Changes in the Coagulation System and Fibrinolytic Activity of the Blood

Disturbance of the process of blood coagulation is known to play an important role in the pathogenesis and outcome of terminal states. It has been established that pecu­liar complications are met during the development of terminal states: namely, haemorrhage is aggravated by thromboses, and an increase of blood coagulation by profuse haemorrhage.

It is customary to call these dis­turbances of haemocoagulation the thrombohaemorrhagic syn­drome. Analysis of the clinical and experimental research carried out by Kruzhilina enabled three phases to be distinguished in the alteration of the blood’s coagulatory properties during hy­poxia. The first phase is one of activation of the procoagulants; during this phase the coagulograms are typical of the prethrombotic state.

The second phase is one of unstable compensation of the blood’s coagulatory and fibrinolytic system which becomes normal with adequate oxygenation and replacement; when hypoxia is aggravated in young patients it can be complicated by hypofibrinogenaemia. The third phase is one of disturbance of the balance between the coagulatory and the fibrinolytic systems, the activity of the former increasing progressively, which leads to the forma­tion of microthrombi. The increase in fibrinolytic activity as a reaction to the formation of thrombi leads to afibrinogenaemia and frequently to death from haemorrhage. In patients who are in a state of severe traumatic shock and have suffered massive loss of blood and a terminal state due to various causes, the func­tional state of the coagulation system is disturbed in the direction both of hypocoagulation and of hypercoagulation.

In obstetric practice haemorrhage as a result of hypocoagula­tion is the cause of 8 to 11 per cent of all cases of blood loss. Loss of blood, we know, is one of the leading causes of maternal mortality. It is thus not a coincidence that at the conference on thrombo-embolism, coagulation, and haemorrhage several papers were devoted to this problem.

The development of coagulopathic haemorrhage, it has been established, can be caused by abortions not induced in hospital, when the fertilized egg has been in the uterus for a long time, embolism by the amniotic fluid, premature detachment of the pla­centa, intra-uterine death of the foetus, traumatic rupture of the uterus or of the birth canals, severe toxaemia of pregnancy, mas­sive intravenous transfusion of preserved blood.

Underlying slowing of the process of coagulation there is pri­marily a reduction in the level of procoagulants, especially of fibrinogen, and an increase in fibrinolytic activity. The develop­ment of hypofibrinogenaemia and of afibrinogenaemia as a result of a drop in fibrinogen production is met rather seldom, and mainly in hepatic deficiency. Much more frequent is a decrease in the blood’s fibrinogen concentration as a result of massive loss of blood or of formation of thrombi with the corresponding deposi­tion of fibrin in the retroplacentary haematoma. The formation of compounds of heparin with fibrinogen and thrombin, which have an anticoagulant action, is also of no small importance. When coagulation is disturbed on a background of uterine atonia or hypotonia calling for massive haemotransfusions it leads to the development of particularly massive haemorrhage difficult to treat.

Reduction in the coagulatory capacity in blood is observed in surgical practice when intervention is accompanied with massive loss of blood or with hypoxia due to atelectasis and pulmonary oedema as a result of activation of fibrinolysis, and also in the first few hours after a severe trauma as a result of a drop in fibrinogen concentration and an increase in fibrino­lytic activity.

In cases of disturbance of coagulation therapy should be directed to increasing procoagulants, repressing fibrinolytic activity, and normalizing peripheral and microcirculation. For these purposes warm blood, fibrinogen, plasma, protein, albumin, epsilon-aminocaproic acid, Trasyiol, paraminomethylbenzoic acid, and blood substitutes possessing rheologic activity are administered intra­venously.

A quite acute problem is that of the prophylaxis and treatment of coagulopathic haemorrhage due to intravascular coagulation. Injection of heparin has been suggested in order to avoid fibrino­gen impoverishment of the blood as a result of intravascular coa­gulation. But we find only isolated reports in the literature of use of this prepara­tion for haemorrhage due to an intravascular activation of the coagulatory system leading to intravascular formation of thrombi, hypofibrinogenaemia, and afibrinogenaemia.

Much attention was devoted to this problem at the International Congress on urgent problems of reanimatology. Successful heparin treatment of hypocoagulation due to intravas­cular coagulation in obstetric practice was reported by Bouvier, Larcan and Cristol, who obtained good results in treating patients suffering from massive haemorrhage. Prompt application of such therapy is of great importance. Baille et al. recommended begin­ning the administration of heparin in the early stages of hyper-coagulation, when coagulation time by the Lee-White method is five minutes, and subsequently to keep coagulation time within ten to fifteen minutes by means of repeated injections of heparin. A rapid diagnosis of consumption coagulopathia can be obtained by determining the number of thrombocytes and fibrinogen content, and by photometric study of fibrinolysis. In those cases when it is not possible to ascertain the true cause of the fibrino­lysis, heparin and fibrinogen can be administered simultaneously.

Heparin, of course, prevents further intravascular coagulation; nonetheless its use in haemorrhage cases is a problem requiring further study and refinement.

Excess secretion of heparin into the blood, as we know, is neu­tralized by protaminsulphate, and decomposition of its complexes with fibrinogen and other protein substances is facilitated by a concentrate of endogenous serotonine.

According to the data of the Mobile Reanimation Centre, haemorrhage exceeding 1000 ml had been observed in 665 maternity cases in the preceding five years, disturbances of the coagulatory systems being observed in 14 per cent of cases. When the fibrinogen concentration of the blood was low and there was an increase of fibrinolytic activity, all pa­tients received 12 to 14 grams of fibrinogen and up to 1200 or 1500 ml of a 6 per cent solution of epsilon-aminocaproic acid. In addition warm blood, taken directly from the donor, freshly pre­pared packed erythrocytes and thrombocytes, and native and con­centrated plasma were transfused.

The cure rate was 73 per cent of the cases observed. The out­come of the treatment, it should be noted, depended greatly on the degree and duration of the haemorrhage. Thus, in the group of patients losing under 3000 ml of blood, 85 per cent were cured, but only 39 per cent of those losing more than 3000 ml. The highest mortality was observed with massive blood loss due either to afibrinogenaemia or to reduced contractile functioning of the uterus.

After prolonged haemorrhage, of course, despite normalization of the coagulation system and haemostasis, especially with pro­tracted hypotension, patients die in the later periods from grave changes in the parenchymatous organs.

From the literature and the experience of the Mobile Reanimation Centre, it might be thought that a main task in treating such a pathological state was to prevent massive, pro­longed loss of blood by timely conservative treatment and obste­tric surgical intervention.

Nevertheless the problem of the tactics of treatment in cases of delayed coagulation is far from being completely solved. It has now been established that in some pathological processes, hypocoagulation gives way to hypercoagulation, in particular an in­crease in the activity of the blood’s coagulation system is observed in obstetric practice in combined trauma of the birth canals. But in various types of pathology hypercoagulation develops at different times, and with massive discharge of thromboplastic substances into the blood stream it is far from always diagnosed. In patients suffering from severe traumatic lesions maximum hypercoagulation occurs during the tenth day according to the findings of Kukel et al., but as early as the second day approximately one patient in three shows an increase in fibrinogen concentration from 148 mg per cent to 408 mg per cent and a pro­gressive slowing of fibrinolytic activity is observed. In illustration of this system we have included the coagulometric readings of two patients admitted to the reanimation department of the Hospital with severe multiple injuries and in states of III-IV de­gree shock.

In this connection substances increasing blood’s coagulation capacity in cases of coagulopathic haemorrhage in patients brought out of terminal states and states of severe shock should only be administered in strict accord with the readings, and under control of the state of the coagulation and fibrinolytic systems.

For evaluating the development of either hypercoagulation or hypocoagulation, it is not so much the absolute value as the alte­ration in the concentration ratios of the factors of the coagulation and fibrinolytic systems that counts.

There can be no doubt that the development of thrombo-embolic complications is no less dangerous than coagulopathic haemor­rhage. Its main cause is an increase in blood coagulation capacity. The findings of several authors indicate that hypercoagulation is to be observed during the postoperational period in cases of myo­cardial infarction, severe multiple trauma, and of certain other pathological conditions. The experiments carried out by Markosian et al. showed that stimulation of the sympathetic sectors of the vegetative nervous system, of the adrenergic elements of the reticular formation, and of certain nuclei in the hypothalamus, and certain hormones all have considerable effect on the biosynthesis and production of procoagulants.

The development of hypercoa­gulation is encouraged, in addition, by insufficient oxygenation of the blood and hypochromic anaemia, with which, as a rule, hyperfibrinogenaemia, thrombocytosis and a shortening of blood coa­gulation time are to be observed. In the opinion of some authors, fibrinolytic activity decreases, and in the opinion of others, increa­ses. According to the data of several mortuaries, the num­ber of patients dying from thrombo-embolic complications has in­creased in recent years. In most cases these complications develop on the third to eleventh day after operation. Mortality is particu­larly high in thrombo-embolism of the stem and branches of the pulmonary arteries. Most authors recognize three forms of embo­lism of the pulmonary artery, as concerns its clinical course — (1) fulminating; (2) rapid; and (3) slow. Half the patients dying of it do so in the first hour after their accident, 30 to 40 per cent during the first 24 hours.

The Mobile Reanimation Centre had 28 patients be­tween the ages of 25 and 50, under observation for thrombo-em­bolism of the pulmonary artery; only six survived, those with the slow form of thrombosis of the branches of the pulmonary artery. The main components of the therapy employed were the administration of large doses of direct action anticoagulants in combination with fibrinolysin and cardiac glucosides. The all-round effect of heparin in physiological processes is well known. Apart from its normalizing effect on the coagula­tion system, heparin improves microcirculation and increases resistance to hypoxia.

The experience of our clinic and the findings of other authors indicate that timely administration of heparin and fibrinolysin in the needed doses avoids, and in many cases eliminates, thrombo­embolic complications of various pathological states. There is reason to hope that successful development of thoracic and vascu­lar surgery, and of anaesthesiology and reanimatology will help reduce mortality from this dread complication. Nonetheless it is quite correct that first place is given at present to the prophylaxis of thrombo-embolic complications, in which a major role may be played by the coagulation wards already set up, and specialized departments for treating patients with haemostatic disorders. In addition it is necessary to improve general practitioners know­ledge on questions of theory of coagulation.

Proper and timely evaluation of the coagulability of the blood can undoubtedly help apply the most useful pathogenetic therapy and consequently to create the most favourable conditions for res­toration of the organism’s functions.