Bovine thrombin-induced inhibitor of factor V and bleeding risk in postoperative neurosurgical patients. Report of three cases.

Three patients are reported who developed topical bovine thrombin-induced antibodies to clotting factor V following neurosurgical procedures. In each patient the coagulopathy occurred within 8 to 13 days following exposure to topical bovine thrombin at surgery. Two of the three had previously been exposed to bovine thrombin during cardiothoracic surgery. The three patients were identified by detection of a prolonged prothrombin time, ranging from 20.5 to 39.8 seconds. The patient with the highest factor V level (0.12 U/ml) experienced gastrointestinal bleeding, which ceased when the factor V level increased to more than 0.20 U/ml. One patient required a ventriculostomy. In that case the prothrombin time and factor V level failed to improve following administration of vitamin K, 10 units of fresh frozen plasma, and platelet transfusions; the factor V level temporarily increased from 0.03 to 0.32 U/ml following a 2-day course of intravenous gamma globulin (1 gm/kg/day). Plasmapheresis has also been reported to be transient benefit in the treatment of this coagulopathy. In most patients the factor V level rises and the prothrombin time improves toward normal within 3 to 6 weeks following surgical exposure. The individuals identified likely represent only a fraction of the patients who develop the coagulopathy. The latter either do not bleed or are not sufficiently challenged in the postoperative period for the bleeding risk to be tested. It is concluded that bovine thrombin-induced coagulopathy may occur following surgical exposure to topical bovine thrombin and may result in both postoperative morbidity and mortality in a subset of patients.

Redo cardiac surgery: late bleeding complications from topical thrombin-induced factor V deficiency.

Bovine thrombin-induced factor V deficiency was though to be a very rare acquired coagulopathy, with only three documented cases. We report a series of nine patients seen during a period of 32 months; these patients had normal preoperative coagulation profiles, and this unique coagulopathy developed 1 to 2 weeks after cardiovascular operations. The coagulopathy was characterized by a markedly elevated prothrombin time (40.9 +/- 5.8 seconds), an elevated activated partial thromboplastin time (96.3 +/- 12.2 seconds), a study positive for lupus anticoagulation (9/9), and markedly decreased levels of factor V (0.09 +/- 0.03 U/ml) and factor XI (0.04 +/- 0.02 U/ml), respectively. All patients had been exposed to commercially available bovine thrombin during prior cardiovascular or vascular operations and received a second bovine thrombin challenge during the latest procedure. Coagulopathic bleeding developed in four of the nine patients. Bleeding was unrelated to absolute fall in factor V level, but cessation of hemorrhage appeared to correlate with improvement in factor V level. Treatment with vitamin K, fresh frozen plasma, and platelet infusion were all unsuccessful in altering prothrombin time or factor V levels. Intravenous gamma globulin was used in three patients, two of whom were bleeding. All three patients showed a transient increase in factor V levels. Bleeding stopped in one of the two patients; the other continued to bleed and subsequently died. The third patient was treated prophylactically to increase factor V levels in preparation for flap reconstruction of his sternum. His factor V level increased from 0.26 to 0.49 U/ml, and he underwent the procedure without incident. Bovine thrombin-induced factor V deficiency may have been previously unrecognized. This deficiency should be suspected in patients who have undergone redo cardiovascular operations and in whom marked elevations in their prothrombin time occur 7 to 10 days after exposure to bovine thrombin. The resulting coagulopathy, although usually self-limited, has the potential to produce devastating bleeding complications. Intravenous gamma globulin (1 gm/kg during each of 2 days) has been used to increase factor V levels transiently but its role in therapy of this coagulopathy requires further investigation.

Repeated dose administration of desmopressin acetate in uncomplicated cardiac surgery: a prospective, blinded, randomized study.

The effects of single or repeated doses of desmopressin on blood loss were examined in uncomplicated cardiac surgery, while assessing the potential for thrombogenic side effects. Seventy patients undergoing elective coronary artery bypass grafting (CABG) were studied. Patients were randomized into three blinded groups: Group I received DDAVP (0.3 micrograms/kg), IV, after cardiopulmonary bypass (CPB) and 12 hours later in the Intensive Care Unit (ICU); Group II, DDAVP (0.3 micrograms/kg), IV, after termination of CPB and saline (placebo) 12 hours later in the ICU; Group III, saline (placebo) IV after CPB and 12 hours later in the ICU. Blood loss and bleeding time decreased for Group I at 24 hours (P < 0.04) when compared to Group III; however, blood product replacement, as well as intraoperative and total blood loss at 36 hours, were not different among treatment and control groups. There were four myocardial infarctions recorded in Group I, two in Group II, and one in Group III. These differences were not found to be statistically significant. It is concluded that in routine CABG the prophylactic use of single or repeat dose DDAVP does not effectively decrease blood loss or blood product replacement.

Liver transplantation: intraoperative changes in coagulation factors in 100 first transplants.

Six intraoperative blood samples were obtained at intervals from each of 100 individuals undergoing their first liver transplants. The patients fell into the following diagnostic categories: postnecrotic cirrhosis 28, primary biliary cirrhosis 20, sclerosing cholangitis 19, miscellaneous diseases 14, carcinoma/neoplasia 12 and fulminant hepatitis 7. Coagulation factor values in the initial (baseline) blood samples varied by patient diagnosis. In general, all factor levels were reduced except factor VIII:C, which was increased to almost twice normal. The slight intraoperative changes in factors II, VII, IX, X, XI and XII suggested that a steady-state relationship existed between depletion (consumption/bleeding) and repletion (transfusion, transit from extra- to intravascular space), even in the anhepatic state. In contrast, there were rapid and very significant falls in factor VIII and fibrinogen and a less pronounced decrease in factor V, all reaching their nadirs in early to mid-Stage III. The cause of these coagulation changes appears to be activation of the fibrinolytic system.

Comparative efficacy of nonheated and heat-treated factor IX complex concentrate in treatment of hemophiliacs with inhibitors.

To determine if heat-treated factor IX complex concentrate is as effective as nonheated factor IX complex concentrate for treatment of subjects with hemophilia A and antifactor VIII antibodies (inhibitor patients), we have retrospectively reviewed consecutive home treatment records of ten inhibitor patients who had been receiving nonheat-treated factor IX complex concentrate (NHT-Konyne) and subsequently converted to heat-treated factor complex concentrate (Konyne-HT) when it was licensed in late 1984. Overall, 162 of 284 (57%) separate bleeding episodes treated with NHT-Konyne and 53 of 80 (66.3%) separate bleeding episodes treated with Konyne-HT required only one treatment course of approximately 60-75 U/kg. The distribution of bleeding sites and the absolute factor IX unitage required per treatment episode were similar for both preparations. These data suggest that the percentage of hemophilic inhibitor patients responding to factor IX complex concentrate remains at least 50%, as was reported several years ago in a controlled study, and that inhibitor bypass activity has not altered by heat treatment.

Prognostic importance of antibodies to human immunodeficiency virus by recombinant immunoassay and Western blot techniques in HIV antibody-positive hemophiliacs.

Antibodies to specific HIV viral antigens were measured by ELISA recombinant proteins representing gag and env amino acid sequences of human immunodeficiency virus (HIV) (E. I. du Pont de Nemours, Wilmington, DE) and by a Western blot system using biotinavidin detection (Biotech Research Labs, Rockville, MD) on 36 HIV antibody-positive hemophiliacs (HTLV-III ELISA, du Pont) on whom date of seroconversion was known and on whom serial samples where available between 1977 and 1986, representing 2-8 years following seroconversion. The 36 included 9 acquired immunodeficiency syndrome (AIDS) and 27 non-AIDS (7 AIDS-related complex (ARC); 4 other HIV class IV, 16 asymptomatic) patients. The development of AIDS was preceded 1-4 years by loss or lack of antibody to gag (p15, 24, or 55) and/or to pol (p31, 53, or 64), each p less than 0.001, compared with non-AIDS patients. Correlation between Western blot and recombinant assays was good except in one Western blot p24 (gag) only seroconverter who showed strong reactivity to env by recombinant assay. In conclusion, HIV antibody patterns appear to show prognostic significance in HIV-infected hemophiliacs.

HIV transmission to female sexual partners of HIV antibody-positive hemophiliacs.

To study heterosexual transmission of the human immunodeficiency virus (HIV), 21 HIV antibody-positive hemophiliacs and their 21 spouses-sexual partners were evaluated. None belonged to other AIDS risk groups. HIV antibody was detected in four (19 percent) of the female partners. HIV was isolated from peripheral blood lymphocytes of one hemophiliac (4.8 percent), and one female partner (4.8) was antibody-positive. None of the couples engaged in anal intercourse. Compared with HIV antibody-negative female partners, HIV antibody-positive female partners were younger (P less than .05), had younger hemophiliac partners (P less than .05), and were likely (although not significantly so) to engage in oral sex (P = .08) and to have had more than one sexual partner in the previous 5 years (P = .08). Condoms were used all the time by only eight couples (40 percent), and pregnancy occurred in two other couples (9.5 percent), despite prior counseling. These data confirm the low frequency of heterosexual transmission of HIV from HIV antibody-positive hemophiliacs to their female sexual partners and suggest, moreover, that this may be due to the low rate of HIV infectivity in HIV seropositive hemophiliacs exposed to HIV. Further, these data document the need to design more effective educational programs to prevent heterosexual transmission of HIV.

1986 update of HIV seroprevalence, seroconversion, AIDS incidence, and immunologic correlates of HIV infection in patients with hemophilia A and B.

A cohort of 181 patients with hemophilia A (149) and hemophilia B (32) cared for at the Hemophilia Center of Western Pennsylvania was followed to determine human immunodeficiency virus (HIV) seroprevalence, seroconversion rate, and clinical and immunologic correlates of HIV infection. By December 1986, 82 (45%) were HIV seropositive, and of these, ten (12%) had developed AIDS, 28 (34%) had symptomatic HIV infection (CDC class III, IV), of whom 14 (17%) had AIDS-related complex (ARC), and 44 (54%) had asymptomatic HIV infection (CDC class II). The HIV seropositive group included 82% of those treated with factor VIII concentrate (97% severe, 5% moderate), 48% of those treated with factor IX concentrate (92% severe, 8% moderate), 10% of those treated with cryoprecipitate (67% severe, 33% moderate), and none of those treated with fresh frozen plasma. Based on 77 serially sampled HIV seropositive hemophiliacs (1977 to 1986), peak seroconversion occurred in 1982, with 14% (11 of 77) occurring since 1984. With increasing time from seroconversion, both T4 lymphocyte number and function (the latter measured by growth in soft agar [T colony assay]) progressively declined; T4 number declined to 135 +/- 26/mm3 (SEM), and colony count declined 1193 +/- 537 (control 3851 +/- 387) by 5 years after seroconversion. In those developing AIDS, total T4 fell below 100/mm3 (33 +/- 8/mm3) at diagnosis. In this cohort, the overall AIDS incidence is 5.5% (12% among the HIV seropositive) and in those seropositive 5 or more years, the AIDS incidence approaches 32%.

Liver transplantation in hemophilia A.

Four patients with hemophilia A have undergone liver transplantation in our institution, three successfully. The first was a 21-year-old man with chronic active hepatitis (CAH) in whom the effects of previous abdominal operations prevented the satisfactory technical insertion of the new liver. He died intraoperatively. The second patient was a 15-year-old boy with CAH who began to synthesize factor VIII coagulant activity (F VIII:C) within 18 hours of successful liver transplantation and has continued to do so for almost 2 years (F VIII:C range 0.89 to 3.20 U/mL). The first 2 months of his postoperative course were complicated by infections, but since that time he has done well and has returned to school. The third patient was a 48-year-old man with portal fibrosis and severe ascites. He synthesized F VIII:C (range 0.96 to 1.50 U/mL) within six hours after reestablishment of circulation through the new liver. His postoperative course was complicated by numerous infections, and he died with sepsis and an acquired immunodeficiency-like syndrome 4 months after transplantation. The fourth patient was a 47-year-old mild hemophiliac with CAH who produced adequate factor VIII:C levels following transplantation (range 0.79 to 2.80 U/mL). These patients demonstrate that liver transplantation in hemophiliacs with end-stage liver disease may be lifesaving and results in correction of the F VIII:C deficiency and associated hemorrhagic tendency.

Antibody responses to immunization of patients with hemophilia with and without evidence of human immunodeficiency virus (human T-lymphotropic virus type III) infection.

Antibody responses after immunization with 23-valent pneumococcal polysaccharide and trivalent influenza virus vaccines were evaluated in 30 adults with hemophilia and in 17 healthy controls. The 30 patients with hemophilia included 13 who were human immunodeficiency virus (HIV) antibody positive with acquired immune deficiency syndrome (AIDS) or AIDS-related complex (group 1), 11 who were asymptomatic HIV antibody positive (group 2), and six who were asymptomatic HIV antibody negative (group 3). Sera were obtained before and 4 weeks after immunization, and levels of antibody were measured by enzyme-linked immunoassay or by hemagglutination inhibition assay. All three groups of patients with hemophilia showed significantly higher preimmunization geometric mean titers of antibodies (groups 1 and 2, fivefold, group 3, 2.8-fold higher), with little increase after pneumococcal vaccine, when compared with controls. Defective humoral responses were noted in groups 1 and 2, with depressed antibody responses after influenza vaccine, significantly elevated levels of IgG and IgM, and depressed blastogenic responsiveness to pokeweed mitogen. Group 3 demonstrated normal responses to pokeweed mitogen, normal antibody responses to influenza vaccine, and normal level of IgG and IgM, although levels of IgG and IgM were higher than those of controls. These data suggest that humoral immune abnormalities are found frequently in patients with hemophilia who are HIV antibody positive. Further, prolonged administration of blood products, regardless of the recipient's HIV status, appears to be associated with polyclonal activation of B cells for T-independent but not T-dependent antigens.

Blood use in liver transplantation.

During the first 5 years (1981-1985) of the liver transplantation program in Pittsburgh, a total (preoperative, intraoperative, and postoperative) of 18,668 packed red cell units, 23,627 fresh-frozen plasma units, 20,590 platelet units, and 4241 cryoprecipitate units was transfused for the procedures. This represents 3 to 9 percent of the total of blood products supplied by the Central Blood Bank to its 32 member hospitals. Six hundred thirty-six (636) transplants were performed on 485 patients in two hospitals: the Presbyterian University Hospital (564 beds) and Children's Hospital of Pittsburgh (236 beds). All of the blood components used in the operations were procured and released by the Central Blood Bank. This report describes some of these findings.

Acute renal failure due to high-grade obstruction following therapy with epsilon-aminocaproic acid.

An 18-year-old man with mild factor VIII deficiency developed hematuria and, subsequently, acute renal failure due to high-grade urinary obstruction by clots during therapy with cryoprecipitate, epsilon-aminocaproic acid, and acetazolamide administered for ocular trauma. Discontinuation of therapy with the latter two agents and induction of a brisk diuresis with intravenous (IV) fluid therapy resulted in return of renal function concomitant with spontaneous clot passage. A review of previous literature suggests that hemophiliacs may be more susceptible than nonhemophiliacs to high-grade urinary obstruction due to clot formation when epsilon-aminocaproic acid is administered during episodes of hematuria. Acute flank pain, fever, and delayed dense nephrograms on IV pyelogram are characteristic of the syndrome and distinguish it from other forms of acute renal failure associated with epsilon-aminocaproic acid.

Sigmoidovesicular fistula in a hemophiliac with diverticular disease.

A sigmoidovesicular fistula developed in a hemophiliac from a spontaneous sigmoid intramural hematoma. As the hemophiliac population lives longer as a result of improved factor therapy, they will develop more of the diseases and complications of age.

Decrease and rapid recovery of protein C after plasma exchange.

The anticoagulant protein, protein C (PC), was measured after 40 plasma exchanges (PEs) in 26 patients treated for a variety of disorders, most of which were immunological in nature. After 27 PEs involving exchange of 50 percent of the plasma volume with albumin and saline, mean PC activity and antigen decreased in parallel to about one-half normal levels, with good correlation between the two assays. Antithrombin III and prothrombin decreased to about the same levels as PC, with no significant differences between the percentage changes for either protein. After five PEs, during which exchange of larger plasma volumes was performed (86%), the percentage change of PC was greater than after the 50 percent exchange (38 +/- 22 vs. 55 +/- 24). To study postexchange recovery, PC was also measured serially for up to 24 hours after eight PEs (50% exchange). At 24 hours postexchange, PC levels did not differ significantly from pre-exchange levels. This study demonstrates that decreases in PC are in proportion to the volume of plasma exchanged during PE. However, PC levels returned to normal within 24 hours after PE, so that any hemostatic imbalance induced by low PC should be transient.

AIDS retrovirus antibodies in hemophiliacs treated with factor VIII or factor IX concentrates, cryoprecipitate, or fresh frozen plasma: prevalence, seroconversion rate, and clinical correlations.

Antibodies to the AIDS retrovirus, specifically to human T cell lymphotropic virus, type III, and AIDS-associated retrovirus, were detected with increasing prevalence in a population of 190 hemophiliacs from western Pennsylvania between 1981 and 1984: 7.7% in 1981, 20.0% in 1982, 45.5% in 1983, and 62.5% in 1984. The seropositive included approximately three fourths of those receiving factor VIII concentrate, nearly one third of those receiving factor IX concentrate, nearly one fifth of those receiving cryoprecipitate, and none of those receiving fresh frozen plasma. The seroconversion rate, determined on 43 seropositive hemophiliacs from this group who were serially sampled, was 0% in 1977, 4.7% in 1978, 4.9% in 1979, 2.6% in 1980, 10.5% in 1981, 52.9% in 1982, 87.5% in 1983, and 100% in 1984. Of 27 seropositive for three or more years (since 1982 or before), four (15%) have developed AIDS and seven (26%), diffuse lymphadenopathy (ARC); of 16 seropositive for less than three years, none has developed AIDS and three (19%) have developed ARC. The mean time from seroconversion to onset of ARC, 0.8 +/- 0.2 years (SEM), was shorter (P less than .001) than the time to onset of AIDS, 4.1 +/- 0.6 years. These findings confirm the widespread presence of AIDS retrovirus and support the association of these retroviruses with the acquired immunodeficiency syndrome and related conditions.

General surgery in adult hemophiliacs.

From 1976 to 1984, 23 operations were performed on 22 patients with hemophilia (18 patients with factor VIII and four with factor IX deficiency). Elective procedures included resection of abdominal aortic aneurysm, liver transplantation, vagotomy/pyloroplasty, insertion of Mousseau-Barbin tube, colectomy, cholecystectomy, inguinal herniorrhaphy (four patients), colonoscopy/polypectomy, mediastinoscopy, arteriovenous fistula for dialysis, anal fistulectomy, and miscellaneous skin and soft-tissue procedures (five patients). Emergency operations were appendectomy (two patients), repair of bleeding liver biopsy site, and repair of an incarcerated inguinal hernia. There were two deaths (9%) within 30 days of operation, neither directly caused by the coagulopathy. Four patients had bleeding after surgery, which was treated with additional cryoprecipitate or factor concentrate. There were no nonhemorrhagic complications. Before operation, appropriate replacement therapy with factor VIII concentrate, cryoprecipitate, or fresh-frozen plasma was provided. Coagulation factor levels were measured before operation and monitored daily after operation. Generally, factor levels were raised to at least 1.0 U/ml and maintained at greater than 0.5 U/ml for 7 to 14 days after operation. However, when patients were treated with fresh-frozen plasma, plasma exchange was performed and factor levels of approximately 0.35 U/ml were achieved before surgery. We conclude that operations in patients with hemophilia can be accomplished safely with careful monitoring of coagulation factor levels and appropriate replacement therapy.