Urgent reversal of warfarin with prothrombin complex concentrate.

BACKGROUND: When life-threatening bleeding occurs in patients on warfarin, timely reversal becomes imperative. In the USA, warfarin effect is commonly reversed with fresh frozen plasma (FFP). The use of FFP is complicated by delays in correction, volume overload and often, inadequate correction. OBJECTIVE: Evaluate the feasibility and efficacy of a protocol for rapid administration of prothrombin complex concentrate (PCC) in the setting of the urgent need for reversal of warfarin. METHODS/PATIENTS: We instituted a policy for rapid delivery and administration of PCC. Appropriate patients received 25-50 U kg(-1) of PCC. The prothrombin time (PT)/International Normalized Ratios (INR) was recorded before and immediately after dosing, and 24 h postdosing. Patients requiring surgical interventions were cleared for the operating room (OR) immediately. Fifty-eight patients were treated, with a median age of 75.5 years (range 26-92). RESULTS: The median INR on presentation was 3.8 (1.4-52.8). Immediately following PCC administration the median INR was 1.3 (0.9-5.7), only two patients with INRs exceeding 2.0. The benefit was maintained at 24 h with a median INR of 1.5 (1.1-3.4). Four patients experienced thrombotic events during their hospitalization, (two deep vein thrombosis, two non-q-wave myocardial infarction) although none was attributed to PPC therapy. CONCLUSIONS: PCC administration is an effective treatment modality for the correction of warfarin anticoagulation in the urgent setting. Advantages over FFP include more timely correction, absence of volume overload and potentially more complete correction. Broader use of PCC in this setting appears to be appropriate.

Phenotypic expressions of CCR5-delta32/delta32 homozygosity.

OBJECTIVE: As blockade of CC-chemokine receptor 5 (CCR5) has been proposed as therapy for HIV-1, we examined whether the CCR5-delta32/delta32 homozygous genotype has phenotypic expressions other than those related to HIV-1. DESIGN: Study subjects were white homosexual men or men with hemophilia who were not infected with HIV-1. In this study, 15 CCR5-delta32/delta32 homozygotes were compared with 201 CCR5 wild-type (+/+) subjects for a wide range of clinical conditions and laboratory assay results ascertained during prospective cohort studies and routine clinical care. CCR5-delta32 genotype was determined by polymerase chain reaction, followed by single-stranded conformational polymorphism analysis. RESULTS: Hypertension and conditions attributable to hemophilia were the only diagnoses frequently found in clinical records of CCR5-delta32/delta32 study subjects. Based on blood pressure measurement and treatment history, CCR5-delta32/delta32 homozygotes had a 2.8-fold higher prevalence of hypertension than age-matched CCR5-+/+ study subjects (95% confidence interval [CI], 1.2-6.4; p = .01); none of the homozygotes had severe hypertension. Hematologic measures were generally similar across the genotypes, but total lymphocyte counts were approximately 20% higher in CCR5-delta32/delta32 study subjects than in CCR5-+/+ study subjects (p < .05). Among patients with hemophilia who were infected with hepatitis C virus (HCV), mean alanine aminotransferase levels were 117% higher among CCR5-delta32/delta32 homozygotes (p < .05), but serum HCV levels did not differ by CCR5-delta32 genotype. CCR5-delta32/delta32 homozygous study subjects had a lower prevalence of antibodies to measles virus than those with other genotypes, but this association was not confirmed in a group of blood donors. The prevalence of antibodies to nine other common viruses, HBV, and HCV was not related to CCR5 genotype. CONCLUSIONS: CCR5-delta32/delta32 homozygotes are generally similar to wild-type persons. Confirmatory investigations are required to determine whether hypertension, increased lymphocyte counts, and higher hepatic enzyme levels in the presence of HCV infection represent true phenotypic expressions of this genotype. CCR5-delta32/delta32 homozygosity does not provide broad protection against viral infections.

Coagulation factor IX: successful surgical experience with a purified factor IX concentrate.

The use of plasma-derived coagulation factor concentrates has been marked by the transmission of viral agents. Infusions of factor IX complex concentrates have been additionally complicated by inappropriate thrombosis. Use of these concentrates in the neonate, in those with liver disease, and in surgical patients results in increased risk for this complication. Twenty patients have been infused with a purified coagulation factor IX concentrate for fall-off and recovery studies. A two-compartment model indicated an initial phase half-life of 4.06 +/- 2.86 hr and a beta phase half-life of 20.0 +/- 3.8 hr following the administration of AlphaNine, Coagulation Factor IX (Human). In vivo recovery was 62.7% +/- 13.8%, with an average factor IX coagulant level of 73% +/- 16% at 15 min after the infusion of a mean dose of 45 U/kg. Thirteen previously transfused patients with hemophilia B underwent major orthopedic or general or dental surgery using this purified factor IX. Operative outcomes were excellent in all patients. No excessive bleeding was noted. There was no laboratory or clinical evidence for a disseminated intravascular coagulopathy. The excellent surgical outcomes observed in this multitransfused group with biochemical evidence for active liver disease demonstrates the utility and safety of a purified coagulation factor IX concentrate.

Delayed complications from fine-needle biopsies of solid masses of the abdomen.

A prospective study was conducted from 1977 through 1983, to determine the incidence of complications, particularly bleeding, after fine needle biopsy for suspected malignancy of the abdomen and pelvis. Hematocrits before and after the biopsy procedure, medical record follow-up, and review by a coagulation specialist were used to identify bleeders. We performed 395 biopsies on 360 patients. Thirteen percent of the patients had bothersome pain either during or after the biopsy. Hematocrit drops of 3% or more were found in 51 (12.7%) of the patients; nine were determined to be a direct result of the biopsy procedure. Our results and review of the literature suggest that there are complications, including delayed bleeding, yet few are life threatening. We caution, however, that adequate follow-up to identify bleeders is very important in patients having fine-needle biopsies of solid masses of the abdomen.

Spontaneously acquired anti-factor VIII antibodies: report of a patient with adenocarcinoma of the prostate.

Anti-factor VIII antibodies, inherited or acquired inhibitors of the factor VIII molecule, have not been reported previously in the urological literature. Although more common in hemophiliac patients who have received multiple transfusions, this anticoagulant may be the cause of severe hemorrhage in nonhemophiliac patients. We describe a patient with carcinoma of the prostate and an unsuspected anti-factor VIII antibody, who experienced excessive postoperative bleeding and prolonged hospitalization following a vesicolithotomy and bilateral orchiectomy. A prolonged partial thromboplastin time and a significant decrease in measurable factor VIII clotting activity in a patient with no history of bleeding problems are essential clues in making the diagnosis of a factor VIII inhibitor. This coagulation defect is treated best with prothrombin complex concentrates, which contain vitamin K dependent clotting factors.

Additional evidence for more than one agent of human non-A, non-B hepatitis. Transmission and passage studies in chimpanzees.

Evidence supporting the existence of two agents of human non-A, non-B hepatitis was obtained by the inoculation of chimpanzees sequentially with serum from a chronically infected human (Inoculum I) and with fibrinogen prepared from pooled plasma (Inoculum IV), each of which had transmitted non-A, non-B hepatitis to humans. Passage inoculations of serum samples obtained during the acute stages of chimpanzee infections transmitted by either the agent in Inoculum I or IV also transmitted non-A, non-B hepatitis to additional chimpanzees. Transmission and passage of the agent in Inoculum IV were conducted in chimpanzees which previously had recovered from infection by the agent in Inoculum I. Cytoplasmic tubules in hepatocytes, which have been described during non-A, non-B hepatitis, were observed by electron microscopy in liver biopsies obtained during all infections transmitted by the agent in Inoculum I. These cytoplasmic tubules were not detected in liver biopsies from chimpanzees infected by Inoculum IV, except in one chimpanzee inoculated by Inoculum IV without prior exposure to the agent in Inoculum I. The cytoplasmic tubules observed in this study were found to be composed of transverse bands arranged with a periodicity of approximately 17 nm. These studies suggest that two different agents or distinct serotypes of human non-A, non-B hepatitis may have been present in these inocula, although reactivation of latent infection or reinfection could not be ruled out completely.

Autoplex versus proplex: a controlled, double-blind study of effectiveness in acute hemarthroses in hemophiliacs with inhibitors to factor VIII.

In view of uncontrolled observations and anecdotal reports suggesting that the activated PCC, Autoplex, was much more effective than standard (non-activated) PCC in controlling bleeding in hemophiliacs with inhibitors, a controlled double-blind study was designed to compare the effectiveness of Autoplex and Proplex. Acute hemarthrosis was chosen for study as this common but non-life-threatening lesion lends itself well to controlled study. A single dose of "unknown" product (Autoplex 75 FECU/kg; Autoplex 50 FECU/kg; or Proplex 75 FIX U/kg) was given, and effectiveness was judged at 6 hr. By all criteria of efficacy, there were no significant differences between the products. It is noteworthy that a single dose of PCC was judged effective in 50% of episodes, a figure that is consistent with other published clinical trials. In this model, no additional benefit was derived from using the activated PCC, Autoplex, in either dosage.

Obstetric care of the affected carrier of hemophilia B.

Hemophilia B (factor IX deficiency) is an X-linked recessive clotting disorder similar to hemophilia A. In both diseases, phenotypic expression of the disorder may occur in significant numbers of heterozygous carriers. This is presumably due to random inactivation of one of the two X chromosomes of the female carrier as described by the Lyon hypothesis. Described herein is the obstetric care of a severely affected heterozygous carrier of hemophilia B. Predelivery automated plasma exchange was used to raise factor IX levels successfully. Commercial factor concentrates were avoided. The Lyon hypothesis is discussed in detail, and recommendations are made for the care of the clotting factor-deficient gravid woman.

Hereditary dysfibrinogenemia in a patient with thrombotic disease.

A new case of congenital dysfibrinogenemia, in which the patient has severe thrombotic disease, is reported. The abnormal fibrinogen molecules are characterized by normal fibrinopeptide release with thrombin and defective polymerization in the formation of fibrin. Clotting times with ancrod and reptilase are significantly prolonged. All other coagulation tests (except those for fibrinogen function) are normal, and the patient has no other underlying disease. The apparent paradox of defective fibrinogen, which clots abnormally and is yet associated with thrombotic disease, can be explained by further analysis of the patient's fibrinogen. The two important functional properties of this fibrinogen are: (1) it forms fibrin gels that are extremely rigid, and (2) the fibrin is highly resistant to lysis by plasmin. Thus, although the abnormal fibrinogen forms defective clots, the fibrin that is formed cannot be removed by the fibrinolytic system. These results provide a molecular explanation for the thrombotic disease in this patient. This abnormal fibrinogen appears to have unique characteristics and has been designated as fibrinogen Chapel Hill Ill.

Treatment of a high titer anti-factor-VIII antibody by continuous factor VIII administration: report of a case.

Daily administration of large doses of factor VIII concentrate in a hemophiliac with a high titer factor VIII inhibitor resulted in marked reduction in the titer and response of the inhibitor to factor VIII administration and made possible elbow and bilateral knee replacements under conventional factor VIII coverage. Studies performed during the course of treatment indicated that the reduction in the inhibitor was the result of specific tolerance to factor VIII.

Soft-tissue hemorrhage in hemophiliac patients. Computed tomography and ultrasound study.

Fifty-four hemophiliac patients underwent a total of 94 studies using computed tomography (CT), ultrasound, or both. Not only common bleeding sites such as the iliopsoas muscles but also several unusual sites were encountered: these included the iliac bone, bowel wall, mesentery, rectus abdominis muscle, retroperitoneum, bladder wall, and scrotum. Both modalities gave comparable results, and each was helpful in (a) establishing the diagnosis, (b) evaluating the extent of bleeding and its effect on adjacent organs, and (c) demonstrating regression after treatment.