Haemostatic failure

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Chapter 91 Haemostatic failure

Failure of haemostasis is common in critically ill patients and may be complex and multifactorial in pathogenesis. As haemostatic failure may complicate a wide range of medical, surgical and obstetric disorders, definitive diagnosis and specific therapy can significantly impact on outcome. Frequently, complex tests are required for definitive diagnosis, but the urgency of the situation cannot always wait for the results, and therapy may be initiated on clinical evidence with minimal laboratory information. Consultation with a clinical haematologist is strongly recommended.

NORMAL HAEMOSTASIS

The haemostatic system is a delicately controlled component of the host defence system, the role of which is to initiate haemostasis where and when required and in adequate, but not in excessive, amounts. The system closely interacts with other components of the host defence system, including the acute stress responses, inflammation, healing and immune functions. There has been a paradigm shift in our understanding of the haemostatic system from one of interacting humoral factors to an integrated cell-based system.^1,² In view of the increasing range of focused therapies available that act on the haemostatic system to modulate its activity, it is important that core aspects of the structure and function of the system are summarised.

The conversion of blood from its fluid to solid state is an increasingly understood physiological process. The triad of vascular constriction, platelet plugging and fibrin clot formation forms haemostatic plugs and provides the framework on which haemostasis operates (Figure 91.1) and sets the scene for healing to occur. Thrombin is the potent proteolytic enzyme of the coagulation sequence converting fibrinogen to fibrin-soluble monomers, which subsequently polymerise to form the fibrin clot. Fibrinogen is the bulk protein of the coagulation system and fibrin is the end-product of this cascade of proteolytic activity, in which precursor coagulation proteins are activated to potent proteolytic enzymes, with the aid of cofactors, to produce active precursors further down the coagulation ‘amplifier’. The polymerised fibrin is further acted on by factor XIII to form a stable fibrin clot. The process of thrombin generation in small amounts initially occurs in relationship to tissue factor-bearing cells and the process is subsequently transferred to the activated platelet surface where amplification occurs.

Figure 91.1 Overview of the haemostatic system. APC, activated protein C; AT III, antithrombin III; FBP, fibrinogen breakdown product; FDP, fibrinogen degradation product; ICs, immune complexes; TFPI, tissue factor pathway inhibitor; vWF, von Willebrand factor.

Following injury, vascular constriction reduces bleeding, and allows time to initiate haemostasis. With large volume haemorrhage, resulting systemic hypotension is an important physiological mechanism to minimise blood loss and facilitate stabilisation of the haemostatic plug. Controlled or ‘tolerated’ hypotension is now accepted as an important aspect of managing critical haemorrhage.^3,⁴ This vascular constriction is further accentuated by vasoconstrictors released in association with platelet plug formation. Vascular endothelial cells play an active part by synthesising substances which act at the membrane surface and/or interact with platelets and the coagulation system (e.g. prostacyclin, antithrombin III, plasminogen activator, von Willebrand factor, thrombomodulin, heparin cofactor II and nitric oxide).⁵ Following the initial vascular reactions, successful haemostasis depends on adequate numbers of functioning platelets, coagulation cascade function, and poorly understood contributions from red cells and leukocytes.

The coagulation system is triggered via the extrinsic pathway, by which damaged tissues expose tissue factor (TF). Tissue factor is a membrane-bound protein present in cells surrounding the vascular bed. Factor VII and VIIa (a small amount circulates normally in the blood) are bound to TF activating factor X. Factor Xa interacts with the cofactor Va to form prothrombinase complexes with the generation of a small amount of thrombin on the cell surface. Factor IX is also activated by the TF/VIIa complex; it does not play a significant role in the initiation phase of coagulation, but diffuses across to platelets in the vicinity that have adhered in proximity to the site of the TF-bearing cells binding to a specific platelet surface receptor and interacting with cofactor factor VIIIa, leading to activation of factor X directly on the platelet surface. The concept of the intrinsic and extrinsic systems is more of historical and laboratory significance as it is now clear that such a division is artificial, but the concept still has value in performing and assessing haemostatic laboratory tests.

Von Willebrand factor (vWF) is a multimeric glycoprotein that plays a central role in haemostasis by mediating adhesion of platelets to the exposed subendothelium and linking the primary vascular/platelet phase with coagulation by being the carrier protein for coagulant factor VIII which dissociates from vWF to form a complex on the activated platelet surface with IXa (tenase complex) to activate factor X to Xa. Further vWF is released from Weibel–Palade bodies in nearby endothelial cells and platelet α-granules. Platelets interact with vWF via their surface glycoprotein Ib-IX-V complexes. This slows their motion along the subendothelium, allowing receptor interaction leading to platelet binding to collagen. Adhesion to collagen is facilitated by the GPIa-IIa receptor. GPIIb-IIIa can then bind vWF, fibrinogen, fibronectin, vitronectin and thrombospondin, providing further important sites of anchorage for the spreading platelet. The initiation phase of platelet plug formation leads to the development of a platelet monolayer over the injured subendothelium. With the concomitant activation of the coagulation cascade there is local generation of thrombin. Thrombin is a potent platelet agonist via the protease-activated receptor (PAR) to produce a haemostatic plug. Further extension occurs by platelet recruitment by platelet agonists, such as thrombin and mediators, adenosine 5-diphosphate (ADP) and thromboxane A2 released directly from platelets. P-selectin is expressed during activation and also plays a role in platelet-to-platelet cohesion.

Parallel to and within the coagulation system are complex feedback mechanisms to ensure fine-tuning and protection against inappropriate and excessive activation.⁶^–⁸ There are several inhibitory proteins, including antithrombin III, thrombomodulin, proteins C and S, tissue factor pathway inhibitor as well as the fibrinolytic system, which are all important in controlling the degree and site of fibrin formation. Indeed, thrombin itself acts as either a procoagulant or an anticoagulant depending on context. Massive activation, as may be seen in trauma and severe infections, can precipitate systemic activation, but in general, the system is well controlled and activity is localised to the area of the stimulus. Perturbations in this complex defence system can produce a wide range of clinical disorders from excessive arterial or venous thrombosis, microvascular obstruction and atheroma to haemostatic failure.

SYSTEMIC HAEMOSTATIC ASSESSMENT

There may be clinical features suggesting local or generalised failure of the haemostatic system (Figure 91.2). Clinical history is important, especially with respect to previous bleeding problems, family history, comorbid medical conditions and medications. The nature of surgery or an invasive intervention may have haemostatic issues that need specific consideration.

Figure 91.2 Coagulation tests.

TESTS OF THE HAEMOSTATIC SYSTEM

Tests of whole blood clotting time and clot observation do not generally have a role in assessing haemostasis. However, in emergency settings, while waiting for laboratory results, observation of blood collected into a glass tube and maintained at 37°C for clot formation, size, retraction and possible lysis may provide crude information of a possible coagulopathy. The thromboelastogram is a more accurate and controlled procedure for ‘holistic’ assessment of the haemostatic system at the bedside, but requires close attention to technique and quality control. In most clinical settings, laboratory haemostatic screening tests are readily available, with near-patient testing techniques continuing to improve. A full blood count, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen level, D-Dimer ± thrombin clotting time (TCT) provide a broad screen for most clinically significant haemostatic disorders ⁹^–¹¹ (Figure 91.3). Based on these results, and following consultation with a haematologist, further specific tests of haemostasis may be performed (e.g. mixing studies, factor assays, platelet function tests and test of fibrinolytic function). In broad terms:

• PT tests the integrity of the extrinsic system

• APTT the intrinsic system

• TCT fibrinogen conversion

• D-Dimer assay measures the breakdown products from lysis of fibrin

Figure 91.3 Investigations for a suspected haemostatic defect. FDPs, fibrinogen degradation products.

The haemostatic system optimally functions at 37°C and laboratory coagulation tests are performed at 37°C. Hypothermia may severely impair a patient’s systemic and local haemostasis despite the system being structurally intact and laboratory tests normal.

The laboratory investigation of a patient with a potential haemostatic defect depends on the degree of urgency. It may be necessary to administer blood component therapy without a definitive haemostatic defect being established. In elective settings, the defect can be accurately identified, problems pre-empted and specific blood component therapy administered prophylactically or therapeutically. A detailed clinical history and screening laboratory investigations prior to elective procedures will often avert undiagnosed emergency haemostatic crises.

There are several important principles in the collection of blood samples for haemostatic investigations. Most samples are collected into citrated tubes and the amount of anticoagulant in the tube is related to the intended amount of blood to be collected into the tube. It is important that the correct amount of blood is added to the tube and gently mixed. Attention to venepuncture technique is crucial and rapid transfer of the sample to the laboratory is important. Contamination of the sample with tissue factor due to traumatic venepuncture will activate the sample and invalidate results. Collection from vascular access lines may result in diluted or heparin-contaminated samples. Incorrect laboratory results may be more dangerous to a patient than no results at all.

PLATELET FUNCTION TESTS

Platelet function tests are used for the diagnosis of platelet disorders.^12,¹³ In recent years there has been increasing interest in the use of platelet function tests to monitor antiplatelet therapy. Unfortunately, platelet function testing is poorly standardised and good quality control is commonly lacking. The diagnostic utility of some of the newer simpler assays of platelet function have been evaluated in a range of clinical settings, but their value remains controversial.

A popular technology is the platelet function analyser (PFA-100) in which citrated whole blood is placed in a disposable cartridge containing a membrane coated with collagen/adrenaline or collagen/ADP into which a microscopic aperture has been cut. With high shear rates contact of blood with the membrane causes platelets to aggregate and occlude the aperture. The time to occlude the aperture is recorded as the end-point and referred to as the closure time.¹⁴ The technique is simple and rapid, but subject to a number of variables such as the platelet count, haematocrit, ABO blood group and plasma vWF levels. A normal result has a high negative predictive value and is increasingly becoming popular as a screening test for platelet dysfunction; however, false positive and negative results may occur. The test is more sensitive than the bleeding time which is now generally regarded as an obsolete test.

THROMBOELASTOGRAM (TEG)

Thrombelastography was originally described 50 years ago, but failed to establish a role in routine laboratory haemostasis testing. Improvements in the technology, especially standardisation and computerisation, have now made the TEG a valuable tool for monitoring haemostasis as a holistic dynamic process supplementing the long-standing conventional coagulation screens. The TEG measures the viscoelastic properties of blood as it clots under low shear conditions. The patterns of changes in shear elasticity provide information about the kinetics of clot formation, growth, strength and stability of the formed clot. The TEG is increasing being used as a point of care test, providing ‘real time’ information about a patient’s haemostatic function.¹⁵

CONGENITAL HAEMOSTATIC DEFECTS

Congenital bleeding disorders are relatively uncommon and are usually confined to a single defect. It is important to identify the defect so that specific replacement therapy can be given preoperatively or to arrest a particular episode of bleeding.

THE HAEMOPHILIAS

HAEMOPHILIA A (CLASSIC HAEMOPHILIA)

Haemophilia A is an X-linked disorder due to a deficiency of factor VIII. The mainstay of haemophilia treatment is coagulation factor replacement.^16,¹⁷ Coagulation factor concentrates or recombinant factor VIII are given to prevent bleeding and to control existing haemorrhage. The dose of clotting factor is calculated on the basis that one unit of coagulation factor is that amount present in 1 ml of pooled normal plasma. An individual with a plasma volume of 3000 ml would have 3000 U of the clotting factor in the circulation. If such person was a haemophiliac with <1% factor VIII level in the plasma, a dose of 3000 U of factor VIII would be required to raise the plasma level to 100% of normal.

Experience has demonstrated that doses of 15–20 U/kg body weight will control most haemarthroses, but doses of up to 30 U/kg are required for muscle haematomas or for the prevention of dental bleeding. Raising clotting factor levels to 100% of normal is indicated for severe bleeding (e.g. intracranial or intra-abdominal haemorrhage), but there is considerable patient variation in response to specific doses, and empirical ‘dose-finding’ may be necessary. Measurement of factor VIII levels following replacement therapy is helpful. A factor VIII concentration of 25%, usually achieved with a dose of 15 U/kg, controls joint bleeding, whereas a level of 50%, generally obtained with a dose of 30 U/kg, prevents bleeding following tooth extraction. Clotting factor is given when a haemophiliac undergoes invasive procedures, including minor invasions such as arterial blood gas sampling.

The half-life of factor VIII in the circulation is approximately 12 hours. On this basis, doses are repeated 12-hourly if it is necessary to maintain a specific plasma concentration of the factor. Clotting factor assays are performed near the end of this 12-hour period in order to confirm that adequate levels for haemostasis are being achieved. Concentrate may also be given by continuous infusion.

HAEMOPHILIA B (CHRISTMAS DISEASE)

Haemophilia B due to factor IX deficiency is less common than classic haemophilia. The general principles of management are similar, with factor IX concentrates or recombinant products being used.

VON WILLEBRAND’S DISEASE

Von Willebrand’s disease (vWD), the commonest of the hereditary haemostatic disorders, with a prevalence of approximately 100 symptomatic persons per million, is due to a quantitative or qualitative defect in von Willebrand factor (vWF). Patients with defective vWD may have mucocutaneous bleeding consistent with platelet dysfunction, or spontaneous deep tissue bleeding similar to that of haemophiliacs.

Classification of vWD is complex and controversial. Therapy may be determined by the specific subtype and expert haematological consultation is important.^18,¹⁹ Clinical heterogeneity is reflected in the classification of subtypes corresponding to specific pathophysiological mechanisms.

In most cases desmopressin (DDAVP) is effective therapy, but replacement therapy may be needed for the rarer severe subtypes. DDAVP induces a haemostatic state via release of factor VIII and vWF; 0.3 μg/kg is infused slowly over 30 minutes immediately prior to surgery or to establish haemostasis in the bleeding patient. Antifibrinolytic agents may also be useful when not contraindicated as a thrombotic risk. If replacement therapy is indicated, cryoprecipitate or factor VIII concentrates containing vWF should be administered.

CONGENITAL PLATELET DISORDERS

Congenital platelet disorders are rare, the commonest severe disorder being Glanzmann’s thrombaesthenia.²⁰ Platelet transfusions may be required for acute bleeds or in relation to elective surgery; DDAVP ± antifibrinolytic therapy and recombinant factor VIIa may all have a role.

ACQUIRED HAEMOSTATIC DISORDERS

The acquired disorders of coagulation are usually more complex and multifactorial than the hereditary disorders. A unified approach is essential for the successful management of these potentially life-threatening situations, and transfusion therapy cannot be isolated from other treatment.

CRITICAL HAEMORRHAGE AND MASSIVE BLOOD TRANSFUSION

The nature and management of haemostatic defects secondary to acute and/or massive blood loss and transfusion remains poorly understood.²¹ The coagulopathy of trauma is characterised by non-surgical bleeding from mucosal lesions, serosal surfaces, wounds and vascular access sites. Hypothermia, acidosis and haemodilution are commonly present, occasionally with features of disseminated intravascular coagulation (DIC). DIC typically occurs acutely after trauma when brain, fat, amniotic fluid or other potent thromboplastins enter the circulation. It may occur less acutely when endothelial inflammation or failure reduces clearing of activated coagulation factors. The coagulopathy of trauma should be anticipated in massive transfusion situations and there is increasing support for early treatment with plasma, which may prevent or delay its onset.

Further aggravation of the complications of massive blood transfusion can be avoided or minimised if correctable defects in the haemostatic system are identified (Table 91.1). The relative importance of the different potential mechanisms responsible for haemostatic failure is difficult to determine, but the identification of correctable defects will avoid or minimise complications. Haemostatic failure correlates poorly with the volume of transfusion or components administered, but better with the nature of the insult, degree of hypovolaemia, and time to resuscitation. Trauma patients with major coagulopathy and microvascular haemorrhage usually have abnormal laboratory parameters prior to massive blood transfusion. Except for severe abnormalities, haemostatic laboratory parameters correlate poorly with clinical evidence of haemostatic failure. Thrombocytopenia and impaired platelet function are probably the most consistent significant haematological abnormalities, correction of which may be associated with control of microvascular bleeding.

Table 91.1 Possible factors contributing to haemostatic failure following massive blood transfusion

Coagulation deficiency from massive blood loss is initially confined to factors V and VIII. APTT, PT and fibrinogen assay should be performed, but the urgency of the situation does not usually allow for other specific factor assays, and fresh frozen plasma (FFP), cryoprecipitate or factor concentrates should be infused if the test results are abnormal. Correction of hypofibrinogenaemia is probably more important than thought previously.²² A case can be made for prophylactic FFP in infusions in patients with massive blood loss which has been replaced with red cell concentrates and plasma substitutes. Hypothermia must be avoided, recognised and treated rapidly.²³ Potential problems associated with large volume stored blood replacement are summarised in Table 91.2.

Table 91.2 Potential problems with stored blood components

Failure to correct deficiency

Inadequate correction of deficiency

Blockade of reticuloendothelial system (microaggregates, coagulation)

Microvascular pathophysiology (ARDS, MSOF)

Accentuation of free radical pathology (leukocytes, iron)

Activation and consumption of the haemostatic system

Hyperkalaemia, hypocalcaemia, hypothermia

Vasoactive effects (hypotension)

Hyperbilirubinaemia

With ongoing bleeding with associated microvascular oozing, various approaches may be taken. Having ensured that all identifiable haemostatic defects have been corrected, questions arise as to the roles of fresh blood and, more recently, recombinant activated factor VII (rFVIIa).²⁴ The use of freshly collected whole blood remains controversial and is an ‘emotive’ subject needing some comment.^25,²⁶ The provision of fresh whole blood can present logistic, ethical and safety problems needing consideration. Many transfusion medicine specialists categorically state that there is never an indication for fresh whole blood. Such dogma can be difficult to defend in the clinical setting of the massive haemorrhage and transfusion syndrome where pathophysiology remains poorly understood and specific blood component therapy may be ineffective. The current author, from his own experience and on the basis of current evidence, feels that the following statements reasonably summarise the current status of fresh blood transfusion:

• Fresh blood provides immediately functioning oxygen-carrying capacity, volume and haemostatic factors in the one product

• The number of allogeneic donors to whom a patient is exposed can be reduced

• Problems associated with infusion of massive volumes of stored blood can be minimised/avoided

• The risk of transfusion-related viral infections is potentially higher than fully tested and stored blood

• The benefit in controlling haemorrhage probably relates to the presence of immediately functioning platelets

HAEMOSTATIC FAILURE ASSOCIATED WITH LIVER DISEASE

The liver is the production site of nearly all the factors involved in the formation and control of coagulation (Table 91.3). Bleeding in association with liver disease can be difficult to manage. There may be a combination of excessive consumption of coagulation factors and impaired synthesis of both clotting factors and coagulation inhibitor proteins. Excessive activation of fibrinolysis may occur and defective clearing of activated clotting factors compounds the problem. Moreover, the effects of massive blood loss, shock and transfusion must also complicate the problem.

Table 91.3 Haemostatic disturbances in liver disease

Deficiency of vitamin K-dependent clotting factors II, VII, IX, X

Deficiency of fibrinogen and factor V

Dysfibrinogenaemia

Disseminated intravascular coagulation

Excessive fibrinolytic activity

Circulating anticoagulants

Platelet abnormalities

Haemostatic defects due to deficient vitamin K-dependent coagulation factors (in patients with predominantly cholestatic liver disease) may be rapidly reversed with vitamin K therapy, and blood transfusion may not be required. If the abnormality is not reversed by vitamin K, hepatocellular damage is likely to be present and FFP is appropriate replacement therapy.²⁷ When an elective procedure is planned, prophylactic FFP is appropriate. Low fibrinogen levels in liver disease usually indicate advanced disease and are associated with a poor prognosis, or the presence of DIC. Cryoprecipitate is generally the most readily available form of fibrinogen if concentrates are not available.

DISSEMINATED INTRAVASCULAR COAGULATION ²⁸

Disseminated intravascular coagulation (DIC) is a pathophysiological process and not a disease in itself. Clinical manifestations of DIC relate to occlusion of the microvessels during the obstructive phase of the syndrome and haemorrhage secondary to consumption of plasma and cellular components of the haemostatic system.²⁹

Perpetuation of the process may be due to continuation of the stimulus and/or consumption of the natural inhibitors of haemostasis. DIC thus results, due to inappropriate, excessive and uncontrolled activation of the haemostatic process. This may initially occur with adequate compensation when defects may only be demonstrable in laboratory tests. If the initiating disorder is severe enough, the clinical syndrome of uncontrolled acute DIC will result with a systemic bleeding state, usually with associated end-organ failure. A compensatory secondary fibrinolysis occurs, which in some cases may accentuate the bleeding.

PATHOPHYSIOLOGY

DIC is characterised by the consumption of clotting factors and platelets within the circulation, resulting in varying degrees of microvascular obstruction due to fibrin deposition (Figure 91.4). When significant platelet and coagulation factor consumption occurs, bleeding may become a major feature.

Figure 91.4 The pathophysiology and management of disseminated intravascular coagulation (DIC). AT III, antithrombin III; FFP, fresh frozen plasma; RES, reticuloendothelial system.

Mechanisms which may inappropriately activate the haemostatic system include:

• Activation of the coagulation sequence by release of tissue thromboplastins into the systemic circulation, e.g. following extensive tissue trauma, during surgery, malignancy and during an acute intravascular haemolysis.

• Vessel wall endothelial injury causing platelet activation followed by activation of the haemostatic system, predominantly via the intrinsic pathway (e.g. Gram-negative sepsis from endotoxin release, viral infections, extensive burns, prolonged hypotension, hypoxia or acidosis).

• Induction of platelet activation (e.g. septicaemia, viraemia, antigen–antibody complexes and platelet activation).

CLINICAL FEATURES

The clinical presentation of DIC varies, with patients showing thrombotic, haemorrhagic or mixed manifestations in various organ systems. The major clinical problem and presenting feature of acute DIC is bleeding. This may manifest as generalised bruising or bleeding at sites of therapeutic or traumatic invasion (venepuncture sites and surgical wounds). DIC may occur in association with a wide range of clinical disorders (see Table 91.5). When DIC occurs in acutely ill patients with multisystem organ failure the prognosis is poor. DIC may, in some patients, be an agonal event and should not be treated.

LABORATORY FINDINGS

Results of tests may be variable and difficult to interpret. Significant DIC can be present despite normal standard coagulation tests (i.e. PT, APTT and TCT). The key tests in diagnosis are those that provide evidence for excessive conversion of fibrinogen to fibrin within the circulation and its subsequent lysis. Platelet–fibrin clots create a mesh in the microcirculation in which passing red cells may be traumatised, resulting in red cell fragmentation and haemolysis. The blood film may demonstrate fragmentation of the red cells (microangiopathic haemolytic anaemia), but this is more commonly seen in chronic DIC, especially in association with malignancy.

The diagnosis is usually based on a combination of the appropriate clinical picture with a supportive pattern of laboratory tests of the haemostatic system ²⁷ (Table 91.4). Thrombocytopenia and hypofibrinogenaemia with prolongation of the APTT, PT and TCT in conjunction with an elevation of fibrin degradation products (D-Dimer test) are supportive evidence for the diagnosis. The D-Dimer test is specific for fibrin breakdown versus primary fibrinogenolysis. More specialised test such as elevation of fibrinopeptide A and reduced levels of antithrombin III add further weight to the diagnosis.

Table 91.4 Laboratory test for the diagnosis of disseminated intravascular coagulation

Analysis	Early	Late
Platelet count	↓	↓↓
Activated partial thromboplastin time (APTT)	↑	↑↑
Prothrombin time (PT)	↑	↑
Thrombin clotting time (TCT)	↑	↑
Fibrin degradation products (D-Dimer assay)	↑	↑↑
Hypofibrinogen	↓	↓↓
Other coagulation factors II, VII, VIII, X	↓	↓↓
Coagulation inhibitors: antithrombin III, protein C	↓	↓↓↓
Blood film	Usually normal in early stages	Fragmented red cells + in subacute or chronic cases
Supplementary and research tests: prothrombin fragment 1+2, thrombin–antithrombin complex (TAT complex), procalcitonin (PCT), plasmin–antiplasmin complexes (PAP complex)	↑	↑

Table 91.5 Conditions associated with disseminated intravascular coagulation

In chronic DIC the laboratory findings are different from those in acute DIC. Many of the usual tests of haemostasis are normal or near normal. The platelet count may be normal, as may many of the haemostatic factors. However, this is a compensated state in which there is increased turnover of each of the haemostatic components. D-Dimer is elevated in this setting and a microangiopathic red cell picture is seen on the peripheral blood film.

DISORDERS ASSOCIATED WITH DIC

DIC may occur in association with a wide range of clinical disorders (Table 91.5).

THERAPY

The management of DIC remains controversial, but removal or treatment of the initiating cause is important in conjunction with general resuscitation. The early recognition of DIC and initiation of management may allow the patient to survive hours or days, granting sufficient time for definitive diagnosis and treatment of the inciting disorder. Blood component therapy should be given to the haemorrhaging patient, but the use of heparin should only be considered in selected cases.

• Fresh frozen plasma (FFP) contains all the coagulation factors and the main inhibitors, antithrombin III and protein C, in near-normal quantities and should be used if haemorrhage is occurring.^30,³¹

• Cryoprecipitate contains all the components of the factor VIII complex, as well as fibrinogen, factor XIII and fibronectin in concentrated form. Between 5 and 10 units should be infused in conjunction with the fresh frozen plasma.

• Platelet transfusion may be indicated in the presence of life-threatening haemorrhage; however, this is a controversial subject and the patients tend to be resistant if the initiating cause of the DIC has not been controlled.

• It is likely that replacement therapy with antithrombin III concentrates and possibly other inhibitors of haemostasis will find a greater role in therapy.³⁰ Successful treatment of the bleeding phase of DIC probably depends to a variable degree on the patient being able to ‘switch off’ the coagulation system. Correction of depleted coagulation inhibitor levels, reticuloendothelial blockade and impaired or excessive fibrinolysis may be important.

• In general, heparin should only be used after initial adequate replacement therapy has failed to control bleeding. The decision to use heparin should not be undertaken lightly, or without due consultation. Small doses should be used initially (e.g. 50–100 units/kg body weight followed by 10–15 units/kg per hour), adjusted according to the clinical and laboratory response. Heparin is especially valuable in certain specific clinical situations, including acute promyelocytic leukaemia, the early stages of amniotic fluid embolism and immediately following a severe incompatible blood transfusion.

Management of sudden massive obstetric haemorrhage is similar to other cases of DIC except that the onset is more likely to be fulminant and unexpected and associated with greater depletion of coagulation factors, especially fibrinogen, due to marked fibrinolysis. Fresh blood is possibly warranted in some of these cases where bleeding does not stop quickly. Once the uterus has been emptied and contracted, the haemostatic failure quickly resolves. There is increasing interest in a possible role for rFVIIa in this setting.

OUTCOME

Factors which may affect the outcome of DIC include:

• the nature of the initiating event

• the host factors (e.g. state of reticuloendothelial system, levels of inhibitors of coagulation and fibrinolytic activity, hepatic synthetic function)

• the extent of end-organ damage sustained during the thrombotic phase and from shock caused during the haemorrhagic phase

ANTITHROMBOTIC THERAPY

The availability of an increasing variety of antithrombotic agents, and wider clinical use of antithrombotic therapy generally, has inevitably resulted in an increase in iatrogenic bleeding in patients presenting with other medical conditions (e.g. trauma, surgery and invasive procedures) and intensivists must be aware of the methods for rapid reversal of therapy.^32,³³ Bleeding problems in patients on well-controlled anticoagulation are usually due to surgery, trauma or a local lesion (e.g. peptic ulceration). Otherwise, bleeding is due to over-anticoagulation, sometimes as a result of drug interactions. Elective surgery in this group of patients needs careful planning if haemorrhagic and thrombotic complications are to be avoided. Patients on antithrombotic therapy involved in traumatic events are a challenge in whom there is the risk of progression of the original insult, increased risk of posttraumatic complications, and mortality.

ORAL ANTICOAGULANT AGENTS

Oral anticoagulant agents induce a controlled deficiency of the vitamin K-dependent clotting factors (II, VII, IX and X), the anticoagulant action being measured by prolongation of PT (INR). The indications for reversing vitamin K antagonists depend on the clinical situation and the indication for therapy. Reversal of over-anticoagulation depends on the degree of overactivity and on the presence, or not, of haemorrhage. In most cases vigorous intervention is unnecessary and the oral anticoagulation can be temporarily ceased. Short-term reversal or temporary reversal is achieved by administration of FFP. Prothrombin complex concentrate will effectively and rapidly reverse the anticoagulant effects of warfarin, including protein C correction, and have a role in anticoagulant overdose. Previous concerns about coagulation activation do not appear to be a problem with current products.

Long-term reversal requires vitamin K, but care must be taken not to give an excessive dose if it is planned that the patient needs to return to oral anticoagulation in the long term. For most surgical interventions or invasive procedures an INR of 1.5 or less is accepted as safe. This can usually be achieved by temporarily ceasing medication.

HEPARINS

With the wide clinical use of fractionated low molecular weight (LMW) heparins, this subject has become more complex. Heparins act by potentiating the action of antithrombin III, a natural coagulation inhibitor. Unfractionated heparin acts in neutralising both thrombin and factor Xa, in contrast to the LMW heparins which predominantly neutralise factor Xa. The anticoagulant effect of unfractionated heparin is usually measured by prolongation of the APTT. LMW heparins do not prolong the APTT, are generally administered on weight basis and are not routinely monitored by a laboratory test. When monitoring is required, the anti-Xa assay is used.

ANTIPLATELET AGENTS

Antiplatelet agents are being used increasingly for prophylaxis and therapy of arterial disease, and many of the non-steroidal anti-inflammatory agents are also platelet-inhibitory drugs. Aspirin has an irreversible effect on platelet function and platelet function tests may show abnormalities for up to 10 days after medication. Most of the other non-steroidal anti-inflammatory drugs have a reversible effect lasting a matter of hours or occasionally days. Perioperative bleeding is usually mild, but occasionally may be serious, depending on the surgery, and in some situations a platelet transfusion may be necessary. In other cases, the patient may already have a mild haemostatic defect (e.g. von Willebrand’s disease) and aspirin may have a synergistic effect, leading to major haemostatic failure.

Agents such as clopidogrel act as inhibitors of platelet aggregation by selectively inhibiting the binding of ADP to its platelet receptor by irreversibly modifying the platelet ADP receptor and, as a result, ADP-mediated activation of the GPIIb/IIIa complex. As with aspirin, platelets exposed to clopidogrel are affected for their lifespan and recovery of normal platelet function occurs as new platelets are produced.

REVERSAL OF ANTITHROMBOTIC AGENTS

Life-threatening bleeding in patients on warfarin requires urgent reversal and this is best achieved with prothrombin concentrate (PCC) administration in conjunction with FFP depending on the factor VII level of the PCC.³⁴^–³⁶ The advantages of PCC over FFP include more timely correction, absence of volume overload and potentially better restoration of the vitamin K-dependent coagulation factors. Vitamin K₁ is essential for sustained reversal, but the dose should be determined on the basis of whether temporary reversal is indicated. When there is an indication to continue warfarin therapy, vitamin K₁ should be administered in a dose that will lower or maintain the INR to a safe, but not subtherapeutic, range and will not cause resistance once warfarin is reinstated.

Immediate reversal of heparin activity can be achieved with protamine sulphate. Although formulas have been quoted for the reversal of heparin (e.g. 1 mg protamine sulphate will neutralise 100 units of heparin), it is better to titrate the dose using APTT after an initial empirical dose of 50 mg. Protamine sulphate should be injected slowly by the intravenous route. Protamine is not without risk, as it may itself impair coagulation and be associated with anaphylactoid reactions. It is not possible to reverse the effects of LMW heparins, and rFVIIa may have role in critical bleeding settings.

Antiplatelet agents, particularly acetylsalicylic acid, clopidogrel and GPIIb/IIIa inhibitors, now have a central role in preventing arterial thrombosis. Clinicians are now regularly confronted by balancing the haemorrhagic risks associated with these agents, especially in the perisurgical setting, against the thrombotic risks associated with their discontinuation. It is generally agreed that continuing acetylsalicylic acid during vascular surgery procedures and in most other settings in which the bleeding risk is likely to be low is acceptable. It is generally recommended that clopidogrel be ceased 5 days before surgery to allow regeneration of half the platelet pool. Although withdrawal of the competitive GPIIb/IIIa inhibitors at the beginning of surgery will decrease the risk of bleeding, it should be emphasised that thrombotic events in patients waiting for urgent myocardial revascularisation are a significant risk and acceptance of perioperative bleeding risk may take priority. Patient blood management techniques to minimise blood loss and transfusion should be used.³⁷ Platelet concentrate transfusions may be indicated in the acute setting.

NEWER ANTITHROMBOTIC AGENTS

Limitations of the currently available antithrombotic agents continue to stimulate research into new anticoagulants with improved pharmacological activity and safety.³⁸

Targets of action include:

• the factor VIIa/tissue factor pathway inhibition – recombinant nematode anticoagulant peptide c2 and tissue factor pathway inhibitor

• factor Xa inhibitors – fondaparinux, idraparinux, razaxaban

• factor Va and VIIIa pathway inhibition with recombinant activated protein C, soluble thrombomodulin

• thrombin inhibitors – hirudin, bivalirudin, argatroban, ximelagatran, dabigatran

Independent of their mode of action, these agents all have the potential to cause bleeding complications.

Reversal agents do not exist for the majority of these newer agents. Recombinant activated factor VIIa may have a role in controlling bleeding, but more experience will be needed with the use of these newer agents and their bleeding risks.

ACQUIRED INHIBITORS OF COAGULATION

Major haemostatic failure may be seen with rare inhibitors of coagulation factors. Autoantibodies against factors VIII (commonest), IX, X, V and vWF have been reported. A coordinated approach to haemotherapy is essential if bleeding is to be arrested. The patients are relatively resistant to factor replacement therapy and removal of the offending autoantibody by plasma exchange and replacement with FFP ± factor concentrates is indicated. Recombinant activated factor VII may have a role yet to be defined.

PRIMARY FIBRINOLYSIS

This rare acquired disorder of haemostasis is in reality primary fibrinogenolysis because circulating plasmin is responsible for an uncontrolled proteolytic attack on the coagulation system (particularly factor VIII and fibrinogen). The disorder may complicate specific types of surgery (e.g. neurosurgery, pulmonary and prostate) or malignancy. Rapid recognition of this potentially devastating failure of haemostasis is essential if appropriate antifibrinolytic and blood component therapy (FFP and cryoprecipitate) is to be effective. With streptokinase and tissue plasminogen activator therapy of arterial and venous disease, problems of excess lysis may occur.

EXTRACORPOREAL CIRCULATION CARDIAC SURGERY

A range of haemostatic disturbances may be associated with extracorporeal circulation, most commonly cardiopulmonary bypass, and the clinician must constantly balance the risks of bleeding versus thrombosis.³⁹ The abnormalities are generally directly related to the time on bypass and are more likely to be seen in multiple valve replacements or re-operations. Fresh blood components have generally been advocated in cardiac bypass surgery to ensure optimal oxygen delivery and function of the haemostatic components of blood. Haemostatic failure usually becomes apparent in the operating room or soon after and appropriate laboratory investigations should be performed to allow logical therapy. It is pointless infusing large volumes of plasma products or platelets if heparin has not been adequately reversed. Increased fibrinolytic activity may in some cases also contribute to bleeding.

A predictable thrombocytopenia occurs after extracorporeal blood circulation. The postoperative platelet count in the majority of cardiac bypass patients is seldom below 100 000/μl, but platelet functional defects may contribute to bleeding and occasionally platelet concentrates are indicated. Increasingly, rFVIIa is being used to control bleeding associated with cardiac surgery. More evidence is required before definitive recommendations can be made.⁴⁰

THROMBOCYTOPENIA AND QUALITATIVE PLATELET DEFECTS

IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP)

ITP is an autoimmune disorder where autoantibodies (IgG) are directed against the platelets, which are subsequently destroyed by the monocyte–macrophage system, predominantly in the spleen. ITP is typically a disease of children and young adults. The acute form is more commonly identifiable as postinfectious, and recovery over weeks to months is the usual natural history. The course of the chronic form is variable and may spontaneously recover, but more commonly needs specific intervention.

Therapy of ITP remains controversial.⁴¹ Corticosteroids should generally be regarded as short-term therapy. In adults, the majority of patients respond with a rise in the platelet count. After an initial high dose (50–75 mg) of prednisolone a day until response occurs, the dose is gradually reduced. There is little evidence that corticosteroids will raise the platelet count in acute disease. However, their short-term role in reducing the incidence of bleeding, which is highest in the first weeks, may be important. High dose i.v. immunoglobulin is effective in most patients and is specifically indicated in fulminant acute disease, preoperatively and in pregnancy.

THROMBOTIC THROMBOCYTOPENIC PURPURA

Thrombotic thrombocytopenic purpura (TTP) is a disorder in which platelet aggregates form within the microvasculature, resulting in tissue ischaemia and infarction. Red blood cell fragmentation occurs, resulting in haemolysis, and the systemic platelet clumping leads to thrombocytopenia. This condition and its management are discussed in more detail in Chapter 90.

DRUG-INDUCED THROMBOCYTOPENIA

The clinical presentation of drug-induced thrombocytopenia may be as variable as ITP. Some may have a dramatic and fulminant presentation with marked haemostatic failure. Drugs with a particular reputation for inducing thrombocytopenia include quinine (also in bitter drinks), quinidine, antituberculous drugs, heparin, sedormid, thiazide diuretics, penicillins, sulphonamides, rifampicin and anticonvulsants.

Heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) is an important and potentially life-threatening complication of heparin therapy.⁴²^–⁴⁴ An immune reaction occurs to heparin after 7–10 days of therapy, at which time the patient’s platelets aggregate and thrombocytopenia develops; this reactivity can be demonstrated by a variety of laboratory tests. In contrast to other causes of drug-induced thrombocytopenia, there may be arterial, microvascular or venous thrombosis associated with the platelet aggregation. The best way to avoid this potentially devastating complication is to keep heparin therapy as brief as possible, and be always alert to the diagnostic possibility. The incidence is less with the use of LMW heparins, and if cross-reactivity is not demonstrated in the heparin antibody test, LMW heparins or heparinoids may have a part to play in therapy.

Quinine-induced immune thrombocytopenia with haemolytic uraemic syndrome (HUS) can be a severe drug reaction, characterised by the onset of chills, sweating, nausea and vomiting, abdominal pain, oliguria and petechial rash following quinine or quinidine exposure. Quinine-dependent platelet-reactive antibodies can usually be identified. Plasma exchange in conjunction with renal dialysis has been found to be a beneficial adjunct to therapy.