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Disseminated Intravascular Coagulation: Diagnosis and Treatment of a Hemorrhagic Diathesis after Prostatectomy
Vol. 108, December Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1972 by The Williams & Wilkins Co.
DISSEMINATED INTRAVASCULAR COAGULATION: DIAGNOSIS AND TREATJVIENT OF A HEMORRHAGIC DIATHESIS AFTER PROSTATECTOMY ROBERT L. PICKENS*
AND
JOHN K. LATTIMER
From the Squier Urological Clinic, Columbia-Presbyterian Medical Center, New York, New York
The of disseminated intravascular coagulation known as consumption coagulopathy or the aenorrn.a syndrome) is recognized as a cause of hemorrhagic diatheses in a wide variety of pathologic entities. This process is thought to represent "a activation of the hemostatic mechanism beyond that normally confined to areas of local vascular injury; the subsequent alterations in fibrinogen and the variations that occur in the other clotting factors, as well as the activation of the fibrinolytic system, are all reflections of the initiating stimulus." 1 Prompt diagnosis and treatment of this syndrome present a challenge. The urologic literature has focused primarily on bleeding disorders secondary to prostatic fibrinolysins2 and fibrinogen inhibitors 3 in patients with metastatic carcinoma of the prostate. Abnormal fibrinolysis is recognized as a secondary event after mtravascular clot formation with depletion of fibrinogen and other essential clotting factors. Recent studies have stressed the possibility of disseminated intravascular coagulation in many metabolic, infectious and surgical conditions. 4 In a recent study, 96 per cent of children with septic shock were found to have disseminated intra vascular coagula,tion. 5 The early diagnosis and successful treatment of disseminated intravascular coagulation in a patient who had undergone prostatectomy for benign prostatic hypertrophy are reported herein.
1, :
Accepted for publication 1972. Read at annual meeting York Section American Urological Association, New York Nev; York, March 24, 1971. ' Sup_ported in part by National Institute of Health Trammg Grant T1AM5451. * Cun_:ent address: United States Public Health Serv~ce Hospital, 6500 Hampton Boulevard, Norfolk VH"g1111a 23508. ' 1 Deykin, D.: The clinical challenge of disseminated mtravascular coagulation. New Engl. J. Med
283: 636, 1970.
.,
Tagnon, H.J., Whitmore, W. F. Jr. and Shulman N. R.: Fibrinolysis in metastatic c~ncer of the pros'. tate. Cancer, !ii: 9, 1952. 3 Seal~, R. A., Jampolis, R. W. and Bargen, J. A.: Syml?osmm on surgical aspects of cancer problem; clottmg defect m the presence of metastatic carcinoma of prostate; case report. Surg. Clin. N. Amer., 31: 1111, 1951. 4 Hathaway, W. E.: Care of the critically ill child: the problem of disseminated intravascular coagulation. Pediatrics, 46: 1970. 6 Corr~gan, J: J., _Jr. . Jordai_i, C. M.: Heparin therapy m septicemia with d1ssemmated intravascufar coagulation. Effect and correction J, 778of hemostatic defects. 2
1970,
.
'
CASE REPORT
S.
169-25-65, an
black man, underwent an uneventful suprapubic rwnc1'Q1·nn'crn~on for benign prostatic hypertrophy. u-·-------prothrombin time platelet count clotting time were normal. The patient had received digitalis prophylactically prior to operation owing to evidence of left ventricular enlargement. Two days postoperatively evidence of congestive heart failure secondary to fluid overload developed. This was treated successfully with fluid restriction and diuretics. The patient was never hypotensive. A low grade temperature persisted although blood cultures were negative. He was maintained on parenteral antibiotic therapy with keflin. The urinary drainage remained bloodtinged. At 7 postoperatively abdominal distension developed, necessitating nasogastric decompression, The patient vomited 1,000 cc bright red blood with a drop in blood pressure 9 days postoperatively, Gastroscopy was performed as an emergency diagnostic measure because of uncontrollable bleeding. This revealed diffuse hemorrhagic gastritis and esophagitis, Bleeding parameters revealed evidence of disseminated intravascular coagulation with elevated PT, partial thromboplastin time (PTT), thrombin time (TT) and depression of fibrinogen to 30 mg. per cent and platelet count to 76,000 per cu. mm. Intravenous heparin therapy, 10,000 units every 6 hours was begun immediately. In addition, the patient received 4 gm. of fibrinogen, 2 units of fresh frozen plasma, 15 units of platelets and contiirnous fresh whole blood, Evaluation of clotting factors after 24 hours of therapy revealed that all parameters had returned to normal. Within 48 hours the bleeding had ending a diathesis that had consumed 42 units of whole blood. Figure 1 is a schematic representation of the key factors in the diagnosis of disseminated intravascular coagulation in this patient and the response of these factors after therapy. Despite neurologic evidence of a cerebrovascular accident secondary to cerebral hemorrhage or to thrombosis, the patient improved and was discharged from the hospital to a nursing home 6 weeks later. He died quietly of unknown causes 4 months after recovery from the hemorrhagic diathesis. DISCUSSION
952
PICKENS AND LATTIMER
RESPONSE OF CLOTTING FACTORS WITHIN 24 HOURS AFTER BEGINNING THERAPY THERAPY (HEPARIN)
FIBRINOGEN - 30 mg%
FIBRINOGEN-365 mg%
(Fibrinogen) (Plate I ets) PLATELETS -107,000
PLATELETS - 76,000 (Fresh frozen plasma)
PT] PTT ELEVATED
TT
( Fresh whole blood)
J
PT PTT NORMAL TT
FIG. 1 SCHEMATIC REPRESENTATION OF STEPS IN NORMAL CLOT FORMATION 8 SITE OF PLASMIN INHIBITION
l
PROTHROMBIN 'INTRINSIC" CLOTTING SYSTEM
(OR) _ _ _ _...
l
FIBRINOGEN
'EXTRINSIC' CLOTTING SYSTEM
THROMBIN--
FIBRIN
,,' --'\
_,_...,'
{ Plasmo,
' ....
I
, . . -.L--.. ,,
.
(I Plosminogen ' J
', .... ____ ......,'
FIG. 2
nated intravascular coagulation. In 1952 Tagnon and associates claimed to be reporting the first case of fibrinolysis secondary to an unknown factor associated with carcinoma of the prostate. 2 In 1953 they demonstrated fibrinolytic activity in extracts of primary prostatic carcinoma and in metastatic deposits. 6 Recently, Brooks reported on a case of disseminated intravascular coagulation in a patient with carcinoma of the prostate. 7 He believed that the prostatic tumor produced an activator that pre' Tagnon, H. J., Schulman, P., Whitmore, W. F., Jr. and Leone, L.A.: Prostatic fibrinolysin; study of a case illustrating role in hemorrhagic diathesis of cancer of the prostate. Amer. J. Med., 16: 875, 1953. 7 Brooks, M. B.: Heparin in the treatment of hemorrhagic diathesis associated with prostatic carcinoma. J. Urol., 102: 240, 1969.
cipitated the clotting mechanism and resulted in defibrination. Current studies on disseminated intravascular coagulation have stressed the wide range of pathologic entities that have been shown to initiate this clottingfibrinolytic cycle with depletion of clotting factors. These entities include bacterial and viral sepsis, surgical conditions such as trauma, burns, hemorrhagic shock, anesthesia and miscellaneous disorders such as drug reactions, malignancies and anaphylactic shock. 4 Corrigan and Jordan studied 26 children with septic shock; in half the patients shock was secondary to gram-negative organisms. They found intravascular coagulation in 96 per cent of these children. 5 Some form of hemorrhage was preseut in 25 patients, with severe genitourinary or gastrointestinal bleeding in 10 patients. Earlier investigators of the shock syndrome associated with gram-negative bacteremia noted evidence of gastrointestinal bleeding in approximately 35 per cent of cases. 8 However, these investigators did not comment on the possibility of disseminated intravascular coagulation as a causative mechanism. Figure 2 is a schematic representation of the normal steps in the clotting process and the response of the fibrinolytic system, with the conversion of plasminogen to plasmin to block the action of thrombin on fibrinogen. This delicately balanced sequence of events is normally coufined to areas of vascular injury. In disseminated intravascular coagulation, this balance is disrupted by the underlying pathologic state. Fibrin consumption and fibrinolysis continue unchecked with eventual depletion of clotting factors, leaving a predisposition to a hemorrhagic state. DIAGNOSIS AND THERAPY
The clinical diagnosis of the syndrome of disseminated intravascular coagulation is based most res Weil, M. H. and Spink, W. W.: The shock syndrome associated with bacteremia due to gramnegative bacilli. Arch. Intern. Med., 101: 184, 1958.
DISSEMINATED INTRAVASCULAR COAGULATION
liably on 3 parameters: 1) fibrinogen level, 2) platelet count and 3)thrombin time. Analysis of prothrombin time, the various numbered factors and euglobulin lysis time have proved to be variable and unreliable. Analysis of fibrinogen degradation products may also be diagnostic; however, this test is not readily available in all laboratories. In our case, early recognition of fibrinogenemia (30 mg. per cent), thrombocytopenia (76,000 per mm. 3) and elevated thrombin time, led to prompt therapy with heparin and conversion of these factors to normal within 24 hours. has stressed the importance of postoperative measurements of these factors in order to detect subtle relative changes. 1 Fibrinogen levels may increase to as much as 1,000 mg. per cent operatively in response to surgical stress. a numerically normal fibrinogen level of 200 to 300 mg. per cent may mask the existence of a serious defibrination reaction. The same is true for the platelet count. In patients with chronic malignancies the platelet count may be as high as 700,000 to per cu. mm. as a base line. The key to therapy of disseminated intravascular coagulation is 1) prompt recognition and treatment of the underlying pathologic disorder and 2) termination of the clotting cycle with heparinization. Our patient was treated for sepsis and congestive heart failure and received intravenous heparin in a dosage of 10,000 units every 6 hours with evidence of cessation of defibrination within 24 hours. Brooks reported a similar response to heparin therapy in his patient after a longer period of time. 7 However, the prognosis for long-term survival rests primarily with correction of the underlying pathologic process. In their study of children in shock, Corrigan and Jordan demonstrated an improvement in the coagulation defects with heparin therapy. However, they emphasized that survival was wholly dependent on the reversal of shock which did not always respond as rapidly as the clotting factors. 5 There are reports of the use of epsilon aminocaproic acid (EACA) to control post-prostatectomy
~----~~-~
953
hemorrhage.9-11 Deykin has summarized current opinion in warning against the indiscriminate use of this agent in coagulation disorders that are characterized intravascular coagulation and consumption of clotting factors. 1 He believes that an anti:fibrinolytic agent of this type will further disrupt the balance between the action of thrombin and plasmin and may lead to overwhelming thrombosis. In 1962 described intravascular thrombosis the administration of epsilon aminocaproic acid to a patient with prostatic carcinoma. 12 He commented that this agent probably had exacerbated a process of intravascular coagulation. SUMMARY
The of disseminated intravascular coagulation (consumption coagulopathy or the defibrination syndrome) has been recognized in a wide of infectious, surgical and metabolic disordiffuse fibrin formation there is a consumption of clotting factors which can be detected most reliably by determination of fibrinogen levels, platelet count and thrombin time. Successful treatment is based 011 correction of the underlying pathology and prompt heparin therapy for restoration of normal coagulation parameters. The use of an anti:fibrinolytic agent like epsilon aminocaproic acid is to be avoided in this syndrome. nunrl»A>,on
9 Vinnicombe, caproic acid in
and Shuttleworth, K. E.: Aminocontrol of haemorrhage after A controlled trial. Lancet, 1: 230,
P., Fletcher, A. P., Alkjaersig, N. : Impairment of hemostasis in the urinary tract: the role of urokinase. J. Lab. Clin. Med., 58: 34, 1961. 11 Pellman, C. M., Ridlon, H. C. and Phillips, L. L.: Manifestation and management of hypofibrinogenemia and fibrinolysis in patients with carcinoma of the prostate. J. Urol., 96: 375, 1966. 12 N aeye, R. L.: Thrombotic state after a hemorrhagic diathesis, a possible complication of therapy with epsilon-aminocaproic acid. Blood, 19: 694, 1962.
THE JOURNAL OF UROLOGY
Copyright © 1972 by The Williams & Wilkins Co.
DISSEMINATED INTRAVASCULAR COAGULATION: DIAGNOSIS AND TREATJVIENT OF A HEMORRHAGIC DIATHESIS AFTER PROSTATECTOMY ROBERT L. PICKENS*
AND
JOHN K. LATTIMER
From the Squier Urological Clinic, Columbia-Presbyterian Medical Center, New York, New York
The of disseminated intravascular coagulation known as consumption coagulopathy or the aenorrn.a syndrome) is recognized as a cause of hemorrhagic diatheses in a wide variety of pathologic entities. This process is thought to represent "a activation of the hemostatic mechanism beyond that normally confined to areas of local vascular injury; the subsequent alterations in fibrinogen and the variations that occur in the other clotting factors, as well as the activation of the fibrinolytic system, are all reflections of the initiating stimulus." 1 Prompt diagnosis and treatment of this syndrome present a challenge. The urologic literature has focused primarily on bleeding disorders secondary to prostatic fibrinolysins2 and fibrinogen inhibitors 3 in patients with metastatic carcinoma of the prostate. Abnormal fibrinolysis is recognized as a secondary event after mtravascular clot formation with depletion of fibrinogen and other essential clotting factors. Recent studies have stressed the possibility of disseminated intravascular coagulation in many metabolic, infectious and surgical conditions. 4 In a recent study, 96 per cent of children with septic shock were found to have disseminated intra vascular coagula,tion. 5 The early diagnosis and successful treatment of disseminated intravascular coagulation in a patient who had undergone prostatectomy for benign prostatic hypertrophy are reported herein.
1, :
Accepted for publication 1972. Read at annual meeting York Section American Urological Association, New York Nev; York, March 24, 1971. ' Sup_ported in part by National Institute of Health Trammg Grant T1AM5451. * Cun_:ent address: United States Public Health Serv~ce Hospital, 6500 Hampton Boulevard, Norfolk VH"g1111a 23508. ' 1 Deykin, D.: The clinical challenge of disseminated mtravascular coagulation. New Engl. J. Med
283: 636, 1970.
.,
Tagnon, H.J., Whitmore, W. F. Jr. and Shulman N. R.: Fibrinolysis in metastatic c~ncer of the pros'. tate. Cancer, !ii: 9, 1952. 3 Seal~, R. A., Jampolis, R. W. and Bargen, J. A.: Syml?osmm on surgical aspects of cancer problem; clottmg defect m the presence of metastatic carcinoma of prostate; case report. Surg. Clin. N. Amer., 31: 1111, 1951. 4 Hathaway, W. E.: Care of the critically ill child: the problem of disseminated intravascular coagulation. Pediatrics, 46: 1970. 6 Corr~gan, J: J., _Jr. . Jordai_i, C. M.: Heparin therapy m septicemia with d1ssemmated intravascufar coagulation. Effect and correction J, 778of hemostatic defects. 2
1970,
.
'
CASE REPORT
S.
169-25-65, an
black man, underwent an uneventful suprapubic rwnc1'Q1·nn'crn~on for benign prostatic hypertrophy. u-·-------prothrombin time platelet count clotting time were normal. The patient had received digitalis prophylactically prior to operation owing to evidence of left ventricular enlargement. Two days postoperatively evidence of congestive heart failure secondary to fluid overload developed. This was treated successfully with fluid restriction and diuretics. The patient was never hypotensive. A low grade temperature persisted although blood cultures were negative. He was maintained on parenteral antibiotic therapy with keflin. The urinary drainage remained bloodtinged. At 7 postoperatively abdominal distension developed, necessitating nasogastric decompression, The patient vomited 1,000 cc bright red blood with a drop in blood pressure 9 days postoperatively, Gastroscopy was performed as an emergency diagnostic measure because of uncontrollable bleeding. This revealed diffuse hemorrhagic gastritis and esophagitis, Bleeding parameters revealed evidence of disseminated intravascular coagulation with elevated PT, partial thromboplastin time (PTT), thrombin time (TT) and depression of fibrinogen to 30 mg. per cent and platelet count to 76,000 per cu. mm. Intravenous heparin therapy, 10,000 units every 6 hours was begun immediately. In addition, the patient received 4 gm. of fibrinogen, 2 units of fresh frozen plasma, 15 units of platelets and contiirnous fresh whole blood, Evaluation of clotting factors after 24 hours of therapy revealed that all parameters had returned to normal. Within 48 hours the bleeding had ending a diathesis that had consumed 42 units of whole blood. Figure 1 is a schematic representation of the key factors in the diagnosis of disseminated intravascular coagulation in this patient and the response of these factors after therapy. Despite neurologic evidence of a cerebrovascular accident secondary to cerebral hemorrhage or to thrombosis, the patient improved and was discharged from the hospital to a nursing home 6 weeks later. He died quietly of unknown causes 4 months after recovery from the hemorrhagic diathesis. DISCUSSION
952
PICKENS AND LATTIMER
RESPONSE OF CLOTTING FACTORS WITHIN 24 HOURS AFTER BEGINNING THERAPY THERAPY (HEPARIN)
FIBRINOGEN - 30 mg%
FIBRINOGEN-365 mg%
(Fibrinogen) (Plate I ets) PLATELETS -107,000
PLATELETS - 76,000 (Fresh frozen plasma)
PT] PTT ELEVATED
TT
( Fresh whole blood)
J
PT PTT NORMAL TT
FIG. 1 SCHEMATIC REPRESENTATION OF STEPS IN NORMAL CLOT FORMATION 8 SITE OF PLASMIN INHIBITION
l
PROTHROMBIN 'INTRINSIC" CLOTTING SYSTEM
(OR) _ _ _ _...
l
FIBRINOGEN
'EXTRINSIC' CLOTTING SYSTEM
THROMBIN--
FIBRIN
,,' --'\
_,_...,'
{ Plasmo,
' ....
I
, . . -.L--.. ,,
.
(I Plosminogen ' J
', .... ____ ......,'
FIG. 2
nated intravascular coagulation. In 1952 Tagnon and associates claimed to be reporting the first case of fibrinolysis secondary to an unknown factor associated with carcinoma of the prostate. 2 In 1953 they demonstrated fibrinolytic activity in extracts of primary prostatic carcinoma and in metastatic deposits. 6 Recently, Brooks reported on a case of disseminated intravascular coagulation in a patient with carcinoma of the prostate. 7 He believed that the prostatic tumor produced an activator that pre' Tagnon, H. J., Schulman, P., Whitmore, W. F., Jr. and Leone, L.A.: Prostatic fibrinolysin; study of a case illustrating role in hemorrhagic diathesis of cancer of the prostate. Amer. J. Med., 16: 875, 1953. 7 Brooks, M. B.: Heparin in the treatment of hemorrhagic diathesis associated with prostatic carcinoma. J. Urol., 102: 240, 1969.
cipitated the clotting mechanism and resulted in defibrination. Current studies on disseminated intravascular coagulation have stressed the wide range of pathologic entities that have been shown to initiate this clottingfibrinolytic cycle with depletion of clotting factors. These entities include bacterial and viral sepsis, surgical conditions such as trauma, burns, hemorrhagic shock, anesthesia and miscellaneous disorders such as drug reactions, malignancies and anaphylactic shock. 4 Corrigan and Jordan studied 26 children with septic shock; in half the patients shock was secondary to gram-negative organisms. They found intravascular coagulation in 96 per cent of these children. 5 Some form of hemorrhage was preseut in 25 patients, with severe genitourinary or gastrointestinal bleeding in 10 patients. Earlier investigators of the shock syndrome associated with gram-negative bacteremia noted evidence of gastrointestinal bleeding in approximately 35 per cent of cases. 8 However, these investigators did not comment on the possibility of disseminated intravascular coagulation as a causative mechanism. Figure 2 is a schematic representation of the normal steps in the clotting process and the response of the fibrinolytic system, with the conversion of plasminogen to plasmin to block the action of thrombin on fibrinogen. This delicately balanced sequence of events is normally coufined to areas of vascular injury. In disseminated intravascular coagulation, this balance is disrupted by the underlying pathologic state. Fibrin consumption and fibrinolysis continue unchecked with eventual depletion of clotting factors, leaving a predisposition to a hemorrhagic state. DIAGNOSIS AND THERAPY
The clinical diagnosis of the syndrome of disseminated intravascular coagulation is based most res Weil, M. H. and Spink, W. W.: The shock syndrome associated with bacteremia due to gramnegative bacilli. Arch. Intern. Med., 101: 184, 1958.
DISSEMINATED INTRAVASCULAR COAGULATION
liably on 3 parameters: 1) fibrinogen level, 2) platelet count and 3)thrombin time. Analysis of prothrombin time, the various numbered factors and euglobulin lysis time have proved to be variable and unreliable. Analysis of fibrinogen degradation products may also be diagnostic; however, this test is not readily available in all laboratories. In our case, early recognition of fibrinogenemia (30 mg. per cent), thrombocytopenia (76,000 per mm. 3) and elevated thrombin time, led to prompt therapy with heparin and conversion of these factors to normal within 24 hours. has stressed the importance of postoperative measurements of these factors in order to detect subtle relative changes. 1 Fibrinogen levels may increase to as much as 1,000 mg. per cent operatively in response to surgical stress. a numerically normal fibrinogen level of 200 to 300 mg. per cent may mask the existence of a serious defibrination reaction. The same is true for the platelet count. In patients with chronic malignancies the platelet count may be as high as 700,000 to per cu. mm. as a base line. The key to therapy of disseminated intravascular coagulation is 1) prompt recognition and treatment of the underlying pathologic disorder and 2) termination of the clotting cycle with heparinization. Our patient was treated for sepsis and congestive heart failure and received intravenous heparin in a dosage of 10,000 units every 6 hours with evidence of cessation of defibrination within 24 hours. Brooks reported a similar response to heparin therapy in his patient after a longer period of time. 7 However, the prognosis for long-term survival rests primarily with correction of the underlying pathologic process. In their study of children in shock, Corrigan and Jordan demonstrated an improvement in the coagulation defects with heparin therapy. However, they emphasized that survival was wholly dependent on the reversal of shock which did not always respond as rapidly as the clotting factors. 5 There are reports of the use of epsilon aminocaproic acid (EACA) to control post-prostatectomy
~----~~-~
953
hemorrhage.9-11 Deykin has summarized current opinion in warning against the indiscriminate use of this agent in coagulation disorders that are characterized intravascular coagulation and consumption of clotting factors. 1 He believes that an anti:fibrinolytic agent of this type will further disrupt the balance between the action of thrombin and plasmin and may lead to overwhelming thrombosis. In 1962 described intravascular thrombosis the administration of epsilon aminocaproic acid to a patient with prostatic carcinoma. 12 He commented that this agent probably had exacerbated a process of intravascular coagulation. SUMMARY
The of disseminated intravascular coagulation (consumption coagulopathy or the defibrination syndrome) has been recognized in a wide of infectious, surgical and metabolic disordiffuse fibrin formation there is a consumption of clotting factors which can be detected most reliably by determination of fibrinogen levels, platelet count and thrombin time. Successful treatment is based 011 correction of the underlying pathology and prompt heparin therapy for restoration of normal coagulation parameters. The use of an anti:fibrinolytic agent like epsilon aminocaproic acid is to be avoided in this syndrome. nunrl»A>,on
9 Vinnicombe, caproic acid in
and Shuttleworth, K. E.: Aminocontrol of haemorrhage after A controlled trial. Lancet, 1: 230,
P., Fletcher, A. P., Alkjaersig, N. : Impairment of hemostasis in the urinary tract: the role of urokinase. J. Lab. Clin. Med., 58: 34, 1961. 11 Pellman, C. M., Ridlon, H. C. and Phillips, L. L.: Manifestation and management of hypofibrinogenemia and fibrinolysis in patients with carcinoma of the prostate. J. Urol., 96: 375, 1966. 12 N aeye, R. L.: Thrombotic state after a hemorrhagic diathesis, a possible complication of therapy with epsilon-aminocaproic acid. Blood, 19: 694, 1962.