JOURNAL
OF SURGICAL
RESEARCH
20, 211-214 (1976)
Thrombocytopenia
in Severe
Bacterial
Infections
L. OPPENHEIMER, M.D., W.M. HRYNIUK, AND A. J. BISHOP, M.D.
M.D.,
Health Sciences Centre, The University of Manitoba, Winnipeg, Canada Submitted for publication December I, 1975
Among the coagulation abnormalities that occur in patients with bacterial, viral, and protozoan infections, thrombocytopenia is the most common [4]. Also, several authors have found evidence of acute disseminated intravascular coagulation (D.I.C.) in many of these patients [3, 41 and have pointed to this phenomenon as one of the causes of thrombocytopenia. Other investigators have reported clinical series of septicemic patients (positive blood cultures) with low platelet counts and no evidence of acute D.I.C. [5, 151. Since thrombocytopenia has been reported also in patients with negative blood cultures and severe infections [3, 4, 81, we elected to study patients admitted to our Intensive Care Unit with severe bacterial infections who developed coagulation abnormalities. MATERIALS AND METHODS Patients. All adult patients admitted to Intensive Care Unit of the Health Sciences Centre in Winnipeg, Manitoba, from September 1973 to August 1974 with a bacterial infection who developed coagulation abnormalities were studied, a total of 28 patients. All patients were treated with antimicrobial agents (adjusted to sensitivities whenever possible), crystalloid and colloid solutions, vasopressors and vasodilators, as required. Eleven patients with very severe thrombocytopenia received platelet transfusions. Patients suspected of vitamin K deficiency were treated accordingly. One patient thought of having D.I.C. was treated with a continuous infusion of aqueous heparin. Laboratory. We considered that acute D.I.C. as opposed to chronic or compensated
D.I.C. occurs when thrombin production leads to widespread deposition of fibrin and consumption of platelets and coagulation factors at a rate that exceedsproduction. In this case, it will be manifested by low platelet counts, elevated fibrinogen degradation products (FDP) and prolonged prothrombin (PT) and partial thromboplastin (PTT) times due to consumption of factors. Platelet counts were obtained by Coulter counter and, in some cases, rechecked by phase contrast microscopy. Prothrombin times were measured utilizing both rabbit and human thromboplastin. The cephalin Celite technique was used for partial thromboplastin time determinations, and FDP were measured by a hemagglutination technique [l l] utilizing sheep red cells. In some cases, factor levels were also obtained. RESULTS Clinical Data
The patients’ ages ranged from 17 to 71 yr. All patients developed hypotension (systolic blood pressure less than 80 mm Hg) at some stage or stages in their clinical course. The overall mortality rate was 58%. Table 1 shows the types of infections encountered. Gram negative organisms were involved in almost 94% of the patients, mostly in mixed infections. Although oozing from intravenous sites and small ecchimosis occurred in some patients, diffuse bleeding was never a problem, even if surgery was performed. No correlation could be made between the degree of thrombocytopenia and the prognosis; but, unless the thrombocytopenia recurred, normalization of the platelet count was asso-
211 Copyright o 1976by Academic Press, Inc. All rights of reproduction in any form reserved.
212
JOURNAL
OF SURGICAL
RESEARCH:
TABLE 1 Clinical Data
Types of infection in 28 patients Peritonitis Septicemia Pneumonia Endometritis Abscess Other Total infections
ciated with survival in all patients in which it occurred (42%). Those who died were thrombocytopenic at the time of death and on postmortem examination had evidence of ongoing infection, either unresponsive to treatment or undiagnosed. Platelet transfusions did not succeed in restoring platelet counts to normal. Coagulation Data
Platelet counts, PT, PTT and FDP titers from the 28 patients at the time of their
FDP
PT
PT
Percentage of patients
Group A. Thrombocytopenia
12 9 8 4 3 3 39 Percentage 7.8 6.2 85.0
Organisms involved Pure Gram negative Pure Gram positive Mixed infections
1976
TABLE 2 Coagulation Abnormalities Number of patients
Infections
VOL. 20, NO. 3, MARCH
only
B. Thrombocytopenia and clotting abnormalities Vitamin K deficiency Exchange transfusion lesion Transient elevation FDP D.I.C. C. Clotting abnormalities with normal platelet counts Vitamin K deficiency
65.0 28.0 7 7 10.5 3.5 7 7
lowest platelet count are shown in Fig. 1. According to these results, the patients were divided in three groups: (A) patients who developed thrombocytopenia only (platelet count less than 100,000/mm3); (B) patients with thrombocytopenia and abnormal coagulation parameters; and (C) patients with normal platelet counts but showing coagulation abnormalities (Table 2). A total of 18 patients (65%) were included in group A. A specific explanation for this phenomenon was not apparent. Eight patients (28%) were included in group B and further studies were consistent with coagulation abnormalities on the basis of vitamin K deficiency in two casesand exchange transfusion lesion in another two cases; three patients showed a transient elevation of their FDP titers with spontaneous normalization, the significance of which is not clear; and, finally, one patient was suspected of D.I.C., but he died of his clostridial septicemia before factor levels could be assessed.Group C included two patients (7%) with vitamin K deficiency.
Platelets,
FIG. 1. Platelet counts, PT, PTT, and FDP values for the 28 patients studied, at the time of their lowest platelet count. The platelet counts are expressed in number of platelets per cubic millimeter, the PT and the PTT in seconds, and the FDP in dilutions. The shaded areas represent normal values. Note that the majority of the platelet counts are abnormal, while the majority of the other values are within normal limits.
DISCUSSION These results are in accordance with other series [5, 151; thus thrombocytopenia is a common phenomenon and a reliable monitoring parameter, while D.I.C. is a rare event, in nonmeningococcal bacterial infections in adult patients.
OPPENHEIMER
ET AL.: THROMBOCYTOPENIA
In our patient population, adults with severe bacterial infections and hypotension, probably many factors played a role in the development of thrombocytopenia. The decreased cardiac output with a peripheral low flow state leading to abnormal pooling, acidosis, and increased oxygen extraction in capillary blood [9, 141, the various drugs given to these patients, the presence of liver disease, and poor nutritional status in some of them [15] could be implicated in this process. Moreover, the fact that we failed to show acute D.I.C. in the majority of the patients does not exclude the presence of compensated consumption which could contribute to the decrease in circulating platelets. Infection by itself has been implicated as a cause of thrombocytopenia and several authors, utilizing Gram negative endotoxin models, have reported a platelet endotoxin interaction in rabbits, dogs, and rats [2, 6, lo]. Endotoxin and platelets form aggregates, the endotoxin disappearing almost completely from the plasma fraction [2, 6, lo]. Complement and other heatlabile factors are consumed in the process [12, 131. These aggregates are selectively trapped by elements of the reticuloendothelial system (RES) [2, lo] and the endotoxin presumably cleared. This accomplished, the platelets are released back into the circulation [7]. Thus, platelets seem to be involved in the clearance of endotoxin from the blood stream. The aggregates formed are found in the capillaries of RES (mainly lung, liver, and kidney) and, although this appears to be a defense response to endotoxemia, conversely, it could be responsible for some of the biological effects attributed to the endotoxins [7]. In conclusion, thrombocytopenia is a common phenomenon in bacterial infections (Riedler reports an overall incidence of 75%); its significance is not clear as yet, but it is a reliable monitoring parameter in patients with bacterial processes and a warning sign of occult infection. Further studies of its own role in shock and infections are called for.
IN BACTERIAL
INFECTIONS
213
SUMMARY Twenty-eight patients with bacterial infections and coagulation abnormalities were studied. Thrombocytopenia was seen in 26 (93%). The coagulopathy was related to vitamin K deficiency in four patients and massive transfusions of stored blood in two. Three patients showed transient FDP elevation without evidence of acute consumption of clotting factors, and in only one patient (3.5%) was D.I.C. diagnosed. Eighteen patients were thrombocytopenic without evidence of another coagulation abnormality. Thus D.I.C. seems relatively rare in bacterial infections, and other mechanisms are required to explain the associated thrombocytopenia. REFERENCES I.
2.
3.
4.
5.
6.
I.
8.
9. 10.
Beller, F. K., and Douglas, G. W. Thrombocytopenia indicating Gram negative infection and endotoxemia. Obster. Gynecol. 41:521, 1973. Braude, A. I., Carey, F. J., and Zalesky, M. Studies with radioactive endotoxin. Correlation of physiologic effects with distribution of radioactivity in rabbits injected with lethal doses of E. coli endotoxin labelled with radioactive sodium chromate. J. Clin. Invest. 34:858, 1955. Cohen, P., and Gardner, F. H. Thrombocytopenia as a laboratory sign and complication of Gramnegative bacteremic infection. Arch. Infern. Med. 177:113, 1966. Corrigan, J. J., Ray, W. L., and May, N. Changes in the blood coagulation system associated with septicemia. N. Engl. J. Med. 279:85 I, 1968. Corrigan, J. J. Thrombocytopenia: A laboratory sign of septicemia in infants and children. J. Pediut. 85:219, 1974. Das, J., Schwartz, A. A., and Folkman, J. Clearance of endotoxin platelets. Role in increasing the accuracy of the stimulus gelation test and in combating experimental endotoxemia. Surgery 74:235, 1973. Des Prez, R., and Marney, S. R. Immunological reactions involving platelets. In S. A. Johnson (Ed.), The Circulating Platelet. Academic Press, New York. Goldenfarb, P. B., Zucker, S., Corrigan, J. J., and Cathey, M. H. The coagulation mechanism in acute bacterial infection. Brir. J. Huematol. 18:643, 1970. Gross, S., Keefer, V., and Liebman, J. Platelets in cyanotic heart disease. Pediatrics 42:651, 1968. Herring, W. B., Herion, J. C., Walker, R. I., and
214
JOURNAL OF SURGICAL
RESEARCH: VOL. 20, NO. 3, MARCH
Palmer, J. G. Distribution and clearance of circulating endot0xin.l. C/in. Invest. 42:79, 1963. 1I. Israels, E. D., Rayner, H., Israels, L. G., and Zipursky, A. A microhemagglutination inhibition assay for the quantitation of fibrinogen breakdown products. J. Lab. Clin. Med. 71:33, 1968. 12. Kane, M. A., May, J. E., and Frank, M. M. Interaction of the classical and alternate complement pathway with endotoxin lipopolysaccharide. J. Clin. Invesr. 52:370,370. 13. McCabe, W. R. Serum complement levels in bacte-
1976
remia due to Gram negative organisms. N. Engl. J. Med. 288:21, 1973. 14. McKay, D. G. Disseminated Intravascular Coagulation. Hoeber Medical Division, Harper and Row, New York, 1965. 15. Riedler, G. F., Straub, P. W., and Frick, P. G. Thrombocytopenia in septicemia. A clinical study for the evaluation of its incidence and diagnostic value. Helv. Med. Acta 36:23, 197I. 16. Wintrobe, M. M. Clinical Haematology. 7th Ed. Lea & Febiger, Philadelphia, 1974.
OF SURGICAL
RESEARCH
20, 211-214 (1976)
Thrombocytopenia
in Severe
Bacterial
Infections
L. OPPENHEIMER, M.D., W.M. HRYNIUK, AND A. J. BISHOP, M.D.
M.D.,
Health Sciences Centre, The University of Manitoba, Winnipeg, Canada Submitted for publication December I, 1975
Among the coagulation abnormalities that occur in patients with bacterial, viral, and protozoan infections, thrombocytopenia is the most common [4]. Also, several authors have found evidence of acute disseminated intravascular coagulation (D.I.C.) in many of these patients [3, 41 and have pointed to this phenomenon as one of the causes of thrombocytopenia. Other investigators have reported clinical series of septicemic patients (positive blood cultures) with low platelet counts and no evidence of acute D.I.C. [5, 151. Since thrombocytopenia has been reported also in patients with negative blood cultures and severe infections [3, 4, 81, we elected to study patients admitted to our Intensive Care Unit with severe bacterial infections who developed coagulation abnormalities. MATERIALS AND METHODS Patients. All adult patients admitted to Intensive Care Unit of the Health Sciences Centre in Winnipeg, Manitoba, from September 1973 to August 1974 with a bacterial infection who developed coagulation abnormalities were studied, a total of 28 patients. All patients were treated with antimicrobial agents (adjusted to sensitivities whenever possible), crystalloid and colloid solutions, vasopressors and vasodilators, as required. Eleven patients with very severe thrombocytopenia received platelet transfusions. Patients suspected of vitamin K deficiency were treated accordingly. One patient thought of having D.I.C. was treated with a continuous infusion of aqueous heparin. Laboratory. We considered that acute D.I.C. as opposed to chronic or compensated
D.I.C. occurs when thrombin production leads to widespread deposition of fibrin and consumption of platelets and coagulation factors at a rate that exceedsproduction. In this case, it will be manifested by low platelet counts, elevated fibrinogen degradation products (FDP) and prolonged prothrombin (PT) and partial thromboplastin (PTT) times due to consumption of factors. Platelet counts were obtained by Coulter counter and, in some cases, rechecked by phase contrast microscopy. Prothrombin times were measured utilizing both rabbit and human thromboplastin. The cephalin Celite technique was used for partial thromboplastin time determinations, and FDP were measured by a hemagglutination technique [l l] utilizing sheep red cells. In some cases, factor levels were also obtained. RESULTS Clinical Data
The patients’ ages ranged from 17 to 71 yr. All patients developed hypotension (systolic blood pressure less than 80 mm Hg) at some stage or stages in their clinical course. The overall mortality rate was 58%. Table 1 shows the types of infections encountered. Gram negative organisms were involved in almost 94% of the patients, mostly in mixed infections. Although oozing from intravenous sites and small ecchimosis occurred in some patients, diffuse bleeding was never a problem, even if surgery was performed. No correlation could be made between the degree of thrombocytopenia and the prognosis; but, unless the thrombocytopenia recurred, normalization of the platelet count was asso-
211 Copyright o 1976by Academic Press, Inc. All rights of reproduction in any form reserved.
212
JOURNAL
OF SURGICAL
RESEARCH:
TABLE 1 Clinical Data
Types of infection in 28 patients Peritonitis Septicemia Pneumonia Endometritis Abscess Other Total infections
ciated with survival in all patients in which it occurred (42%). Those who died were thrombocytopenic at the time of death and on postmortem examination had evidence of ongoing infection, either unresponsive to treatment or undiagnosed. Platelet transfusions did not succeed in restoring platelet counts to normal. Coagulation Data
Platelet counts, PT, PTT and FDP titers from the 28 patients at the time of their
FDP
PT
PT
Percentage of patients
Group A. Thrombocytopenia
12 9 8 4 3 3 39 Percentage 7.8 6.2 85.0
Organisms involved Pure Gram negative Pure Gram positive Mixed infections
1976
TABLE 2 Coagulation Abnormalities Number of patients
Infections
VOL. 20, NO. 3, MARCH
only
B. Thrombocytopenia and clotting abnormalities Vitamin K deficiency Exchange transfusion lesion Transient elevation FDP D.I.C. C. Clotting abnormalities with normal platelet counts Vitamin K deficiency
65.0 28.0 7 7 10.5 3.5 7 7
lowest platelet count are shown in Fig. 1. According to these results, the patients were divided in three groups: (A) patients who developed thrombocytopenia only (platelet count less than 100,000/mm3); (B) patients with thrombocytopenia and abnormal coagulation parameters; and (C) patients with normal platelet counts but showing coagulation abnormalities (Table 2). A total of 18 patients (65%) were included in group A. A specific explanation for this phenomenon was not apparent. Eight patients (28%) were included in group B and further studies were consistent with coagulation abnormalities on the basis of vitamin K deficiency in two casesand exchange transfusion lesion in another two cases; three patients showed a transient elevation of their FDP titers with spontaneous normalization, the significance of which is not clear; and, finally, one patient was suspected of D.I.C., but he died of his clostridial septicemia before factor levels could be assessed.Group C included two patients (7%) with vitamin K deficiency.
Platelets,
FIG. 1. Platelet counts, PT, PTT, and FDP values for the 28 patients studied, at the time of their lowest platelet count. The platelet counts are expressed in number of platelets per cubic millimeter, the PT and the PTT in seconds, and the FDP in dilutions. The shaded areas represent normal values. Note that the majority of the platelet counts are abnormal, while the majority of the other values are within normal limits.
DISCUSSION These results are in accordance with other series [5, 151; thus thrombocytopenia is a common phenomenon and a reliable monitoring parameter, while D.I.C. is a rare event, in nonmeningococcal bacterial infections in adult patients.
OPPENHEIMER
ET AL.: THROMBOCYTOPENIA
In our patient population, adults with severe bacterial infections and hypotension, probably many factors played a role in the development of thrombocytopenia. The decreased cardiac output with a peripheral low flow state leading to abnormal pooling, acidosis, and increased oxygen extraction in capillary blood [9, 141, the various drugs given to these patients, the presence of liver disease, and poor nutritional status in some of them [15] could be implicated in this process. Moreover, the fact that we failed to show acute D.I.C. in the majority of the patients does not exclude the presence of compensated consumption which could contribute to the decrease in circulating platelets. Infection by itself has been implicated as a cause of thrombocytopenia and several authors, utilizing Gram negative endotoxin models, have reported a platelet endotoxin interaction in rabbits, dogs, and rats [2, 6, lo]. Endotoxin and platelets form aggregates, the endotoxin disappearing almost completely from the plasma fraction [2, 6, lo]. Complement and other heatlabile factors are consumed in the process [12, 131. These aggregates are selectively trapped by elements of the reticuloendothelial system (RES) [2, lo] and the endotoxin presumably cleared. This accomplished, the platelets are released back into the circulation [7]. Thus, platelets seem to be involved in the clearance of endotoxin from the blood stream. The aggregates formed are found in the capillaries of RES (mainly lung, liver, and kidney) and, although this appears to be a defense response to endotoxemia, conversely, it could be responsible for some of the biological effects attributed to the endotoxins [7]. In conclusion, thrombocytopenia is a common phenomenon in bacterial infections (Riedler reports an overall incidence of 75%); its significance is not clear as yet, but it is a reliable monitoring parameter in patients with bacterial processes and a warning sign of occult infection. Further studies of its own role in shock and infections are called for.
IN BACTERIAL
INFECTIONS
213
SUMMARY Twenty-eight patients with bacterial infections and coagulation abnormalities were studied. Thrombocytopenia was seen in 26 (93%). The coagulopathy was related to vitamin K deficiency in four patients and massive transfusions of stored blood in two. Three patients showed transient FDP elevation without evidence of acute consumption of clotting factors, and in only one patient (3.5%) was D.I.C. diagnosed. Eighteen patients were thrombocytopenic without evidence of another coagulation abnormality. Thus D.I.C. seems relatively rare in bacterial infections, and other mechanisms are required to explain the associated thrombocytopenia. REFERENCES I.
2.
3.
4.
5.
6.
I.
8.
9. 10.
Beller, F. K., and Douglas, G. W. Thrombocytopenia indicating Gram negative infection and endotoxemia. Obster. Gynecol. 41:521, 1973. Braude, A. I., Carey, F. J., and Zalesky, M. Studies with radioactive endotoxin. Correlation of physiologic effects with distribution of radioactivity in rabbits injected with lethal doses of E. coli endotoxin labelled with radioactive sodium chromate. J. Clin. Invest. 34:858, 1955. Cohen, P., and Gardner, F. H. Thrombocytopenia as a laboratory sign and complication of Gramnegative bacteremic infection. Arch. Infern. Med. 177:113, 1966. Corrigan, J. J., Ray, W. L., and May, N. Changes in the blood coagulation system associated with septicemia. N. Engl. J. Med. 279:85 I, 1968. Corrigan, J. J. Thrombocytopenia: A laboratory sign of septicemia in infants and children. J. Pediut. 85:219, 1974. Das, J., Schwartz, A. A., and Folkman, J. Clearance of endotoxin platelets. Role in increasing the accuracy of the stimulus gelation test and in combating experimental endotoxemia. Surgery 74:235, 1973. Des Prez, R., and Marney, S. R. Immunological reactions involving platelets. In S. A. Johnson (Ed.), The Circulating Platelet. Academic Press, New York. Goldenfarb, P. B., Zucker, S., Corrigan, J. J., and Cathey, M. H. The coagulation mechanism in acute bacterial infection. Brir. J. Huematol. 18:643, 1970. Gross, S., Keefer, V., and Liebman, J. Platelets in cyanotic heart disease. Pediatrics 42:651, 1968. Herring, W. B., Herion, J. C., Walker, R. I., and
214
JOURNAL OF SURGICAL
RESEARCH: VOL. 20, NO. 3, MARCH
Palmer, J. G. Distribution and clearance of circulating endot0xin.l. C/in. Invest. 42:79, 1963. 1I. Israels, E. D., Rayner, H., Israels, L. G., and Zipursky, A. A microhemagglutination inhibition assay for the quantitation of fibrinogen breakdown products. J. Lab. Clin. Med. 71:33, 1968. 12. Kane, M. A., May, J. E., and Frank, M. M. Interaction of the classical and alternate complement pathway with endotoxin lipopolysaccharide. J. Clin. Invesr. 52:370,370. 13. McCabe, W. R. Serum complement levels in bacte-
1976
remia due to Gram negative organisms. N. Engl. J. Med. 288:21, 1973. 14. McKay, D. G. Disseminated Intravascular Coagulation. Hoeber Medical Division, Harper and Row, New York, 1965. 15. Riedler, G. F., Straub, P. W., and Frick, P. G. Thrombocytopenia in septicemia. A clinical study for the evaluation of its incidence and diagnostic value. Helv. Med. Acta 36:23, 197I. 16. Wintrobe, M. M. Clinical Haematology. 7th Ed. Lea & Febiger, Philadelphia, 1974.
