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Acquired disorders ofcoagulationVickie McDonald

AbstractNormal coagulation is a balance between pro- and anti-thrombotic mech-

anisms. Haemorrhage occurs when factors that promote thrombus forma-

tion are dysfunctional/absent and may be due to inherited or acquired

factors. The most common acquired abnormalities seen in the clinical

setting are covered in this article including vitamin K deficiency and

warfarin therapy, liver disease, disseminated intravascular coagulation,

platelet disorders and vascular disorders. Patients bleeding on warfarin

therapy need urgent INR testing and reversal with vitamin K and/or

prothrombin complex concentrate. Patients with liver disease have

complex haemostatic changes and the management of bleeding depends

on the site and severity of bleeding. Disseminated intravascular coagula-

tion may complicate many clinical situations and needs prompt actionwhen patients are bleeding. Acquired dysfunction of platelets is

commonly encountered in clinical practice, often in association with

drug therapy such as aspirin.

Keywords antiplatelet drugs; bleeding; disseminated intravascular

coagulation; liver disease; vascular abnormalities; vitamin K deficiency;

warfarin

Introduction

The normal coagulation process is a balance between pro- and anti-

thrombotic mechanisms.Haemorrhagicdisorders occurwhen there

is deficiency or dysfunction of part or parts of the haemostatic

system (platelets, coagulation factors or the blood vessel wall).

Acquired disorders of coagulation are much more likely to be

encountered in clinical practice than inherited disorders, and clin-

ical features vary from simple bruising to life-threatening bleeding.

History

Establish the type of bleeding, precipitating factors and the

severity and frequency of bleeding. The patients medical history

may give a clue, if it affords evidence of liver or kidney disease,

and a careful drug history is critical.

Examination

Look for evidence of associated systemic disease, such as signs of

liver disease or lymphadenopathy. Examine the mucosal surfaces

such as the skin, mouth and joints for bruises, petechiae and

signs of bleeding. Bruises suggestive of an abnormal bleeding

tendency are usually large, and occur with minimal trauma and

in atypical sites, such as the trunk.

Investigations

Initial investigations should include:

full blood count and blood film examination

coagulation screen

prothrombin time (PT)

activated partial thromboplastin time (APTT)

fibrinogen

If PT or APTT are prolonged, a 50/50 mix of the patients

plasma with normal plasma will distinguish between an

inhibitor or a clotting factor deficiency

Renal and liver function.

Additional investigations, such as factor assays or platelet

studies, will depend on the initial history, examination and

baseline investigations.

Vitamin K deficiency and warfarin therapy

Vitamin K is essential for the function of coagulation factors II,

VII, IX and X, and anticoagulants proteins C and S. Deficiency

occurs as a result of malabsorption or (rarely) dietary deficiency

and leads to a prolonged PT.

Warfarin inhibits the effect of vitamin K on clotting factors

and the international normalized ratio (INR) is used to monitor

its effect. The risk of major haemorrhage in patients taking

warfarin is about 2% per year and management depends on the

INR and severity of bleeding.1 If the INR is high with no

bleeding, warfarin should be stopped and recommenced whenthe INR falls back into range. If the INR is greater than 5.0,

small doses (1 or 2 mg orally) of vitamin K may be needed with

INR repeated 24 hours later. If the patient has major bleeding,

vitamin K and dried prothrombin complex (prothrombin

complex concentrate (PCC), which contains factors II, VII, IX

and X) should be given to reverse the effect rapidly.2 PCC acts

quickly and a repeat INR can be performed 10 minutes after

administration to see its effect, but its response lasts only a few

hours and vitamin K should be given alongside to establish

a more durable reduction in the INR.1 Fresh frozen plasma

(FFP) is no longer recommended for the reversal of warfarin. 1

PCC is associated with potential for thrombosis and so is

Whats new?

C Prothrombin complex concentrate should be used in preference

to fresh frozen plasma for reversal of warfarin because of its

more rapid onset of action, better efficacy, and because it has

better viral inactivation

C Increasing repertoire of anti-platelet agents for cardiac diseasemeans acquired disorders of platelet function are increasingly

common

C Liver disease is becoming increasingly common and the coag-

ulation abnormalities associated with this are likely to become

more of a clinical burden

Vickie McDonald MA PhD MRCP FRCPath is a Consultant Haematologist at

Guys and St Thomas NHS Foundation Trust, London, UK. Competing

interests: none declared.

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MEDICINE 41:4 228 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.mpmed.2013.01.013http://dx.doi.org/10.1016/j.mpmed.2013.01.013

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used with caution in some groups. Neonates are born with

a low vitamin K concentration and are at risk of haemorrhage if

this is not supplemented.3

Liver disease

Abnormal haemostasis in liver disease is usually multifactorial

(Table 1) and not all patients have associated bleeding.4 The

management of bleeding in patients with liver disease dependson its site and severity. Vitamin K 10 mg orally (or intravenously)

for 3 days may help patients who have associated vitamin K

deficiency. In life-threatening or major bleeding, any potential

source of bleeding, such as varices, should be sought and treated.

In addition, platelets should be given if the platelet count is less

than 50e100 109/litre but recovery may be poor if spleno-

megaly is present. FFP can be used to replace clotting factors in

major haemorrhage when the PT (APTT) is prolonged but large

volumes are often required. PCC has been used off-licence in

patients with liver disease who are bleeding but should be dis-

cussed with a haematologist or expert in this area. In addition,

fibrinogen replacement with cryoprecipitate (or off-licence use of

fibrinogen concentrate) may be required in those patients withlow fibrinogen concentration.

Disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC) is due to inappro-

priate and excessive activation of the haemostatic system.5,6 It

may lead to thrombosis, haemorrhage or both, and purpura

fulminans is the syndrome of DIC with skin necrosis. There are

many triggers, including trauma, infection, malignancy or

placental abruption.5,7 Activation of coagulation leads to micro-

thrombus formation with subsequent consumption of clotting

factors and increased breakdown of fibrin. The clotting factors

become depleted, platelets are consumed and fibrin deposition inthe circulation reduces tissue perfusion and causes mechanical

haemolysis. The patient may bleed from any site but this is often

mucocutaneous. The clotting screen shows a prolonged APTT,

with or without a prolonged PT, and low fibrinogen. In addition,

investigations show thrombocytopaenia, anaemia due to red cell

breakdown (microangiopathic haemolytic anaemia) and raised

D-dimer. Emergency management is discussed in MEDICINE

2013; 41(5).

Massive blood loss

Causes of abnormal clotting after massive blood loss include dilu-

tion, hypocalcaemia and acidosis and are discussed in the article on

Blood transfusion on pages 242e247 of this issue and also in the

article on Emergency management in MEDICINE2013;41(5).

Acquired disorders of platelet function

Acquired platelet disorders (listed below) are much more

common than congenital ones (see Inherited Bleeding Disorders

on pages 231e233 of this issue).

Antiplatelet drugs (e.g. aspirin) irreversibly acetylate

platelet cyclo-oxygenase, impairing thromboxane A2production and platelet aggregation. The effects of aspirin

last approximately 7e10 days. Low-dose aspirin can

prevent thrombosis, but may lead to haemorrhage, espe-

cially from the gastrointestinal tract. Other antiplatelet

drugs include dipyridamole, which inhibits phosphodies-

terase, clopidogrel and GPIIb/IIIa inhibitors.

Uraemia can result in a functional defect in platelets which

may improve with dialysis or DDAVP (desmopressin).

Cardiopulmunary bypass e the bypass circuit may result

in platelet trauma, leading to thrombocytopenia, platelet

fragmentation and platelet function abnormalities.8 With

excessive bleeding, platelet transfusions may be required.

Myeloproliferative disorders e

may be associated with

abnormal platelet function, which can result in thrombosis

or haemorrhage.9 Haemostasis usually improves with

correction of the platelet count.

Vascular disorders

Intact vascular endothelial function and the ability of vessels

to contract are essential in controlling blood loss. Abnormal

vessel walls can result in excessive bleeding and routine

clotting tests are normal. Hereditary disorders include hereditary

haemorrhagic telangiectasia (OslereRendueWeber syndrome),

characterized by fragile telangiectasia and arteriovenous mal-

formations, and collagen vascular disorders (e.g. Ehlerse

Danlossyndrome), characterized by hyperextensible joints and elastic

skin. Acquired disorders include corticosteroid-induced purpura,

HenocheSchonlein purpura and scurvy, which leads to an

acquired collagen abnormality. A

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1 Keeling D, Baglin T, Tait C, et al. Guidelines on oral anticoagulation

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Causes of abnormal coagulation in liver disease

Causes of abnormal

coagulation in liver disease

Coagulation abnormalities

seen in liver disease

C Vitamin K deficiency from

malabsorption

C Defective synthesis of

clotting factors

C Thrombocytopenia due toportal hypertension,

hypersplenism and

reduced thrombopoietin

production

C Abnormal fibrinolysis and/

or intravascular

coagulation

C Prolonged prothrombin time (PT):

due to vitamin K deficiency

leading to reduced synthesis of

factors II, VII, IX and X

C Prolonged activated partialthromboplastin time and PT:

due to reduced synthesis of all

clotting factors

C Low platelet count

C Reduced fibrinogen due to

disseminated intravascular

coagulation

C Prolonged thrombin time

due to dysfibrinogenaemia

C Reduced protein C and S levels

Table 1

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