PRACTICAL THERAPEUTICS

Drugs 44 (6): 963-971. 1992

00 12-6667/92 /00 12-0963/$04 .50/0
© Adis International Limited . All rights reserved.
ORU1215

Disseminated Intravascular Coagulation

Approach to Treatment
Ronald N. Rubin and Robert W. Colman
Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA

Contents
963 Summary
963 I. Pathophysiology
965 2. Diagnosis
965 2.1 Laboratory Findings
966 2.2 Clinical Manifestations
967 3. Treatment Approaches
967 3.1 Management of Acute DIC
969 3.2 Management of Chronic DIC

Summary Disseminated intravascular coagulation (DIC) is a syndrome caused by the systemic genera-
tion of thrombin. Most cases are due to pathological activation of the intrinsic coagulation sys-
tems (e.g. in sepsis), and/or the extrinsic system (e.g. in malignancy and head trauma).
Diagnosis is made by finding abnormalities in at least 3 of 4 laboratory values, namely pro-
thrombin time, platelet count, fibrinogen and fibrinogen/fibrin degradation products. The most
common clinical manifestation of DIC is bleeding, with thrombosis in less than 10% of acute
cases but more frequently encountered in chronic DIC associated with malignancy. Acute DIC
must first be treated by specific therapy of the underlying disease and general support measures.
If serial clinical and laboratory monitoring improves, no further treatment is required. If severe
or life-threatening haemorrhage occurs or a thrombotic event ensues, heparin anticoagulation
followed by aggressive replacement with platelets, fresh plasma and possibly cryoprecipitate is
indicated. Heparin doses should be 'therapeutic' (i.e, adequate to overcome the coagulant forces
that may have produced a relative heparin-resistant state in the blood). Chronic DIe with haem-
orrhage, or more usually thrombosis, should also be treated with heparin; warfarin is ineffective.
If DIC persists because, for example, a tumour does not regress, long term outpatient subcutan-
eous heparin therapy may be required.

1. Pathophysiology temic circulation of patients. Clinical manifesta-

tions may include abnormal coagulation findings,
Disseminated intravascular coagulation (DIC) excessive bleeding, or clinical thrombosis either
is an intermediary syndrome that has as its genesis alone or in some combination. Nonetheless, all
the abnormal generation of thrombin in the sys- cases of DIC are traceable to an initial activation
964 Drugs 44 (6) 1992

of the coagulation cascade and the subsequent gen- Table II. Pathophysiological classification of disseminated
eration of thrombin. Studies have classified under- intravascular coagulation by method of coagulation cascade
activation
lying aetiologies, usually showing high incidence
rates for infections, neoplasm or trauma (Baker Extrinsic pathway Intrinsic pathway
1989; Deykin 1970; Robboy et al. 1972) [Massa-
Neoplasms Gram-negative
chusetts General Hospital in table I). Careful eval-
Acute promyeloctic infections
uation of these apparently disparate situations leukaemia
demonstrates, however, that most cases of DIC are Prostate carcinoma Gram-positive
associated either with pathological activation of the Pancreatic carcinoma infections
contact (intrinsic) coagulation pathway, as best ex- (Trousseau's syndrome)
Massive trauma Viraemias/
emplified by Gram-negative sepsis, or with exces-
rickettsiae
sive presence of tissue factor(s) in the circulation Brain trauma
with activation of the extrinsic coagulation path- Obstetric emergencies
way as seen in carcinomatosis, obstetric emergen- Abruptio placentae
cies or massive trauma (table II). Amniotic fluid embolism

Table I. Pathophysiological classification of disseminated

intravascular coagulation by initiating disease - Massachusetts
General Hospital 1972 (MGH) [Robboy et al. 19721and Temple We reviewed our recent experience of DIC at
University Hospital 1990 (TUH) [Rubin et al. 19901 Temple University Hospital, and demonstrated that
Number of episodes (%)
infection and trauma are leading causative patho-
physiological mechanisms for DIC in a general
MGH TUH
hospital setting (table I). A striking finding was the
I. Tissue injury/damage number ofbrain trauma cases associated with Ole.
Obstetric 1 (2%) 1 (2.5%) This finding supports the hypothesis of tissue fac-
complicat ion tor activation as a trigger for DIC, since animal
Neoplasia 3 (7.5%)
brain extracts have traditionally been used in co-
Adenocarcinoma 7 (12%)
Leukaemia/lymphoma 11 (18%)
agulation laboratories to initiate thrombin gener-
Surgery/trauma 6 (10%) ation in vitro (Van der Sande et al. 1981).
Head trauma 8 (20%) Although thrombin is the keystone effector pro-
Other 2(5%) tein in DIC, other related protein systems may also
II. Endothelial injury be involved. The intrinsic pathway, once activated,
factor XII activation generates bradykinin via factor Xlla and kallikrein
Infections 21 (52.5%)
(Kluft et al. 1987). Bradykinin is a potent vaso-
Gram-negative 6 (10%)
dilator that is probably partially responsible for the
septicaemia
Neisseria meningitis 9 (15%) hypotension associated with Gram-negative sepsis
Gram-pos itive 8 (13%) and Ole. Thrombin itself has the capacity to re-
septicaemia lease plasminogen activators from the endothelial
Viraemia 2 (3%) cells, thus resulting in the activation of the plas-
Other infections 2 (3%)
minogen-plasmin system , which leads to the sec-
III. Miscellaneous 8 (13%) ondary fibrinolysis encountered in most cases of
conditions
DIC (Levin et al. 1984; Sherry 1992). In some cases
Hyper- or 2(5%)
hypothermia
the secondary effects, such as hypotension or sev-
Unknown 3 (7.5%) ere coagulopathy with bleeding due to fibrinolysis
40
and fibrinogen depletion, can completely dominate
Total 60
a DIC picture and obscure the part played by
Disseminated Intravascular Coagulation 965

thrombin. Clinicians must not forget the primary nately, because of the rapid in vivo decrease of such
role of thrombin generation and must concentrate comple xes, it is of limited value. The effects of
their efforts on arresting its formation. The com- thrombin that are measurable include the follow-
plex interactions between the coagulation cascade, ing: formation of fibrin monomers; cleavage of
related protease pathways and DIC are summar- thrombin-specific fibrinopeptides from plasma fib-
ised in figure I. rinogen; production of activated forms of factors
V and VIII; depletion of plasma fibrinogen; aggre-
gation of platelets with resultant thrombocyto-
2. Diagnosis
penia; eventual consumption and depletion of clot-
2.1 Laboratory Findings
ting moieties (such as factors V and VIII) and
clotting inhibitors (such as antithrombin III); and
The above discussion of the pathophysiological secondary activation of plasmin, which further de-
principles involved in DIC syndromes enables hy- pletes fibrinogen by digestion into measurable fib-
potheses to be formulated about laboratory find- rinogen/fibrin degradation products (FOP) that are
ings that might be expected in cases of Ole. readily measurable in serum.
The most direct test would be a measurement Many of the findings listed above lack specific-
of plasma thrombin, which should be elevated . ity or are technically prohibitive for bedside use.
Since thrombin is rapidly inhibited by antithrom- However , a set of data has evolved which corre-
bin III, the closest approach is the measure of lates well with tissue documentation of micro-
thrombin-antithrombin III comple xes. Unfortu- thrombi in the circulation in affected patients as

, . . . - - -- - ..... Cl

1
/c1~

I
Proteases C2 C2 C4-'C4
1---- - -.. Basement -----..... XII
<--':'-'--~ _"',oo~

- Xlla • XIII HMWK

vllI. --- ~HMWKI ~

. . --------i
Kallikrein-----,

Y j
X I - ' Xla Bradykinin

To'" tactor + V'"---------. 1'""_I • Plasm in

~L IX~IXa~/ :: t-PA/ 'S~;;'~A

""'=~='"' X~Xa-...J
PLl~
I Prothrombin I • Thrombin - ---+ FOP

Fig. 1. Plasma protease interactions in disseminated intravascular coagulation. A broken line indicates a reaction demon-
strated only in vitro. Abbreviations: t-PA = tissue plasminogen activator ; u-PA = urokinase ; Scu-PA = saruplase ;
FDP = fibrinogen/fibrin degradat ion products ; HMWK = high molecular weight kininogen; CI , C2, C4 = first, second and
fourth component of complement; PL = platelets.
966 Drugs 44 (6) 1992

Table III. Laboratory criteria for disseminated intravascular 2.2 Clinical Manifestations
coagulation (DIC)

Determination Normal Mean value in

The clinical manifestations of DIC are protean,
DIC(%) as a result of 2 factors. Firstly, as discussed above,
MGH (1972) DIC is an intermediary syndrome invariably caused
by a coexisting primary disease which can vary from
Platelet count (X 109/ L) 150-400 52 (93)a
Prothrombin time (sec) 12 ± 1 18 (90)a abruptio placentae to carcinomatosis or meningo-
Fibrinogen (mg{dl) 2.5 ± 0.5 137 (71)a coccaemia. Thus, very frequently patients will more
predominantly display signs and symptoms of the
a Numbers in parentheses indicate the percentage of patients
with DIC meeting the criteria .
primary disease rather than those of DIC itself.
Abbreviation: MGH = Massachusetts General Hospital (from Secondly, the pathogenesis of DIC involves pri-
Robboy et al. 1972). mary thrombin generation and clotting, but then
frequently results in depletion of coagulation fac-
tors and platelets as well as secondary fibrinolysis,
factors that cause a haemorrhagic state. Thus, a
population of DIC patients theoretically can, and
well as with corroboration by the more technically indeed do, manifest microvascular or macrovas-
difficult methods (Colman et al. 1979; Spero et al. cular thrombosis, severe and often multiple-site
1980). These readily available bedside studies in- haemorrhage, or laboratory abnormality alone
clude prothrombin time (PT), plasma fibrinogen (Baker 1989; Deykin 1970; Robboy et al. 1972)
level, platelet count and measurement ofFDP titre [table IV]. In fact, all of the above may be en-
(table III). When the PT, fibrinogen and platelet countered serially or simultaneously in the same
criteria are all present, DIC is diagnosed with patient.
greater than 90% certainty. If 2 of these 3 are pre- The most common manifestation in DIC
sent, the presence of high titres of FDP results in patients is bleeding. The skin is the usual initial
diagnostic accuracy also approaching 90% (Colman
et al. 1979; Spero et al. 1980). These clinical la- Table IV. Clinical presentation of disseminated intravascular
coagulation
boratory criteria are not perfect, with occasional
cases manifesting the criteria without documenta- Manifestation Incidence (%)
ble DIC (e.g. severe liver disease with coagulation MGH TUH
factor synthesis being impaired, and secondary (54 episodes) (40 episodes)
portal hypertension and hypersplenism lowering
Bleeding 78 40
platelets), and conversely occasional cases with Single site (excluding 6 5
documentable DIC not manifesting a majority of purpura)
these criteria (e.g. DIC in cancer or sepsis mani- Purpura or petechiae only 20 5
festing a normal fibrinogen level). Since plasma Multiple sites 52 30
fibrinogen, an acute phase protein, is usually ele- Thrombosis 9 7.5
vated in such conditions, a normal fibrinogen level Clinically evident 2 2.5
Acral cyanosis 7 2.5
represents a relative hypofibrinogenaemia (Kies et
Microangiopathic haemolysis - 2.5
al. 1980; Rubin et al. 1980). With these few excep-
Abnormal laboratory values 13 52.5
tions, however, proper clinical evaluation com-
only
bined with the classical laboratory tests discussed
above will enable the clinician to empirically di- Abbreviations: MGH = Massachusetts General Hospital (from
Robboy et al. 1972); TUH = Temple University Hospital (from
agnose the presence of DIC with quite a high de- Rubin et al, 1990).
gree of specificity.
Disseminated Intravascular Coagulation 967

site but any site of an invasive procedure (e.g. sur- 3.1 Management of Acute DIC
gical wound, catheter, punctures) or concomitant
pathology (e.g. mucosal erosions) will usually be Patients with acute DIC are commonly criti-
involved as well. Haemorrhage is often subacute, cally ill, often in intensive care units . Thus, the
but with surgical wounds or obstetrical complica- most important therapeutic measures are those di-
tions, bleeding may be massive and acutely life- rected toward ameliorating the underlying disease
threatening. and general patient support measures, including
Thrombosis alone is not common, occurring in fluid replacement, maintenance of blood pressure ,
less than 10% of cases. An exception to this is the and tissue oxygenation. The clinician must then as-
group of patients with a more chronic form ofDIC sess the patient's immediate response to these
associated with malignancy (Trousseau's syn- therapeutic measures and determine if they will al-
low the patient to improve, and assess whether there
drome) in whom refractory migratory and recur-
is a good chance for reasonably rapid, spontaneous
rent thromboembolic episodes are the main feature
recovery . It must be stressed that careful and serial
of the disease (Colman & Rubin 1990; Sack et al.
clinical and laboratory monitoring must be carried
1977). In the more traditional cases, microthrom-
out after the diagnosis is made. In the improving
boses may complicate the picture and manifest as
patient or an individual with a self-limited con-
livido reticularis and severe acral cyanosis, renal
dition causing DIC, no further treatment may be
failure independent of hypotension or obtundation required. However, life-threatening or progressive,
and neurological symptoms. On occasion, an ac- severe continued haemorrhage or a thrombotic
tual skin infarction or digital gangrene is encoun- event due to DIC warrants interruption of throm-
tered. bin formation by heparin anticoagulation, followed
A rare clinical variant of DIC associated with by aggressive replacement treatment with platelets,
extensive microscopic fibrin thrombus deposition fresh plasma and possibly cryoprecipitate. Heparin
is microangiopathic haemolytic anaemia (MAHA), therapy alone may temporarily aggravate bleeding
where the fibrin mesh in the microscopic circula- since the coagulation proteins must be synthesised
tion causes a mechanical, shearing haemolysis of in the liver , the FDP cleared and the platelets pro-
erythrocytes and a severe, unrelenting haemolytic duced by the bone marrow, all of which are time-
anaemia (Kwaan 1987). consuming processes. Similarly, replacement
Laboratory manifestations (see section 2.1) are therapy alone usually is of little avail because of
part of the diagnostic criteria for the syndrome. In the rapid 'consumption' of coagulant proteins and
a significant proportion of cases, laboratory ab- platelets.
normality may be the only manifestation of the Heparin was first successfully used in acute ,
syndrome. With the advent of intensive care med- severe DIC ('purpura fulminans') by Little (1959).
icine, more frequent monitoring of patients and Descriptions of the seemingly paradoxical use of
earlier treatment intervention, we suspect this is an anticoagulant in patients with bleeding mani-
becoming more common (table IV). festations have been reported since then (Allen
1966; Colman et al. 1972; Hjort et al. 1964; Mer-
skey et al. 1967), and benefit both in control of
3. Treatment Approaches clinical symptoms and in survival has been re-
ported (Mant & King 1979).
It has been stated that heparin has significant
To consider the clinical management, it is use- limitations and complications, and may be inef-
ful to divide DIC into acute and chronic, since the fective in the treatment of DIC (Corrigan et al.
former usually presents with bleeding and the lat- 1968; Green et al. 1972; Klein & Bell 1974; Siegel
ter frequently presents with a thrombotic disorder. & Brodsky 1970), or at least that it has not been
968 Drugs 44 (6) 1992

proved experimentally to be of value in such tithrombin III may make heparin less effective. A
patients (Deykin 1970; Straub 1975). This opinion bolus intravenous injection of ~ 10 OOOU may then
has however been derived from studies where be followed by continuous intravenous adminis-
groups of patients with a similar underlying con- tration. Immediately after the heparin has been in-
dition (e.g. sepsis), but with varying degrees of stituted, the bleeding diathesis should be treated by
complicating consumptive thrombohaemorrhagic replenishing the depleted supply of platelets and
disease, were subjected to an uncontrolled study of clotting factors through the use of platelet concen-
heparin efficacy. Since no prospective, random- trates, fresh frozen plasma for factors V and VIII,
ised, controlled study investigating the efficacy of and cryoprecipitate as a source of fibrinogen. An
heparin in DIC has apparently been published to increase of 5 to lOX 109 platelets/L and 0.15 gIL
date, the dilemma for the practitioner is whether of fibrinogen for each respective 'pack' should be
or not to treat a patient because of this lack of data, expected. If consumption is effectively inhibited,
or to utilise the experience with individual cases the infused material will circulate, and blood levels
of severe DIC in which heparin may have been will increase accordingly. From a practical view-
beneficial. point, any increase in platelet count or plasma fib-
An approach to management should concen- rinogen level, or a decrease in the FOP or pro-
trate on the patient's clinical situation. If only la- thrombin time, is an encouraging indication that
boratory evidence of DIC exists without active the consumption process has been interrupted and
bleeding and/or thrombosis, basic support meas- that bleeding is becoming controlled. Failure to
ures and treatment of the underlying disorder raise the suppressed plasma fibrinogen level or to
should suffice. Examples of such situations include decrease the FOP or the elevated prothrombin time
early and effective treatment of infection during probably means that consumption has continued.
sepsis or rapid evacuation of the uterus in patients The possibility that antithrombin III deficiency in
with intrauterine fetal death. The physician should DIC contributes to the severity of the disorder has
be aware of the possibility of 'laboratory' DIC prompted studies of replacement of antithrombin
evolving into clinical DIC and should repeat the III using plasma or concentrates of antithrombin
coagulation studies to document improvement. III (Sunder-Plassmann et al. 1991). While encour-
However, if the haemorrhagic and/or thrombotic aging, these studies are equivocal, perhaps because
complications remain clinically severe and prog- of the wide clinical variability, and more definitive
ress, active transfusion support and anti thrombotic study is needed to establish a basis for such therapy.
therapy (heparin) may be necessary (table V). Such With adequate therapy, the clinical expectation
situations may be encountered in cases of purpura is for bleeding to decrease, although it may require
fulminans, septic shock, and DIC induced by cyto- some days to cease fully. One source of confusion
toxic chemotherapy. in treating presumed DIC is when a patient does
Heparin is administered primarily to inhibit the well despite treatment being 'incorrect' (e.g. trans-
formation of microthrombi, although the domi- fusion without prior heparin administration). Such
nant clinical feature may be haemorrhage. The dose a conclusion may stem from the failure to fully
of heparin should be 'therapeutic', that is, adequate evaluate the contribution made by the improve-
to overcome the coagulant forces that may have ment in the underlying disease, either through its
produced a relative heparin-resistant state in the natural course or because of therapeutic interven-
blood (Colman et al. 1972). Since increased coag- tion . For example, the results of the initial admin-
.ulant activity is present, low dose heparin does not istration of plasma to a patient with abruptio pla-
seem to be indicated. Further, the presence of in- centae (Bachmann 1969; Coopland et al. 1968;
creasing heparin-neutralising components, such as Pritchard & Brekken 1967; Van der Meer et al.
platelet factor 4 or {j-thromboglobulin, also dictate 1966), in whom consumption may be localised in
high doses of heparin. In addition, depletion of an- the uterus, but in whom bleeding is severe and la-
Disseminated Intravascular Coagulation 969

Table V. Treatment of acute, severe disseminated intravascular coagulation (adapted with permission from Colman et at, 1987)

Modality Rationale Comments Expected result

Life-support measures Self-evident Fluids. blood . respiratory care. Maintain cardiac output . gas
pressors, etc. exchange , electrolyte balance.
etc.

Treating the underlying To correct the cause of DIC Dependent on the primary Inhibit or block the complicating
disorder diagnosis pathological mechanism of DIC
in parallel with the response (if
any) of the disorder

Antithrombotic agents To block microthrombus 'Therapeutic ' doses of heparin Prevent fibrin formation , tip the
formation by continuous intravenous balance within the
infusion ; monitor by plasma microcirculation toward
fibrinogen level; continue as long physiological fibrinolysis, allow
as the predisposing clinical state reperfusion of the skin, kidneys,
persists and brain

Transfusion To re-establish normal Infuse platelets and Platelet count and plasma
haemostatic potential once cryoprecipitate for fibrinogen fibrinogen should increase to
thrombosis is blocked by and factors V and VII; repeat as 50% of normal if consumption is
heparin indicated by laboratory and blocked ; bleeding should
clinical observation diminish and stop during an
interval of hours to several days

boratory evidence of DIC is striking. Since the pri- of microthrombi from occluded renal and cerebral
mary course of action in this case is to evacuate vessels may be delayed. Thus, when fibrinolytic in-
the uterus, consumption is effectively terminated; hibitors were administered to patients with severe
coagulant factors or cryoprecipitate then correct the DIC without prior heparinisation, this resulted in
blood deficiency state. Heparin in this circum- catastrophic worsening of the thrombotic state
stance could cause bleeding during the anticipated (Gralnick & Greipp 1971 ; Naeye 1962). Because of
surgical procedure that relieves the patient ofthe this potential for limiting the physiological recov-
underlying pathological process (Pritchard 1968). ery from DIC, fibrinolytic inhibitors are rarely
In contrast, a septic abortion in which DIC is also added to the regimen.
present may not have a benign course (Clarkson et
al. 1969; Heene 1977) even after evacuation of the 3.2 Management of Chronic DIC
uterus. The failure to administer heparin allows
consumption to progress, since the concomitant Although the same general principles apply, the
antibiotic treatment can effectively eliminate the clinical presentation and course of chronic DIC
infection only with the passage of time. states suggest alternative approaches. In contrast to
Since an excessive level of fibrin degradation the acutely ill patient with complicating, severe
products in the blood may contribute to the hae- DIC, other patients may have mild or protracted
morrhagic diathesis, fibrinolytic inhibitors such as clinical manifestations of consumption, or even
aminocaproic acid or tranexamic acid seem ra- subclinical disease manifested only by laboratory
tional to curtail the lysis of microthrombi. The use abnormalities (Colman et al. 1979; Sack et al. 1977;
of fibrinolytic inhibitors may improve haemostasis Straub 1971). The clinical picture generally occurs
by increasing the stability .of newly formed hae- in patients with long-standing illnesses such as
mostatic plugs, but , at the same time, the clearance neoplasms (Anon. 1978; Kierulf & Godal 1972;
970 Drugs 44 (6) 1992

Corrigan JJ Jr, Ray WL, May N. Changes in the blood coagu-

Mosesson et al. 1968; Sack et al. 1977) or auto- lation system associated with septicemia. New England Jour-
immune disease (Nossel et al. 1969). A haemor- nal of Medicine 279: 85 1-856, 1968
Deykin D. The clinical challenge of disseminated intravascular
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Graln ick HR, Greipp P. Thrombosis with epsilon aminocaproic
but even thrombotic processes such as stroke could acid therap y. American Journal of Clinical Pathology 56: 151-
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Green D, Seeler RA, Allen N, Alavi IA. The role of heparin in
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Sack and colleagues (1977), isolated venous throm- mostasis 3: 291, 1977
Hjort PF, Rapaport SI, Jorgensen L. Purpura fulminans: Report
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Kies MS, Posch JJ, Giolma JP , Rubin RN. Hemostatic function
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