Meningococcal purpura: Report of 19 patients treated with heparin

780

May, 1973 T h e Journal of P E D I A T R I C S

Meningococcalpurpura: Report of 19 patients treated ndth beparin Nineteen patients with meningococcal purpura were studied. Arterial hypotension, absence of meningeal signs, coma, normal or low white blood cell count, and low cerebrospinal fluid cell count were signs of severe illness. Some degree of consumptive coagulopathy, a low rate of fibrinolysis, and activation of platelets with release of their clotting and antiplasmin [actors were documented. Heparin was administered to all patients in a dosage adapted to the platelet count. The mortality rate in this series was 2 o[ 19; all other patients had a complete recovery.

Patrick G~rard, M.D., Maurice Moriau, M.D., Alain Bachy, M.D., Paul Malvaux, M.D., ~ and Roger De Meyer, M.D., L o u v a i n , B e l g i u m

intravascular coagulation is a well-documented complication of meningococcal purpura? -~5 Heparin may be a useful therapeutic agent in treatment of it?0, 1~-1s Little ~ was the first to report successful treatment of meningococcemia with heparin. Other reports of individual cases 8, 4, r, 9 and series of patients ~, s, ~2-~ treated with heparin have been published subsequently. Ttle results have been extremely variable, and agreement concerning the value of heparin in this disease is far from complete, possibly because of the differences in criteria for beginning heparin treatment and differences in gravity of the illness. Our purpose is to report our experience with 19 patients with meningoeoccal purpura who D I s s E M I N A T E D

From the Department o[ Pediatrics and Laboratory of Hemostasis and Coagulation,

University o[ Louvain. ~Ref~rint address: Department of Pediatrics, Cliniques Universitaires St. Raphagl, 3000 Louvain, Belgium.

Vol. 82, No. 5, pp. 780-786

had hemostatic abnormalities treated with heparin.

and

were

MATERIALS AND METHODS Nineteen patients were studied, 11 males and 8 females; their ages ranged from 4 months to 13.5 years. Criteria for inclusion in the study were: (l) association of purSee related text, pp. 787 and 900. pura and meningitis, or purpura with shock, whether or not accompanied by meningitis, and (2) subsequent isolation of Neisseria rneningitidis from the pharynx, blood, or cerebrospinal fluid. Cases of meningococcal meningitis without purpura were not included. Patients were divided into three groups according to clinical status at the time of admission. 1'~ Group 1 included four patients with purpura and meningitis but without signs of shock. Group 2 consisted of eight

Volume 82 Number 5

Meningococcat purpura

78 1

Table I. Clinical data at the time of admission No. o[ patients Age range Group 1: Patients withoutshock

4

No. o/patients with meningeal No. o[ patients signs in coma

4 too.-5 yr.

4/4

0/4

Clinical outcome

Complete recovery in all patients

Group 2: Patients in poor per]usion states without circulatory collapse

8

18/~2 yr.--13~2 yr.

8/8

6/8

Complete recovery in all patients

4/7

7/7

Complete recovery in 5 patients Acute tubular necrosis in 1 Two deaths (8 hr. and 28 hr. after admission, respectively)

Group 3: Patients in circulatory collapse

7

1~2 yr.-4~2 yr.

patients admitted with signs of poor peripheral tissue perfusion characteristic of shock but still able to maintain an acceptable blood pressure. Their clinical features included fever, tachycardia, poor peripheral pulses, cold mottled skin, cyanosis of extremities, tachypnea, decreased urinary output, and alteration of consciousness. Systolic blood pressure was above 80 mm. Hg and was frequently associated with a narrowed pulse pressure suggesting high peripheral resistance. Most of these patients had some degree of circulatory collapse soon after admission. In Group 3 there were seven patients admitted in a more advanced state of shock characterized by circulatory collapse with a significantly low systolic blood pressure for age. Before starting any treatment, some of the following coagulation studies were performed: platelet count, recalcificatlon time, prothrombin time, partial thromboplastin time, thrombin time, and fibrinogen assay. 19 Fibrinolysis was estimated by euglobulin lysis time. In five patients, platelet aggregability in the presence of adenosine disphosphate was estimated and levels of platelet factor 3, factor 4, and antiplasmin factor were determined? ~ All patients received high doses of antibiotics parenterally. Three regimens were followed: (1) penicillin (100,000 U. per kilogram per day or more), chloramphenicol (100 mg. per kilogram per day), and sulfisoxazole (150 my. per kilogram per day) in 6 patients; (2) ampicillin (200 to 300 my. per kilogram per day) in 9; and (3) ampi-

cillin with another antimicrobial agent in 4. The duration of antibiotic therapy extended from 10 to 21 days. Shock was intensively treated by infusion of fresh plasma, fresh blood or isotonic electrolyte solutions and by the administration of cardiotonic agents according to repeated measurements of central venous pressure, arterial blood pressure, heart rate, and urinary output. 21 High doses of steroids (30 rag. per kilogram of body weight of methylprednisolone, given intravenously) were administered to 7 of the 15 patients admitted in shock for their beneficial cardiocirculatory, metabolic, and cellular protective effects?2, 2s Heparin was administered to all patients soon after admission. In patients with shock, an initial dose of 50 U. per kilogram was given intravenously. It was followed by a daily dose in units per kilogram equal to the platelet count divided by 500 given intravenously at 4 to 6 hour intervals. Heparin was discontinued after the cutaneous lesions had cleared and the platelet count, prothrombin time, and partial thromboplastin time had returned to normal. The duration of heparin therapy varied from 6 to 20 days. RESULTS

Some clinical data are shown in Table I. The delay between onset of symptoms and admission varied between 5.5 and 96 hours, with a tendency for patients in Group 3 to be admitted earlier. Absence of meningeal signs was found only in patients in '"deep" shock (Group 3). Coma was present in all Group 3 patients and in 6 of the 8 pa-

7 82

Gdrard et aI.

The Journal o/ Pediatrics Ma;, 1973

WBC mm 3

25 0 0 0 -

9 20 000

CSF Et/mm 3

o

t

120

-

9

I00~ 15000 -

9

15 0 0 0

CORTISOL /g %

-9

9 9

11 0 0 0

80

-

o

I0

9

0009

5 000

-

9 9

-

9 1 000-

7000

3000-:i ~ I mo :~

60

9

9 o

40

o

2o

!

Fig. 1. Laboratory data at time [] = Group 1, patients without Group 2, patients in poor perfusion circulatory collapse; Q) ~ Group circulatory collapse.

of admission. shock; 9 states without 3, patients in

dents in Group 2; it lasted from 4 to 72 hours. The extension of cutaneous lesions was extremely variable and was not related to the degree of shock. Case 18 had mild purpura but massive melena and hematuria: she developed acute tubular necrosis on the second day which was successfully treated with peritoneal dialysis. Case 15 was admitted in a terminal state, was covered with large ecchymoses, and died eight hours later: postmortem examination demonstrated bilateral adrenal hemorrhages and extensive fibrin deposits in adrenals, kidneys, spleen, lungs, and colon. Case 13, who also died, had moderate cutaneous lesions. At autopsy, adrenal hemorrhages and a few fibrin thrombi in kidneys, lungs, adrenals, and lymph nodes were found. All tile other patients recovered without complications. Normal or low white blood cell counts were seen in 5 of the 15 patients admitted in shock (Groups 2 and 3). Low eerebrospinal fluid cell counts (below 30 per cubic millimeter) were found in 2 of the 8 patients in Group 2 and in 4 of the 7 in Group 3. In 8 patients, the plasma cortisol level 24 was determined before any therapy and in all

instances was higher than normal (Fig. 1?. Fig. 2 shows the lesults of coagulation studies performed at the time of admission. Prothrombin time was increased in all but one patient. Partial thromboplastin time, determined in 8 patients, was normal in 2 and increased in 6. The recalcification time was normal in 11 cases, diminished in 3, and increased in one. In 8 patients a normal or slightly diminished thrombin time was observed; in 2 patients it was increased. Fibrinogen was higher than normal in 14 of 15 patients; the only normal value was found in Case 13 who died 28 hours after admission. In all but two patients, the platelet count was diminished; the lowest values were found among the patients in Group 3. The euglobulin lysis time, tested in 14 patients, was never decreased. Platelet function studies done in 5 patients showed hypoaggregability in the presence of adenosine diphosphate and increased thromboplastin (factor 3), antiheparin (factor 4), and antiplasmin activities (Table I I ) . The evolution of the main clotting parameters is represented in Figs. 3 and 4. Norrealization of the mean prothrombin time and partial thromboplastin time was obtained by the fourth day. Mean platelet count reached a minimum on the third day and was followed by a peak between 8 and 10 days. Fibrinogen values were high and never reached normal during the period of observation. DISCUSSION In severe infectious states, increased values for prothrombin time and partial thromboplastin time and the presence of thrombocytopenia are suggestive of consumptive coagulopathy57, is Increased partial thromboplastin time is due mainly to consumption of factors II, V, VII, V I I I , and X. G As shown by Mc Gehee and associates, 6 increased prothrombin time in meningococcemia is related to low levels of {actor VII. Although these authors do not consider this finding indicative of disseminated intravascular coagulation, we think that it can be explained by consumption secondary to contact of blood with tis-

Volume 82 Number 5

Meningococcal purpura

PLATE LE]S (x)03/n'rn 3 )

PROTHROMSIN TIME (%)

FIBRINOGEN {mg/lOOml)

THROMBIN TIME (sec)

P/~RTIAL THROMBOPL ASIIN

783

REC4LIFICATPON TIME (see)

Fig. 2. Coagulation data at time of admission. [] z Group 1, patients without shock; 9 z Group 2, patients in poor perfusion states without circulatory collapse; Q) ~ Group 3, patients in circulatory collapse. T a b l e I I . Q u a l i t a t i v e study of platelets at the time of admission I

Parameters Platelet aggregability in the presence of adenosine diphosphate Microscopic aspect Aggregation time Platelet factor 3 (thromboplastin activity) Platelet factor 4 (antiheparin activity) Platelet antiplasmin factor

1

Normal value

17

++ 9-17 sec. 35-111 U./1011 platelets

0 > 60 450

0 > 60 530

0 > 60 133

+ > 60 300

0 > 60 1,350

199-325 U./1011 platelets

840

990

1,289

911

1,140

35- 51 U./1011 platelets

84

118

102

75

155

sue t h r o m b o p l a s t i n liberated from extensive lesions of small cutaneous vessels. Experimentally, it has been shown that endotoxin activates H a g e m a n factor 2~ a n d destroys 2~ and activates 27 platelets. Activation of the intrinsic p a t h w a y of coagulation a n d release of platelet phospholipids and factor 4 can precipitate extensive disseminated intravascular coagulationY 8, 29 T h e findings of our study are in agreement with the above experimental data, including an increased partial t h r o m b o p l a s t i n time, thrombocytopenia, and high levels of platelet factors 3 and 4. H i g h fibrinogen levels, found in 14 of 15 patients, do not rule out consumption of

coagulation factors. H i g h levels m a y be related to acute infectious states a~ or to the action of the endotoxin itself al a n d m a y represent a decrease from an initially higher value. T h e p o o r prognosis associated with a normal or low fibrinogen level in acute septicemic states has been stressed previously. TM 32 T h e lowest value in our series was found in Case 13, who died. O u r finding of an association of high fibrinogen values, n o r m a l or low t h r o m b i n times, and n o r m a l clot lysis times is in agreem e n t with t h a t of F o n d u a n d associates, 1~ suggesting a low rate or blockage of fibrinolysis. This is an unusual finding in septicemic states since G r a m - n e g a t i v e endotoxins are

784

Ggrard et aI.

The Journal o[ Pediatrics May 1973

PLATELETS x 10O0/rnrn 3 380 340

300

250

220 180 140 "

100

( )

(4)

~

;

3

FIBRINOGEN

; ~i'lO [rng/ 100 ml)

12t18

gAYS

1000

(9) ~I4J

T

z

(~j

(6)

r

8-10

12 14

(6)

{

200 )

2

3

4

6

DAYS

Fig. 3. Evolution of the main clotting tests. Resuits are expressed as mean -+ standard e r r o r of the mean. N u m b e r s in brackets represent n u m b e r of cases tested. Shaded areas represent normal values. All results have been pooled. PROTHROMBIN

TiME ~

I10 90 70

50

(m (~7J

3O ~0 I ]

I 2

I 3

I 4

I 5

I 6

8-110

-/ 12 1B

DAYS

PARTIAL THROMBOPLASTIN TIME (sec)

~2o

I00

80

I

(8/

(sJ

(6)

60

N

~o N }

2

3

| &

6

g l0

12 Ig

DAYS

Fig. 4. Evolution of the main clotting tests. Resuits are expressed as mean -+ standard error of the mean. N u m b e r s in brackets represent n u m b e r of cases tested. Shaded areas, represent normal values. All results have been pooled.

capable of triggering blood coagulation as well as fibrinolysis, as O u r study shows that platelet antiplasmin activity is substantially increased and may be partly responsible for this impairment. The efficacy of heparin in experimental endotoxic or thrombin-induced shock and in clinical disseminated intravascular coagulation is documented. 10-a8, 34 However, among series of meningococcal infections treated with heparin, the results are controversial. Mc Gehee and associates ~ administered heparin to 5 of 6 patients in shock with disseminated intravascular coagulation; 4 of them died. Corrigan and associates 8 used hypotension as the criterian for administration of heparin. In their study of 10 patients with meningococcemia, 4 had hypotension and received heparin; one death was reported. In another study of 26 children in septic shock with hypotension, 1~ these same authors concluded that h e p a r i n had no effects on the survival rate despite an improvement of the coagulation defects. Najjar and associates 10 claimed no benefit from the use of heparin; 6 of 8 patients died but all were "extremely" ill. Winkelstein and associates la reported successful use of heparin in 3 patients with disseminated intravascular coagulation; three others who did not receive heparin died. Fondu and associates 1~ heparinized children after recognition of at least two clinical or biologic signs of grave illness which they had established. Seventeen of their 31 patients were so treated; only two deaths occurred, both in the group of 4 patients reported as "in shock." In our series, the mortality rate was 10.5 .per cent, and the two patients who died belong to the "deep shock" group. By applying the prognostic score of Stiehm and associates s5 to the seven patients in Group 3, we find that 6 had a score of 3 or above. According to these authors, the mortality rate should have been at least 85 per cent; however, only 2 of 6 patients died. The dose of heparin we used was lower than that usually recommended 17, ~s and was calculated to obtain normal blood coagulability rather than hypocoagulability. Moriau 2~

Volume 82 Number 5

described an increased platelet a n t i h e p a r i n activity in patients with severe infections. His observations were confirmed by our study. I n septic patients with a low platelet count, a lower a n t i h e p a r i n activity is expected, and therefore a lower dose of h e p a r i n should be required. W e found that the protocol of heparinization used was effective, physiologic, a n d had the a d v a n t a g e of avoiding overdosage with the subsequent risk of bleeding, which was never observed. I n addition, extensive cutaneous necrosis s~ was not observed a m o n g o u r patients. T h e delays in normalization of paltelet count a n d prot h r o m b i n time were c o m p a r a b l e to those found by C o r r i g a n and associates. 14 A l t h o u g h this study does not demonstrate with certainty the efficacy of h e p a r i n treatm e n t in meningococcal p u r p u r a , we think that the use of this agent is reasonable in all patients having some degree of consumptive coagulopathy. H e p a r i n m a y disrupt the vicious circle of disseminated i n t r a v a s c u l a r coagulation initiated by meningococcal endotoxin a n d thus prevent the u l t i m a t e deposition of fibrin and the bleeding diatheses caused by consumption of blood clotting factors. Final prognosis p r o b a b l y depends on the d e p t h of shock at the time of admission a n d on the degree of irreversibility of established lesions. H e p a r i n must be considered as an adjunctive t h e r a p e u t i c agent a n d must not supersede other aspects of therapy, such as eradication of the causal agent by antibiotics and the intensive t r e a t m e n t of shock. REFERENCES

1. Little, J. R.: Purpura fulminans treated successfully with anticoagulation, J. A. M. A. 169: 36, 1959. 2. Bouhasin, J. D.: Purpura fulminans, Pediatrics 34: 264, 1964. 3. Abildgaard, C. F., Corrigan, J. J., Seeler, R. A., Simone, J. V., and Schulman, I.: Meningococcemia associated with intravascular coagulation, Pediatrics 40. 78, 1967. 4. Antley, R. M., and Me Millan, C. W.: Sequential coagulation studies in purpura fulminans, N. Engl. J. Med. 276: 1287, 1967. 5. Margaretten, W., Csavossy, I., and Me Kay, D. G.: An electron microscopy study of a case of meningococcemia in man, Am. J. Dis. Child. 114: 268, i967.

Meningococcal purpura

785

6. Mc Gehee, W. G., Rapaport, S. I., and Hjort, P. F.: Intravascular coagulation in fulminans meningococcemia, Ann. Intern. Med. 67: 250, 1967. 7. TSnz, O., and Aufdermaur, F.: Erfolgreiche behandlung eines Waterhouse-Friderichsensyndroms mit Heparin, Schweiz. Med. Woehenschr. 97: 1611, 1967. 8. Corrigan, J. J., Jr., Ray, W. L., and May, N.: Changes in the blood coagulation system associated with septicemia, N. Engl. J. Med. 279: 851, 1968. 9. Dennis, L. H., Cohen, R. J., Schachner, S. H., and Conrad, M. E.: Consumptive coagulopathy in fulminant meningococcemia, J. A. M. A. 205" 183, 1968. 10. Abildgaard, C. F.: Recognition and treatment of intravascular coagulation, J. PEDIATR. 741 163, 1969. 11. Evans, R. W., Glick, B., Kimball, F., and Lorell, M.: Fatal intravascular consumption coagulopathy in meningococcal sepsis, Am. J. Med. 46: 910, 1969. 12. Najjar, S. S., and Ahmad, M.: Heparin therapy in fulminant meningococcemia, J. PEDIATR. 75: 449, 1969. 13. Winkelstein, A., Songster, L., Caras, T. S.: Berman, H. H., and West, W. L.: Fulminant meningococeemia and disseminated intravascular coagulation, Arch. Intern. Med. 124: 55, 1969. 14. Corrigan, J. J., Jr., and Jordan, C. M.: Heparin therapy in septicemia with disseminated intravaseular coagulation. Effect on mortality and on correction of hemostasis defects, N. Engl. J. Med. 283: 778, 1970. 15. Fondu, P., Blum, D., Denolin-Reubens, R., and Dubois, J.: Relation entre les manifestations cliniques et les troubles de Ia coagulation dans 31 cas de m~ningococcfimie. Evaluation de l'efficacit6 d'une h6parinoth6rapie pr6coce, Acta Paediatr. Belg. 24: 231, 1970. 16. Mc Kay, D. G.: Disseminated intravascular coagulation. An intermediary mechanism of disease, New York, 1965, Harper & Row, Publishers, p. 493. 17. Hathaway, W. E.: Care of the critically ill ehiId: The problem of disseminated intravascular coagulation, Pediatrics 46: 767, 1970. 18. Karpatkin, M.: Diagnosis and management of disseminated intravascular coagulation, Pediatr. Clin. North Am. 18: 23, 1971. t9. Gram, H. C.: A new method for determination of the fibrin per cent in blood and plasma, J. Biol. Chem. 49: 279, 1921. 20. Moriau, M.: Inhibiteurs naturels de la fibrinolyse et ph6nomhnes thromboh6morragiques, Editions ARSCIA, Bruxelles, 1970, p. 286, and Editions Maloine, Paris, 1970. 21. Thal, A. P.: Shock. A physiological basis for treatment, Chicago, 1971, Year Book Medical Publishers, Inc., p. 230. 22. Motsay, G. J., Alho, A., Jaeger, T., and Lillehei, R, C.: Effects of eorticosteroids on the circulation in shock: experimental aI~d clinical results, Fed. Proc. 29: 186t, 1970.

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G~rard et al.

23. Schumer, W., and Nyhus, L. M.: The role of corticoids in the management of shock, Surg. Clin. North Am. 49: 147, 1969. 24. Kolanowski, J., and Pizarro, M.: Determination du cortisol plasmatique et urinaire par comp6tition, Ann. Endocrinol. 29: 473, 1968. 25. Mason, J. W., Kleeberg, U., Dolan, P., and Colman, R. W.: Plasma kallikrein and Hageman factor in Gram-negative bacteria, Ann. Intern. Med. 73: 545, 1970. 26. Cohen, P., Braunwald, J., and Gardner, F. H.: Destruction of canine and rabbit platelets following intravenous administration of carbon particles or endotoxin, J. Lab. Clin. Med. 66: 263, 1965. 27, Horowitz, H. I., Des Prez, R. M., and Hook, E. W.: Effects of bacterial endotoxin on rabbit platelets. II. Enhancement of platelet factor 3 activity in vitro and vivo, J. Exp. Med. 116: 619, 1962. 28. Kitzmiller, J. L.: Septic shock: An eclectic review, Obstet. Gynecol. Surv. 26: 105, 1971. 29. Rodriguez-Erdmann, F.: Intravascular activation of the clotting system with phospholipids. Production of the generalized Shwartzmann reaction with platelet factor 3, Blood 26: 541, 1965. 30. Goldenfrab, P. B., Zucker, S., Corrigan, J.

The .lourna! o[ Pediatrics May 1973

31.

32.

33.

34.

35. 36.

J., Jr., and Cathey, M. H.: The coagulation mechanism in acute bacterial infection, Br. J. Haematol. 18. 643, 1970. Egeberg, O.: Antihemophilie A factor (factor VIII) and fibrinogen in human bIood. A study on the question of a closer correlation between the levels of the two factors, Scand. J. Clin. Lab. Invest. 14: 230, 1962. Hardaway, R. M., James, P. M., Jr., Anderson, R. W., Bredenberg, C. E., and West, R. L.: Intensive study and treatment of shock in man, J. A. M. A. 199: 779, 1967. Horwitz, D. L., Moquin, R. B., and Herman, C. M.: Coagulation changes of septic shock in the sub-human primate and their relationship to hemodynamic changes, Ann. Surg. 175: 417, 1972. Good, R. A., and Thomas, L.: Studies on the general Shwartzmann reaction. IV. Prevention of the local and generalized Shwartzmann reaction with heparin, J. Exp. Med. 97: 871, 1953. Stiehm, E. R., and Damrosch, D. S.: Factors in the prognosis of meningoeoccal infection, J. PEDIaTR. 68: 457, 1966. De Coninck, A.: Syndrome de WaterhouseFriderichsen avec gangrene g~n~ralis~e des extr~mit~s, Ann. Chir. Plast. 14. 50, 1969.