«DESPITE the employment of a number of remedies that have been suggeMted for the control and prevention of bleeding in patients with obstructive ...»
In I894, Corin anid Ansiaux" had already observed that the blood of dogs poisoned with phosphorus remainied incoagulable. Spontaneous haemorrhages in the tissues of some of these animals were also seeni. Doyoni " found that dogs given 25 to 50 c.c. of chloroform by stomach tube died after a few days and that blood drawn from the carotid artery shortly before death failed to clot. This alterationi in the coagulability of the blood was correlated by Doyon, Morel and Billet 3 with the hepatic necrosis that followed the administrationi of chloroform, anid that was responisible for the death of the animals.
The same findings were present in phosphorus poisoning. More recently Kerr, Horwitz, anid Whipple 62 have found that in the liver injury attenidinig the subcutaneous injection of l)hospllorus in dogs the animals die in about five days. The blood remains incoagulable a(ld multiple haemorrhages are usually present.
Doyoni anid his co-workers " have also nioted that the injection of a centigram of atropin per kilo inito the meseniteric veini of a dog causes the blood to become inicoagulable. Injectionis of atropini inito the saphenous vein or into the splenic or renal artery were without effect oni the coagulability of the blood. Hepatic artery injections elicited the same effect as portal inijections.'3 Later they observed that the forcible injectionl of atropin into the commoni bile-duct had the same effect on blood coagulation as when initroduced inito a meseniteric vein.25 In the rabbit or guinea pig, common bileduct or iimeseniteric veini injectionis of atropin produced no alteration in blood clotting.' A gram of ox-bile per kilo injected into the meseniteric vein of a dog caused the blood to become inco)agulable.28 Two to three times this amount when injected into a systemic vein did not alter the coagulation of blood.32 When I c.c. per kilo of io per cent. solutioni of taurocholic or glycocholic acid was inijected into the mesenteric vein of a dog, the blood also became incoagulable. Following the injection of 5 c.c. of ox-bile into the meseniteric vein of a rabbit, the blood failed to clot when shed.3 The rabbit died two hours after the inijection.
The inicoagulability of the dog's blood followinig the introduction of Witte's peptone into a systemic vein, as first observed by Schmidt-Muhlheim,87 Doyon also attributes to an action on the liver.36 After forceful inijection of Witte's peptone into the common bileduct of a dog (.oi gram of peptone per kilo dissolved in 30 to 40 c.c. of normal saline) a marked lowering of blood pressure accompanied by failure of the blood to clot occurred.26 After excision of the liver in the dog,' and in the frog,2" 23 Doyon and his associates observed that the blood failed to clot. Mann and Magath 79 state that certain constant changes in the coagulation of the blood are present following hepatectomy in dogs, but do not discuss the nature of the changes observed.
These experiments indicate very definitely that destruction or injury of liver tissue and interference with or diminution of liver function may seriously alter blood coagulation. The nature of the mechanism or nmechanisms by which these changes are brought about is not clear. In the alteration of coagulation observed following liver excision it would appear that something essential for blood coagulation had been removed with the liver. Doyon and his co-workers state that liver extirpation removes the source of fibrinogen.
Foster and \Whipple 47 in a study of blood fibrin state that all available data points to the liver as the only potential source of fibrinogen in the body.
Williamson, Heck, and Mlann,144 on the contrary, have indicated that the liver is not necessary for the regeneration of fibrinogen.
OWEN H. WANGENSTEENThe incoagulability of the blood in the experimental animal following mesenteric vein and common bile-duct injections of atropin, ox-bile, and bile salts, and the failure to elicit this alteration after systemic vein or artery injection would indicate that some anticoagulant is liberated following liver injury. Doyon 15, 16 has found that the perfusion of an extirpated dog's liver with saline imbues the perfusion fluid with anticoagulant properties.
When such a liver was perfused with the blood from another dog, the blood used also became incoagulable. Doyon 16 has been able to extract anticoagulant substances from other organs and has suggested that these substances are nucleoproteins. Several years before, Conradi 10 had been able to show that the pressure juice of many organs may inhibit the extravascular clotting of blood. Following the injection of thymus and liver extract of calves intravenously in rabbits, Boggs 4 found that in many instances the blood remained incoagulable when shed.
3. The Clinical Occutrrence of the Tendency to Hcmorrhage.-Though there is no absolute correlation between the duration and intensity of icterus and the tendency of patients with obstructive jaundice to bleed, most instances that came under observation with abnormalities of coagulation have usually had biliary obstruction for some time. Of fifty-eight patients that died of hoemorrhage after operations on the biliary tract for the relief of obstructive jaundice in Swedish Hospitals, Petren 98 found that fifty had been jaundiced for three weeks or more. In only eight instances was the icterus of less than three weeks standing. The duration of jaundice was from five to eight weeks in the patients reported here. Kehr59 refers to an instance of death from cholemic bleeding after operation when jaundice had been present only for five days.
In a previous section of this paper it has been pointed out that the retention of bile in the organism per se is probably not responsible for the tendency of icteric patients to bleed or for the alteration in blood coagulation. The explanation lies rather in the injury of liver tissue and diminution of liver function consequent upon the biliary obstruction.
The tendency to spontaneous haemorrhage in catarrhal jaundice is practically unknown. Alteration in the manner in which the shed blood of such patients clots is also unusual. Bleeding and abnormalities of blood coagulation in patients with acute yellow atrophy of the liver, 2, 45 hepatic cirrhosis, or extensive metastasis in the liver,90 are not unusual. Haemorrhages following clinical poisoning, with phosphorus or chloroform in which severe liver injury may occur are well known.58a, 86 Following jaundice of septic origin in which hepatic necrosis obtains, bleeding may also occur.92' 115 Mayo-Robson,"00 Arnsberger ' and Quenu 100 have called attention to the increased liability of patients to bleed with biliary obstruction when the obstructing mechanism is due to malignancy in the bile-ducts, over that present in patients with stone or stricture interrupting the bile flow. Quenu felt that the combination of malignancy and icterus predisposed toward hemorrhage. Undoubtedly, the more complete biliary obstruction and consequently greater liver destruction accounts for the more frequent abnormalities
HAEMORRHAGIC DIATHESIS OF OBSTRUCTIVE JAUNDICEof coagulation seen in such patients. Judd and Counsellor 6 have recently demonstrated that greater dilatation of the duct system of the liver obtains in obstruction due to carcinoma, than that seen following biliary obstruction due to stone or stricture. In congenital obliteration or atresia of the bile-ducts, haemorrhage is a frequent cause of death.0', Petren " states that after operations for the relief of biliary obstruction, haemorrhage may occur independent of age, sex, the nature of the operation performed or of the agent responsible for the block in the extra hepatic bile passages. In most instances where bleeding occurred it obtained shortly following operative intervention. In an instance reported here bleeding commenced seven days after operation. Bleeding after the first week Petren found to be unusual. Petren98 cites a few instances, however, in which dangerous or fatal haemorrhage occurred in patients whose jaundice had already subsided following operation.
4. The Relation of Calcium to Bleeding. Since calcium was recommended by Wright in I89I for the control of hwemorrhage, its use has been adapted to a variety of conditions. Good results attending the employment of calcium have been noted in haemorrhages from the nose and lung as well as from hemorrhoids and after childbirth. Calcium was first used in the treatment of bleeding associated with obstructive jaundice by Mayo-Robson.'03 Today it is looked to as the most dependable agent in the protection against post-operative haemorrhage in patients with obstructive jaundice.
Wright stated that the coagulation of blood in hemophilia and in normal patients could be hastened by the administration of one gram of calcium chloride thrice daily.
Boggs' fed rabbits calcium chloride by stomach tube and made intravenous injections with a consistent lowering of the coagulation time. Denk and Hellman 's state that the oral administration of calcium in man increases the coagulability of the blood when the time already is normal, lower than normal, or delayed. Schmerz and Wischo 112 injected calcium lactate intravenously in o.io gram doses in patients with a normal blood coagulation. A shortening of the clotting time within ten minutes following the injection was regularly observed. After eleven to twelve hours the coagulation time was still decreased and only returned to the initial level after 24 hours. Maendl 7 in 1920 stated that he had treated the haemorrhages of pulmonary tuberculosis for three years with good results by the intravenous injection of 5 to IO c.c. of a IO per cent. solution of calcium chloride.
Van Lier "' and Addis 1 have been unable to increase the coagulability of the blood in hospital patients by the oral administration of calcium. Loewenstein and Politzer 4 observed no effect after giving calcium lactate by mouth, but found that the intravenous injection of calcium chloride always lowered the coagulation time even in patients in whom the blood clotted normally.
Rey 102 obtained consistent increases in the blood calcium of dogs following the subcutaneous and intravenous administration of calcium oxide. Heubner and Rona found that the blood calcium in cats increased to two to three times normal after the intravenous injection of calcium chloride. After two hours, the blood calcium was normal again. Jansen 53 has shown that the oral administration of only the soluble salts of calcium will increase the blood calcium. Calcium bicarbonate was most effective in this respect with an increase of 57.2 per cent. in the blood calcium following oral ingestion.
An hour or two following the intravenous injection of calcium chloride, Jansen found the calcium level in the blood normal again.
The use of calcium as it is employed today in our country in the prophylaxis against haemorrhage in obstructive jaundice, as well as when the coagulation is already delayed, has been brought about largely through the efforts of Walters 133, 144 of the Mayo Clinic. In I92I, following the intraOWEN H. WANGENSTEEN venous injection of 5 c.c. of a IO per cent. solution of calcium chloride, once daily on three successive days as a pre-operative measure, Walters was able to report a marked reduction in post-operative mortality from haemorrhage in obstructive jaundice. Two years later Judd and Lyons 56 reported I43 operations on the common bile-duct with eight deaths. In none of these instances, the authors state, was hoemorrhage a factor in the cause of death.
More recently Judd 54 has reported I42 operations on the common bile-duct with eleven deaths. Jaundice was present in some degree in I04 patients and in four of the eleven deaths haemorrhage was a factor in the lethal outcome.
The fact that deaths occur from spontaneous haemorrhage in- patients with biliary obstruction as well as after operation upon such patients indicates, however, that the intravenous use of calcium has not solved the problem of haemorrhage in jaundice.
The belief that the delay in coagulation and the haemorrhagic tendency of obstructive jaundice are due to a lack of calcium in the blood has already been referred to. That the bile acids in the blood are probably not responsible for the aJteration in blood coagulation has been pointed out. It has been mentioned that the retention of bile pigments in obstructive jaundice is thought to cause a functional deficiency in calcium and to render the blood calcium less available to participate in the process of blood coagulation. An actual quantitative deficiency of the blood calcium, however, does not obtain.
In parathyroid tetany in which a quantitative diminution of blood calcium occurs, no prolongation of the clotting time nor tendency to haemorrhage obtains. Kottman and Lidsky f observed an accelerated coagulability of the blood in two dogs with experimental parathyroid tetany. Simpson and Rasmussen 11 failed to observe any alteration in the coagulation of blood in experimental parathyroid tetany.
Hammarsten ' was the first to show that in the first step in the clotting of blood, calcium was essential for the activation of prothrombin (thrombogen), into thrombin, but that the interaction of thrombin and fibrinogen to form fibrin could take place in the absence of calcium. Since then, Vines, 132 has found that the presence of ionized calcium is not necessary to clotting, and Stuber and Focke 124 have produced clots in the absence of calcium.
It has recently been found that following the administration of parathyroid hormone (Collip) to normal patients, or to patients with parathyroid tetany, that the blood calcium can be increased at will. Gordon and Cantarow 4 observed a consistent reduction in the clotting time following the use of parathyroid extract in patients with normal coagulation time. A change in coagulation was noted four hours after the injection and the maximum change after ten to fifteen hours. In fourteen cases of jaundice (ten obstructive) with normal blood coagulation, Cantarow, Dodek and Gordonu" found the response to parathyroid extract injection to be similar to that observed in non-jaundiced patients.