms to ask about in

order to assess the risk of bleeding. A personal history

of bleeding is predictive of bleeding risk.

There is increasing evidence that the bleeding history

will be most discriminatory when a standardised and

validated questionnaire is used to obtain this informa-

tion. Such a questionnaire tested in patients with von

Willebrand disease is available at www.med.unc.edu/

isth/ssc/collaboration/Bleeding_Type1_VWD.pdf?searchterm=questionnaire+von+willebrand+disease.

This tool also provides a useful approach to other

inherited and acquired bleeding disorders. If three or

more symptoms are found, further investigation for a

bleeding disorder is warranted.

3

Figure 1. Overview of haemostasis extrinsic and intrinsic pathways.

VesselInjury

Contact withdamaged vessels

XI

XIIa

XIa

VIIIa (vWF)

Va

Fibrinogen

XIII

VIIa IXa IX

AdrenalineThromboxane

Adenosinediphosphate

PLATELETREACTION

COAGULATIONCASCADE

Xa

Stable haemostatic plug

Subendothelialcollagenexposure

Plateletadhesion (vWF)

Plateletaggregation

Tissue factor

Definition of vonWillebrand disease

von Willebrand disease is

an inherited disorder that

impairs the bloods ability

to clot properly as a result

of a quantitative or

qualitative defect of von

Willebrand factor (vWF).

In normal haemostasis,

platelets adhere to the

exposed subendothelium

at the site of vascular

injury to form a

haemostatic plug.

vWF has two important

functions: Help platelets adhere to

the subendothelium atthe site of vascular injury.

Protects coagulation

factor VIII from degrading

and delivers it to the site

of vessel injury.

von Willebrand disease

is the most common

inherited bleeding disorder,

affecting as many as 1%

of the population.

Pro-thrombin(factor II)

Fibrin

Thrombin


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By adopting this approach, the GP will have a

good idea as to whether: A bleeding disorder is present. The disorder is inherited or acquired. The disorder involves primary or secondary

haemostasis as suggested by the type of bleeding

(mucosal vs non-mucosal bleeding) and timing

(immediate vs delayed). The underlying bleeding tendency has been aggra-

vated by drugs or acquired inhibitors interfering

with haemostasis.

A tendency to epistaxis, menorrhagia, easy skin

bruising or mild increased bleeding associated with

minor surgery or minor trauma may suggest a defect

in primary haemostasis, such as von Willebrand dis-

ease. The bleeding can be difficult to define as abnor-

mal because there is usually a subjective component.

Spontaneous haemarthroses and spontaneous

haematomas are usually indicative of moderate to

severe coagulation factor deficiency, in particular

factor VIII and IX (haemophilia A and B, respectively).

The exception is patients with factor XI deficiency

where mucosal bleeding symptoms predominate.

The symptoms and presentations of haemophilia

A and B are the same, but haemophilia A is much

more common. Recurrent painful joint bleeding and

muscle haematomas can dominate the clinical course

of severely affected patients leading to progressive

joint deformity. Such patients may also have a his-

tory of profuse post-circumcision haemorrhage,

extensive ecchymoses in childhood, previous life-

threatening operative and post-traumatic bleeding,

and spontaneous intracerebral haemorrhage.

A family history of a bleeding disorder (transmit-

ted in an X-linked fashion) is expected but not

always present. Up to 30% of new cases of

haemophilia are due to new gene mutations.

Patients with mild haemophilia may present in

adulthood with unusual postoperative bleeding.

Carriers of haemophilia A or B may or may not

have bleeding symptoms, depending on their base-

line factor level, which may be variable because of

random X chromosome inactivation. These clinical

features can also be seen in moderate and severe

deficiencies of factors II, V, VII and X and,

rarely, fibrinogen. With the exception of severe

Table 1: Causes of abnormal bleeding.

Congenital Acquired

Disorders of primary von Willebrand disease Antiplatelet drugs

haemostasis Thrombocytopenia Thrombocytopenia

Disorders of platelet function Renal failure

(eg, thrombocytopathies) Primary bone marrow diseases

(eg, myelodysplasia,

myeloproliferative disorders)

Disorders of secondary Deficiencies of coagulation Anticoagulants (eg, vitamin K

haemostasis factors: haemophilia A and B antagonists)

(factors VIII and IX) and Liver failure

deficiencies of factors XI, V Vitamin K deficiency

and VII and, although rare, II and XIII Acquired factor inhibitors

Other Collagen disorders (eg, Scurvy

Ehler Danlos syndrome)

Table 2. Symptoms suggestiveof a bleeding disorder.

Epistaxis Cutaneous bleeding Minor bleeding wounds Oral cavity bleeding Gastrointestinal bleeding Postpartum haemorrhage Muscle haematomas or haemarthrosis Tooth extraction Surgery Menorrhagia

Adapted from Rodeghiero F. Journal of Thrombosis and

Haemostasis2005; 3:2619-26.


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von Willebrand disease with associated factor VIII

of less than 5%, haemarthroses are rarely seen

with other disorders of primary haemostasis.

Laboratory testingBlood samples must be taken and handled cor-

rectly to be confident of obtaining valid coagula-

tion test results. Difficult venepuncture, an excess

citrate-to-plasma ratio because of erythrocytosis,

incorrect filling of collection tubes, undisclosed

drug contamination (eg, heparin or antiplatelet

drugs) or the time elapsed from sample collection

to analysis can all effect results. Therefore, testing

should only be undertaken by specialised labora-

tories. When abnormal results are identified, the

tests should be repeated to confirm the diagnosis.

In patients with a suspicious clinical history,

coagulation testing should be used to confirm the

presence of and determine the precise type of

bleeding disorder (abnormality in primary or sec-

ondary haemostasis). History and clinical exami-

nation should dictate the tests ordered.

The laboratory work-up (figure 2, page 6)

should be organised to identify the specific defect

in haemostasis. Start with screening studies to find

the abnormal phase of haemostasis involved: a full

blood count and film, activated partial thrombo-

plastin time (aPTT), international normalised

ratio (INR) and thrombin time (TT) provide an

initial assessment of platelet numbers and mor-

phology and a screen for defects in coagulation.

Patients who have a prolonged aPTT or INR

should have mixing studies performed to differen-

tiate between a factor deficiency and the presence

of a factor inhibitor. In this assay, plasma from the

patient and normal plasma are mixed in a 1:1

ratio and the aPTT or INR is calculated at 37Cimmediately after incubation and at varying times,

typically at 30, 60 and 120 minutes.

When the disorder is a factor deficiency, the

initially abnormal aPTT or INR will correct to

normal after mixing and remain corrected with pro-

longed incubation. If a prolonged aPTT is due to a

lupus (non-specific) inhibitor, the immediate mixing

and incubation will show no correction because the

inhibitor remains present in the mixed plasma. In

the presence of an acquired neutralising factor

antibody, such as an acquired factor VIII inhibitor,

the aPTT will be prolonged before mixing and

may or may not correct itself immediately on

mixing, but will be prolonged or remain pro-

longed with incubation. Acquired factor VIII

inhibitor occurs most commonly in the elderly, but

has also been described in postpartum women and

children. Extensive ecchymoses and soft tissue

bleeding are more common among these patients

than in those with inherited haemophilia. Patients

with haemophilia A and B can develop inhibitors

to factor VIII and IX, respectively.

Patients with acquired von Willebrand disease

may also have a prolonged aPTT, if the level of

von Willebrand factor antigen (vWF:Ag) is low,

thereby reducing factor VIII levels. Acquired von

Willebrand disease is usually associated with lym-

phoproliferative disorders but can be seen in other

conditions including autoimmune disease, myelo-

proliferative disorders and valvular disease.

There has been much interest in the possibility

that global tests, such as the PFA-100 test (an in

vitro platelet function assay), could be used to

assess overall haemostatic potential. While this

may be of value in further investigating platelet

function in vitro, this test is not widely available

and is best performed in consultation with a

haematologist.

Beyond the initial screening tests, second-level

tests should take into account the features of the

bleeding history and focus on the specific factors

of haemostasis found to be abnormal in screening.

For example, a female with easy bruising and

excessive bleeding after dental extraction should

have specific tests for von Willebrand disease and

platelet function disorders performed. Similarly, a

male with a personal history of spontaneous joint

bleeding and a family history of bleeding shouldbe tested for both haemophilia A and B.

The ability of laboratory testing using the aPTT

to detect single factor deficiencies involved in the

intrinsic coagulation pathway (factors VIII, IX, XI

and XII) varies depending on the coagulometer

and test reagent being used. In general, the aPTT

will not be prolonged if a single factor level is

reduced in the range of 30%-50%. Therefore,

specific testing for factors VIII, IX and XI must be

performed to adequately evaluate for the diagnostic

possibilities of haemophilia A and B and factor XI


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deficiency. Deficiencies of coagulation factorsinvolved in the extrinsic and common pathways of

haemostasis (factors VII, X, V and II) are less

common than defects of primary haemostasis or

haemophilias. Prolongation of the INR alone or in

addition to a prolonged aPTT depends on the spe-

cific factor that is deficient. The diagnosis of each

condition will require specific factor assays for con-

firmation.

In disorders of primary haemostasis, all screening

coagulation test results can be normal. If the bleeding

history is suspicious a targeted set of studies must be

performed to comprehensively evaluate platelet func-tion. Platelet morphology, aggregometry and, if neces-

sary, platelet secretion and the enumeration of dense

granules should be requested.

Look for von Willebrand disease, the most

common bleeding disorder, by assaying vWF:Ag, ris-

tocetin co-factor activity, collagen binding and factor

VIII concentrations. vWF:Ag concentration can be

affected by several pre-analytical variables. It may be

increased above baseline by vigorous exercise, stress

and inflammation, and varies with menses, being

lowest in the first 1-3 days of the menstrual cycle.

von Willebranddisease testing von Willebrand factor

antigen assay Ristocetin co-factor

activity or collagen

binding assay If abnormal von

Willebrand diseasetest, repeat with

multimer studies to

confirm. If high

clinical suspicion,

repeat testing

Plateletdisorders Platelet

morphology

and number Platelet

aggregation

(arachadonic

acid, collagen,

adenosine

diphosphate,

ristocetin) Repeat

abnormal

platelet

aggregation

studies

Figure 2. Laboratory testing for a patient with a positive bleeding history.

Prolonged aPTTIntrinsic pathway factors Factor VIII Factor IX Factor XI

Prolonged INRExtrinsic pathway factors

Factor VII Factor X Factor V Factor II

Prolonged TT Fibrinogen If all initial screening tests are

normal consider factor XIII

screening

Initial screening tests Full blood count including platelet morphology and liver function testsActivated partial thromboplastin time (aPTT) International normalised ratio (INR) Thrombin time (TT) PFA-100

Disorders of primaryhaemostasis

Ristocetin is an antibiotic that causes agglutination in normal

blood. In von Willebrand disease, abnormal agglutination occurs.

Disorders of secondary

haemostasisCoagulation factor deficiencies


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7

Hormonal therapy may increase vWF:Ag levels,

but the lower doses of oestrogen in second- and

third-generation oral contraceptive pills tend not to

cause this affect.

Individuals with a type O blood group generally

have lower vWF:Ag levels. Therefore, testing on

2-3 occasions should be performed before confirm-

ing or ruling out the diagnosis of von Willebrand

disease in a woman with excessive mucocutaneous

bleeding. If there is laboratory evidence of von

Willebrand disease, additional testing is necessary

to identify the sub-type of the disease, including

von Willebrand factor multimer assay, ristocetin-

induced platelet aggregation assay and factor

VIII-binding assay if type 2N von Willebrand

disease (a factor VIII deficiency caused by a

decreased affinity of vWF for factor VIII) is

suspected. These latter tests require expertise

and experience to produce reliable results and

are only available in a few laboratories.

Any patient identified with a bleeding disorder

should be referred to a haematologist to assess the

appropriate long-term treatment plan.

Case study 1A 35-year-old female presents with a history

of menorrhagia. Gynaecological causes have

been excluded.

Menorrhagia is a loss of more than 80mL

of blood per menstrual cycle, usually the

amount required to cause iron-deficiency

anaemia. Although a complaint of heavy men-

strual loss can be subjective, predictors of

menorrhagia include menses lasting more

than eight days, passage of clots, flooding at

night, iron-deficiency anaemia or a need for

blood transfusion or iron infusion.

What other aspects of the patients history are

important to evaluate?

Unexplained menorrhagia is a common presenting

symptom in women with congenital bleeding disor-

ders. Ask them about a family history of bleeding

disorders and a personal history of excessive bleed-

ing with tooth extraction, delivery, miscarriage or

surgery because a positive response increases the

likelihood of an underlying bleeding disorder being

present. Bleeding disorders that are most likely to

be identified with this presentation are von

Willebrand disease, platelet function disorders

and, less commonly, factor XI deficiency. Carriers

of haemophilia A and B uncommonly present with

menorrhagia.

What coagulation tests would you order?

Initial screening tests should be ordered to identify

the abnormal phase of haemostasis. This history

of mucocutaneous bleeding is more likely to be a

disorder of primary haemostasis, although it is not

specific to any particular disorder of primary

haemostasis. Perform all of the further tests to

investigate for defects of primary haemostasis.

Patients with von Willebrand disease typically

have a normal aPTT and INR, and specific testing

for von Willebrand disease should be performed.

Similarly, platelet function disorders can only be

detected by studies assessing primary haemostasis,

such as PFA-100, and platelet aggregometry

assays.

An abnormality in either the aPTT or INR

requires specific coagulation testing for

haemophilia A and B, and factor XI deficiency,

respectively.

Case study 2An 18-year-old male presents with a sponta-

neous left knee haemarthrosis seven days after

elective knee arthroscopy.

What other aspects of the patients history are

important to evaluate?

If haemarthrosis occurs after a minor surgical pro-

cedure the possibility of a coagulation factor defi-

ciency, in particular haemophilia A and B, should

be considered. Ask about previous major andminor bleeding episodes, such as spontaneous

muscle haematomas, profuse bleeding after

circumcision or extensive ecchymoses in child-

hood. A family history of a diagnosed bleeding

disorder, especially where only males are affected

(X-linked), increases the likelihood of

haemophilia A and B being diagnosed.

What coagulation tests would you order?

Initial screening tests should be undertaken paying

particular attention to the aPTT and INR levels. If


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bleeding disorders march 2008

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