Guidelines for the Diagnosis and Management of Disseminated

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Guidelines for the diagnosis and management of disseminated

intravascular coagulation

Summary

The diagnosis of disseminated intravascular coagulation (DIC)

should encompass both clinical and laboratory information.

The International Society for Thrombosis and Haemostasis

(ISTH) DIC scoring system provides objective measurement of

DIC. Where DIC is present the scoring system correlates with

key clinical observations and outcomes. It is important to

repeat the tests to monitor the dynamically changing scenario

based on laboratory results and clinical observations. The

cornerstone of the treatment of DIC is treatment of theunderlying condition. Transfusion of platelets or plasma

(components) in patients with DIC should not primarily be

based on laboratory results and should in general be reserved

for patients who present with bleeding. In patients with DIC

and bleeding or at high risk of bleeding (e.g. postoperative

patients or patients due to undergo an invasive procedure) and

a platelet count of


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included. A draft guideline was produced by the writing group,

revised and agreed by consensus. Further comment was made

by the members of the haemostasis and thrombosis task force

of the BCSH. The guideline was reviewed by a sounding board

of approximately 40 UK haematologists, the BCSH and the

Committee of the British Society for Haematology and

comments were incorporated where appropriate. Criteria used

to quote levels and grades of evidence are as outlined in

Appendix 7 of the Procedure for Guidelines commissioned

by the BCSH (http://www.bcshguidelines.com/process1.asp#

appendix7) (see Appendix 1).

The guidance may not be appropriate for all patients and

individual patient circumstances may dictate an alternative

approach.

Disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC) is a clinicopath-

ological syndrome which complicates a range of illnesses. It is

characterised by systemic activation of pathways leading to andregulating coagulation, which can result in the generation of

fibrin clots that may cause organ failure with concomitant

consumption of platelets and coagulation factors that may

result in clinical bleeding (Fig 1). The spectrum of DIC and its

management are the subject of recent reviews (Levi, 2004,

2005). The purpose of this guideline is to briefly outline the

pathogenesis and associations of DIC and to review and grade

the evidence that is available with regard to the diagnosis and

treatment of the syndrome.

Associations and pathogenesis

DIC never occurs in isolation and recognition that a patient

has a clinical disorder which may result in the development of

DIC is the key to appropriate investigation and management.

DIC may arise in patients with a wide spectrum of disorders

including sepsis, malignancy, trauma, liver disease and vascular

anomalies. It is also seen when pregnancy is complicated by

placental abruption or amniotic fluid embolism and may

complicate poisoning, envenomation and major transfusion

reactions (Table I). All of these conditions share the ability to

induce systemic activation of coagulation either by activating

cytokines as part of a systemic inflammatory response or by

causing the release of, or exposure to, procoagulant substances.

The pathogenesis of DIC is complex and centres on the

enhanced generation of thrombin in vivo. The contributing

components include increased tissue factor expression, sub-

optimal function of natural anticoagulant systems, dysregula-

tion of fibrinolysis and increased anionic phospholipid

availability.

Diagnosis of DIC

There is no single laboratory test that can establish or rule out

the diagnosis of DIC. Thus, it is of utmost importance to assess

the whole clinical picture, taking into account the clinical

condition of the patient, the diagnosis, and all available

laboratory results. As such, a diagnosis of DIC should be made

based on an appropriate clinical suspicion supported by

relevant laboratory tests. Also, DIC is an extremely dynamic

situation and the tests are a snapshot of this dynamic state. In

addition, the underlying clinical condition can have an

influence on the laboratory tests. However, a combination oftests when repeated in a patient with a clinical condition

known to be associated with DIC can be used to diagnose the

disorder with reasonable certainty in most cases (Bick, 1996;

Levi et al, 1999; Toh & Dennis, 2003). This concept has been

taken into consideration by the International Society of

Thrombosis and Haemostasis (ISTH) (Taylor et al, 2001).

Laboratory studies used in the diagnosis and evaluation of

patients with DIC need to reflect the changes in haemostatic

function and keep pace with the critical nature of the

condition. Screening assays for haemostatic function, such as

Underlying disorder associated with DIC

Systemic activation of coagulation

Widespread fibrin deposition

Microvascular thrombosis

Organ failure

Bleeding

Thrombocytopenia and

coagulation factor

deficiency

Consumption of platelets

and coagulation factors

Fig 1. Processes in DIC.

Table I. Conditions associated with DIC.

Sepsis and severe infection

Trauma

Organ destruction e.g pancreatitis

Malignancy

Solid tumours

Leukaemia

Obstetric

Amniotic fluid embolism

Placental abruption

Pre-eclampsia

Vascular abnormalities

Large haemangiomata

Vascular aneurysm

Severe liver failure

Toxic and immunological insults

Snake bites

Recreational drugs

ABO transfusion incompatibility

Transplant rejection

Guideline

2009 Blackwell Publishing Ltd, British Journal of Haematology, 145, 2433 25


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the prothrombin time (PT), activated partial thromboplastin

time (aPTT) or platelet count, provide important evidence of

the degree of coagulation factor consumption and activation.

In addition, the extent of fibrin formation can be indirectly

gauged through measurements of its lysis, through assays such

as those that measure fibrin D-dimers. Also reviewed here are

other methods, available in some specialist laboratories, which

can measure specific parameters. The extent to which these add

to already available information from the above tests will be

discussed. An analysis of five reports of patient groups with

DIC, with a total of over 900 patients described suggests that

the laboratory abnormalities reported, in decreasing order of

frequency, are thrombocytopenia, elevated fibrin degradation

products, prolonged PT, prolonged aPTT, and a low fibrin-

ogen (Al-Mondhiry, 1975; Siegal et al, 1978; Mant & King,

1979; Spero et al, 1980; Wilde et al, 1989).

Platelet count

A reduction in the platelet count or a clear downward trend atsubsequent measurements is a sensitive (though not specific)

sign of DIC. Thrombocytopenia is a feature in up to 98% of

DIC cases with the platelet count


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aPTT do not exclude activation of the haemostatic system

(Olson et al, 1989) and repeat monitoring is required. It

should also be emphasised that the PT, not the International

Normalized Ratio (INR), that is to be monitored; the latter

being validated only for oral anticoagulant monitoring. The

thrombin time (TT) may be performed in ill patients with

suspected DIC. It does not have a place in the agreed scoring

system but may be used along with a reptilase time to

exclude heparin contamination of samples in patients with

prolonged APTT.

Fibrinogen

Measurement of fibrinogen has been widely advocated as a

useful tool for the diagnosis of DIC but in fact is not very

helpful in most cases (Levi & Ten, 1999). Fibrinogen acts as an

acute-phase reactant and despite ongoing consumption, plasma

levels can remain well within the normal range for a long period

of time. In a consecutive series of patients, the sensitivity of a

low fibrinogen level for the diagnosis of DIC was only 28% andhypofibrinogenemia was detected in very severe cases of DIC

only (Levi et al, 1999). Fibrinogen levels can be normal in as

many as 57% of patients (Spero et al, 1980). Sequential

measurements of fibrinogen might be more useful and provide

diagnostic clues. The BCSH guidelines on fibrinogen assays

suggest the use of the Clauss method in clinical situations where

DIC is suspected although it should be borne in mind that the

measured fibrinogen level may be influenced by interference on

the assay from high FDP levels (Mackie et al, 2003).

Blood film

Fragmented red blood cells, although reported in patients with

DIC, rarely constitute >10% of the red cells. However, in some

cases of chronic DIC with elevated D-dimers but normal

coagulation screening assay results, the presence of fragmented

red cells can provide confirmatory evidence (Spero et al, 1980).

The finding of fragments is neither sensitive nor specific to

DIC. When they are seen in increased numbers, other potential

diagnoses, such as thrombotic thrombocytopenic purpura

(TTP) and other causes of thrombotic microangiopathy,

should be considered.

Global haemostatic profiles

New point-of-care testing methods have been described based

on thromboelastography (TEG) techniques that have linked

diagnostic changes to haemostatic dysfunction (Zuckerman

et al, 1981). Though these tests have been reported to be

abnormal in septic patients, their diagnostic sensitivity/spec-

ificity for DIC is unclear (Collins et al, 2006). The prevailing

evidence for TEG use relates more to predicting blood loss in

cardiovascular surgery (Mongan & Hosking, 1992).

More recently, an atypical light transmittance profile on the

aPTT has been associated with DIC (Downey et al, 1997; Toh

et al, 2000). Referred to as the biphasic waveform, this

abnormality occurs independently of prolongation in the

clotting times and, through prospective studies, has been

shown to be a simple, rapid and robust indicator of DIC

(Downey et al, 1998; Bakhtiari et al, 2004; Dempfle et al,

2004b; Matsumoto et al, 2006). In a 1187-patient study on all

consecutive admissions into the intensive therapy unit, there

was an increasing positive predictive value for DIC with

increasing waveform abnormality and the latter often precede

any abnormality in the more conventional parameters used for

diagnosing DIC (Downey et al, 1998). However, its perfor-

mance is limited to specific photo-optical analysers that display

clot formation over time.

Other markers of haemostasis

The natural anticoagulants antithrombin and protein C are

often reduced in DIC and these have been shown to have

prognostic significance (Conway & Rosenberg, 1988; Fourrier

et al, 1992; Mesters et al, 1996; Faust et al, 2001). Theavailability of chromogenic assays rather than a reliance on

ELISA techniques has meant that results can be made available

more rapidly. Nonetheless, their general availability is still

limited and single determinations are neither sensitive nor

sufficiently specific for DIC.

In very rare cases purpura fulminans develops secondary to

profound acquired deficiency of protein S. This is most

commonly described following varicella infection. Although

management strategies for this specific indication are not clear

the association is notable.

Scoring system

The ISTH Sub-Committee of the Scientific and Standardiza-

tion Committee (SSC) on DIC has recommended the use of a

scoring system for overt DIC (Taylor et al, 2001; Toh & Hoots,

2007). Based on the Japanese Ministry of Health and Welfare

score, which has demonstrated a close correlation between an

increasing score and increasing mortality (Wada et al, 1995),

the ISTH criteria proposes a 5-step diagnostic algorithm to

calculate a DIC score, utilising simple laboratory tests that are

available in almost all hospital laboratories (Table II). The

presence of an underlying disorder known to be associated

with DIC is a prerequisite for the use of the algorithm. For

overt DIC, a cumulative score of five or more from prolongedPT, reduced platelets and fibrinogen, and elevated fibrin-

related markers (e.g. D-dimer or FDP) was proposed. The

scoring system pertains to conditions that are associated with

both acute onset DIC, e.g. sepsis, and chronic DIC, e.g.

vascular malformations and aneurysms.

The ISTH overt DIC score has been shown to be sensitive to

DIC of infective and non-infective aetiologies (Gando et al,

2005; Matsumoto et al, 2006). Compared to blinded expert

assessments for DIC, Bakhtiari et al(2004) found the sensitivity

of the ISTH overt DIC score to be 91% with a specificity of

Guideline



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97%. A strong correlation between an increasing DIC score and

mortality has been demonstrated by several studies, For each

DIC point, increases in the odds of mortality of 1 25129 have

been demonstrated (Bakhtiari et al, 2004). Several other studies

have similarly confirmed that the presence of overt DIC by the

ISTH algorithm is independently predictive of mortality

(Gando et al, 2005; Sivula et al, 2005; Cauchie et al, 2006).

These studies show that patients with sepsis and DIC, according

to the scoring system, have a significantly higher mortality of

43%, as compared with 27% in patients without DIC. Indeed,

scoring for DIC has added prognostic value in better predicting

mortality than the use of the acute physiology and chronic

health evaluation (APACHE) II scores alone (Angstwurm et al,

2006). For each DIC point in the system, the odds ratio (OR)

for mortality was 129, whereas in comparison, for each

APACHE point the OR for mortality was 107.

Recommendations

The diagnosis of DIC should encompass both clinical and

laboratory information (Grade C, Level IV).

The ISTH DIC scoring system provides objective mea-

surement of DIC. Where DIC is present, the scoring system

correlates with key clinical observations and outcomes

(Grade C, Level IV).It is important to repeat the tests to monitor the

dynamically changing scenario based on laboratory results

and clinical observations (Grade B, Level III).

Treatment of DIC

General

Key to the treatment of DIC is the specific and vigorous

treatment of the underlying disorder. In many cases the DIC

will spontaneously resolve when the underlying disorder is

properly managed. Examples are the administration of anti-

biotics and/or surgical drainage in patients with DIC due to

severe infection and sepsis. However, in some cases additional

supportive treatment, specifically aimed at the coagulation

abnormalities, may be required.

Recommendation

The cornerstone of the treatment of DIC is treatment of the

underlying condition (Grade C, Level IV).

Plasma and platelets

Low levels of platelets and coagulation factors may increase

the risk of bleeding. However, blood component therapy

should not be instituted on the basis of laboratory results

alone, but is indicated in patients with active bleeding, in

those requiring an invasive procedure and those who are

otherwise at risk for bleeding complications. The threshold fortransfusing platelets depends on the clinical state of the

patient. In general, platelet transfusion is administered to

patients who bleed and who have a platelet count of

240 109).

It may be necessary to use large volumes of plasma to correct

the coagulation defect. Initial doses of 15 ml/kg of fresh frozen

plasma (FFP) are suggested although there is evidence that a

dose of 30 ml/kg produces more complete correction of

coagulation factor levels. Coagulation factor concentrates, such

as prothrombin complex concentrate, come in small volumes,

but lack essential factors, such as factor V. Moreover, in older

literature caution is advocated with the use of prothrombin

complex concentrates in DIC, since it may worsen the

coagulopathy due to traces of activated factors in the

concentrate. It is, however, not clear whether this is still

relevant for the concentrates that are currently in use. Specific

deficiencies in fibrinogen can be corrected by administration of

purified fibrinogen concentrates or cryoprecipitate. A dose of3 g would be expected to raise plasma fibrinogen by around

1 g/l. This can be given as approximately four units of FFP,

two cryoprecipitate pools (10 donor units) or as 3 g of a

fibrinogen concentrate. The response to component therapy

should be monitored both clinically and by repeating platelet

counts and coagulation tests following administration.

There are some reports of the successful use of recombinant

factor VIIa in patients with DIC and life-threatening bleeding.

However, the efficacy and safety of this treatment in DIC is

unknown and it should be used with caution.

Table II. ISTH Diagnostic Scoring System for DIC.

Scoring system for overt DIC

Risk assessment: Does the patient have an underlying disorder

known to be associated with overt DIC?

If yes: proceed

If no: do not use this algorithm

Order global coagulation tests (PT, platelet count, fibrinogen,

fibrin related marker)

Score the test results

Platelet count (>100 109/l = 0,


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Recommendations

Transfusion of platelets or plasma (components) in patients

with DIC should not primarily be based on laboratory

results and should in general be reserved for patients that

present with bleeding (Grade C, Level IV).

In patients with DIC and bleeding or at high risk of

bleeding (e.g. postoperative patients or patients due to

undergo an invasive procedure) and a platelet count of


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placebo group (relative risk reduction 194%, 95% confidence

interval, 66305). A post hoc analysis showed that patients

with DIC had the highest benefit of activated protein C

treatment (Dhainaut et al, 2004). Later studies confirmed the

ability of activated protein C to normalise coagulation

activation during severe sepsis (De Pont et al, 2005).

Administration of recombinant human activated protein C

increases the risk of major bleeding from approximately 20%

to 35% and the risk of intracerebral haemorrhage from 01%

to 03%, respectively in septic patients (Bernard et al, 2003,

2004; Abraham et al, 2005). In all studies with recombinant

human activated protein C, patients with severe thrombocy-

topenia (


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committee of ongoing trials with recombinant thrombomod-

ulin (ART-123, Artisan, US).

C. H. Toh has three issued patents related to the aPTT wave

form.

J. Thachil has no conflict of interest to declare.

H. G. Watson has no conflict of interest to declare.

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Appendix 1

Classification of evidence levels

Ia Evidence obtained from meta-analysis of randomised

controlled trials.

Ib Evidence obtained from at least one randomised controlledtrial.

IIa Evidence obtained from at least one well-designed con-

trolled study without randomization.

IIb Evidence obtained from at least one other type of well-

designed quasi-experimental study*.

III Evidence obtained from well-designed non-experimental

descriptive studies, such as comparative studies, correlation

studies and case studies.

IV Evidence obtained from expert committee reports or

opinions and/or clinical experiences of respected author-

ities.

Classification of grades of recommendations

A Requires at least one randomised controlled trial as part of a

body of literature of overall good quality and consistency

addressing specific recommendation. (Evidence levels Ia,

Ib).

B Requires the availability of well conducted clinical studies

but no randomised clinical trials on the topic of recom-

mendation. (Evidence levels IIa, IIb, III).

C Requires evidence obtained from expert committee reports

or opinions and/or clinical experiences of respected author-

ities. Indicates an absence of directly applicable clinicalstudies of good quality. (Evidence level IV).

Guideline


Guidelines for the Diagnosis and Management of Disseminated

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