US experience with recombinant factor VIIa for surgery and other invasive procedures in acquired haemophilia: analysis from the Hemostasis and Thrombosis Research Society Registry.

INTRODUCTION: Acquired haemophilia (AH) is a rare disorder caused by autoantibodies against factor VIII. AIM: The Hemostasis & Thrombosis Research Society (HTRS) Registry was used to monitor the safety of recombinant FVII (rFVIIa). This study aims to report data from the HTRS Registry regarding safety and efficacy of rFVIIa for haemostatic management of surgeries and other invasive procedures in patients with AH. METHODS: For each rFVIIa-treated procedure, the initial dose, total dose, average infused dose, number of doses and treatment duration were calculated. Efficacy was assessed on a 4-point scale. RESULTS: Of 166 registered patients with AH, 37 patients underwent 58 procedures [30 (51%) rFVIIa-treated]. The median (range) age of all patients undergoing procedures was 70 (13-93) years; for rFVIIa-treated patients, 74 (28-89) years. Approximately 67% (39/58) of all procedures were elective. Overall, the most common procedures were endoscopy (12) and central venous access device (10); rFVIIa was used preoperatively (11), postoperatively (13) and during six follow-up procedures during ongoing postoperative rFVIIa treatment. The median (range) initial dose was 90.0 (44-187) µg kg(-1) preoperatively and 106.0 (56-270) µg kg(-1) postoperatively. For rFVIIa-treated episodes with a reported outcome, 20 (91%) were rated excellent/good or no additional agents used and 2 (9%) were rated as poor/ineffective requiring a switch to another bypassing agent. No thromboembolic events were reported. CONCLUSIONS: Adequate haemostasis was provided for 91% of rFVIIa-treated procedures at doses largely conforming to the package insert. No safety concerns were reported.

Sweet's syndrome without granulocytosis.

BACKGROUND: Sweet's syndrome (SS), acute febrile neutrophilic dermatosis, has been linked to hematologic malignancies and presents with characteristic edematous dermal plaques. Peripheral blood neutrophilia is frequently seen in association with SS and is one of the diagnostic criteria. OBJECTIVE: To report the clinical, laboratory, and hematologic data of four patients with myeloid leukemia who developed SS after chemotherapy. Three of these patients were neutropenic. METHODS: A retrospective study of four patients with SS and hematologic malignancies was undertaken. Three patients had de novo acute myelogenous leukemia and one was in the acute blast crisis of chronic myelogenous leukemia. RESULTS: Sweet's syndrome was not originally suspected in these patients because of the low peripheral white blood cell counts caused by chemotherapy. All of the patients presented with fevers, arthralgias, and an eruption. They had been treated with antibiotics because of a presumed infection. Once the correct diagnosis was made and oral prednisolone was started, a rapid response followed. CONCLUSIONS: Sweet's syndrome should be considered in the differential diagnosis when acute myeloid leukemic patients develop skin lesions and unexplained fevers regardless of the peripheral blood counts.

Human fibroblast adhesion to fibrinogen.

Fibrinogen and fibrin mediate the adhesion of many cell types. In this report, the adhesion sites for human dermal fibroblasts on fibrinogen are identified and characterized. Fibroblasts showed a time- and dose-dependent adhesion to fibrinogen. Using a combination of synthetic peptide mimetics, monoclonal antibodies, and recombinant fibrinogens, two major classes of adhesive sites were identified. One class was RGD-dependent and involved the RGD sites in the alpha chain of fibrinogen. alpha V integrins present on fibroblasts appeared to mediate this adhesion. Inhibition studies showed that the RGD-independent site was blocked by an ICAM-1 antagonist peptide. Furthermore, the inhibition was additive with RGD peptide inhibition and accounted for essentially all of the fibroblast adhesion. Together, these results suggest that fibroblast adhesion to fibrinogen is mediated by both alpha V integrins and ICAM-1.

Evaluation of the fibrinolytic system in calves implanted with an artificial heart and ventricular assist device.

Thromboembolism is a serious complication of prolonged use of intracirculatory devices such as total artificial hearts (TAH) and ventricular assist devices. The authors have evaluated alteration in the hemostatic system associated with long-term use of TAH and ventricular assist devices. This article reports results of a prospective evaluation of the fibrinolytic system in four calves implanted with TAHs and four with ventricular assist devices. Blood fibrinolytic activity measured with a solid phase radiometric assay was elevated in two of four TAH calves; plasma plasminogen activity was increased in three. Plasma plasminogen activator activity was undetectable (normal) in all animals. Slight to moderate hypofibrinogenemia was noted in all TAH calves. Calves implanted with a left ventricular assist device had mostly normal blood fibrinolytic activity, fibrinogen, and plasminogen levels. Fibrinogen survival was measured in two calves with ventricular assist devices and three with TAH and was in the normal range in all of these animals. No significant thrombotic lesions were noted at autopsy in five calves that died or were electively killed. These observations suggest enhanced activation of the fibrinolytic system in some calves implanted with a TAH. This may offer a measure of protection against thrombosis in some animals.

Congenital afibrinogenemia.

Congenital afibrinogenemia is a rare disorder with unusual clinical manifestations. The disease is inherited as an autosomal recessive trait and consanguinity is common among affected families. Clinical manifestations range from minimal bleeding to catastrophic hemorrhage. Congenitally afibrinogenemic patients seem to be peculiarly susceptible to spontaneous rupture of the spleen. Coagulation tests which depend on clot formation as an end point may be infinitely prolonged and abnormalities of platelet function are usually present. The diagnosis is established by demonstrating trace or no immunoreactive fibrinogen. The disease is caused by markedly reduced or absent synthesis of fibrinogen by liver cells, but the genetic defect remains unknown. Bleeding episodes can be effectively treated with cryoprecipitate. Purified virally inactivated fibrinogen concentrates have been used in Europe and may soon be widely available.

Platelet and fibrinogen survival in calves implanted with artificial heart and ventricular assist device--correlation with autopsy findings.

The two main ingredients of blood clots formed on artificial surface are platelets and fibrinogen. In this study, we measured platelet and fibrinogen survival in calves implanted with total artificial heart (TAH) and left ventricular assist device (LVAD), and correlate these data with autopsy findings. Platelet survival with autologous 111In-labeled platelets was performed on nine calves implanted with TAH and five with LVAD. Fibrinogen survival with 131I-labeled homologous fibrinogen was performed on six calves with TAH and three with LVAD. Platelet survival was significantly shortened in both groups of animals: 5.89 +/- 0.52 days, control 6.46 +/- 0.31 days, p = 0.0013; fibrinogen survival was normal: 8.79 +/- 1.20 days, control 8.64 +/- 1.16 days. At autopsy two calves with TAH had multiorgan thromboembolism. Two other animals with TAH and four with LVAD had focal renal infarcts. Most animals had minor clot formation within the prosthetic device. Major septic complications occurred in four calves with TAH and one with LVAD. Continuous platelet activation by artificial surface probably explains the shortened platelet survival and thromboembolic complications.

Hematologic and hemostatic complications associated with long-term use of total artificial heart: clinical and experimental observations.

The two most serious complications associated with long-term use of a total artificial heart (TAH) are thromboembolism and infection. In this article, we review our experience in one patient implanted with a pneumatic TAH for 396 days, and in 24 calves implanted with the same type of device for 70 to 353 (median 150) days. During his survival with the TAH, our patient suffered several thromboembolic episodes despite adequate anti-coagulation with warfarin. Autopsy showed widespread thrombotic lesions, mostly in the brain. Throughout his survival, the patient had markedly elevated plasma beta-thromboglobulin and fibrinopeptide A levels, indicating sustained activation of platelets and the coagulation system secondary to blood contact with the artificial surface. Long-term use of TAH in calves causes significant mechanical hemolytic anemia and a small reduction in the total leukocyte and neutrophil counts. The platelet count normalized to preimplantation levels by 25 to 35 weeks. At autopsy, thrombotic lesions and organ infarction were noted in 13 calves, and major septic complications were documented in 10 animals. Although impressive gains in the clinical and experimental use of TAH were achieved during the last 15 years, thromboembolism and infection remain challenging problems.

Hemostatic abnormalities in two patients implanted with total artificial hearts.

Patients implanted with total artificial hearts (TAH) suffer frequent thromboembolic complications. The authors report results of continuous monitoring of multiple hemostatic parameters and autopsy findings in two patients implanted with TAH. Case 1 who used a TAH for 10 days and then underwent orthotopic transplantation died of fungal infection 7 days later. At autopsy, mycotic and nonmycotic thrombi were found in the brain, kidneys, spleen, and large bowel. Case 2, who survived 396 days with a TAH, suffered multiple thrombotic episodes despite adequate anticoagulation with warfarin. Autopsy revealed widespread thrombotic lesions mostly in the brain and lungs. Both patients had markedly elevated plasma beta-thromboglobulin and fibrinopeptide A levels throughout their survival, indicating sustained activation of platelets and coagulation secondary to blood contact with artificial surface. Other factors such as infection, liver damage, and acute pancreatitis might have also contributed to activation of hemostasis. As used in the authors two patients, antiplatelet drugs and warfarin seem to be ineffective in preventing artificial heart-related thromboembolic complications.

Synthesis of vitamin K-dependent proteins by cultured human tumor cells.

The observation that warfarin inhibits the growth and metastasis of certain types of clinical and experimental tumors suggests a role for vitamin K in tumor biology. We have investigated synthesis of vitamin K-dependent proteins in four malignant (lung epidermoid carcinoma, melanoma, colon adenocarcinoma, and breast adenocarcinoma) and three normal (colon epithelium, breast epithelium, and fibroblasts) cell lines of human origin grown in tissue cultures. Our results show the following: 1) Vitamin K-dependent carboxylase activity is present in all of the malignant and normal cell lines studied. 2) The malignant as well as normal cell lines synthesize a family of vitamin K-dependent proteins. Microsomal precursors of these proteins with apparent molecular mass of 74, 62, and 34 kDa are common to all malignant and normal cell lines whereas precursors of higher and lower molecular mass seem to be synthesized by some but not all tumor cell lines. 3) The 74 kDa precursor synthesized by colon carcinoma and breast carcinoma was positively identified as a precursor of protein S.

Hematologic abnormalities and thromboembolic complications in calves implanted with pneumatic artificial hearts. Long-term studies and autopsy findings.

The purpose of this study was to assess hematologic abnormalities and thromboembolic complications related to long-term use of the pneumatic artificial heart (PAH). Laboratory data and autopsy findings were analyzed from 24 calves that survived 70-353 (150 +/- 82) days after implantation of a PAH. Compared with baseline levels, the hemoglobin was significantly lower, and the plasma hemoglobin and serum LDH significantly higher, throughout the follow-up period. The platelet count decreased during the first 10-30 weeks, but returned to preoperative levels by week 35. Platelet survival in 4 calves in stable condition was normal, and the leukocyte count and absolute neutrophil count were within normal limits. At autopsy, thrombotic complications and organ infarction were noted in 13 calves, and major septic complications were documented in 10 animals. The authors' observations indicate that thromboembolism and infection are major complications of long-term use of the PAH.

Hemostatic effects of hormonal stimulation in patients with metastatic prostate cancer.

Hemostatic abnormalities are common in patients with metastatic malignancy and are attributed, in part, to materials secreted by tumor cells. Tumor stimulation might therefore cause further perturbation of hemostasis. This article reports observations on the effects of androgen stimulation on multiple hemostatic parameters in patients with metastatic prostate cancer. Testosterone was given before chemotherapy in an experimental protocol designed to increase tumor sensitivity to cytotoxic agents. The following parameters were measured on day 0 (before) and days 2 and 4 of fluoxymesterone administration: PT, APTT, platelet count, plasma betathromboglobulin (BTG), platelet factor 4 (PF4), fibrinogen, fibrin(ogen) split products (FSP), factor VIII coagulant activity (VIII C), von Willebrand factor antigen (vWF Ag), fibrinopeptide A (FPA), antithrombin III (AT III), and protein C antigen (PC). Ten patients were studied during 17 cycles of hormonal stimulation. Baseline levels of BTG, PF4, fibrinogen, FSP, factor VIII C, vWF Ag, and FPA were significantly elevated compared with normal control. Although androgen stimulation resulted in elevation of BTG, FPA, and FSP levels by day 4 in many patients, the changes for the entire group were not statistically significant. Other parameters remained unchanged or were only slightly elevated. Two patients developed laboratory evidence of disseminated intravascular coagulation (DIC) but were clinically unaffected. Our data suggest that most patients with metastatic prostate cancer show evidence of ongoing activation of platelets, coagulation, and fibrinolysis. In a few individual patients, androgen stimulation of this hormonally dependent tumor may cause further activation of platelets, coagulation, and fibrinolysis.

Dysfibrinogenemia and lupus anticoagulant in a patient with recurrent thrombosis.

We describe the coagulopathy of a 65-year-old woman with a thrombotic disorder associated with dysfibrinogenemia and lupus anticoagulant (LA). The patient's prothrombin time (PT), partial thromboplastin time (PTT), thrombin time (TT), and batroxobin time were prolonged and could not be corrected by mixing with equal volumes of normal plasma. Fibrinogen quantitation showed approximately twice as much immunoreactive as thrombin-clottable protein. The batroxobin and thrombin clotting times of the patient's isolated fibrinogen were prolonged and could not be corrected by mixture with normal fibrinogen. Turbidimetrically assessed fibrin monomer aggregation in response to thrombin, ancrod, or batroxobin and fibrin monomer reaggregation experiments disclosed clearly delayed onset and a lower maximum opacity. In other turbidimetric and clotting-time experiments, the patient's fibrinogen displayed a dose-dependent inhibition of the reaggregation of normal fibrin. Fibrinopeptide A and B release rates and sialic acid content were normal. Assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of reduced samples, the subunit structure of the patient's fibrinogen and its fully cross-linked fibrin was normal. The presence of LA was established by two techniques, the blood thromboplastin inhibition test and the platelet neutralization procedure (PNP). A positive PNP could not be produced by mixing afibrinogenemic plasma with the patient's purified fibrinogen. The patient's inactivated serum and her isolated IgG prolonged the PT and PTT of normal plasma but showed no inhibitory effect on the clotting of purified normal fibrinogen.(ABSTRACT TRUNCATED AT 250 WORDS)

Natural history of human immunodeficiency virus infections in hemophiliacs: effects of T-cell subsets, platelet counts, and age.

Serial T-cell subsets and platelet counts were determined in a cohort of 84 hemophiliacs in whom time of seroconversion for human immunodeficiency virus (HIV) antibody could be ascertained. An abrupt decrease in the number of T-helper (T4) cells was seen in 9 patients 12 to 24 months before the acquired immunodeficiency syndrome (AIDS) was diagnosed (p = 0.0007 compared with those who did not develop AIDS). Thrombocytopenia also was associated with an increased risk for AIDS (p = 0.02), as was older age at the time of seroconversion (p = 0.03). Ten patients developed AIDS at 24 to 95 months after seroconversion, for a cumulative incidence (+/- SE) of 18.0% +/- 7.1% at 6 years. Hemophiliacs who had T4 cell counts of less than 200 cells/microL had a 50% +/- 16% cumulative incidence of AIDS within 2 years, indicating that decreasing or very low T4 cell counts have predictive value for the development of AIDS. Furthermore, the data suggest that thrombocytopenia and older age may be markers for a cofactor that increases the risk for AIDS in hemophiliacs.

Platelet release in hemophilia.

Platelet function abnormalities have been described in some patients with hemophilia. This study reports measurements of plasma beta-thromboglobulin (BTG) and platelet factor 4 (PF4), sensitive and specific markers of platelet alpha-granule release in 72 hemophiliacs. Patients were studied on multiple occasions depending on their clinical condition and the treatment given. Stable patients without recent bleeding showed significantly elevated BTG levels: 29.72 +/- 12.77 ng/ml, control 23.22 +/- 8.22, p = 0.006. This appears to be independent of the presence of liver disease, human immune deficiency virus infection (HIV) and the acquired immune deficiency syndrome (AIDS). The increased BTG level seems to correlate with the severity of the disease as reflected by the frequency of bleeding and the quantity of factor concentrate used but not with plasma factor VIII or IX procoagulant activity. Patients who have experienced recent bleeding showed a marked rise in BTG level (77.26 +/- 51.37 ng/ml, p = 0.0002), indicating enhanced in vivo platelet activation. These observations suggest that enhanced platelet release in hemophilia most likely reflects sustained activation of hemostasis secondary to frequent bleeding characteristic of the severe form of the disease.

The therapeutic use of peritoneal macrophages in infected leukaemic patients.

Ten patients with acute leukaemia and infection unresponsive to antibiotics received single or multiple transfusions of peritoneal cells, mainly macrophages, obtained from donors undergoing peritoneal dialysis for renal failure. In six patients the cultures became negative and the temperature returned to normal and remained there, in two, there was temporary return of the temperature to normal and two patients showed no response. No significant side-effects were encountered. No changes in leukaemic blast cell numbers were seen in any of the patients.

Tumor interaction with vascular endothelium.

Clinical and experimental observations suggest that tumor-induced endothelial cell (EC) injury may be one of several initial events in the establishment of tumor metastases. This work investigates tumor-induced EC injury and the interaction between tumor-damaged EC and platelets. We used cultured bovine EC and extracts of four cultured human malignancies. EC injury was assessed by 51Cr and lactic dehydrogenase (LDH) release. Incubation of EC with melanoma, breast carcinoma or lung carcinoma caused significant LDH and 51Cr release, whereas colon cancer seemed ineffective. Increased adhesion of platelets to tumor-injured EC was noted. These observations indicate that certain varieties of tumor cause EC injury. Adhesion of platelets to tumor-injured EC results in the formation of platelet-tumor thrombi at the endothelial surface, an event that may initiate tumor invasion of the vessel wall.

The fibrinolytic system in experimental prostate tumor.

Hypofibrinogenemia and disseminated intravascular coagulation are common events in patients with metastatic prostate carcinoma. This study tests the hypothesis that prostate tumor growth and metastasis is associated with sustained activation of fibrinolysis secondary to increased release of plasminogen activator. We implanted an androgen-insensitive prostate tumor into an inbred strain of rats and serially measured plasminogen, plasminogen activator, plasmin and fibrinogen. Control groups included animals without tumor and a group implanted with transitional cell bladder carcinoma, a locally infiltrating tumor not usually associated with hemostatic complications. Our results showed a significant and steady rise in plasma plasminogen activator, plasmin and fibrinogen levels in animals implanted with prostate cancer. This, however, is not specific for prostate tumor. Similar, perhaps more profound changes were noted in animals implanted with the transitional cell carcinoma.

Primary lymphomas of the small intestine: east-west contrast.

Primary small intestinal lymphoma (PSIL) represents a heterogenous group of disorders with variable clinical and pathologic features and a characteristic age, socioeconomic, and geographic distribution. In developed countries, PSIL usually occurs as a localized ileal tumor, shows a bimodal age distribution, and most frequently presents with abdominal pain and obstructive symptoms. Histologically, most of these tumors are diffuse histiocytic, lymphocytic, or undifferentiated lymphomas. Other variants of PSIL, collectively referred to as immunoproliferative small intestinal disease, occur most often among young patients of poor socioeconomic status in Third World countries, mostly in the Middle East and Mediterranean area. They are characterized by involvement of long loops of the upper small intestine and commonly present with abdominal pain, diarrhea, malabsorption, and clubbing of the fingers. A subgroup of these patients shows a serological abnormality with the appearance of part of the alpha heavy chain of IgA in the serum. Histologically, the lesion appears as a dense diffuse lymphoplasmacytic infiltrate of the mucosa of the upper jejenum or duodenum. A form of malignant lymphoma of true histiocytic origin complicates long-standing celiac disease. The contrasting clinical, epidemiological, histopathological, and immunological features of these variants of PSIL raise interesting questions about the pathogenesis of small bowel lymphoma.