The cause of coagulopathy after peritoneovenous shunt for malignant ascites.

Thirty-five patients with malignant ascites who received a peritoneovenous shunt were studied to determine the type and duration of postoperative coagulopathy. Coagulation factors were measured before and on the first and third day after the placement of a Denver peritoneovenous shunt; 1 to 10 L of ascites was removed at operation. Levels of platelets, antithrombin III, plasminogen, antiplasmin, fibrinogen, and factors V and VIII decreased by the first postoperative day but did not change further through the third day. The levels of fibrinolytic split products increased on day 1 but were lower by day 3. The platelet count reduction by the third day correlated with the hematocrit change (-0.031). The prothrombin and activated partial thromboplastin times remained normal postoperatively. The patterns of change were similar for patients with positive (n = 18) and negative (n = 17) ascites cytologic findings, with elevated (n = 24) and normal (n = 11) preoperative fibrinolytic split product levels, and elevated bilirubin value (greater than 25 mumol/L; n = 9), and no jaundice (n = 26). Bleeding did not occur. The data indicated that plasminogen-rather than thromboplastin-activated fibrinolysis occurred and that platelet reduction was largely dilutional. The reactions were not progressive when ascites was removed operatively.

Preoperative coagulation indices in patients with morbid obesity.

Preventive measures against venous thromboembolism are used frequently in surgical patients with morbid obesity because the risk has been claimed to be higher than usual. We addressed this risk in 81 morbidly obese patients by measuring preoperative plasma proteins associated with coagulation and by correlating variations in these indices to excess weight, liver histology, patient sex, tobacco use and serum triglycerides. Plasma levels of antithrombin III and plasminogen were normal in these patients. Plasma fibrinogen concentrations were elevated in 34 percent of patients; the values did not relate to excess weight and they correlated negatively (P less than 0.04) with increasing serum triglycerides and grades of liver fat content. Premenopausal women had higher plasminogen and fibrinogen levels than menopausal women or men, although their mean levels were normal. Smokers had lower plasminogen levels than nonsmokers (P less than 0.01). However, none of the measured levels of preoperative coagulation proteins identified increased risk for venous thrombosis in cohorts of this population, and the coagulation indices were not different from those reported in normal weight patients.

Abnormalities of the fibrinolytic system as a cause of upper extremity ischemia: a preliminary report.

Abnormalities of the fibrinolytic system can result in unusual or unexplained clotting that occurs spontaneously or after minor trauma. We identified five patients with limb-threatening arterial thrombosis of the upper extremity associated with either a low level of plasminogen or an abnormal immunoreactive plasminogen. All patients had extensive thrombosis of the brachial, radial, and ulnar arteries. Two patients had concomitant thrombus of the subclavian artery, which in one patient was associated with distal embolization to the hand. There was no evidence of atherosclerosis in any patient. Detection of an abnormal plasminogen level was done by immunoelectrophoresis of the patient's serum with antiplasminogen sera. In these patients a separate immunoreactive band located near the anode and distinct from the normal single plasminogen band was detected. Because of extensive thrombosis of the arterial system, exploration of the brachial artery, as well as the origin of all the forearm vessels, was necessary for complete balloon catheter thrombectomy. Prompt diagnosis and treatment are necessary to prevent the catastrophic complication of arm or hand amputation. Patients with an abnormal plasminogen level should receive perioperative heparin therapy and long-term warfarin to prevent recurrent thrombotic episodes.

A platelet aggregating factor in thrombotic thrombocytopenic purpura: initial activity, fluctuations, and removal by plasma exchange.

A factor capable of aggregating normal platelets was found in the plasma of six consecutive patients with thrombotic thrombocytopenic purpura (TTP). The activity of the aggregating factor in whole plasma, the cold protein fraction from plasma and the residual supernatant was monitored during each patient's course of therapeutic plasma exchange. Although two patients demonstrated the highest level of aggregating activity at the time of diagnosis, the level fluctuated in five of six patients. Increasing levels of activity were usually accompanied by signs of clinical deterioration. Activity repeatedly within the normal range was not seen until remission of the syndrome. Neutralization of the aggregating activity in vivo through removal of patient plasma and replacement with fresh frozen plasma (plasma exchange) was accomplished less readily and less predictably than by mixing patient plasma and normal plasma in vitro. Use of the aggregating factor level in evaluating the need of plasma exchange is discussed.

Severe bleeding diathesis associated with invasive aspergillosis in transplant patients.

A severe bleeding disorder developed in eight renal transplant patients with invasive aspergillosis. The hemorrhagic diathesis was characterized by wound oozing, severe upper and lower gastrointestinal tract hemorrhage, and mucosal bleeding at other sites. This unusual coagulopathy was characterized by a prolonged thrombin time, which was corrected with protamine sulfate, and an abnormal Reptilase time. The bleeding disorder antedated the diagnosis of invasive aspergillosis in all cases. The probability that the coagulopathy was due to proteolytic enzymes elaborated by Aspergillus sp. is discussed.

Abnormal plasminogen: a genetically determined cause of hypercoagulability.

An inherited disorder of the fibrinolytic system has been discovered as a cause of unusual clotting. An abnormal immunoreactive plasminogen was identified in eight patients who presented with unexplained thrombosis. Six patients presented with spontaneous arterial or venous thrombosis, and two patients developed postoperative occlusion of an arterial reconstruction. Five of the six patients with spontaneous thrombosis had recurrent episodes involving both the arterial and venous system at time intervals between the thrombotic episodes varying from 1 month to several years. Detection of an abnormal plasminogen was made by immunoelectrophoresis of the patient's serum with an antiplasminogen sera. In normal patients, plasminogen migrates as a single band toward the anode. In these eight patients a separate immunoreactive band located nearer the anode and distinct from the normal band was detected. Examination of family members of two patients identified a similar abnormal plasminogen with an overall incidence suggestive of an autosomal dominant inheritance pattern. This study suggests the presence of a genetically determined plasminogen variant resulting in a functional deficiency of the plasminogen system causing a reduction of fibrinolytic activity and a latent thrombotic tendency. Recommended treatment is long-term warfarin anticoagulation.

Cardiopulmonary bypass for patients with previously documented heparin-induced platelet aggregation.

Heparin-dependent intravascular coagulation is a widely recognized syndrome in which heparin acts as a hapten for an antiplatelet antibody and causes accelerated intravascular thrombosis and thrombocytopenia that may culminate in organ loss, hemorrhagic diathesis, and even death. Diagnosis is made in vitro by observing heparin-stimulated aggregation of normal platelets suspended in the patient's platelet-poor plasma. Treatment consists of cessation of heparin and use of antiaggregating agents with or without warfarin sodium. Management of patients with prior heparin-dependent intravascular coagulation who require cardiopulmonary bypass has not been reported. We now have successfully managed three such patients and herein present guidelines for management. Each patient was undergoing heparin therapy and manifested hallmark heparin tachyphylaxis, thrombocytopenia, and increased thrombotic symptoms (further venous thrombosis after cardiac catheterization in two cases and exacerbation of unstable angina in the other). In vitro aggregation studies were abnormal. Heparin was stopped, and antiaggregative therapy was begun with good response in each instance. In vitro studies were done serially until the antiplatelet antibody reaction had vanished (usually 4 to 8 weeks), and coronary revascularization was then conducted with full heparinization. Further heparin exposure postoperatively was avoided. There was no perioperative evidence of intravascular thrombosis or bleeding diathesis, and in vitro heparin-dependent aggregation did not recur. We conclude that patients with previously documented heparin-dependent intravascular coagulation can safely sustain the massive heparin rechallenge of cardiopulmonary bypass, provided that in vitro aggregation has ceased and rechallenge therapy is not prolonged.

Factor VIII competitive enzyme assay: observations in von Willebrand's variants and hemophiliacs.

The competitive enzyme-linked immunoassay (CELIA) was used to quantitate factor VIII antigen in plasma from 24 patients with von Willebrand's disease (VWD), VWD variant or hemophilia A. This demonstration of CELIA's clinical usefulness is significant because the simplicity and efficiency of the technique make it suitable for use in many health-related institutions regardless of size or sophistication.

Competitive enzyme-linked immunoassay for Factor VIII antigen.

We describe a competitive enzyme-linked immunoassay for Factor VIII antigen. Binding of anti-factor VIII to solid-phase Factor VIII antigen is competitively inhibited by the free factor VIII antigen that is to be measured. The amount of anti-Factor VIII bound to solid-phase VIII is measured by applying in sequence a heterologous bridging antibody and a soluble antibody/enzyme immune complex. The soluble complex used was rabbit antiperoxidase/horseradish peroxidase. Peroxidase activity is inversely proportional to the Factor VIII antigen concentration in the original test plasma and is measured spectrophotometrically. The assay can be performed in as little as 4 h with only a microtiter plate, antisera, antigen, and a spectrophotometer. It is sensitive to 0.05 units of Factor VIII antigen per milliliter, and reproducibility, linearity, and normal range are similar to those reported for other techniques.

Heparin induced platelet aggregation: in vitro confirmation of thrombotic complications associated with heparin therapy.

Eleven patients who developed thromboembolic complications while receiving heparin were studied for a possible adverse reaction to heparin as the cause of their progressive thrombosis. Fifteen additional patients who were receiving heparin for recurrent thromboembolism, but who did not develop signs of thrombotic complications, were studied as patient controls. The most significant finding was an abnormal in vitro aggregation response to heparin alone in all of the patients who developed complications who were tested for it (64 percent). None of the patient controls demonstrated this abnormality. In addition, thrombocytopenia was noted in all of the former but in only one of the latter. Results of prothrombin times, fibrinogens and fibrin split products eliminated disseminated intravascular coagulation as the cause of the thrombocytopenia in the majority of cases. Finally, an approach to the early detection of the abnormal heparin response is presented and guidelines for its therapeutic management are recommended.

Hypercoagulability: a cause of vascular access failure.

In a group of 58 patients requiring tertiary vascular access procedures for maintenance of hemodialysis, 29 patients who thrombosed well-functioning fistulas were evaluated for both antithrombin deficiencies as well as platelet hyperaggreability. Thirteen of these 29 patients were found to have one or more coagulation defects. Following correction of the hypercoagulable state, tertiary vascular access procedures, using autologous tissues, were 100% successful in these 13 patients.

Plasmapheresis in the treatment of renal allograft rejection.

Thirty-four patients with renal allograft rejection unresponsive to conventional therapy underwent plasmapheresis. Twenty-four patients evidenced prompt and marked improvement and were discharged. Seventeen of these are presently stable off dialysis. Ten patients were not improved and required return to dialysis and/or transplant nephrectomy. Four hour warm, complement-dependent crossmatches which had become positive following transplant became negative following plasmapheresis in 3 patients who now have stable long-term function. Plasmapheresis appears promising in the treatment of refractory acute renal allograft rejection.

Human platelet aggregation and cAMP system--cAMP level, adenyl cyclase, phosphodiesterase.

The possibility of a direct and casual relationship between various parameters of the adenosine 3',5'-cyclic monophosphate (cAMP) system, e.g., the level of cAMP, adenyl cyclase activity and phosphodiesterase activity, and platelet aggregation was studied by measuring the effects of various environmental conditions, as well as metabolic inhibitors, aggregating agents and aggregation inhibitors upon these parameters. A competitive binding technique using 3H labeled cAMP was used to determine the level of cAMP in intact platelets, and a high performance liquid chromatographic method was developed to measure the adenyl cyclase and phosphodiesterase activities in the platelet membrane fraction. Although the availability of substrate adenosine triphosphate (ATP) correlated well with the amount of cAMP produced, and in turn the availability of cAMP seemed to have a direct effect upon the reversibility of shape changes induced by the various stimuli, the only effect upon aggregation concerned the extent to which it occurred. No direct correlation of the level of cAMP with either the actual inhibition or activation of the aggregation mechanism was observed.

Platelet aggregation and the ouabain-insensitive ATPase. Ecto-ATPase, reflection of membrane integrity.

The ecto-ATPase activity of washed human platelets has been characterized by a higher-performance liquid chromatographic method. Mg++ was found to stimulate ecto-ATPase activity more strongly than Ca++. The combination of Mg++ and Ca++ at increasing concentrations caused diminishing activity levels. Elevated ecto-ATPase activity was also found in platelets incubated with prostaglandin E1 (PGE1) or potassium cyanide (KCN). It is proposed that the increase of ecto-ATPase activity is related to the extrusion or exposure of plasma membrane containing a ouabain-insensitive ATPase. The role of ecto-ATPase in platelet aggregation is discussed in light of these findings.

Effects of dibutyryl cyclic adenosinemonophosphate and prostaglandin E1 on platelet aggregation and shape changes.

Prostaglandin E1 (PGE1) exerted an immediate inhibitory effect upon the induction of platelet aggregation by adenosinediphosphate, epinephrine, thrombin, bovine fibrinogen, or sodium fluoride, whereas dibutyryl cyclic adenosinemonophosphate (DBcAMP) produced a delayed type of inhibition of aggregation induced by these same agents. In addition, however, both PGE1 and DBcAMP, as well as adenosinetriphosphate (ATP) and Mg++, restored, with incubation, the washed platelets to a more discoid shape. Platelet aggregability also correlated well with platelet shape. All of these findings suggest the possibility of mediation of the delayed type of inhibition through restoration of the platelet membrane by increasing the level of metabolically active ATP or the availability of cations. They tend, however, to exclude the possibility that PGE1 exerts its immediate inhibitory effect through the increase of platelet cAMP.

Adenosine diphosphate-induced platelet aggregation in the states of hypercoagulability.

One hundred and seven patients with congestive heart failure, myocardial infarction and arteriosclerotic heart disease were studied by adenosine diphosphate-induced platelet aggregation, fibrinogen levels and ethanol gelation test. Both increases and decreases in platelet aggregation were observed. A significantly high percentage of patients showed a decreased platelet aggregation which was especially marked in the more acute as opposed to the less acute phase. In addition, most patients exhibited a marked shift from abnormal to normal platelet aggregation or vise-versa within a short time period. This pattern of platelet aggregation suggests an active role of platelets in the states of hypercoagulability. The hypercoagulability of these patients was further substantiated by a high percentage of positive ethanol gelation tests and high fibrinogen levels.

Inhibitory effects of ATP on platelet aggregation: cation interaction and shape change.

Adenosine triphosphate (ATP) has more than one effect in its inhibition of platelet aggregation. In addition to its direct competition with adenosine diphosphate (ADP), ATP may suppress the aggregation mediated via a cation interaction and a restoration of platelet shape.