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Acquired disorders of

Vickie McDonald
Normal 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 deciency 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 action
when 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 deciency;
The normal coagulation process is a balance between pro- and anti-
thrombotic mechanisms. Haemorrhagic disorders occur whenthere
is deciency 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.
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.
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.
Initial investigations should include:
full blood count and blood lm examination
coagulation screen
prothrombin time (PT)
activated partial thromboplastin time (APTT)
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 deciency
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 deciency and warfarin therapy
Vitamin K is essential for the function of coagulation factors II,
VII, IX and X, and anticoagulants proteins C and S. Deciency
occurs as a result of malabsorption or (rarely) dietary deciency
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.
If the INR is high with no
bleeding, warfarin should be stopped and recommenced when
the 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.
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.
Fresh frozen plasma
(FFP) is no longer recommended for the reversal of warfarin.
PCC is associated with potential for thrombosis and so is
Whats new?
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 efcacy, and because it has
better viral inactivation
Increasing repertoire of anti-platelet agents for cardiac disease
means acquired disorders of platelet function are increasingly
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.
MEDICINE 41:4 228 2013 Elsevier Ltd. All rights reserved.
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.
Liver disease
Abnormal haemostasis in liver disease is usually multifactorial
(Table 1) and not all patients have associated bleeding.
management of bleeding in patients with liver disease depends
on its site and severity. Vitamin K 10 mg orally (or intravenously)
for 3 days may help patients who have associated vitamin K
deciency. 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 10
/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,
brinogen replacement with cryoprecipitate (or off-licence use of
brinogen concentrate) may be required in those patients with
low brinogen concentration.
Disseminated intravascular coagulation
Disseminated intravascular coagulation (DIC) is due to inappro-
priate and excessive activation of the haemostatic system.
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.
Activation of coagulation leads to micro-
thrombus formation with subsequent consumption of clotting
factors and increased breakdown of brin. The clotting factors
become depleted, platelets are consumed and brin deposition in
the 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 brinogen. 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 MEDICINE 2013; 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 A2
production 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.
excessive bleeding, platelet transfusions may be required.
Myeloproliferative disorders e may be associated with
abnormal platelet function, which can result in thrombosis
or haemorrhage.
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. EhlerseDanlos
syndrome), characterized by hyperextensible joints and elastic
skin. Acquired disorders include corticosteroid-induced purpura,
HenocheSch onlein purpura and scurvy, which leads to an
acquired collagen abnormality. A
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
Vitamin K deciency from
Defective synthesis of
clotting factors
Thrombocytopenia due to
portal hypertension,
hypersplenism and
reduced thrombopoietin
Abnormal brinolysis and/
or intravascular
Prolonged prothrombin time (PT):
due to vitamin K deciency
leading to reduced synthesis of
factors II, VII, IX and X
Prolonged activated partial
thromboplastin time and PT:
due to reduced synthesis of all
clotting factors
Low platelet count
Reduced brinogen due to
disseminated intravascular
Prolonged thrombin time
due to dysbrinogenaemia
Reduced protein C and S levels
Table 1
MEDICINE 41:4 229 2013 Elsevier Ltd. All rights reserved.
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