CHAPTER 6

62

Essential Guide to Blood Coagulation, Second Edition. Edited by Jovan P. Antovic, Margareta

Blombäck. © 2013 John Wiley & Sons, Ltd. Published 2013 by John Wiley & Sons, Ltd.

Investigation of increased bleeding tendencyMargareta Holmström and Lars Göran Lundberg

Department of Medicine, Coagulation Unit, Karolinska Institutet;

Hematology Centre, Karolinska University Hospital, Stockholm, Sweden

Introduction

When investigating an increased bleeding tendency, a detailed history is

important. With regard to sampling, a number of screening analyses are

of primary interest.

If the patient presents with only small, shallow bruises, has no heredity

and the screening analyses are normal, there is generally no need for

further investigations. However, if the patient has a manifest history of

bleeding and/or heredity, a coagulation specialist should be consulted

even if the screening analyses appear to be normal.

Diagnosis

The keystone of the diagnosis is the history of bleeding (Box 6.1), which

is often more instructive than many laboratory analyses. The history is

informative preoperatively and in connection with an investigation of

hemostatic defects. Further investigation is usually based on the bleeding

history and the results of screening analyses.

Evaluating a case history can be diffi cult and calls for experience to

distinguish between what may be normal as opposed to defi nitely patho-

logic. Spontaneous muscle or joint bleeding is almost always associated

with severe hemophilia or other total coagulation factor defi ciencies,

sometimes also with severely defective platelet function. If nose bleeds or

bleeding after tooth extraction or menorrhagia has required medical treat-

ment, they are also more likely to indicate a hemostatic defect. Frequent

bleedings, perhaps of various origins, also indicate a hemostatic defect. If

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Investigation of increased bleeding tendency | 63

a close relative is known to have a verifi ed specifi c defect, measurement

of the factor in question is usually mandated.

Box 6.1 Suggested questions for bleeding history (yes/no)

Do you bruise easily?

Do you often have nose bleeds?

Do you bleed abnormally from a cut or other wound?

Do your gums often bleed?

Have you had any muscle bleedings?

If yes, what was the cause?

Have you had any joint bleedings?

If yes, what was the cause?

Have you had a tooth extracted?

If yes, did you bleed for more than 5 hours afterwards?

Have you undergone any surgery?

If yes, what for?

Have you bled abnormally after surgery?

Have you been given blood or plasma for bleeding from surgery?

Do you have plentiful menstrual bleeding (menorrhagia)?

Have you had a delivery?

Have you had abnormal bleeding after a delivery/abortion?

If so, did you receive transfusion of blood or plasma?

Which drugs do you use (including contraceptives)?

Do you suffer from any liver, kidney or blood disease?

Heredity – have any of your relatives had problems with bleeding after

surgery, delivery, tooth extraction, or other severe bleeding?

Laboratory testsRecommended screening analyses include platelet count, PT(INR), APT

time, fi brinogen and bleeding time.

Note: testing of bleeding time requires skilled personnel in order obtain

reliable results (see also Chapter 3).

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64 | Essential guide to blood coagulation

Reasons for pathologic screening analyses and further actions

Causes of prolonged bleeding time• Bleeding time lengthens during pregnancy (normally not above the

upper reference limit) and is prolonged in connection with decreasing

extravascular fl uid. Diseases involving the connective tissue can result

in prolonged bleeding time.

• Drug effects (ASA, clopidogrel, NSAID, antiepileptics, and certain

antidepressive drugs).

• Thrombocytopenia (platelet count below 80 × 109/L). For causes, see

below. The number of platelets is crucial for adequate primary hemo-

stasis. Levels above 50 × 109/L are usually suffi cient but bleeding time

can be prolonged even at 80 × 109/L.

• For patients with a bleeding time of more than 900  sec, who do not

respond to desmopressin (Octostim) (see also Chapter 4), request an

investigation with certain special platelet tests (a referral to a coagula-

tion unit is advisable).

To investigate thrombocytopenia when a coagulation disorder is not

likely, contact a hematologist. In this context, hemostatic disorders

include the following.

• von Willebrand disease (VWD). However, bleeding time may be normal

in a mild form of VWD. Analyze VWF (VWF functional (VWF:RCo

or VWF:GPIbA) and VWF antigen) and FVIII, and calculate the ratios

FVIII/VWF:Ag and VWF:Ag/VWF:RCo or VWF:GPIbA.

• Acquired platelet function defects due to liver damage, kidney damage,

autoimmune disease such as SLE, platelet inhibitory drugs, increased

fi brinolysis.

• Hereditary platelet function disorders, for example Glanzmann thrombas-

thenia and Bernard–Soulier syndrome.

• Disseminated intravascular coagulation (DIC). Platelets are consumed as a

result of extensive activation of coagulation. Peripheral bleedings (e.g.

ecchymoses and bleeding in the gums) already indicate a platelet func-

tion defect and therefore bleeding time measurements are not neces-

sary. See Chapter 16.

• Bleeding time may be prolonged in FV and FXI defi ciency.

Causes of thrombocytopenia

Investigation and treatment of thrombocytopenia is normally

handled by a hematologist. In the rare situations where the under-

lying diagnosis is made of a primary coagulation disorder, such

as VWD type 2B or Bernard–Soulier syndrome, further treatment

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Investigation of increased bleeding tendency | 65

is managed in a specialized coagulation unit. Discussion with a

coagulation specialist is usually of value in emergency conditions

such as DIC, HIT.

So-called pseudothrombocytopenia is often caused by platelet aggre-

gation in EDTA tubes. Check platelet count in citrate tubes or heparin

tubes for comparison.

Hereditary thrombocytopenias• Isolated (autosomal dominant)

• Combined with qualitative defect (e.g. Bernard–Soulier (see above),

May–Hegglin, Wiscott–Aldrich)

• Combined with other defects (e.g. VWD type 2B, Fanconi syndrome)

• Thrombocytopenia with absent radius (TAR).

Acquired thrombocytopeniaIncreased peripheral destruction• Idiopathic thrombocytopenic purpura (ITP)

• Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic

syndrome (HUS). See Chapter 16

• Drugs (i.e. heparin). See Chapter 16 (HIT).

Reduced production• Aplastic anemia

• Malignant blood diseases

• Metastases to bone marrow from tumors

• Drugs

• Megaloblastic anemia, B12 or folate defi ciency

• Alcohol damage to bone marrow.

Abnormal distribution• Sequestering in an enlarged spleen.

Causes of prolonged activated partial thromboplastin time (APT time)

Check that the sampling was not done with a heparinized needle and/

or that the patient is treated with low molecular or standard heparin

(LMH/UFH).

Possible causes• UFH treatment (LMH can also cause some prolongation of APT time)

• VKA treatment

• Hemophilia A/B; often also in more severe forms of VWD

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66 | Essential guide to blood coagulation

• FXI defi ciency

• FXII defi ciency (APT time often greatly prolonged). By itself, this defi -

ciency does not lead to an increased bleeding tendency

• Defi ciency of any of the coagulation factors II (prothrombin) and FX

can also cause a prolonged APT time; such defi ciencies are usually

demonstrated better in a PT(INR) analysis

• Circulating anticoagulants (antibodies against a coagulation factor)

• Lupus anticoagulant/phospholipid antibodies

• Severe liver insuffi ciency

• Disseminated intravascular coagulation (DIC). See Chapter 16.

APT time is not prolonged in defi ciency of FVII or FXIII.

Note that a normal APT time does not rule out mild coagulation dis-

orders, such as mild hemophilia A or B or VWD. So if a disorder is still

suspected clinically even though APT time is normal, a specifi c coagula-

tion factor investigation should be performed.

Causes of elevated PT(INR)

• Liver damage/disease with defective synthesis of coagulation factors

• VKA treatment: Waran® (warfarin), Sintrom® (acenocoumarol),

Marcoumar® (phenprocoumon) or treatment with thrombin or Xa

inhibitors

• Vitamin K defi ciency (resorption disorder), intravenous nutrition for

more than 5 days, long-term antibiotic treatment

• Hereditary coagulation defect (FVII, FX, FII (prothrombin))

• Amyloidosis (can cause acquired FX defi ciency)

• Antibodies against any of above-mentioned factors or against

tissue factor. A pronounced lupus anticoagulant sometimes elevates

PT(INR)

• Newborns and healthy children up to 2 years of age have elevated

PT(INR) values

• Seriously ill and prematurely born children have abnormally high

PT(INR) values compared with healthy newborns

• Disseminated intravascular coagulation. See Chapter 16.

Investigation of bleeding tendency: practical aspects

Elective investigation in non-acute bleeding tendencyReferrals for consultation can be sent to coagulation specialists in the

local or referral hospital. The referral must include the bleeding history

and results of screening tests.

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Investigation of increased bleeding tendency | 67

Preoperative investigationA preoperative investigation is required in order to avoid unnecessary

bleeding complications. Take a bleeding history and, if this is positive,

screening samples. In urgent cases, contact the on-call coagulation doctor.

If the patient has thrombocytopenia only, contact a hematologist.

Acute investigation in postoperative or post-traumatic bleedingFor patients with a known bleeding disease, always immediately contact

the on-call coagulation doctor at the referral hospital or the patient’s

regular center for proposals concerning sampling and treatment. See

Chapter 4.

For other patients, fi rst determine hemoglobin platelet count, APT

time, PT(INR), and fi brinogen.

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