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DISSEMINATED INTRAVASCULAR COAGULATION

M. VERSTRAETE
Center for Thrombosis and Vascular Research, Department of Medical Research, Campus Gasthuisberg, University of Leuven, B-3000 Leuven, Belgium.

In a dynamic circulatory system, acceleration of the blood coagulation sometimes followed by a secondary activation of the fibrinolytic system, develops in a hypercoagulable state, which can lead to an increased consumption of platelets and of some clotting factors. These changes, which may occur rapidly or at a more chronic pace, can induce an abnormal bleeding, small-vessel obstruction and single or multiple organ dysfunction; even latent forms exist. As well the clinical picture as the pattern of laboratory results most often are complex and change by the hour as the background situation worsens or improves (1,2).

The term disseminated intravascular coagulation (D.I.C.) is not entirely correct but came into use when it was recognized that, in both experimental and clinical conditions, accelerated fibrin deposition in various organs, e.g brain, kidney, lung, could be a result of defibrination; it is thought likely that in normal conditions fibrin is continuously being formed-on the vascular wall and lysed at a slow rate. The acceleration of this normal condition is termed D.I.C., which is not a disease in itself; it is a pathophysiological reaction with many apparently different aetiologies, and any discussion of diagnosis and management must first examine the underlying mechanism as they affect man.

THE EXPERIMENTAL MODEL

Numerous clinical conditions are known in which D.I.C. can occur (Table 1) many of the detailed studies on the pathogenic mechanism involved have been made by necessity in laboratory animals, particularly in the generalized Schwartzman reaction in the rabbit.

The intravenous injection of thrombin, thromboplastin, some snake venoms, or successive injections of Escherichia coli endotoxin can induce the entire spectrum of D.I.C. in animals. The former three examples are direct triggers which activate the coagulation cascade at several intermediate stages, leading to thrombin generation, fibrin deposition, platelet consumption with tissue damage, and concomitant (reactive) fibrinolysis. Endotoxins and antigen-antibody complexes cannot activate the coagulation sequence directly but will do so only when they link with certain mediators and then may work only by damaging tissues and relaxing a direct trigger.

TABLE 1
CLINICAL CONDITIONS WHICH CAN BE ASSOCIATED WITH DISSEMINATED INTRAVASCULAR COAGULATION

Acute forms :

o amniotic fluid embolism

o septic abortion

o fat embolism

o incompatible blood transfusion

o oligaemic shock

o snake bite

o massive trauma

Subacute forms

o abruptio placentoe

o eclampsia

o acute hepatic failure

o burns

o cardiac surgery

o dissecting aortic aneurysm

o haemolytic uraemic syndrome (Gasser-syndrome)

o head injury

o heat stroke

o respiratory distress syndrome

o severe haemolytic disease of the newborn

o thrombotic thrombocytopenic purpura

o numerous infections (Aspergillosis, Ebola, Dengue, Malaria, psittacosis, Rocky mountain spotted fever, septicaemia to various microorganisms, typhoid fever, yellow fever)

Chronic forms

o hydatiform mole

o pre-eclampsia

o dead foetus syndrome

o giant haemangioma (Kasabach-Merritt syndrome)

o neuroblastoma

o carcinomatosis

o decompensated liver cirrhosis

o organ transplantation

o splenectomy

o siccle-cell disease

o purpura gangrenosa

o malignant hypertension

o disseminated lupus erythematosus

PATHOGENESIS IN MAN

Three major types of cell injury may activate the coagulation system in man (3):

1. injury or damage to the endothelial cell (e.g. in many microbial illnesses, antigen-antibody complexes), which by impeding prostacyclin formation (PG12) favours platelet deposition against the vascular wall; in addition any exposure of collagen to the circulating blood activates the coagulation factor XII (Hageman factor) and subsequently the coagulation cascade through the intrinsic pathway,

2. tissue injury (e.g. in diffuse malignancy, abruptio placentae), which releases tissue thromboplastin and in the presence of factor VII activates the extrinsic coagulation system, and

3. red cell (e.g. malaria or incompatible blood transfusion), leucocytes or platelet injury, which increases the availability of phospholipid, a component needed for both the intrinsic and extrinsic coagulation systems.

The outcome of these different initiating mechanisms is the formation of the serine protease factor X, which converts prothrombin to thrombin in the circulating blood. In case the activated coagulation factors cannot be rapidly cleared by the liver, a widespread fibrin deposition due to free thrombin activity may follow, and fibrinogen derivatives, as well as fibrin monomers formed due to excessive enzyme-induced proteolysis. A secondary fibrinolytic response to fibrin deposition results from activation of the plasminogen activator from endothelium. The plasmin thus formed can exaggerate the hypofibrinogenaemia and generates fibrin-(ogen) degradation products (FDP). Some Of the larger FDP (fragments X and Y) have a direct antithrombin action and the smaller D and E fragments interfere with fibrin formation by inhibiting its polymerisation; smaller polypeptides also inhibit some platelet functions.

Coagulation components besides fibrinogen which are normally consumed during the coagulation process are f.i. prothrombin, factor V and factor VIII. Platelet counts drop as aggregation occurs and as platelets are incorporated in microthrombi and to exposed collagen.

The amount of fibrin deposited in tissues is generally highest in the smallest vessels but may be influenced by the local rate of blood flow and the activity of local clearance mechanisms. The effects of fibrin deposition are those of ischaemia of the organ concerned (e.g. renal cortex, lung, pituitary, adrenals, liver, brain, spleen, skin, gastrointestinal tract ... ), varying from minor hypoperfusion to infarction. Passage of red cells through fibrin strands can also cause red blood cell distortion and fragmentation and subsequent haemolysis (microangiopathic haemolytic anaemia). Damaged red cells may also release ADP causing further local platelet aggregation.

Once the praecursor of the Hageman factor (XII) is being converted, it can activate directly or indirectly three other proteolytic enzyme precursors present in plasma : prekallikrein (resulting in the formation of the potent vasodilator bradykinin), complement (the first component) and the already mentioned plasminogen system.

LABORATORY RECOGNITION OF D.I.C.

Diffuse intravascular coagulation present both the haematologist and clinician with three dilemmas. First the dilemma of clinical suspicion, then the dilemma of timely recognition by laboratory tests and finally with the dilemma of whether and how to treat the condition.

Clinical suspicion of the existence of D.I.C. is often low down on the list of differential diagnoses in any peculiar clinical situation. By the time the appropriate laboratory tests are carried out and reported, the picture is already confused by previous antibiotic and steroid therapy, fluid replacement and often blood transfusion : D.I.C. is indeed not a static state - it changes by the hour for better or for worse. Laboratory tests must provide rapid results for sensible decisions. Not one test is diagnostic; collating several results may give a pattern compatible with D.I.C. at the time the blood samples were taken.

Two dogmatic statements can be made : (a) only absolute normality of all tests to be described excludes D.I.C. at time of testing and (b) the results of one set of tests giving abnormal results can be misleading and repetition at frequent intervals is therefore essential.

The tests which give results within one hour are valuable and useful; tests which take several hours are of little use as a guide to diagnosis or treatment of the acute clinical problem, but can give valuable information on the more rare forms of chronic D.I.C.

Tests giving a result within one hour

1. Packed cell volume : a centrifuges blood sample may reveal anaemia, jaundice or intravascular haemolysis.

2. Blood film : the classical appearance of fragmented or distorted red cells (Burr-cells) are most often seen in acute cases and suggest subacute D.I.C. when present; Burr-cells suggest that fibrin was deposited in the kidney or that carcinomatosis exists; artificial heart valves also cause fragmentation of red cells. Distorted red cells have a low sedimentation rate except when the fibrinogen level is very low.

3. Platelet count : in the presence of a normal platelet count D.I.C. is less likely or exists in a compensated form. Mechanical particle counters should not be relied on as they also count "debris" or dust that circulates in D.I.C.; phase contrast microscopy is therefore to be recommended.

4. Plasma thrombin clotting time : especially when made more sensitive by dilution of the thrombin to give a clotting time in normal plasma of 16-18 seconds (circa 2.5 units thrombin/ml) is a simple test measuring depletion of fibrinogen or the presence of fibrin(ogen) degradation products which interfere with the proteolytic action of thrombin or the rate of fibrin polymerisation.

5. Plasma reptilase clotting time : this snake enzyme (Available as a laboratory reagent from Pentapharm, Bazel.) is also sensitive to FDP but is not affected by heparin which not infrequently is used in these circumstances.

6. Fibrinogen level : a rapid estimation of fibrinogen is very useful as this level is often drastically reduced in overt decompensated D.I.C. Rapid methods based on the polymerisation time are less sensitive to fibrin(ogen) degradation products (F.P.T.-Dil (Fibrinogen Polymerization Time Test, A. Christiaens Pharmaceuticals S.A., Brussels)) (4). The fibrinogen titre, using doubling dilution of citrated plasma while not strictly scientific, shows linearity when compared with other methods (unless the fibrinogen drops to less than 0.5 g/1) and provides reliable and reproducible results in unskilled hands.

7. The one stage prothrombin time : is a simple and useful confirmatory test as it measures depletion of factor V and fibrinogen but is also sensitive to fibrin(ogen) degradation products and can therefore be is leading.

8. Specific assay for factor V : has a confirmatory nature.

9. Ethanol gel or protamine sulphate precipitation test : thrombin splits two fibrinopeptides (A and B) from fibrinogen leaving fibrin monomers which form soluble macromolecular complexes with fibrinogen (mol.wt.+ 1.000.000). Alternatively when fibrin or fibrinogen is broken down by plasmin the two largest fragments (X and Y) are still thrombin clottable and can form large soluble molecule complexes with fibrinogen or fibrin monomer. These macromolecules can produce a gel when 70% ethanol is added 6. The complexes dissociate in the presence of protamine sulphate 7 so that fibrin monomers now polymerize to fibrin and precipitate. The ethanol test is the more reproducible one and suggests that monomer-complexes or monomer-X-Y-complexes exist, and therefore that thrombin is being generated at the time of testing.

10. Assessment of antithrombin III - thrombin complex : this approach is based on the finding that the antithrombin III molecule may be altered when it complexes with thrombin and a neoantigen is being exposed. A simple latex test (8) is presently being evaluated at a larger scale and provided its sensitivity and specificity are high enough and relate well with diffuse intravascular thrombosis, a simple method for its detection would become available.

INTERESTING BUT TIME CONSUMING TESTS

Fibrin(ogen) degradation products (FDP) in serum : the larger fragments (X,Y,D,E) formed when fibrinogen or fibrin is degraded by plasmin still retain the antigenetic sites of the fibrin(ogen) molecule; the smaller fragments subsequently broken down not. Therefore the four larger fragments can be detected in serum by various immunoassay techniques in serum, after clottable fibrin has been removed and in vitro lysis prevented. These tests do not differentiate fibrin degradation proclucts from those of fibrinogen and are timeconsuming. The most commonly used techniques are the tanned red-cell haemagglutination inhibition immunoassay (Wellcome kit HA-14) (9,10) and two forms of agglutination tests (Wellcome kit HA-13, Thrombo-Wellcotest) (11,12).

In addition, fibrinogen degradation products have a brief life and can disappear from the circulation in a few hours after an isolated episode of D.I.C.

Specific assay for factor VIII is reliable only in this context when a twostage assay is performed which again is neither simple nor rapid.

OTHER, LESS USEFUL AND MOST OFTEN TIME-CONSUMING TESTS

Factor VIII-antigen : one knows that the factor VIII molecule loses its coagulant activity during activation but retains its immunological reactivity as can be demonstrated using serum. In plasma the coagulant part and the factor VIIIantigen part are usually present in a 1:1 ratio in the factor VIII molecule. In D.I.C. the coagulant fraction drops and the factor VIII-antigen rises (13).

Fibrinopeptide A : is being split off from the A alpha chain of fibrinogen by thrombin and can be measured; would a simple assay exist it would be highly interesting to diagnose incipient D.I.C. (14)

ß2-thromboglobulin : is a platelet-specific protein released when platelets are damaged and can be measured by an immunoassay (15).

Platelet factor 4 : is a heparin inhibiting activity released when platelets are damaged. Its assay is not very sensitive except by an immunotechnique which is time-consuming.

Plasminogen : its level can be lower when the secondary lysis is intense; this information is therefore confirmatory only.

DECOMPENSATED, COMPENSATED AND OVERCOMPENSATED D.I.C.

Three main patterns of laboratory results can be obtained in D.I.C. : decompensated, compensated and overcompensated intravascular coagulation (16,17).

TABLE 2 (according to Sharp, 1977) (18)
PATTERN OF LABORATORY RESULTS TO BE EXPECTED IN D.I.C.

 

Decompensated


Compensated


Over-compensated


Platelet count


Reduced (lte 100.000 μl)


Normal or reduced


Normal


Plasma thrombin time


Prolonged ++


Prolonged +


Prolonged + or +-


Plasma Reptilase time


Prolonged ++


Prolonged +


Prolonged + or +-


Fibrinogen level


Reduced


Normal


Raised


Fibrin(ogen) degradation product level


Raised ++


Raised +


Raised +


One-stage prothrombin time


Prolonged


Normal


Normal


Activated partial thromboplastin time


Prolonged


Normal


Shortened


Factor VIII level


Reduced


Normal


Raised


Ethanol gel test


Positive


+-


+-


There is no doubt when the "decompensated pattern" is found that D.I.C. exists in the patient. The problem is still whether these results signify a past recovering episode, a progressing state, or a developing defect; thus the need for sequential testing can an evaluation be made accurately.

The compensated pattern is common and difficult to interpret; it may indicate a mildly abnormal proteolytic activity or ongoing D.I.C. This pattern may precede an explosive episode of D.I.C. within a few hours or days (19). Some consider these results as highly suggestive for early D.I.C. and a call for anticoagulation; in the opinion of many investigators they point the way to further sequential testing.

The over-compensated form is often considered as a "hypercoagulable state"; it may occur in case of recovery of D.I.C. or as an indication of build-up of abnormal proteolytic activity. Its significance in the time sequence of D.I.C. can only be judged in the light of previous results in the clinical picture.
PRINCIPLES OF MANAGEMENT

In view of the diversity of the primary conditions in which D.I.C. can occur, the dynamic nature of the process and its occurrence in acute or chronic forms, only general principles of treatment can be stated.

Two basic rules of management can be made (a) treatment of the underlying condition and supportive treatment come first expansion of blood volume, if depleted and in case of shock, control of acidosis and electrolyte imbalance are of prime importance (20); (b) in the presence of serious bleeding and a laboratory pattern of acute haemostatic failure, replacement of the depleted blood components : fresh dextran 70 or plasma protein fraction to expand the blood volume. In case of many acute self-limiting D.I.C. as in abruptio placentae no further treatment is neccesary once the uterus is evacuated.

In case the underlying condition is not known, if the clinical situation deteriorates and/or if the laboratory tests indicate a worsening situation in spite of supportive or replacement therapy, heparin therapy must seriously be considered. Opinion is still divided on this matter but continuous intravenous heparin administration seems to have been life-saving in certain situations:

1. in amniotic fluid embolism when the diagnosis is quickly recognized. Without further delay, a bolus of 10.000 U heparin should be given intravenously,

2. in mismatched transfusion "rapid heparinisation" may prevent severe renal damage,

3. in cancer patients with multiple metastases, continuous D.I.C. can be reversed by heparin and stop distressing haemorrhage,

4. in acute (promyelocytic) leucaemia heparin may stop the intravascular coagulation and reduce bleeding particularly when also platelets are given to correct a thrombocytopenia,

5. in septic abortion retained products in-utero should be eliminated and heparin treatment started immediately in septicaemie. Antibiotic therapy is the first treatment in association with heparin,

6. in D.I.C. due to severe heat stroke and purpura gangrenosa (or fulminans) and prior to induced labour in the dead foetus syndrome heparin was shown to be at least beneficial.

The continuous intravenous heparin infusion must be carefully monitored to minimize the bleeding risk. Probably due to released anti-heparin platelet factor 4 many patients require a high initial dose (e.g. 3.000 U/h) but it is safer to start with 1.000 U/h and increase the dose depending on the results of laboratory monitoring.

Inhibitors of fibrinolysis as aminocaproic acid, tranexamic acid or aprotinin are likely to do more harm than good. Clinical experience with streptokinase or urokinase is mainly limited to the haemolytic uraemic syndrome and purpura gangrenosa.

REFERENCES
1. 1.Verstraete, M., Vermylen, C., Vermylen, J., Vandenbroucke, J. (1965) American Journal of Medicine, 38 : 899.
2. 2.Verstraete, M., Vermylen, J., Collen, D. (1974) Annual Review of Medicine, 25 : 447.
3. 3.Colman, R.W., Robboy, S.J., Minna, J.D. (1972) American Journal of Medicine, 52 : 679.
4. 4.Vermylen, D., De Vreker, R.A., Verstraete, M. (1963) Clinica Chimica Acta, 8 : 418.
5. 5.Sharp, A.A., Howie, B., Biggs, R., Methuen, D.T. (1958) Lancet, 2 : 1309.
6. 6.Godal, H.C., Abildgaard, U. (1966) Scandinavian Journal of Haematology, 3 : 342.
7. 7.Latallo, Z.S., Wegrzynowicz, Z., Budzynski, A.Z.(1971) Scandinavian Journal of Haematology, Suppl. 13 : 151;
8. 8.Collen, D., De Cock, F., Cambiaso, C.L., Masson, P. (1977) European Journal of Clinical Investigation, 7 : 21.
9. 9.Merskey, C., Kleiner, G.J., Johnson, A.J. (1966) Blood, 28 : 1.
10. 10.Merskey, C., Johnson, A.J., Lalezari, P. (1971) Scandinavian Journal of Haematology, Suppl. 13 83.
11. 11.Allington, M.J. (1971) Scandinavian Journal of Haematology, Suppl. 13 115.
12. 12.Svanberg, L., Hedner, U., Astedt, B. (1974) Acta Obstetrica et Gynecologica, 53 : 81.
13. 13.Denson, K.W.E. (1977) Thrombosis Research, 10 : 107.
14. 14.Nossel, H.L., Yudelman, I., Canfield, R.E., Butler, V.P., Spanondis, K., Wilner, G.D., Qureshi, G.D. (1974) Journal of Clinical Investigations, 54:43.
15. 15.Ludlam, C.A., Cash, J.D. (1976) British Journal of Haematology, 33 : 239.
16. 16.Owen, C.A., Jr., Bowie, E.J.W., Cooper, H.A. (1973) Thrombosis Research, 2 : 251.
17. 17.Cooper, H.A., Bowie, E.J.W., Owen, C.A., Jr. (1974) Mayo Clinics Proceedings, 49 654.
18. 18.Sharp, A.A. (1977) British Medical Bulletin, 33 265.
19. 19.Sherman, L.A., Wessler, S., Avioli, L.V. (1973) Archives of Internal Medicine, 132 : 446.
20. 20.Hardaway, R.M. (1966) Charles Thomas, Springfield.
ADDENDUM
Blood collection for the ethanol gelation test or protamine sulphate test

Blood is collected with a minimum of stasis from an antecubital vein through a 18 gauge, disposable needle, discarding the first 2-3 ml. Nine parts of blood are collected into a precooled lusteroid tube, containing one part of 0.1 M sodium citrate solution. The contents are immediately thoroughly mixed, kept on melting ice, and centrifuged (3.000 r.p.m., 1.200 g) for 30 min. at 4ºC within one hour. The platelet-poor plasma is transferred to another lusteroid tube, kept at + 4ºC, and the tests carried out within 2 hours after venipuncture

Performance of the ethanol gelation test

0.5 ml of plasma is transferred to a glass tube (10 x 80 mm). After incubation for 3 min. in a waterbath at 20ºC (in order to obtain temperature equilibrium), 0.15 ml of 50 percent ethanol solution (96 percent ethanol diluted with distilled water) is added with blow out pipette. The tube is shaken thoroughly in order to assure adequate and rapid mixing, and then left undisturbed. After exactly 10 min. the tube is tilted once slowly to the horizontal position and thus inspected. The results are recorded as follows - plasmas showing a gel are considered as positive - plasmas containing no grossly visible particulate matter, and plasmas showing discrete granules are considered as negative.

Performance of the protamine sulphate test

0.4 ml of platelet-poor fresh citrated plasma is transferred to a glass tube (10 x 80 mm). After incubation for 3 min. in a waterbath at 37ºC, 0.04 ml of 1 percent solution of protamine sulphate in 0.15 NaCI is added. After 3-5 min. the tube is examined visually and the result estimated as :

negative : no change, or some cloudiness

positive : + to +++ depending whether a small precipitate, conglomerated precipitate, fibrin strands or solid clot are formed respectively.
DISCUSSION
P. Brès : Are the ""helmet cells"" constantly found in cases of DIC and do they appear at the very beginning or at the threatening stage of DIC ?
M. Verstraete : They are not constantly found and they are not necessarily present at the beginning of the phenomenon. The first evidence of DIC is the decrease of platelets, of fibrinogen, and of factor V and the presence of fibrine monomers. It can be detected with a simple test, called the ethanol gelation test, all what is needed is some ethanol.
L. Eyckmans : Blood smears can be made in most field conditions. If platelets are not observed in a smear, is this sufficient to diagnose DIC ?
M. Verstraete : When the blood was collected properly, the complete absence of platelets in a situation where intravascular coagulation is suspected, is highly indicative, I would say.
T.E. Woodward : Why was a question mark placed after heparin under therapy ?
M. Verstraete : Heparin has been given in a number of conditions where DIC was presumed but not proven. Heparin in a bleeding disorder is potentially dangerous, if it is not due to DIC. When DIC is proven, heparin has to be given under certain conditions. It should be given after administration of fibrinogen: both have to be combined. Not fibrinogen first because the coagulation system is activated. Adding fibrinogen to it, results in its precipitation. Thus as soon as heparin administration is started, start the fibrinogen infusion.
M. Dietrich : You also put a question mark after "antifibrinolytic agents". I think indeed antifibrinolytic agents are absolutely contraindicated in this condition since they may increase the DIC.
M. Verstraete : If the intravascular coagulation is induced by gram-negative sepsis or by viruses or by antigenantibody complexes in these specific indications, there is no point whatsoever to inhibit fibrinolysis which is the natural defence line in the body to dispose of these fibrine monomers and fibrine threads. So the message is quite clear, don't do it, because it is harmful.

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