C o m p l e m e n t
C o n s u m p t i o n
Intravascular A n t e c e d e n t HERMAN E. BRANSON, M.D.,
in A c u t e
C o a g u l a t i o n
D i s s e m i n a t e d w i t h o u t
I m m u n o p a t h o l o g y LARRY L. WYATT, D.O.,
GOTTFRIED SCHMER,
F.A.C.P., AND
M.D.
From the Department of Laboratory Medicine, Divisions of Coagulation and Immunology, of the Univer Washington, School of Medicine and Hospital, Seattle, Washington ABSTRACT
ACUTE disseminated intravascular coagulation (aDIC) is the most significant of the coagulopathies. 18 The etiologies of the syndrome are varied and multitudinous. 25 Shock or hypotension is often linked with the hemorrhagic diathesis of aDIC. Although fibrinogen concentration, platelet count, fibrinogen degradation product assays, and coagulation factor screening tests (e.g., partial thromboplastin time, prothrombin time, thrombin time) have
traditionally been employed to diagnose and follow the syndrome, the interpretation of these values is not always unambiguous. T h e laboratory data in cases of aDIC do not always correlate with the clinical picture. Therapy with blood and blood products may serve in many instances only to obscure the meaning of such data. 8,28,31 This study on complement was undertaken in the hope of providing an additional laboratory modality by which the clinician could assess the clinical status of Received August 18, 1975; received revised manu- a patient with a potentially life-threatening script January 26, 1976; accepted for publication acute consumptive process. T h e interJanuary 26, 1976. relationships of the coagulation, fibrinolyAddress reprint requests to Dr. Branson: Departtic, complement, and kallikrein-kinin ment of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington 98195. enzyme effector systems are now being 967
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Branson, Herman E., Wyatt, Larry L., and Schmer, Gottfried: Complement consumption in acute disseminated intravascular coagulation without antecedent immunopathology. Am J Clin Pathol 66: 9 6 7 - 9 7 5 , 1976. Complement component C3, component C4, and total hemolytic complement CH 50 were measured in blood from ten patients with acute disseminated intravascular coagulation (aDIC) syndromes. The study group was selected on the basis of history to exclude antecedent immunologic, infectious, or hepatic disease. The mortality rate was high (90%), the average duration of illness short (8.5 days), and the utilization of blood products extensive. T h e behaviors of C 3 and C4 were found to be analogous to fibrinogen, plasminogen, antiplasmin, and platelets. CH 50 activity paralled C3 and C4, as well as results of the soluble coagulation factor screening tests. It is concluded that serum complement is consumed as part of the multisystem dysfunction, aDIC, and that in conjunction with traditional indicators it may be utilized to gauge the severity of this syndrome. (Key words: Complement consumption; C3, C4 and CH 50 ; Acute disseminated intravascular coagulation.)
968
BRANSON, WYATT AND SCHMER
elucidated. Common activators (e.g, plasmin, Hageman factor) and inhibitors {e.g., c^-macroglobulin, a1 antitrypsin) have already been found. 27 ' 29,35 The complement system rather than the kallikrein-kinin system was chosen for this study because it is more widely available. Complement activation is also important because it is capable of producing indiscriminate membrane damage and potentiating or exacerbating shock through its metabolic intermediates. 16'17-24
empirically to alterations of complement values in the critically ill and the frequent association of this phenomenon with DIC. 6 These investigators supplied no documentation of complement consumption and made no attempt at correlation with coagulation or fibrinolytic indices. Ten patients who had aDIC syndromes from the University of Washington-affiliated hospitals comprised the study group. Samples of blood were obtained serially as long as the durations of illness permitted. All patients were screened for hepatic disease, immunologic disease, and infection. A coagulation screening battery comprised of tests of hematocrit, prothrombin time, partial thromboplastin time, thrombin time, fibrin-fibrinogen split products, fibrinogen, and urea solubility was secured for every patient. C3, C4 and CH 50 were also determined for all patients during the consumptive episode. In addition, plasminogen and antiplasmin were assayed in samples from six patients. It appears that low quantities of component C3, component C4, and low CH 50 titers are an integral part of the aDIC syndrome and as such represent an additional test system for assessing the status of hemorrhagic diatheses with concomitant shock regardless of etiology. Materials and Methods Patients T h e study covered a 145-day period (July 15, 1973 to December 6, 1973), during which we reviewed 771 screens from the University of Washington-affiliated hospitals (the University of Washington Hospital Medical Center, Harborview Medical Center, and the Seattle Veterans Administration Hospital). Eighty probable aDIC syndromes were culled from this group of 260 patients. This number was reduced to 29 on the basis of the availability of clinical and laboratory data.
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Complement component consumption has been measured in many clinical settings. Altered complement levels traditionally are associated with immunologic, infectious, and hepatic diseases or dysfunctions. 5a2 ' 26 In the past, coagulopathies have only occasionally been associated with complement abnormalities. Bokish and coworkers measured all complement components except Clr and C7 by radial immunodiffusion in dengue hemorrhagic shock syndrome victims and found all except C9 to be depressed. 1 Cross-reactivity between closely related strains of group B arboviruses was postulated to elicit an anamnestic response resulting in the hypercatabolic consumption of complement components. The severity of the shock and clinical symptoms correlated well with the severity of the consumption coagulopathy. The most severly ill patients in this study (Group IV) had coagulation and fibrinolytic values compatible with aDIC as defined in this study. No control group with aDIC and concomitant non-immunologic shock syndromes was included in the study. Tomar and associates examined the probability that C3 consumption was solely the result of plasmin activity by comparing the low levels of C3 in 16 DIC patients with normal C 3 levels in urokinase-treated patients. 36 Unfortunately, nine of the 16 patients had active infections at the time of assay, which may have at least partially responsible for depression of this component. Frank and Atkinson alluded
A.J.C.P. —Vol. 66
December 1976
COMPLEMENT AND INTRAVASCULAR COAGULATION
Of the 29, 14 were excluded from the study because of well-documented active infection, hepatic disease, or immunologic disease. Five patients were eliminated from the study because they did not manifest hemorrhagic tendencies, blood pressure
969
abnormalities, or decreased urinary output despite laboratory values compatible with aDIC. T h e final ten patients comprising the study group were diagnosed as having acute DIC according to the modified criteria of McKay as outlined below.19
The average duration of the acute consumptive episode was 3.8 days, with a range of 1 to 7 days. Only one of ten patients (i.e., Patient 1) survived the coagulopathies. A total of 38 coagulation screens was performed on study group patients, 4/38 (11%) prior to the onset (in 4/10 patients) and 34/38 (89%) following the onset of DIC. All ten patients mainfested the major criteria, while only 5/10 had discernible microangiopatic hemolytic anemia and only 3/10 had necropsy findings compatible with DIC. Of the two patients screened prior to the onset of the acute consumptive episode neither had laboratory data
compatible with DIC. None of the remaining eight patients had a clinical history compatible with an antecedent coagulopathy. All ten patients received blood and blood products from the Puget Sound Blood Center during their consumptive episodes. No other therapeutic agent was employed in the direct therapy of the coagulopathies. Laboratory Methods Complement components C3 and C4 were assayed by radial immunodiffusion. 15 CH 50 was determined by established bio-
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 6, 2016
Major Criteria A. Clinical Criteria 1. Hemorrhagic diathesis (i.e., protracted heavy bleeding from any site necessitating therapy with blood and blood products) 2. Hypotension or shock 3. Oliguria or anuria Laboratory B. La boratory Criteria Normal. Values Patient Values 1. Fibrinogen/fibrin degr idation 5 ± 3.0 /Mg/ml (FDP) s 4 0 ixg/m\ (116 ju,mol/l) (15 ± 9 Atmol/1) s i 7 5 mg/dl 285 ± 50 mg/dl 2. Fibrinogen (8.27 ± 1.45 jLtmol/1) (5.09 fimoVl) 250,000 ± 40,000///,!
C o n s u m p t i o n
Intravascular A n t e c e d e n t HERMAN E. BRANSON, M.D.,
in A c u t e
C o a g u l a t i o n
D i s s e m i n a t e d w i t h o u t
I m m u n o p a t h o l o g y LARRY L. WYATT, D.O.,
GOTTFRIED SCHMER,
F.A.C.P., AND
M.D.
From the Department of Laboratory Medicine, Divisions of Coagulation and Immunology, of the Univer Washington, School of Medicine and Hospital, Seattle, Washington ABSTRACT
ACUTE disseminated intravascular coagulation (aDIC) is the most significant of the coagulopathies. 18 The etiologies of the syndrome are varied and multitudinous. 25 Shock or hypotension is often linked with the hemorrhagic diathesis of aDIC. Although fibrinogen concentration, platelet count, fibrinogen degradation product assays, and coagulation factor screening tests (e.g., partial thromboplastin time, prothrombin time, thrombin time) have
traditionally been employed to diagnose and follow the syndrome, the interpretation of these values is not always unambiguous. T h e laboratory data in cases of aDIC do not always correlate with the clinical picture. Therapy with blood and blood products may serve in many instances only to obscure the meaning of such data. 8,28,31 This study on complement was undertaken in the hope of providing an additional laboratory modality by which the clinician could assess the clinical status of Received August 18, 1975; received revised manu- a patient with a potentially life-threatening script January 26, 1976; accepted for publication acute consumptive process. T h e interJanuary 26, 1976. relationships of the coagulation, fibrinolyAddress reprint requests to Dr. Branson: Departtic, complement, and kallikrein-kinin ment of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington 98195. enzyme effector systems are now being 967
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 6, 2016
Branson, Herman E., Wyatt, Larry L., and Schmer, Gottfried: Complement consumption in acute disseminated intravascular coagulation without antecedent immunopathology. Am J Clin Pathol 66: 9 6 7 - 9 7 5 , 1976. Complement component C3, component C4, and total hemolytic complement CH 50 were measured in blood from ten patients with acute disseminated intravascular coagulation (aDIC) syndromes. The study group was selected on the basis of history to exclude antecedent immunologic, infectious, or hepatic disease. The mortality rate was high (90%), the average duration of illness short (8.5 days), and the utilization of blood products extensive. T h e behaviors of C 3 and C4 were found to be analogous to fibrinogen, plasminogen, antiplasmin, and platelets. CH 50 activity paralled C3 and C4, as well as results of the soluble coagulation factor screening tests. It is concluded that serum complement is consumed as part of the multisystem dysfunction, aDIC, and that in conjunction with traditional indicators it may be utilized to gauge the severity of this syndrome. (Key words: Complement consumption; C3, C4 and CH 50 ; Acute disseminated intravascular coagulation.)
968
BRANSON, WYATT AND SCHMER
elucidated. Common activators (e.g, plasmin, Hageman factor) and inhibitors {e.g., c^-macroglobulin, a1 antitrypsin) have already been found. 27 ' 29,35 The complement system rather than the kallikrein-kinin system was chosen for this study because it is more widely available. Complement activation is also important because it is capable of producing indiscriminate membrane damage and potentiating or exacerbating shock through its metabolic intermediates. 16'17-24
empirically to alterations of complement values in the critically ill and the frequent association of this phenomenon with DIC. 6 These investigators supplied no documentation of complement consumption and made no attempt at correlation with coagulation or fibrinolytic indices. Ten patients who had aDIC syndromes from the University of Washington-affiliated hospitals comprised the study group. Samples of blood were obtained serially as long as the durations of illness permitted. All patients were screened for hepatic disease, immunologic disease, and infection. A coagulation screening battery comprised of tests of hematocrit, prothrombin time, partial thromboplastin time, thrombin time, fibrin-fibrinogen split products, fibrinogen, and urea solubility was secured for every patient. C3, C4 and CH 50 were also determined for all patients during the consumptive episode. In addition, plasminogen and antiplasmin were assayed in samples from six patients. It appears that low quantities of component C3, component C4, and low CH 50 titers are an integral part of the aDIC syndrome and as such represent an additional test system for assessing the status of hemorrhagic diatheses with concomitant shock regardless of etiology. Materials and Methods Patients T h e study covered a 145-day period (July 15, 1973 to December 6, 1973), during which we reviewed 771 screens from the University of Washington-affiliated hospitals (the University of Washington Hospital Medical Center, Harborview Medical Center, and the Seattle Veterans Administration Hospital). Eighty probable aDIC syndromes were culled from this group of 260 patients. This number was reduced to 29 on the basis of the availability of clinical and laboratory data.
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 6, 2016
Complement component consumption has been measured in many clinical settings. Altered complement levels traditionally are associated with immunologic, infectious, and hepatic diseases or dysfunctions. 5a2 ' 26 In the past, coagulopathies have only occasionally been associated with complement abnormalities. Bokish and coworkers measured all complement components except Clr and C7 by radial immunodiffusion in dengue hemorrhagic shock syndrome victims and found all except C9 to be depressed. 1 Cross-reactivity between closely related strains of group B arboviruses was postulated to elicit an anamnestic response resulting in the hypercatabolic consumption of complement components. The severity of the shock and clinical symptoms correlated well with the severity of the consumption coagulopathy. The most severly ill patients in this study (Group IV) had coagulation and fibrinolytic values compatible with aDIC as defined in this study. No control group with aDIC and concomitant non-immunologic shock syndromes was included in the study. Tomar and associates examined the probability that C3 consumption was solely the result of plasmin activity by comparing the low levels of C3 in 16 DIC patients with normal C 3 levels in urokinase-treated patients. 36 Unfortunately, nine of the 16 patients had active infections at the time of assay, which may have at least partially responsible for depression of this component. Frank and Atkinson alluded
A.J.C.P. —Vol. 66
December 1976
COMPLEMENT AND INTRAVASCULAR COAGULATION
Of the 29, 14 were excluded from the study because of well-documented active infection, hepatic disease, or immunologic disease. Five patients were eliminated from the study because they did not manifest hemorrhagic tendencies, blood pressure
969
abnormalities, or decreased urinary output despite laboratory values compatible with aDIC. T h e final ten patients comprising the study group were diagnosed as having acute DIC according to the modified criteria of McKay as outlined below.19
The average duration of the acute consumptive episode was 3.8 days, with a range of 1 to 7 days. Only one of ten patients (i.e., Patient 1) survived the coagulopathies. A total of 38 coagulation screens was performed on study group patients, 4/38 (11%) prior to the onset (in 4/10 patients) and 34/38 (89%) following the onset of DIC. All ten patients mainfested the major criteria, while only 5/10 had discernible microangiopatic hemolytic anemia and only 3/10 had necropsy findings compatible with DIC. Of the two patients screened prior to the onset of the acute consumptive episode neither had laboratory data
compatible with DIC. None of the remaining eight patients had a clinical history compatible with an antecedent coagulopathy. All ten patients received blood and blood products from the Puget Sound Blood Center during their consumptive episodes. No other therapeutic agent was employed in the direct therapy of the coagulopathies. Laboratory Methods Complement components C3 and C4 were assayed by radial immunodiffusion. 15 CH 50 was determined by established bio-
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 6, 2016
Major Criteria A. Clinical Criteria 1. Hemorrhagic diathesis (i.e., protracted heavy bleeding from any site necessitating therapy with blood and blood products) 2. Hypotension or shock 3. Oliguria or anuria Laboratory B. La boratory Criteria Normal. Values Patient Values 1. Fibrinogen/fibrin degr idation 5 ± 3.0 /Mg/ml (FDP) s 4 0 ixg/m\ (116 ju,mol/l) (15 ± 9 Atmol/1) s i 7 5 mg/dl 285 ± 50 mg/dl 2. Fibrinogen (8.27 ± 1.45 jLtmol/1) (5.09 fimoVl) 250,000 ± 40,000///,!
