Download Bleeding disorders in critical care patients

Bleeding and thrombosis
INTRODUCTION
Bleeding may often complicate the care of critically ill patients. Excessive haemorrhage after surgery
or trauma is the commonest bleeding disorder in Intensive Care Units (ICU) patients. It would be
unusual for patients to present to the ICU with a primary diagnosis of clotting dysfunction; in most
instances, bleeding is a secondary problem leading to further instability in an already critically ill
patient. The extent of the clotting dysfunction may vary with time and it is important for the critical care
clinician to anticipate these changes with ongoing treatment of the primary disorder.
Many of our critically ill patients are inherently at risk of thrombotic events, which may lead to referral
to the ICU or arise in patients already in the unit. A simplistic view of coagulation and thrombosis would
focus only on excessive bleeding and major thrombotic events. With advances in our understanding of
the complexity of blood coagulation and its control mechanisms, we may develop new strategies and
therapies to actively manage critically ill patients who present with disordered bleeding or thrombosis.
Listed below are references which comprehensively cover many of the coagulation abnormalities that
are encountered in critically ill patients.
You will find an electronic version of the Hirsh article on the following website [Education/ACCP
Evidence-based Guidelines/Current ACCP Guidelines]
The tasks in this module emphasise a practical approach to bleeding and thrombotic disorders as they
present to the critical care clinician.
1/ BLEEDING DISORDERS IN CRITICAL CARE PATIENTS
Critically ill patients who present with excessive bleeding should have comprehensive resuscitation
measures instituted immediately. There should also be concurrent efforts to identify the source of the
bleeding and to distinguish discrete, anatomically localised bleeding from more diffuse bleeding.
Patients with localised anatomical bleeding
Initial assessment
The assessment of an ICU patient with localised bleeding includes a review of relevant recent history,
the findings on physical examination and a review of coagulation tests and imaging studies where
appropriate.
Bleeding may be immediately obvious presenting with visible blood loss and haemorrhagic shock.
Lower volume blood loss may occasionally present in a dramatic fashion if the bleeding occurs in a
confined space (e.g. brain, spinal cord, or pericardial sac) leading to specific loss of function.
Resuscitation efforts include attention to the circulation and to the adequacy of the airway and
ventilation. See the PACT module on Airway management
.
In patients with large volume gastrointestinal (GI) or pulmonary haemorrhage, securing a clear airway
and establishing adequate assisted ventilation may be required while completing the initial
assessment. Large bore peripheral or central intravenous (i.v.) cannulae are placed and intravenous
volume therapy is instituted urgently in patients with shock to achieve an acceptable perfusion
pressure. Rapid and repeated clinical examination to quantify the rate of ongoing blood loss is
essential. The haemodynamic response to i.v. volume therapy, changes in vasopressor requirement
and serial measurements of haemoglobin, lactate and base excess give a more reliable indication of
the severity of haemorrhagic shock. All of these assessments must be incorporated seamlessly into
the global care of the critically ill patient. For more information see the PACT module on
Hypotension
.
C OMMUNIC ATI ON
Blood is sent for cross matching and the Transfusion Laboratory is
informed of the potential for ongoing urgent requests for blood products.
An appropriate number of units of cross-matched red blood cells should be
ordered and made available to the ICU as soon as possible.
Laboratory studies
In addition to blood for group and cross match, initial laboratory studies such as full blood count,
coagulation screen and blood chemistries should be undertaken. Near-patient testing including arterial
blood gas analysis, lactate concentration, base excess, and whole blood clotting tests should be
readily available.
Postoperative bleeding
C OMMUNIC ATI ON
In assessing postoperative bleeding, the clinician needs to be fully aware of
the extent of the surgical procedure, the intra-operative care provided, and
the background medical problems including any recent medication the
patient has taken. Early direct discussion with your surgical and
anaesthesia colleagues is required in understanding the intra-operative
difficulties encountered.
Bedside examination should include an immediate assessment of surgical drain output and a search
for evidence of more covert bleeding. The abdomen may be tense and distended and there may be an
associated decrease in chest wall and lung compliance. With an increase in intra-abdominal pressure,
central venous pressure (CVP) monitoring becomes less helpful in identifying patients who are
bleeding excessively.
If the measured rate of blood loss remains excessive or the patient becomes increasingly unstable,
prompt surgical re-exploration should be considered.
N OTE
Senior surgical colleagues should be involved in the re-exploration.
rauma-related bleeding
You may be asked to assist in the initial resuscitation and
management of trauma patients with excessive bleeding. Massive
transfusion is defined as the replacement of one or more blood
volumes in a 24-hour period. Most patients requiring massive
transfusion have a combination of vascular injury and coagulopathy.
Most patients requiring
massive transfusion have a
combination of vascular injury
and coagulopathy
If the patient is in a satisfactory haemodynamic state, or the major site of bleeding is not clearly known,
the physical examination should be supplemented with appropriate diagnostic imaging or endoscopic
examination. Abdominal ultrasound examination or computerised tomography (CT) examination of the
thorax or abdomen can identify the presence of bleeding and any other associated injuries.
See the following references and the PACT modules on Transportation
further information.
Treatment of patients with localised anatomical bleeding
and Multiple trauma
for
For patients with discrete localised bleeding, initial treatment efforts should be primarily directed towards
physically limiting further blood loss by surgical exploration, angiographic embolisation, or endoscopic
therapy.
With regard to trauma-related bleeding, the time interval between injury and urgent surgery for excessive
bleeding should be kept to a minimum.
C OMMUNIC ATI ON
T HINK
How is the management of patients with excessive bleeding organised? Is there a team
approach? Think of improvements.
If the patient becomes haemodynamically unstable in the emergency department or the CT room in spite of
active resuscitation measures, immediate transfer to an operating room should be considered. Patients with
penetrating injuries are more likely to require urgent surgery for control of bleeding.
Physical means to limit further blood loss
Surgical exploration has the potential to clearly identify the source of bleeding and apply immediate
definitive therapy even in very unstable patients. Exclusion of other potential sources of bleeding and
evacuation of any associated haematoma may also be achieved.
A staged damage control approach is worth emphasising. Brief initial surgery primarily focused on control
of bleeding and decontamination (e.g. pelvic ring stabilisation, arterial clamping, abdominal packing) is
followed by a period of rewarming, correction of acid-base abnormalities and coagulopathy in the ICU.
Hyperventilation and high intra-thoracic pressures should be avoided in these hypovolaemic patients. If
there is continued instability despite the above measures, consideration should be given to urgent
angiographic embolisation to reduce the rate of blood loss. Finally, when the patient is in a more stable state,
definitive surgical repair can be undertaken.
In patients with less severe bleeding, angiographic embolisation can limit further blood loss. Some vascular
beds have sufficient collateral supply and can be embolised empirically, such as uterine artery embolisation
after postpartum haemorrhage. Endoscopic therapies have an established place in the treatment of GI
bleeding.
Volume and timing of resuscitation fluids
Crystalloid solutions are used universally as the initial resuscitation fluid in patients with shock. However,
once the initial hypotension has been corrected, the volume and rate of infusion of resuscitation fluids
should be carefully controlled while maximal efforts are undertaken to physically reduce the rate of blood
loss. During this time, the intravascular filling pressures should be maintained as low as is compatible with
acceptable tissue perfusion.
T HINK
Which i.v. fluids should you use for resuscitation in a bleeding trauma patient and what are
acceptable blood pressure goals.
In patients with an already compromised coagulation, resuscitation with large volumes of colloid solutions
may have an anti-haemostatic effect.
Hypothermia and acidosis
Explain how hypothermia influences coagulation.
The coagulation system operates most efficiently at normal body temperature and pH.
Hypothermia (below 34 °C) reduces coagulation factor enzymatic activity. It prolongs the prothrombin
time (PT) and activated partial thromboplastin time (APTT), impairs platelet function and activates
fibrinolysis.
Acidosis reduces the activity of tissue factor-FVIIa complex and FXa/FVa complex. Acidosis inhibits
thrombin generation and reduces fibrinogen concentration and platelet count.
In all ICU patients with haemorrhagic shock, core temperature and acid-base status should be measured
regularly. Active measures to minimise the decrease in core body temperature should be instituted
immediately. Targeted resuscitation measures should restrict the development of both acidosis and
hypothermia.
Blood component replacement therapy
Transfusion of blood products should be guided by repeated clinical assessment and laboratory monitoring.
What are the general complications of blood product transfusion?
Red blood cell transfusion
Patients who are exsanguinating should be resuscitated with crystalloid solution and red blood cell
transfusion. (In an emergency this may be O negative blood). Note that red cell transfusion does not replace
coagulation factors or platelets. A restrictive transfusion policy (haemoglobin 7-9 g/dl) is safe in most
patients but patients with myocardial ischaemia, traumatic brain injury or septic shock are often transfused
to a Hb of 10 g/dl.
Explain how patients can develop hypocalcaemia after red blood cell transfusion.
In addition to oxygen carriage, there is some evidence that red cells support thrombin generation.
Platelet transfusion
The following are general guidelines for platelet transfusion in the setting of active bleeding:
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T HINK
Platelet count <50 x 10 9/l
Platelet count <75 x 10 9/l when additional risk factors are present (DIC or hyperfibrinolysis,
sepsis, concurrent anti-platelet medication, uraemia)
Platelet count <100 x 10 9/l in patients with severe brain injuries and massive haemorrhage.
What are the guidelines for platelet transfusion in your ICU?
Fresh frozen plasma
Fresh frozen plasma (FFP) or solvent/detergent-treated human plasma is indicated for the treatment of
significant bleeding accompanied by a PT or APTT more than 1.5 times control. The traditional dose of 1015 ml per kg body weight may have to be exceeded in massive bleeding. Due to the short half-life of FVII,
repeat FFP transfusion every 6-8 hours may be required. Other indications for transfusing FFP are limited:
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DIC with bleeding
Warfarin reversal
Invasive procedure in patient with prolonged PT
Factor V deficiency
Thrombotic thrombocytopenic purpura (plasma exchange).
What are the essential components of FFP?
Cryoprecipitate (or equivalent)
Cryoprecipitate is used for the treatment of significant bleeding associated with acquired or congenital
hypofibrinogenaemia (fibrinogen concentration <1 g/l). Although fibrinogen levels increase after
cryoprecipitate, there are no randomised trials to demonstrate improved clinical outcome.
Other than the recommendations above, there are no universally accepted triggers for transfusion of
platelets, FFP, cryoprecipitate or fibrinogen concentrates, but local guidelines from your haematology
service should be consulted. The timing of platelet and coagulation factor administration should be carefully
considered. It may be prudent to delay transfusion of these products until an initial high rate of loss has been
controlled by the physical means outlined above.
Recombinant factor VIIa
Recombinant activated factor VII (rFVIIa) has been licensed for use in haemophilia patients who have
developed inhibitor antibodies to administered factor VIII. There are now many case reports of the use of
rFVIIa in patients with complex multifactorial haemorrhage and in Jehovah's Witness patients but few
randomised controlled trials.
Administration of rFVIIa should only be considered in consultation with the haematology
service and after concerted efforts to achieve optimal surgical haemostasis, normothermia
with minimal acidosis and best practice use of platelets and coagulation factors.
Both arterial and venous thrombotic events have been reported after rFVIIa therapy. Confirmatory trials,
particularly with regard to survival benefit and thrombotic risk, are awaited before there should be more
widespread use of this agent.
Pharmacological agents
Aprotinin is a serine protease inhibitor which directly inhibits plasmin as well as other serine proteases.
Tranexamic acid and epsilon aminocaproic acid are synthetic lysine analogs which also decrease
fibrinolysis. These agents have been reported to decrease bleeding after cardiac surgery. However,
recent studies have suggested an increased risk of stroke, myocardial infarction and renal failure
following aprotinin. At present, despite a large number of trials, guidelines for the use of anti-fibrinolytic
agents remain unclear.
Desmopressin (DDAVP) increases vascular endothelial release of von Willebrand factor (vWF) and
FVIII. There is conflicting evidence for the efficacy of desmopressin in reducing peri-operative bleeding
and the risk of thrombotic events after administration.
Patients with diffuse bleeding
In contrast to anatomically localised bleeding, there are multiple interacting causes (impaired platelet
or coagulation factor function or accelerated clot dissolution) for diffuse bleeding in critically ill patients
and the relative importance of these factors may change over time. Deficient haemostasis leading to
generalised oozing is usually associated with a primary underlying pathologic process. A systematic
approach is essential to correctly identify the major underlying problems and plan effective treatment.
The critical care clinician should enlist the assistance of the haematology service as early as possible if
the bleeding continues to be problematic.
Clinical assessment
It is important to note a history of diffuse bleeding that has required ongoing treatments in the past.
Oozing from venipuncture sites, petechiae or easy bruising is suggestive of a platelet disorder.
Bleeding due to a coagulation factor disorder may have a more covert or delayed presentation, such
as intramuscular or retroperitoneal haematoma and haemarthroses.
What haematology laboratory data would support the diagnosis of disseminated intravascular
coagulopathy?
Diffuse bleeding in ICU patients
Disseminated intravascular coagulopathy
Disseminated intravascular coagulopathy (DIC) is characterised by widespread activation of
coagulation and fibrinolysis. It is always secondary to an underlying pathophysiologic state. DIC may
contribute to the pathogenesis of multi-organ failure and the presence of DIC is an independent
predictor of mortality.
Name the clinical conditions associated with DIC.
Pathophysiology of DIC
DIC is triggered by excessive amounts of pro-coagulant material (e.g. tissue factor) in the vasculature,
usually from endothelial cell injury. In sepsis, the most common cause of DIC in critically ill patients,
platelet-endothelial cell interaction leads to widespread thrombin generation, with coagulation factor
and platelet consumption. The fibrinolytic system is also activated leading to high concentrations of
FDPs and D-dimer.
Shock, acidosis and hypoxia contribute to further endothelial injury and the low flow state reduces the
clearance of activated coagulation factors.
Clinical features of DIC
The major clinical sign of acute DIC is diffuse bleeding from mucosal surfaces or surgical and
venipuncture sites. A chronic compensated DIC state associated with thrombotic injuries in highly
perfused organs (kidney, brain, lung) is less commonly seen in ICU patients.
T HINK
What are the common causes of DIC? Is the DIC seen in sepsis the same as the DIC seen after
massive transfusion?
A NECDOTE
After massive transfusion, a critically ill trauma patient develops diffuse bleeding from
venipuncture sites and nasal mucosa. There is severe thrombocytopenia, prolongation of the
PT and APTT, and decreased fibrinogen concentrations. Fibrin degradation products are
increased and the D-dimer test is positive. Despite ongoing resuscitation, the patient develops
acute renal failure. No localised source of bleeding is identified. The patient has acute
haemorrhagic DIC.
Diagnosis of DIC
There is no consensus regarding which common laboratory tests are best for the diagnosis of DIC.
The diagnosis is suggested by the onset of diffuse bleeding in a patient with an underlying primary
pathologic state (e.g. sepsis, massive transfusion, polytrauma), a low or rapidly declining platelet
count, prolonged PT, elevated FDPs or D-dimer, and hypofibrinogenaemia. A simple scoring system
for DIC based on the above widely available laboratory tests has been recently validated in critically ill
patients (see table
). A score of 5 or greater is compatible with the diagnosis of DIC.
In the next five patients in your ICU with severe bleeding or sepsis, use the above DIC
scoring system. Discuss its usefulness with your colleagues or supervisor.
Treatment of DIC
Treatment of critically ill patients with acute DIC should be focused initially on comprehensive therapy
for the underlying primary disease process. Resuscitation and supportive therapies to correct hypoxia,
hypovolaemia and acidosis should be instituted immediately. Transfusion of blood products (red blood
cells, platelets and coagulation factors) should be considered in the presence of excessive bleeding.
An acquired protein C deficiency is thought to contribute to a pro-thrombotic tendency in septic
patients with DIC. Patients with sepsis and a high DIC score may benefit from the administration of
recombinant activated protein C (r-APC). Recombinant APC has anti-inflammatory and antithrombotic
and fibrinolytic properties but may be complicated by severe bleeding.
N OTE
The most frequent and serious side effect of r-APC is bleeding.
Diffuse bleeding in liver failure and vitamin K deficiency
Patients with severe hepatic parenchymal damage have a complex disorder of haemostasis as
indicated by a prolonged PT, dysfibrinogenaemia and thrombocytopenia. Despite these abnormalities,
bleeding is uncommon without a precipitating factor such as surgery, liver biopsy or variceal rupture.
What function does vitamin K have in the coagulation cascade?
Because factor VII has the shortest half-life of the vitamin K dependent factors, prolongation of the PT
is the most sensitive early indicator of vitamin K deficiency.
N OTE
Serial PT measurements are used as a global monitor of hepatic synthetic function.
Thrombocytopenia in patients with liver failure may be due to bleeding and the subsequent
resuscitation, a consumptive process (DIC) or splenic sequestration. Vitamin K deficiency may appear
within 48 hours following the onset of acute illness. In patients with liver failure, any cause of vitamin K
deficiency will further reduce hepatic coagulation protein production.
Name three causes of reduced vitamin K absorption from the gut.
It is important to anticipate vitamin K deficiency and prevent it by appropriate
supplementation. It will not make the patient hypercoagulable.
In stable hepatic failure patients without active bleeding, prolonged coagulation tests or
thrombocytopenia do not require specific transfusion therapy. Addition of recombinant factor VIIa to
standard therapy for upper GI bleeding in cirrhotic patients does not improve outcome.
Drug-induced diffuse bleeding
In critically ill patients, the connection between diffuse bleeding and a specific medication is often
difficult to make due to the multiple ongoing pathologic processes and the multiple therapeutic agents
used. After exclusion of other causes of diffuse bleeding, the diagnosis is suggested by a temporal
relationship between starting a medication and the onset of diffuse bleeding and the improvement in
bleeding or platelet count on discontinuation of a specific medication.
Drug-induced thrombocytopenia after chemotherapy or immune-mediated mechanisms (heparininduced thrombocytopenia) are well recognised in critically ill patients. Many commonly used drugs
(cephalosporins, trimethoprim-sulfamethoxazole, linezolid, digoxin, non-steroidal anti-inflammatory
agents) are associated with thrombocytopenia that may contribute to diffuse bleeding in ICU patients.
In addition, many anticoagulant or anti-platelet drugs are used therapeutically in critically ill patients
(see table, below).
Anticoagulation and antiplatelet medication
Further details of these agents are available
Treatment of drug-induced diffuse bleeding
In patients with significant drug-induced bleeding, in addition to immediately withholding the drug,
coagulation factor and platelet transfusions can decrease the rate of blood loss.
One of the proposed advantages of therapeutic anticoagulation with unfractionated heparin in critically
ill patients is that protamine can be used to rapidly reverse the anticoagulant effect.
Active bleeding in a patient taking warfarin is treated by withholding further doses of warfarin and
administration of vitamin K or FFP. Vitamin K (2-4 mg) may be given orally for non-urgent reversal of
an inappropriately high INR prior to elective surgery. Intravenous administration of vitamin K (5-10 mg)
restores hepatic vitamin K levels within 4-6 hrs. High doses of vitamin K will make subsequent reintroduction of warfarin therapy more difficult.
N OTE
For urgent reversal of warfarin in life-threatening haemorrhage, FFP (15 ml/kg) should
be used, or alternatively Prothrombin Complex Concentrate (50 units per kg) may be
considered.
A patient is admitted to the ICU with a massive upper gastrointestinal bleed. She is maintained
on warfarin for atrial fibrillation. Her INR is 8.0. What are the management priorities and what
measures will correct her coagulopathy?
In the next ten patients with a bleeding disorder, analyse cause(s) and how it is treated.
What complications do you see?
2/ THROMBOTIC DISORDERS IN CRITICAL CARE PATIENTS
Under normal circumstances, haemostatic mechanisms remain dormant but when activated, a balance
is achieved between clot formation and prevention of clot propagation beyond the site of injury. This
complex and dynamic equilibrium can be influenced by multiple factors.
Thrombosis occurs when there is decreased blood flow, damage to vascular endothelium, a
hypercoagulable state (Virchowâs triad) or a combination of these factors. The consequences of
thrombotic occlusion are decreased tissue perfusion distal to an arterial occlusion (e.g. myocardial
infarction) or decreased drainage of blood proximal to a venous thrombosis (e.g. deep venous
thrombosis).
Embolisation occurs when part of a thrombus breaks off and travels distally, leading to strokes, limb or
mesenteric ischaemia in the case of arterial thrombosis or pulmonary embolism (PE) in the case of
venous thrombosis.
Venous thromboembolism
Venous thromboembolism (VTE) is a spectrum of disorders ranging from deep venous thrombosis to
pulmonary embolism. Pulmonary emboli often present abruptly and are associated with substantial
morbidity and mortality. Among patients who die in ICUs, PE is identified in up to 27% of post-mortem
examinations.
The incidence of DVT and fatal PE has been shown to be reduced by thromboprophylaxis, so it is
imperative that prophylaxis is reviewed daily for all high-risk ICU patients.
Even when appropriate thromboprophylaxis has been administered, DVT and PE may still occur.
What are the common risk factors for a thrombotic event?
In the next ten patients, check for risk factors for thrombosis. How many do
have a combination of risk factors? What is done to prevent a thrombotic event?
It is important to recognise that many pro-thrombotic factors are inherently present in critically ill
patients. If there is also a past or family history of thrombosis, there is a substantially increased risk of
further thromboembolic events while the patient remains critically ill.
The most common inherited pro-thrombotic disorder is Factor V Leidin, which is due to a single base
mutation. The abnormal FV produced is more resistant to degradation by activated protein C leading to
an increased risk of VTE events. Less common inherited disorders include Protein C deficiency,
Protein S deficiency and antithrombin deficiency. The extent to which these and other mutations
interact with clinical factors known to predispose to VTE is not clear.
T HINK
Keep the common congenital and acquired causes of thrombophilia in mind when
taking a history.
Acquired thrombophilic states may be associated with the use of specific medication (pro-haemostatic
or anti-fibrinolytic therapy, heparin-induced thrombocytopenia).
T HINK
Which drugs may cause a thrombophilic state?
Myeloproliferative disorders (polycythaemia rubra vera, primary thrombocythaemia), antiphospholipid
syndrome and homocysteinuria may also be associated with an increased risk of thrombosis.
Combined pharmacologic and mechanical prophylaxis
Combined
pharmaco
and
mechanica
prophylax
3/ NORMAL HAEMOSTASIS AND LABORATORY INVESTIGATION OF BLEEDING
Normal haemostasis
Blood coagulation (haemostasis) is a host defence mechanism that minimises blood loss after vascular
endothelial injury. Complex interactions take place between the vascular endothelium, platelets and
coagulation proteins to produce a platelet plug at the site of vessel injury, which is subsequently
reinforced by fibrin mesh. Strict local control mechanisms avoid unnecessary propagation of the clot
beyond the site of injury.
The cell-based model of
coagulation Adapted from
Hoffman M, Munroe DM.
A cell-based model of
hemostasis.
Thromb Haemost 2001;
85: 958-965.
PMID 11434702
Platelet plug formation
After vessel injury, the primary haemostatic response is the formation of a platelet plug to close the
defect in the vessel wall. Platelet activation occurs after exposure to subendothelial epinephrine, ADP,
TxA2 and thrombin. Activated platelets are anchored at the site of injury by binding with von Willebrand
factor in the subendothelial matrix (GPIb receptors).
Fibrinogen bridges are formed between adjacent activated platelets (GPIIb/IIIa receptors) leading to
platelet aggregation.
After aggregation, platelets release a variety of mediators, which lead to further platelet aggregation
and vasoconstriction.
Activated platelets expose important phospholipids on their surface, which facilitate the assembly of
appropriate coagulation proteins and the subsequent formation of a fibrin clot.
For more information, see the following reference.
Formation of fibrin mesh
Rather than a sequential step-like process, it is now appreciated that fibrin formation involves the
clustering together of specific coagulation factors in close proximity on phospholipid surfaces, leading
to an exponential increase in their enzymatic activity and the local production of fibrin on the surface of
the initial platelet plug.
In relation to the commonly used coagulation tests, the ‘classical’ model showing intrinsic, extrinsic and
common coagulation pathways is shown in the diagram on the next screen.
The ‘classical’ model
Control mechanisms to prevent clot propagation
Once the clot has been formed, several control processes act to prevent propagation of the clot beyond the
site of injury. Prostacycline and nitric oxide produced by uninjured vascular endothelium adjacent to the site
of injury inhibit platelet activation. Procoagulants are carried away to be metabolised, and endothelial-bound
inhibitors (including antithrombin and others) inhibit factors FVa, FVIIIa, FXa and FVIIa/TF as well as
thrombin.
Fibrinolysis
The role of the fibrinolytic system is to ensure that the formation of the fibrin clot is localised to the site
of vessel injury. Fibrinolytic (plasminogen and tPA) and anti-fibrinolytic (thrombin activatable fibrinolytic
inhibitor) proteins are simultaneously bound to fibrin in the clot as it is being assembled. In addition,
alpha-2-antiplasmin and plasminogen activator inhibitor (PAI-1) inhibit non-fibrin-bound plasmin and
tPA. This is shown in the diagram on the next screen.
PA = Plasminogen activator,
tissue (t) and urinary (U)
PAI = PA inhibitor
TAFI = Thrombin activatable
fibrinolysis inhibitor
Laboratory assessment of bleeding
Platelet count
Many factors contribute to a low platelet count such as surgical bleeding, dilution following
resuscitation or consumption as part of DIC.
Give five causes of low platelet count.
An elevated platelet count (>500 x 109/l) may be reactive (infections, after surgery, especially
splenectomy) or associated with chronic myeloproliferative or myelodysplastic disorders.
Coagulation tests
Prothrombin time and INR
The prothrombin time (PT) is used to test the activity of coagulation factors in the extrinsic (tissue
factor, FVII) and common pathway (FX, FV, prothrombin and fibrinogen). To take account of local
differences in tissue factor (TF) preparations used in the PT test, the results are often expressed as an
international normalised ratio (INR). The INR is the ratio of the patient PT compared to normal control
raised to the power of the International Sensitivity Index. A specific index is assigned to each batch of
locally produced TF which compares its performance to an international standard.
Causes of a prolonged PT (or INR)
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Warfarin therapy
Vitamin K deficiency
Severe liver failure
Deficiencies of extrinsic pathway factors (TF, FVII)
Deficiencies of common pathway factors (FX, FV, prothrombin and fibrinogen)
Antiphospholipid antibodies with anti-prothrombin activity.
Explain how warfarin therapy can cause a prolonged PT .
Activated partial thromboplastin time
Phospholipid and negatively charged particulate matter (silica, celite, kaolin) are added to plasma to
generate a fibrin clot. Abnormalities in the intrinsic (prekallikrein, high molecular weight kininogen, FXII,
FXI, FIX, FVIII) and common (FX, FV, prothrombin and fibrinogen) pathways will result in prolongation
of the activated partial thromboplastin time (APTT).
Causes of prolonged APTT
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Heparin therapy (or heparin contamination of sample)
Haemophilia A (deficiency of FVIII)
Haemophilia B (deficiency of FIX)
Haemophilia C (deficiency of FXI)
Antiphospholipid syndrome ('lupus anticoagulant')
von Willebrand disease (severe).
Fibrinogen concentration
In patients with diffuse bleeding, both the PT and APTT are likely to be prolonged when fibrinogen
concentration is decreased.
Thrombin time
The thrombin time (TT) measures the rate of conversion of fibrinogen to polymerised fibrin after the
addition of thrombin to plasma.
Causes of prolonged TT
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Heparin therapy (or heparin contamination of sample)
Thrombin inhibitors (hirudin, argatroban, danaparoid)
Hypofibrinogen and dysfibrinogenaemia
Fibrinogen degradation products (FDPs) and D-dimers
High concentrations of serum proteins which interfere with fibrin polymerisation (e.g.
multiple myeloma, amyloidosis).
Complete a table showing the three tests (TT, PT, APTT) and list the abnormalities indicated by
prolongation together with a list of the common causes of that abnormality.
FDPs and D-dimer
Elevated FDPs are indicative of lysis of fibrinogen and non-cross-linked fibrin, whereas increased Ddimers indicate lysis of already cross-linked fibrin. High concentrations of FDPs have an anticoagulant
effect by inhibiting fibrin polymerisation and platelet function.
Patterns of abnormal coagulation test results
The primary utility of prolonged coagulation tests (PT, APTT, or TT) is to indicate coagulation factor
deficiency or the presence of inhibitors.
Patients with a prolonged PT but a normal APTT have a problem in the extrinsic system (FVII). The
common causes of this include warfarin therapy, chronic liver failure, and vitamin K deficiency.
Patients with a normal PT but prolonged APTT have a problem confined to the intrinsic pathway.
The common causes of this include heparin therapy or contamination, antiphospholipid antibodies,
Haemophilia A and von Willebrand disease.
If the PT and APTT are both prolonged, the problem is likely to be an inherited defect in the final
common pathway or a more complex acquired disorder of multiple pathways.
If both the PT and APTT are normal and the patient has diffuse clinical bleeding, the causes include
thrombocytopenia, platelet dysfunction, or von Willebrand disease.
C OMMUNIC ATI ON
Consult the haematology service for bleeding in patients with persistent
prolongation of coagulation times.
Whole blood clotting tests
Activated clotting time
The activated clotting time (ACT) is used to monitor the anticoagulant effect of higher doses of heparin that
are sufficient to infinitely prolong the APTT.
Thrombelastography / Rotation Thrombelastometry
The end point of the coagulation tests mentioned above is the detection of fibrin formation.
Thrombelastography (TEG®) / Rotation Thrombelastometry (ROTEM®) monitor the viscoelastic
properties of both clot formation and fibrinolysis. Further information on the specific details and
methods of working of these machines can be obtained from the manufacturers' websites.
4/ SPECIAL CONSIDERATIONS IN CRITICAL CARE PATIENTS
Anticoagulation and anti-platelet medication
Coagulation factor inhibitors
Heparin
Unfractionated heparin (mixture of 3000-30 000 Da highly sulfated glycosoaminoglycan fragments) is
used therapeutically in a wide variety of thrombotic conditions. Heparin has also been used
prophylactically to prevent venous thromboembolism and in flush solutions for intravascular catheters.
Heparin is associated with a 1000-fold increase in endogenous antithrombin (AT) activity leading to
inactivation of thrombin, FXa, FIXa and many other factors in the coagulation and fibrinolytic pathway.
Heparin has no anticoagulant effect in the absence of AT. Low dose heparin is monitored by the APTT,
whereas higher doses of heparin are monitored using the activated clotting time (ACT).
Low molecular weight heparin
Low molecular weight heparins (LMWH) are purified from unfractionated heparin to a mean molecular
weight of 5000 Da. LMWHs have a longer half-life than unfractionated heparin and are primarily used
for thromboembolic prophylaxis although higher doses can be used therapeutically. Empiric dosing is
used both prophylactically and therapeutically, although anti-Xa/heparin assay may be used to monitor
therapy.
Fondaparinux
Fondaparinux is a synthetic analog of the antithrombin-binding pentasaccharide sequence found in
heparin and low molecular weight heparin. It produces its anticoagulant effect by binding to AT and
enhancing AT’s inhibition of FXa. It has no direct activity against thrombin. Fondaparinux is
administered subcutaneously once daily. This agent has been shown to be as effective as LMWH in
the treatment of deep venous thrombosis (DVT) and as effective as unfractionated heparin in the
treatment of PE.
Warfarin
During the hepatic production of prothrombin, FVII, FIX, FX, Protein C and Protein S, vitamin K is
oxidised to an inactive form (vitamin K epoxide). Warfarin antagonises the regeneration of the active
form of vitamin K leading to the production of haemostatically defective coagulation proteins. Warfarin
therapy is monitored by changes in the PT or INR.
Platelet inhibitors
Cyclo-oxygenase inhibitors
Aspirin irreversibly inhibits platelet cyclo-oxygenase, an enzyme necessary for the synthesis of
thromboxane A2 (TxA2). Although aspirin is used widely, it is a relatively weak antiplatelet agent and
resistance may occur in up to 30% of patients.
Non-steroidal anti-inflammatory drugs (NSAIDs) reversibly inhibit the same cyclo-oxygenase enzyme
and platelet function returns to normal 24 hours after the last dose.
Platelet ADP and GP IIb/IIIa receptor antagonists
Clopidogrel irreversibly inhibits the adenosine diphosphate-(ADP) dependent pathway of platelet
glycoprotein (GP) IIb/IIIa receptor activation. Dual therapy with aspirin and clopidogrel is commonly
used after percutaneous coronary intervention. Platelet GP IIb/IIIa receptor antagonists (abciximab,
tirofiban, eptifibatide) are potent platelet inhibitors but used less frequently than clopidogrel in acute
coronary syndromes and after coronary artery angioplasty. Patients on these medications are at
increased risk of excessive bleeding after trauma or emergency surgery.
Post-cardiac surgery bleeding and thrombosis
Postoperative bleeding can be severe in patients after complex cardiac surgery. Up to 5% of cardiac
surgery patients require an urgent re-exploration for excessive bleeding with or without tamponade.
Aortic valve surgery patients have a higher risk of postoperative bleeding than coronary revascularisation patients. Surgical re-exploration should be considered in patients with brisk bleeding as
evidenced by high mediastinal drain output (e.g. >400 mls/hr), arterial hypotension, increasing
vasopressor requirements or signs of tamponade. Most re-explorations are carried out within the first
24 hours after surgery, usually within 5-6 hours of ICU admission.
There are many factors contributing to excessive post-cardiac surgery bleeding, including preoperative
platelet and coagulation factor abnormalities, surgical bleeding, use of intra-operative anticoagulation,
and the presence of DIC.
A TEG®-based algorithm has been reported to reduce the number of patients who require platelet or
coagulation factor transfusion compared to a similar group of patients managed with more
conventional tests and protocols.
Warfarin therapy is started after heart valve surgery once the risk of perioperative bleeding has
decreased and any risk-associated procedures (e.g. removal of epicardial pacemaker wires) have
been completed. If warfarin is discontinued for any reason, there is a risk of thrombosis of mechanical
heart valves. Because of the lower velocity of blood flow, the risk of thrombosis is greater for mitral
valve prosthesis compared to aortic valve prosthesis. The risk of valve thrombosis is also increased in
patients with the older ball and cage type prosthesis, particularly if they develop atrial fibrillation.
A patient has been admitted to the ICU following abdominal aortic aneurysm surgery. She is
maintained chronically on warfarin for a mechanical heart valve. How do you manage her
anticoagulation? When is it safe to restart her warfarin?
A patient is admitted to the ICU following an aortic root replacement. He is bleeding briskly from
his thoracostomy and mediastinal tubes. At what point should surgical re-exploration be
considered? What laboratory studies would be helpful and what blood products would you order for
the patient?
Anticoagulation for extracorporeal circuits
Diversion of blood into an extracorporeal circuit either intermittently or continuously is increasingly
used in critically ill patients. Renal replacement therapy, plasmapheresis, hepatic failure support and a
range of cardiovascular and respiratory (ventricular assist devices, extracorporeal membrane
oxygenation) support devices require anticoagulation to prevent thrombosis in the extracorporeal
circuits. Heparin is the commonest anticoagulant in extracorporeal circuits. Bolus (loading) doses
and/or infusions of heparin have been used; the dose being adjusted by bedside measurement of the
ACT.
Fibrin strands may appear at first in parts of the circuit where flow is reduced or around the outside of
the intravascular portion of the dialysis catheters. The use of arterial catheters, the physical size of the
catheters and rate of blood flow through the circuit all influence the thrombotic risk and the dose of
anticoagulant required.
Most intermittent renal replacement programmes use a bolus of heparin at the start of dialysis and
repeat (top-up) as required throughout the treatment. Heparin infusions are used for continuous renal
replacement.
In patients with heparin-induced thrombocytopenia, all heparin including LMWH must be avoided in the
extracorporeal circuit. Anticoagulation options include citrate anticoagulation or direct thrombin
inhibitors (lepirudin: recombinant hirudin).
Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia (HIT) is a transient autoimmune pro-thrombotic disorder initiated
by heparin.
There are two types of HIT, type I (95% of all HIT cases) begins a few days after starting heparin and
is due to heparin binding to platelet membrane causing ADH release and platelet aggregation. HIT
type I is self-limiting and rarely requires stopping heparin.
HIT type II (5% of all HIT cases) usually begins 5-14 days after starting heparin, or sooner if the patient
was previously exposed to heparin.
The diagnosis of HIT is based on the detection of HIT antibodies in
conjunction with a falling platelet count in a patient receiving heparin
with or without evidence of thrombosis. The commonly used ELISA
testing has good negative predictive value but a low positive
predictive value. A more precise diagnosis may be made with the
14C-serotonin release assay but this test is not widely available.
Demonstration of platelet aggregation after addition of heparin and
normal platelets to the patient's plasma also supports the diagnosis.
An increase in platelet count 1-3 days after stopping heparin also
lends support to the diagnosis.
Enzyme-Linked
ImmunoSorbent Assay
HIT frequency depends on the type of heparin used as well as patient group.




N OTE
Unfractionated heparin is associated with a higher incidence of HIT than LMWH.
Surgical patients have a higher frequency of HIT than either medical or obstetric patients
with the same heparin exposure.
Postoperative orthopaedic patients receiving unfractionated heparin have the highest HIT
frequency (5%) and require more intensive platelet count monitoring.
Pregnant women receiving LMWH have an almost negligible risk of HIT.
The more unfractionated heparin used, the more likely patients are to develop
HIT.Although LMWHs are less likely to trigger the formation of HIT antibodies
than unfractionated heparin, there is a high degree of cross reactivity, so that
LMWHs should also be avoided in HIT.
About 30% of patients with HIT will develop venous and arterial thrombotic episodes, which mandates
immediate withdrawal of all heparin even from the intravascular catheter flush solution. Although these
patients have low platelet counts and occasionally may have excessive bleeding, platelet transfusion
can worsen intravascular thrombosis. An alternative anticoagulant should be administered even if
there is no thrombosis evident at that time. Direct thrombin inhibitors (lepirudin, argatroban) are
therapeutic alternatives to heparin. Other anticoagulant drugs used in HIT include the heparinoid,
danaparoid. Early introduction of warfarin therapy should be avoided as it has been associated with
skin necrosis. There is a 5-20% frequency of new thrombosis despite treatment of HIT patients with
direct thrombin inhibitors.
Skin ulceration has been described in renal failure patients who develop HIT. On
skin biopsy, extensive microthrombi within dermal blood vessels should prompt
a search for HIT and a prothrombotic state.
Explain how heparin can cause thrombocytopenia and thrombosis.
Invasive procedures in anticoagulated patients
N OTE
Invasive procedures are associated with an increased risk of bleeding or
haematoma formation in anticoagulated patients.
The timing of administration of anticoagulant medication and the transfusion of selected blood products
should be carefully considered in relation to urgent surgical or invasive procedures in critically ill
patients.
Placement and removal of intravascular devices
Placement of central venous catheters (CVCs) in anticoagulated patients is associated with increased
risk of bleeding. Use of ultrasound imaging devices may increase the incidence of satisfactory catheter
placement. It is common practice to treat thrombocytopenia with platelet transfusion prior to removal of
large bore intravascular devices including intra-aortic balloon pumps.
The guidelines outlined above
should also be considered in critically ill patients scheduled for
interventional radiology procedures or pericardial catheter placement or removal.
Lumbar puncture
Lumbar puncture (LP) is contraindicated in all fully anticoagulated patients because of the risk of
developing an expanding epidural haematoma with consequent cord compression.
In patients on low dose unfractionated heparin (5000 units bd SC), LP should be deferred for four
hours after the last dose. Low dose warfarin (INR <1.5) is a relative contraindication to LP and each
patient should be assessed individually with respect to risk / benefit.
LP should be deferred for 24 hours after the last preceding dose of therapeutic LMWH (full
anticoagulation) and for 12 hours after the last preceding dose of prophylactic LMWH.
Lumbar puncture should be deferred for at least 24 hours after thrombolytic drugs (streptokinase, tPA).
Prior to LP, the PT, APTT and fibrinogen concentration should be checked.
In all patients, anticoagulation should not be restarted until four hours after LP or removal of an
epidural catheter.
Jehovah' Witnesses
Most clinicians are aware that Jehovah's Witness patients may refuse to accept blood products even if
that is associated with greater morbidity and mortality. In 2000 and again in 2004, Jehovah's Witness
church elders reaffirmed that the four primary components of blood: red cells, white cells, platelets and
plasma should not be transfused. However, transfusion of fractionations of these primary components
may be acceptable to individual Jehovah's Witness patients. Potentially acceptable fractionations
include immunoglobulins, albumin and purified factor VIII and IX (haemophiliac preparations have
been available for use in individual Jehovah's Witness patients who will accept these products since
1978). In treating individual critically ill Jehovah's Witness patients, it is essential to identify which
fractions of the 'primary components' are acceptable and not to assume that they will refuse all blood
products. Many may consider using isolated protein fractions such as erythropoietin (normally
suspended in human serum albumin), prothrombin complex concentrates, cryoprecipitate,
haemoglobin substitutes and rFVIIa.
It is also worth considering blood salvage techniques that maintain the continuity of extracorporeal
blood with the patient's circulation.
For information on ethical considerations, see the PACT module on Ethics
reference.
and the following
Congenital bleeding disorders
Although uncommon, inherited coagulation disorders will occasionally be encountered in the
investigation of excessive bleeding in critically ill patients. Some patients will already be aware of their
condition, whereas very mild disorders may not be identified until abnormal bleeding is being
investigated. It is important to engage with the haematology service to ensure that these patients are
receiving appropriate therapy.
von Willebrand disease
Type I von Willebrand disease is the most common inherited bleeding disorder. von Willebrand factor
(vWF) binds platelets to subendothelial structures, so that the symptoms of von Willebrand disease are
very similar to that of platelet deficiency or dysfunction (mucosal bleeding, nose bleeds, menorrhagia).
The concentration of vWF and FVIII are lower than normal. Increased endogenous release of vWF
from vascular endothelium and platelets can occur during stress states and this often minimises
symptoms during minor trauma and surgery. The vasopressin analog desmopressin can also increase
endogenous vWF release.
Haemophilia
Haemophilia A (FVIII deficiency) and Haemophilia B (FIX deficiency) are X-linked disorders. Patients
with severe disease (FVIII levels <2%) will be diagnosed in childhood and will require regular
replacement therapy. Many adult patients with severe disease are currently undergoing joint
replacements as a result of recurrent episodes of haemarthroses.
Haemophilia C (FXI deficiency) is an autosomal recessive disorder and is less common. Patients with
mild FXI deficiency may appear normal and only be identified on screening tests (prolonged APTT).
CONCLUSION
Bleeding and thrombotic disorders pose significant threats to critically ill patients. In the initial
assessment of haemorrhagic patients, it is important to identify a localised source of bleeding which
may be controlled by physical means such as surgery, angiographic embolisation or endoscopic
therapy. Brief initial surgery to control bleeding and further resuscitation in the ICU, followed by
definitive surgery when the patient is in a more stable state should be considered. Low volume
resuscitation and judicious use of blood products are important parts of this concept. A coordinated
team approach is essential for care of these extremely vulnerable patients.
Diffuse bleeding is often a secondary problem and requires comprehensive treatment of the primary
process in conjunction with blood product support.
It is vital to recognise that critically ill patients are inherently at increased risk of thrombotic events. ICU
patients should be regularly examined for signs of DVT or PE and all patients should be considered for
thromboprophylaxis. All patients with a documented VTE should be anticoagulated. Placement of vena
caval filters should be considered in patients with contraindications to anticoagulation or in patients
with recurrent PE despite adequate anticoagulation. Patients with a documented PE and shock should
be considered for thrombolysis or surgical embolectomy. Better understanding of the mechanisms
which control blood clotting and high-quality diagnostic imaging has led to more rational therapies for
critically ill patients with bleeding and thrombotic disorders.
PATIENT CHALLENGES
You are asked to come to the Accident and Emergency Department to assist in the resuscitation
of a previously healthy 17-year-old male following a knife attack. On clinical examination, his main
injuries consist of multiple abdominal stab wounds. He has been brought to your hospital in extremis
where his trachea is intubated and his lungs are mechanically ventilated. A portable chest radiograph
shows satisfactory tube placement and no evidence of pneumothorax.
Learning issues
PACT module on Multiple trauma
Initial assessment
What advice do you give regarding airway management and mechanical ventilation in this
patient?
Learning issues
PACT module on Airway management
PACT module on Mechanical ventilationn
The haemoglobin concentration on the initial full blood count is 9.2 g/dl.
How do you interpret this result?
Learning
issues
Initial assessment
The patient remains hypotensive despite crystalloid resuscitation. A decision is made to transfer the
patient to the operating room.
Learning issues
PACT module on Hypotension
Should the patient have an abdominal CT examination prior to surgery? Give reasons.
Learning issues
Localised bleeding
At laparotomy, free blood is found in the peritoneum. Lacerations are identified in the small bowel, liver
and portal vein. The patient undergoes repair of the small bowel and portal vein laceration. Abdominal
packs are used to control the bleeding from the liver. Resuscitation is continued intra-operatively with
12 units of red blood cells, four units of fresh frozen plasma, one pool of platelets, in addition to
crystalloid and colloid resuscitation. Drains are placed in the sub-hepatic space and the abdomen is
closed.
The patient is transferred to the Intensive Care Unit (ICU) on moderate doses of vasopressors. The
patient is hypothermic with bleeding from the drains and evidence of generalised oozing. The surgical
wound dressing is already heavily bloodstained.
Learning issues
Physical means to limit further blood loss
Blood component replacement therapy
What factors are contributing to the excessive bleeding in this patient?
Learning issues
Postoperative bleeding
A persistently high rate of loss has prompted consideration of either returning to the operating room or
to pursuing other physical methods (e.g. angiographic embolisation) to treat a localised source of
bleeding. Direct discussion with your surgical and anaesthesia colleagues is needed to fully appreciate
the intra-operative findings.
What resuscitative action do you take?
Learning issues
Haemodynamic targets in bleeding patients
PACT module on Haemodynamic monitoring
What else might aggravate the bleeding and what action do you take?
Learning issues
Hypothermia aggravates bleeding
With continued i.v. volume therapy at the bedside, you are carefully observing for an excessive rate of
blood loss leading to progressive haemorrhagic shock. You attempt to define a clear point when it is
appropriate to transfer the patient back to the operating room or to the angiography suite and you
ensure there are at least six units of red blood cells immediately available for transfusion for this
patient.
Learning issues
Haemostatic failure as indication for further intervention
What laboratory studies do you request?
Learning issues
Testing of coagulation
Over the next hour, the abdominal drain output remains persistently high with high rates of i.v. volume
therapy and vasopressors required to maintain haemodynamic stability. The patient is taken back to
the operating room. The major source of bleeding identified at laparotomy is the liver laceration. After
evacuation of haematoma and continuation of the resuscitation intra-operatively, the abdomen is again
packed and the patient is returned to the ICU, but with continued diffuse bleeding.
His haemoglobin is 7.3 g/dl, PT is 32 seconds (1.6 times normal) and APTT is 90 seconds (twice
normal) and the platelet count is 45 x 109/l.
Learning issues
Diffuse bleeding postoperatively
What blood products would you administer?
Learning issues
Red cell transfusion
Blood product transfusion
As red blood cells are being transfused, you notice frequent ventricular ectopy, including runs of nonsustained ventricular tachycardia on the patient monitor.
How might this be related to the patient's resuscitation?
Learning issues
Massive haemorrhage
Should you consider administration of recombinant Factor VIIa?
Learning issues
Recombinant Factor VIIa
Should you consider administration of anti-fibrinolytic agents?
Learning issues
Pharmacological agents
You are successful at initial stabilising of the patient and correcting the coagulopathy. However, the
patient continues to have a transfusion requirement of approximately one unit of red blood cells every
other day. His nurse asks you if he should receive prophylaxis for deep venous thrombosis (DVT).
Learning issues
Deep venous thrombosis
What is the risk that your patient might develop a DVT? What, if any, thromboprophylactic
measures would you implement?
Learning issues
Thromboprophylaxis in the ICU
What are the indications for an IVC filter?
Learning issues
Inferior vena caval filters
You are asked to assess a 48-year-old male patient who is acutely unwell four days after colon
resection for caecal cancer. His cancer was diagnosed after investigation of anaemia. The patient had
been anticoagulated (warfarin) for three months prior to his surgery for a significant lower limb deep
venous thrombosis (DVT). Warfarin was stopped five days before colon surgery and his
anticoagulation was continued with low molecular weight heparin (LMWH) while awaiting surgery. Preoperative INR was 1.2. The surgery was uncomplicated but the estimated blood loss was greater than
expected. LMWH was re-started two days after surgery.
On examination, he is diaphoretic, tachypnoeic and hypotensive. His temperature is 38 °C and his
abdomen is mildly distended. The primary surgical service requests that you admit the patient to the
ICU.
Learning issues
Differential diagnosis
What are the potential causes for the signs and symptoms in this patient?
Learning issues
Post laparotomy complications
PACT module on Abdominal problems
What investigations would you order?
Learning issues
Laboratory assessment of bleeding
His full blood count shows a satisfactory haemoglobin concentration, a mildly elevated white blood cell
count and a normal platelet count. ECG and cardiac enzymes are normal. CT pulmonary angiogram
shows proximal pulmonary artery filling defects. Echocardiogram shows right ventricular (RV)
distension. With the above results, the request for CT of the abdomen is cancelled.
What is the diagnosis and what are the predisposing factors?
Learning issues
Pulmonary embolism
Predisposition to thromboembolic disease
What therapy should be considered in this patient and why?
Learning issues
Anticoagulation for pulmonary embolism
Is thrombolysis indicated in this patient?
Learning issues
Thrombolytic therapy in pulmonary embolism
Contraindication to thrombolysis
You administer intravenous unfractionated heparin to anticoagulate the patient. Cautious intravenous
fluid therapy and norepinephrine (noradrenaline) is administered to maintain satisfactory perfusion
pressure.
Learning issues
General support for PE patients
Is an inferior vena caval (IVC) filter indicated in this patient?
Learning issues
Inferior vena caval filter
The patient's respiratory distress and hypotension responded rapidly to fluid therapy, vasopressors
and anticoagulation. In addition to unfractionated heparin, oral warfarin is also administered to the
patient. When the patient is being discharged to the ward, you advise the primary surgical team to
measure the INR on a daily basis and adjust the dose of warfarin accordingly. When therapeutic
anticoagulation is achieved with warfarin, the unfractionated heparin can be stopped.
How long should the patient remain on warfarin?
Learning issues
Duration of warfarin therapy
If further surgery were required while the patient is taking warfarin e.g. for reversal of ileostomy,
how should his anticoagulation be managed?
Learning issues
Treatment of drug-induced diffuse bleeding
Ten days after starting unfractionated heparin the patient develops severe pain in a mottled pulseless
lower limb. A progressive thrombocytopenia is noted on the full blood count.
What complication may have developed and what investigations would you order?
Learning issues
Heparin-induced thrombocytopenia
What therapy should be considered in this patient?
On reflection, these cases illustrate some of the complexities and controversies in the management of
bleeding and thrombotic events in critically ill patients. Several points merit emphasis:




Multiple factors contribute to excessive bleeding in critically ill patients.
A comprehensive management approach is required.
Physical means (surgery, angiographic embolisation, endoscopic therapy) should be used
primarily to treat excessive bleeding from a localised site.
 Indications for transfusion of blood products are suggested.
 Hypothermia and acidosis should be aggressively treated.
 Diffuse bleeding is almost always a secondary process. Treatment involves blood product
support and definitive therapy for the primary pathologic state.
 Critically ill patients are at increased risk of venous thrombotic events.
 Thromboprophylaxis should be considered in all patients.
 High-quality diagnostic imaging is required to identify PE.
 Echocardiography can identify right heart failure in patients with PE.
 Anticoagulation is indicated for all patients with VTE.
 Thrombolysis is indicated in patients with a definite diagnosis of PE and associated shock.
 Surgical embolectomy is an alternative to repeat thrombolyis for recurrent PE.
 IVC filters are indicated for patients with definite contraindications to anticoagulation or
recurrent PE after adequate anticoagulation.
 HIT, a complication of anticoagulation with heparin and low molecular weight heparin, may
present with venous or arterial thrombotic events. Warfarin and platelet transfusion should
be avoided. Antithrombin agents are indicated.
Q1. DIC is suggested by which one of the following
A. Elevated D-dimer levels
True
False
B. Hypofibrinogenaemia
True
False
C. Prolonged clotting time (APTT, PT)
True
False
D. All of the above
True
False
E. None of the above

Q2. A 46-year-old male with cirrhosis is admitted to your ICU following a massive gastrointestinal
haemorrhage. The patient is not actively bleeding at present. Laboratory analysis shows an INR of
8.0, PT-20, APTT-70, platelet count of 10 x 109/l. All of the following would be appropriate except
A. The administration of vitamin K, 5-10 mg, intravenously
True
False
B. The administration of prothrombin complex concentrate or FFP, 15 ml/kg
True
False
C. Transfusion of 6 units or one pool of random donor platelets
True
False
D. Continuous infusion of cryoprecipitate
True
False
E. Withhold pharmacologic thromboprophylaxis
True
False
Q3. A patient is being initiated on warfarin therapy for venous thromboembolism. The patient is receiving
therapeutic doses of heparin and the APTT is currently 1.5 times the control value. Whe is it appropriate
to discontinue heparin in this setting?
A. 48 hours after beginning warfarin
True
False
B. Once an INR of 2.0 has been achieved
True
False
C. 24 to 48 hours after an INR of 2.0 has been achieved
True
False
D. 12 hours after the first dose of warfarin is given
True
False
E. It is not necessary to administer heparin in this setting
True
False
Q4. A 24-year pregnant female in her first trimester sustains a left femur fracture in a motor vehicle
crash. As she is recovering from her orthopaedic surgery, she is diagnosed with a DVT. What is the
appropriate initial therapy?
A. Anticoagulant therapy is contraindicated given risk of adverse effects on the
fetus
True
False
B. An IVC filter should be placed
True
False
C. The patient should receive 5000 units of unfractionated heparin, subcutaneously,
twice each day
True
False
D. The patient should receive intravenous heparin and should be started on warfarin
True
False
E. The patient should receive low molecular weight heparin, dose adjusted for body
weight (e.g. enoxaparin 1 mg/kg subcutaneously every 12 hours)
True
False
A. A large proportion of patients who develop thrombocytopenia while on heparin
therapy will develop HIT
True
False
B. The risk of HIT is higher in patients receiving low molecular weight heparin
compared to patients receiving unfractionated heparin
True
False
C. Once HIT is diagnosed, all unfractionated heparin products should be
discontinued and the optimum therapy of thrombotic complications is low
molecular weight heparin
True
False
Q5. Which of the following regarding heparin-induced thrombocytopenia (HIT) is true?
D. Hirudin sulfate analogs are indicated in the treatment of HIT to inhibit thrombin
formation
True
False
E. Warfarin is indicated for the treatment of thrombotic complications of HIT
True
False