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   .

COMMUNICATION 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

COMMUNICATION 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.

NOTESenior 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   and Multiple trauma   for further information.

Treatment of patients with localised anatomical bleeding

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.

COMMUNICATION

THINK 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.

THINK 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:

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.

THINK 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 10-15 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:

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.

THINK What are the common causes of DIC? Is the DIC seen in sepsis the same as the DIC seen after massive transfusion?

ANECDOTE 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.

NOTEThe 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.

NOTESerial 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 (heparin-induced 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 anti-platelet 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 re-introduction of warfarin therapy more difficult.

NOTEFor 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.

THINK 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).

 

THINK 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 pharmacologic and mechanical

prophylaxis

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 inhibitorTAFI = 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)

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

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

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 D-dimers 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.

COMMUNICATION 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 re-vascularisation 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 circuitsDiversion 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.

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.

NOTEThe 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

NOTEInvasive 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   and the following reference.

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 non-sustained 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. Pre-operative 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 levelsTrueFalse

B. HypofibrinogenaemiaTrueFalse

C. Prolonged clotting time (APTT, PT)TrueFalse

D. All of the aboveTrueFalse

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, intravenouslyTrueFalse

B. The administration of prothrombin complex concentrate or FFP, 15 ml/kgTrueFalse

C. Transfusion of 6 units or one pool of random donor plateletsTrueFalse

D. Continuous infusion of cryoprecipitateTrueFalse

E. Withhold pharmacologic thromboprophylaxisTrueFalse

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 FalseQ4. 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

Q5. Which of the following regarding heparin-induced thrombocytopenia (HIT) is true?

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

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