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«DESPITE the employment of a number of remedies that have been suggeMted for the control and prevention of bleeding in patients with obstructive ...»

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Zimmerman tested the effect of the administration of parathyroid extract in large doses to normal dogs and after experimental bile-duct obstruction, as well as in normal patients and in patients with jaundice. An end-point for coagulation was used which for normal dogs was twenty-five minutes and for patients thirty minutes. Twenty-four to forty-eight hours later, when the coagulation time was again determined, Zimmerman observed no change from the initial reading.* * Petren ' used an end-point which for normal patients was thirty-eight to forty minutes. Delay in the extravascular clotting of blood by this method, when not marked, would appear to be demonstrated with greater certainty than by methods in which the usual end-point is eight minutes or less.

HIEMORRHAGIC DIATHESIS OF OBSTRUCTIVE JAUNDICE

Lee and Vincent" state that the "calcium in vitro" test in which it is demonstrated that venous blood from j'aundiced patients can be made to clot more rapidly in vitro following the addition of calcium bears evidence that there is a deficiency of available calcium in obstructive jaundice. Morawitz and Bierich ' have also shown, however, that the same acceleration of the clotting of jaundiced blood can be brought about by the addition of tissue extract. They observed that tissue juice when added to the blood of cholemic patients in vitro caused the blood to clot three times more rapidly than normal blood.

There is, however, some evidence that would indicate a disturbance of calcium metabolism in obstructive jaundice. A number of years ago Pawlow9 observed that dogs with complete biliary fistula frequently developed osteoporosis. The same change was later noted in patients with biliary fistula by Seidel.6 The loss of calcium from the body depots and the inability to assimilate fat has been described by Duttman " as the cause of the osteoporotic changes in bone in biliary fistula. The same loss of calcium from the body depots is said to occur in obstructive jaundice6 and the excretion of fat in the stools is well known. King, Bigelow, and Pearce a found markedly lowered calcium values in the bones of dogs with obstruction of the common bile-duct. The osteoporotic changes described by Seidel in patients with biliary fistula have also been noted in patients with continued biliary obstruction."6 Recently Kuttner 69 has reported parenchymatous hemorrhages following operation in a patient with a biliary fistula of one and one-half years' duration. The bleeding responded promptly to calcium therapy.

Walters and Bowler 135 noted that after the intravenous injection of a given dose of calcium chloride in jaundiced dogs, that only half the increase in the blood calcium occurs that is seen following the same injection in normal dogs. The lethal dose of calcium chloride for jaundiced dogs injected intravenously was found by Walters and Bowler to be greater than for normal animals.

These facts, together with the observations of Buchbinder and Kern,8 and of Kirk and King,' previously referred to, indicate that a disturbance of calcium metabolism may be present in obstructive jaundice. The relation of this disturbed calcium metabolism to the tendency of jaundiced patients to bleed, however, is not very clear, nor does it appear to be very direct. No denial of the suggestion of Schloessmann"0 that calcium may improve the liver function and thus lessen the liability to bleed in icterus, can be made in the present state of our knowledge concerning liver function and calcium metabolism.

A deficiency of calcium in the circulating blood of patients with biliary obstruction must not be inferred, however, because the intravenous injection of calcium chloride lowers the extravascular clotting time of the blood. It must be kept in mind that most investigators have observed a reduction in the coagulation time of the blood in normal people following calcium administration. Then, too, it is known that a number of other remedies injected into the organism may produce the same effect.

In I904, Boggs ' stated that at that time gelatin was used in Germany almost exclusively to lessen the danger of haemorrhage. Its use as a hemostatic agent Kiister ' says, was known to the Chinese centuries ago. It, too, like calcium has been employed with satisfaction in the treatment of hmemorrhages of many types. Kehr " at one time was an exponent of its use in the treatment of cholemic bleeding and reported three instances in which it was employed successfully for this purpose. Boggs4 obtained a lowering of the coagulation time in rabbits after intravenous or subcutaneous injections of I0 to 30 c.c. of gelatine. Gebele 48 observed a hamostatic action following the subcutaneous injection of gelatine in animals and in man only after loss of blood had already occurred. Negative results following attempts at reduction of the coagulation time in

OWEN H. WANGENSTEEN

normal animals with gelatine are reported by Sackur."'° Zibell,'4 and Schmerz and Wischo,"2 attribute the influence of gelatine on the coagulation of blood to its calcium content. Wildegans "'1 believes that the protein in the gelatine is responsible for this action.

In I909, Von den Velden recommended the injection of 5 to I0 c.c. of a IO to 20 per cent. solution of sodium chloride as a hlemostatic, and mentions an instance of its employment with good effect in the treatment of bleeding in hepatic cirrhosis. Its mode of action he thought to be entirely physical. He felt that an increase in the osmotic pressure of the blood occurred resulting in a dilution of the blood by tissue fluid. A decrease in the clotting time of the blood regularly followed intravenous injections of small amounts of this hypertonic solution in normal patients and animals. Later Von den Velden 13 increased this dosage to I00 c.c. of a I0 per cent. solution of sodium chloride for clinical use. Schenck '" and Boitel 6 are inclined to believe that the beneficial action of calcium chloride in the treatment of the bleeding also occurs through this agency.





Schreiber 114 in 19I3, recommended the intravenous injection of 200 c.c. of a 20 per cent. solution of glucose solution for the same purpose. Kehr ° was a strong advocate of its employment in the treatment of haemorrhage of obstructive jaundice.

Weil '" has employed and recommended the subcutaneous injection of human serum and of the serum from ox-blood in the treatment of hemorrhagic conditions. Perthes 9 during the same year stopped the bleeding following the extraction of teeth in a haemophiliac by the injection of rabbit's blood about the bleeding surface. Quenu '° has followed Weil's suggestion for the treatment of the hemorrhagic diathesis of biliary obstruction and describes good results. Willy Meyer ' has employed the subcutaneous injection of human serum in the treatment of bleeding in jaundice and has found this procedure effective.

Fonio 46 has prepared and used an extract containing the lipoids and blood platelets of blood in the treatment of bleeding of every type with satisfactory results.

In I920,'" after the exhibition of calcium and other haemostatic remedies had been without result, Stephan radiated the spleen and successfully arrested hxmorrhage in a patient who had bled following the removal of a supra-clavicular lymph-node. He later observed that the blood of a normal patient clotted more quickly in vitro after radiation of the spleen.'l Schinz '" noted an acceleration of the extravascular clotting of blood following radiation of the spleen in normal persons but found it ineffective in the bleeding of jaundice. Tichy 1 has noted decrease of the clotting time following radiation of the liver. Szenes '1 noted a shortening of the coagulation time following radiation of a malignant tumor of the thyroid. Muller 8 states that the same effect may be obtained following radiation of any organ and attributes the mode of action to tissue destruction.

Nigst 89 observed a decrease in the coagulation time after radiation of the splenic area in three patients from whom the spleen had previously been removed.

The observation of Foster and Whipple's 4 that radiation of the thorax or abdomen results in a prompt rise in the blood fibrin value is the likely explanation of the influence of radiation on blood coagulation. The tissue injury or destruction following radiation gives rise to an increased blood fibrin.

The value of blood transfusions in the treatment of all h;emorrhagic diatheses is well known and needs no special discussion here. Pendl 9 and Pallin9 have reported instances citing its value in the treatment of bleeding accompanying biliary obstruction.

Not long ago, however, venesection was occasionally used for the control of bleeding, based on the fact that haemorrhage is spontaneously arrested after the acute loss of a large quantity of blood.2 Von den Velden '" had practiced segregating the blood in the extremities for this purpose. As recently as igio, venesection was recommended by Sahli "' for the treatment of bleeding in haemophilia.

Euphyllin has been found by Nonnenbruch and Szyszyka 9 to decrease the coagulation time on injection. Calcium and tissue extract if added to blood in vitro or if injected, appear to decrease the clotting time. Witte's 3 peptone has no influence on coagulation when added to blood in vitro but when injected intravenously, inhibits the clotting of

HAEMORRHAGIC DIATHESIS OF OBSTRUCTIVE JAUNDICE

blood shed subsequently. Atropin injected into the portal circulation of the dog has the same effect but does not influence blood clotting when added in vitro. Sodium citrate inhibits clotting in vitro but may accelerate coagulation when injected into the organism.

Wilkie 143 recommends its use in the treatment of bleeding of biliary obstruction.

This brief recapitulation of the usual and most effective hwemostatic remedies employed in the treatment of haemorrhage has been made only to indicate that an increase in coagulability and a reduction in the clotting time of blood may be effected by a large number of means. A shortening of the time in which blood clots following the successful employment of a certain agent in the arrest of hoemorrhage does not necessarily indicate a deficiency in the organism of the remedy used. Decrease in the clotting time of the shed blood of patients with obstructive jaundice following the intravenous injection of calcium chloride does not signify a functional deficiency of calcium. It only means that calcium is a good remedy to reduce the prolonged extravascular clotting time of the blood in biliary obstruction.

5. The Relation Between Delayed Coagulation and the Tendency to Bleed.-A point that requires emphasis in the discussion of haemorrhage in jaundice is that the entire problem does not hinge on a decreased coagulability of the blood. Mere delay in the extravascular clotting is not responsible for the spontaneous haemorrhages that may obtain in icteric patients. Nor can prolonged bleeding from the operative wound in patients with biliary obstruction be attributed solely to delayed coagulation of blood. The problem of the arrest of haemorrhage in vivo is not as simple as the solution of the process of clotting in vitro.

In the normal circulating blood prothrombin (thrombogen), calcium, and fibrinogen are all present. The circulating blood remains fluid because thrombokinase is present in no great amount, or because an excess of antithrombin is not present.

In the arrest of haemorrhage following operative incision on a patient in whom no haemorrhagic dyscrasia is present, an adequate hwemostasis is obtained by the ligature of the large vessels (arteries and veins). Spontaneous arrest of bleeding ordinarily occurs in the smaller vessels (capillaries, arteries, and venules). Following the exhibition of heat or pressure, or the local application of an astringent the haemostasis in the lesser vessels can be accelerated. The failure of this spontaneous arrest of haemorrhage to occur in the smaller vessels in a haemorrhagic diathesis indicates the inadequate formation of blood platelet thrombi to occlude the vessel, or an inability of the vessel to retract properly. After division the intima of the normal vessel rolls in like the end of a glass tube exposed in a flame. Even the capillaries without muscle tissue in their walls possess an inherent power of contracting when injured.'2' Undoubtedly, this contraction of the smaller vessels is of primary importance in the control of bleeding. Stegemann 120 says that in the finer vessels thrombus formation does not occur and that the contraction of the vessel alone causes internal apposition and arrests bleeding.

OWEN H. WANGENSTEEN

In patients with purpura ha2morrhagica, an improper blood platelet thr'ombus formation due to the deficiency of blood platelets accounts for the tendency to bleed. A deficiency of calcium in the circulating blood has not been adequately demonstrated in any hoemorrhagic disease. In haemophilia, no quantitative diminution of the blood platelets is present. It has been suggested that the etiological factors concerned are a qualitative change in the blood platelets and a deficiency of prothrombin.84 In both haemophilia and the bleeding of obstructive jaundice, a prolonged extravascular coagulation time of the blood and a tendency to bleed after trauma are present. In the haemorrhagic dyscrasia of biliary obstruction a deficient contraction of the smaller vessels and an inadequate blood platelet thrombus formation would appear to be as much responsible for the bleeding in these patients as is the delay in the extravascular clotting of the blood. The dyscrasia does not reside in the blood alone; the blood-vessels must also be implicated.

Morawitz 86 has stressed the importance of determining the bleeding time described by Duke,43 in haemorrhagic conditions. He believes that its determination is much more important than that of the clotting time. He points out that the bleeding time may be prolonged when the coagulation time is normal (Purpura) but knows of no condition in which the bleeding time is normal when the coagulation of the blood is prolonged. In his hands.

haemophilia, jaundice (with a prolonged clotting time), phosphorus poisoning, and experimental hirudin injection always exhibit a prolonged bleeding time.

It would seem that in a disease in which there is a decided tendency to bleed after operative trauma as in jaundice (with prolonged coagulation) or haemophilia that the bleeding time should also be prolonged. If the bleeding time does not determine the tendency to bleed after trauma what does it determine ?



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