Hemostatic Disturbances Research Articles

Haemostatic disturbances in patients bitten by Russell's viper (Vipera russelli siamensis) in Burma

Patients who are severely envenomed by Russell's viper develop DIC which is frequently associated with spontaneous bleeding and incoagulable blood. These haemostatic disturbances may be responsible for death or organ/tissue damage both through haemorrhage and microvascular occlusion by fibrin thrombi. The most striking laboratory features of the coagulopathy developing after Russell's viper bite in the 42 patients studied were depletion of fibrinogen (mean 0.09 g/l, range 0-0.6), factor V (6.5 u/dl, range 0-17), factor X (35 u/dl, range 1-85), factor XIIIa (57 u/dl, range 15-82), plasminogen (61 u/dl, range 10-92), antiplasmin (36 u/dl, range 14-62). Protein C (49 u/dl, range 15-100) and platelets (104 x 10(9)/l, range 25-197). Intense fibrinolytic activity was detected in all cases with marked elevation of FDPs (1614 micrograms/ml, range 350-3000), a large proportion of which were cross-linked (1058 micrograms/ml, range 38-3000). The monospecific Burmese antivenom appeared to be very effective in neutralizing the venom procoagulants and in restoring blood coagulability. Moreover, the unexpectedly normal level of AT III provides a theoretical basis for the use of heparin to enhance the inactivation of those serine proteases present before antivenom administration.

Hemostatic disturbances associated with implantation of an artificial heart

Coagulation and platelet parameters have been assessed following implantation of a Jarvik 7 artificial heart. Initially an ongoing intravascular coagulation could not be overcome with heparin and coumarin. The in vivo formation of thromboxane A 2(as monitored by measurement of the major urinary metabolite) was increased 3–4 fold. Administration of aspirin every second to third day reduced the thromboxane formation dramatically. In parallel to this, the intravascular coagulation subsided, the demand for heparin decreased considerably and the clinical condition of the patient improved. These events provide evidence for a direct link between thromboxane formation and the coagulation cascade. The thromboxane formation was insufficiently suppressed around the 110th postoperative day. Two weeks later the patient suffered a cerebral embolus, followed by a bleeding in the embolized area. This case illustrates the applicability of antiplatelet treatment when the need for efficient antithrombotic treatment is especially pronounced. Aspirin, however, is not the ideal drug for this purpose.

Determination of Soluble Fibrin in Plasma by a Rapid and Quantitative Spectrophotometric Assay

A rapid, sensitive and quantitative spectrophotometric assay of soluble fibrin in plasma samples has been developed. The method is based on the principle that fibrin stimulates the activation of plasminogen by tissue plasminogen activator (t-PA). A sample containing fibrin is incubated with t-PA, plasminogen and a plasmin-sensitive chromogenic substrate. An increase in absorbance which is dependent on the fibrin concentration in the sample is obtained. In plasma samples an initial lag-phase, due to the presence of alpha 2-antiplasmin is observed. However, the change in A405 per square minute during the later part of the reaction was found to be proportional to the fibrin content and to generate linear standard curve intercepts at the origin. The detection limit of bathroxobin-digested fibrinogen added to plasma was about 5 nmol/L. Recovery experiments at 20 and 75 nmol/L levels in plasma samples from healthy individuals were excellent. The "within-run" variation (CV) was determined as 3.7%. The formation of fibrin after addition of minute amounts of thrombin to plasma could be monitored with the method. Plasma from 8 healthy individuals was found to contain about 9.2 +/- 1.9 nmol/L fibrin. Plasma samples from 46 patients with a suspected haemostatic disturbance had higher levels of soluble fibrin (53 +/- 62 nmol/L). Seven of the 46 samples had concentrations above 150 nmol/L.

Value of Blood Coagulation Tests in Ischemic Cerebral Disease

80 patients with transitory ischemic attacks (TIA) and 30 patients with cerebral infarction (CI) were investigated regarding hemostatic disturbances to evaluate selected coagulation test methods for routine laboratory use. The patients were studied a few days after the first appearance of symptoms and at defined times subsequently. The study included measurements of circulating platelet aggregates; platelet adhesiveness, factor-VIII-related antigen (VIIIR:Ag), fibrinolytic activity after venous stasis, alpha-2-antiplasmin activity, and antithrombin III activity. Platelet aggregates and/or adhesiveness were increased in the acute stage in most patients as well as in patients with recurrent attacks. Increased platelet adhesiveness was also found in some patients with nonvascular neurologic diseases. Factor VIIIR:Ag was increased especially in the acute stage and more in patients with recurrent attacks. Diminished fibrinolytic response after venous stasis was found in about 40% of the TIA and in 50% of the CI patients as well as in all patients who died from vascular disease. Antiplasmin activity was increased especially in women. Antithrombin activity was increased during warfarin treatment. The effect of acetylsalicylic acid (ASA) treatment on platelet function was registered only in women but ASA seemed to influence mechanisms other than platelet function, e.g. normalization of factor VIIIR:Ag. Our findings indicate that with methods available for the routine laboratory the measurement of fibrinolytic response to venous stasis, factor VIIIR:Ag and platelet reactivity would be of value in selecting risk patients and following the effect of treatment.

Laboratory Support in the Diagnosis of Coagulation Disorders

In spite of recent advances in knowledge concerning the detailed biochemistry of blood coagulation, the diagnosis of haemostatic disturbances remains an important problem of clinical judgement in many instances. Laboratory support relies initially on a series of screening tests designed to investigate the general nature of blood clotting. Recent interest in these aspects is centred on standardization and quality assurance of methods and results. Procedures have been recommended in an attempt to unify data. Several aspects of conventional laboratory investigations have been modified and the reliability of diagnostic information has been improved. Some relatively recent findings have extended the application to coagulation studies. For example, the discovery of protein C, a potent physiological inhibitor of blood coagulation, has clarified the nature of the clotting disorder in some patients with hereditary thrombosis disease. In addition, close analysis of plasma from patients with systemic lupus erythematosus has stimulated interest in the association between the haemostatic, neurological and immunological abnormalities recorded in these patients. More recently, sophisticated techniques for the diagnosis of many coagulation factor defects have been developed. Carrier detection of the sex-linked disorders is undertaken widely with reasonable success and reliable prenatal diagnosis procedures have been established in specialized centres. Unequivocal information regarding the diagnosis of carrier status in some families is obtained by the use of gene analysis and linked polymorphisms. Precise details of the genes for several clotting factors have been recorded. Future development in this field is likely to improve the clinical course of many coagulation disorders.

Immunoreactive thromboxane B 2 and 6-keto-prostaglandin F 1α in neonatal hyperbilirubinemia

To study the effects of hype rbilirubinemia on platelet thromboxane A 2 (TxA 2) and vascular prostacyclin (PGI 2) production in newborn infants, the stable metabolites of these prostanoids, thromboxane B 2 (TxB 2) and6-keto-prostaglandin F(6-keto-PGF 1α),respectively, were studied in 1α hyperbilirubinemic (serum total bilirubin concentrations between 100 and 320 μmol/1) term infants before and after phototherapy at the age of 2–10 days. The effect of bilirubin on platelet TxA 2 production was also determined in vitro . The production of TxB 2 during spontaneous clotting in infants with moderate hyperbilirubinemia (serum total bilirubin 171–250 μmol/1) was higher than that in infants with mild (serum bilirubin 100–170 μmol/1) or marked (serum bilirubin >250 μmol/1) jaundice. There was, in addition, an inverse correlation (r= −0.625, p<0.01, n=20) between TxB 2 formation and serum total bilirubin concentrations in infants with total bilirubin concentrations over 170 μmol/1. Platelet TxB 2 production was enhanced at low (200 pmol/1), but decreased at high (400–1600 μmol/1) concentrations of bilirubin in vitro . Although phototherapy reduced the serum bilirubin levels, it did not change the TxB 2 generation. Neither hyperbilirubinemia nor phototherapy had any effect on the plasma 6-keto-PGF 1α levels. The results indicate a dual effect of bilirubin on the TxA 2 production in neonatal platelets. This may contribute to the hemostatic disturbances in neonatal hyperbilirubinemia.

Intrarenal blood coagulation induced by ischemia in rats. Heparin and thrombocytopenia does not prevent the intracortical fibrin formation

In various human and experimental renal failures some hemostatic parameters indicate the occurrence of intrarenal blood coagulation (1, 2). However, the fact that the common anticoagulants fail to cure the acute renal failure (3) appears to suggest either that they are ineffective against the intrarenal blood coagulation or no causal relationship exists between the hemostatic disturbances and impaired renal function. Therefore this study was undertaken to investigate the relationship between coagulation and impairment of renal function after a 45-min ischemic period in untreated, heparin-treated and in heparin- plus antiplatelet serum (APS)-treated thrombocytopenic animals.

Filterability and cerebro-vascular thrombosis. Study on the mechanism.

The filterability of red cells was altered in 100 patients with CVA. This disorder appeared to be correlated with risk factors and haemostatic disturbances. The mechanism which links thrombosis with the filterability disorder, mainly depended upon a plasmatic factor. This factor disappeared after the red cells were carefully washed. The hypothesis of products originating from the thrombotic areas amd vasculo-endothelial lesions (mainly fibrin-related products) was supported.

Studies of the Coagulation and Complement Systems during Experimental Rocky Mountain Spotted Fever in Rhesus Monkeys

We studied the coagulation and complement systems during Rocky Mountain spotted fever in Macaca mulatta experimentally infected with Rickettsia rickettsii. Ninety-one percent of monkeys infected intravenously with a high dose (10(6) plaque-forming units [pfu]) and 56% of monkeys infected with low doses (10(-1)-10(2) pfu) of R. rickettsii died after two to four days of illness. With the onset of fever and rickettsemia, animals developed hyperfibrinogenemia, mild thrombocytopenia, prolonged prothrombin and activated thromboplastin times, and increased serum fibrin/fibrinogen degradation products (FDP). Rickettsemia, thrombocytopenia, and FDP were greater in fatally ill monkeys than in survivors. Hemolytic titers of the second and third components of complement were not depressed except in a single surviving monkey that developed peripheral gangrenous ecchymoses at a time when both rickettsemia and agglutinating antibody were present. Thus, although activation and consumption of complement may occur during Rocky Mountain spotted fever, the hemostatic disturbances in fulminant infections seem to be a direct effect of the infectious vasculitis.

Platelets in rat anaphylaxis.

The number of circulating platelets dropped abruptly in the early phase of severe anaphylactic shock (AS) of the rat and could be inhibited by Persantin but not by heparin pretreatment. The results strongly suggest that an aggregating agent, perhaps "platelet aggregating factor", formed or released during anaphylaxis is responsible for the decrease of platelet number. The organ distribution of 51Cr labelled platelets showed that in AS the aggregated platelets were removed from the circulation mostly by the spleen and part of them were trapped in the lung and the small intestine. The remaining platelets retained their functional integrity. The loss of circulating platelets is manifested by the prolongation of rat tail bleeding time and is one of the factors participating in the haemostatic disturbances during anaphylaxis.

Interactions between dextran, fibrinogen and plasma membranes

FITC-labelled dextran has been used to show that there is no complex formation between fibrinogen and dextran and that the ability of dextran to reduce the flexibility of the erythrocyte does not require fibrinogen as an intermediary. Dextran was found to form a loose adherent coat on erythrocyte membranes. It was also found to adhere much more strongly to platelet membranes. It is suggested that this may affect platelet function and be a cause of the haemostatic disturbances sometimes observed after dextran infusion.

Generalized proteolysis in a young woman with Weber-Christian disease (nodular nonsuppurative panniculitis).

A patient with Weber-Christian disease (syn. nodular nonsuppurative panniculitis) is reported. The generalized cellular destruction in this patient resulted in liberation of proteolytic enzymes into the circulation, which led to multiple haemostatic disturbances with haemorrhagic diathesis. The most prominent haemostatic defects were thrombocytopenia with a normal life span of isologous platelets, high levels of AHF-related antigen, hypofibronigenaemia with short fibrinogen survival, low levels of Factor XIII (fibrin stabilizing factor = FSF) and increased amounts of fibrin/fibrinogen degradation products (FDP). Proteolytic enzymes, other than thrombin and plasmin which especially degrade Factor XIII and fibrongen, derived from destroyed cells (probably leukocytes) seem to have been involved in the pathogenesis of the bleeding disorder in this patient.

Effects of green pit viper (Trimeresurus erythrurus and Trimeresurus popeorum) venoms on blood coagulation, platelets and the fibrinolytic enzyme systems: studies in vivo and in vitro.

The hemostatic disturbance caused by venoms of green pit vipers, the poisonous snakes commonly found in Bangkok, was studied in vivo and in vitro . The venoms were shown to possess: (1) clotting activity by thrombin-like action, direct on fibrinogen; this action was, however, not interfered with by heparin; (2) fibrinolytic activity by activating the activator system; (3) a direct aggregating effect on platelets. in vivo , the patients’ conditions usually returned to normal within a few weeks after the bites. The therapeutic approach to treatment of the bleeding problem is discussed.

Haemorrhagic diathesis following transfusion of incompatible blood.

Several reports show the occurrence of a haemorrhagic diathesis which accompanies haemolytic transfusion reactions (Friesen et al 1952, Binder et al 1959, Seldon 1949, Sack &amp; Nefa 1970). Various haemostatic disturbances have been incriminated as causes of that diathesis, such as thrombocytopenia (Hardaway et al 1954), hypofibrinogenaemia (Conley 1952) and circulating anticoagulants (Muirhead 1951). Lately, disseminated intravascular clotting (DIC) has been implicated as the main cause of bleeding in such patients (McKay 1965, Rock et al 1969, Sack &amp; Nefa 1970). We had the opportunity to study a patient with severe haemolytic transfusion reaction due to major blood group incompatible transfusion, causing life‐threatening bleeding. The infrequency of such events and the importance of prompt diagnosis and treatment justifies the publication of this report.

The Effect of Exocrine Pancreas Stimulation on the Coagulation and Fibrinolytic System in Dogs

SummaryThe coagulation and fibrinolytic systems have been investigated in the dogs treated intravenously with secretin, pancreozymin and CCK.There was significant shortening of plastic and glass clotting times, a fall in blood platelet numbers, prolongation of the prothrombin time, and a transitory inhibition of plasma euglobulin fibrinolytic activity. The greatest changes were found after CCK.It should be stressed that the peak changes were earlier and more intense when morphine was given with the hormones.In the authors’ opinion the present findings support the supposition concerning the role of enzymatic toxemia in hemostatic disturbances seen in acute pancreatitis.

Aspirin and Gastric Hemorrhage

Aspirin-induced bleeding from the gastrointestinal tract manifests itself in two forms: the frequent occult loss of blood which reportedly¹occurs in 70% of patients taking repeated doses of aspirin, and the uncommon overt hemorrhage. Two mechanisms have been implicated in the causation of the occult bleeding: local irritation of the gastric mucosa and hemostatic disturbance. The former—evidenced by mucosal congestion and by accumulation of DNA in gastric washings due to excessive epithelial shedding—is unrelated to the presence of hydrochloric acid.²The hemostatic abnormality is essentially that of prolonged bleeding time, probably caused by reduction in platelet stickiness.³ Whereas no intrinsic pathologic lesion of the gastrointestinal tract need be present to account for covert bleeding induced by aspirin, over hemorrhage in patients not suffering from a blood dyscrasia has been described only in association with peptic ulcer or esophagitis. To these known underlying lesions has now been added

Eine neue Blutersippe mit v. Willebrand-Jürgens'scher Krankheit (erbliche Thrombopathie) auf Åland (Finnland)

SUMMARYAnother family in the Åland archipelago (Fennoscandia) suffering from a hemorrhagic disorder (von Willebrand-Jürgens' disease, heredi tary constitutional thrombopathie) is described. This family, so far the largest in the literature, has many common ancestors with the original bleeder families on Åland described in 1926 by v. Willebrand. Of the more than 1300 kindred traced genealogically, 132 (71 women and 61 men) in the five most recent generations have had manifest bleeding disorders in their medical history. Of the ca. 450 living relatives of this family 211 could be examined, and of these 56 females and 50 males were confirmed to be bleeders anamnestically, clinically or, and hematologically. Several cases were analysed exhaustively by modern coagulation tests. The clinical and laboratory hemostatic findings varied widely both inter- and intra-individually. Some patients showed a partial lack of a plasma factor (AHG) coupled with a qualitative platelet defect. Other patients of this family without bleeding disorders had a markedly prolonged bleeding time. The vascular disturbances also vary widely. The consanguinity in this pedigree is unusually high. The autosomal recessive in heritance are discussed. According to the mendelian segregation ratio, a not sex-linked, dominant transmission of the hemmorrhagic diathesis was in question. I has been possible to observe the hemostatic disturbances in 4-5 generations. The penetration of the gene is high, the expressiveness is unsteady.