Antithrombin III: associations with age, race, sex and cardiovascular disease risk factors. The Atherosclerosis Risk in Communities (ARIC) Study Investigators.

Antithrombin III (AT III) is a major inhibitor of blood coagulation, and hereditary deficiency is associated with venous thrombotic disease. The Atherosclerosis Risk in Communities (ARIC) Study, a prospective study of 15,800 middle-aged men and women, measured AT III in its baseline examination. AT III levels were significantly higher in women than men, and in blacks than whites. AT III decreased with age in men but increased with age in women. In age- and race-adjusted analyses, AT III was positively associated with smoking, HDL-cholesterol, triglycerides (men only), and in women, with diabetes and lipoprotein(a). AT III was negatively associated with educational level, body mass index in men, and use of female hormones in women. Most of these associations were confirmed in multivariate analysis. These correlations between AT III and other risk factors must be considered when evaluating AT III as a risk factor for venous or arterial thrombosis.

Quantitative analysis of vascular prostaglandin H synthase mRNA levels by competitive polymerase chain reaction.

Prostaglandin H synthase (PGHS) occupies a central position in the biosynthesis of prostaglandins, thromboxane, and prostacyclin. Expression of this enzyme is enhanced by inflammatory cytokines and phorbol esters. Because of the low abundance of PGHS, PGHS mRNA levels in tissues and cells were difficult to measure accurately. In this study, we quantified vascular PGHS-1 mRNA levels by a competitive polymerase chain reaction assay. The mean basal PGHS-1 level in cultured human umbilical vein endothelial cells (HUVECs) was 24.3 +/- 10.6 amol/microgram RNA. Treatment of the HUVECs with recombinant human interleukin-1 beta at 37 degrees C for 4 hours increased the mRNA to 49.1 +/- 9.1 amol/microgram RNA, a 2.1-fold increase. Treatment of the cells with phorbol 12-myristate 13-acetate at 37 degrees C for 4 hours caused a 1.7-fold increase in the mRNA level. This procedure was utilized to measure PGHS-1 mRNA levels in rabbit abdominal aorta, inferior vena cava, liver, kidney, and lung. The aortic mRNA level (9.2 +/- 1.9 amol/microgram RNA) was about 5 times higher than the inferior vena caval level (2.4 +/- 1.3 amol/microgram RNA) but only slightly higher than the level of other organs. These results reveal a significant difference in PGHS-1 mRNA levels between arterial and venous tissues. The synthase mRNA levels in organs such as liver, kidneys, and lungs do not differ significantly. The PCR assay should be valuable for studying the role of PGHS expression in disease states.

Correlation of plasma protein C levels with cardiovascular risk factors in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study.

To evaluate the association of plasma protein C levels with constitutional, socioeconomic, life-style and biochemical factors important in cardiovascular diseases, we measured protein C levels in 12,290 middle aged (45-64 years) subjects participating in the ARIC study. Protein C levels had a normal distribution with a mean value of 3.17 micrograms/ml. They were higher in women than men and in whites than blacks; higher in postmenopausal women and further increased by hormonal supplements. The age influence was inconsistent and was considered to be inconsequential. Protein C levels were positively correlated with body mass index, LDL-cholesterol, HDL-cholesterol, and triglycerides and negatively associated with cigarette smoking. These factors should be taken into consideration when establishing normal protein C levels and when analyzing the relation between protein C and arterial and venous thrombotic disorders.

Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study.

Several coagulation proteins have been implicated as possible risk factors for the development of atherosclerotic diseases, among which are factor VIII and von Willebrand factor. As part of the Atherosclerosis Risk in Communities (ARIC) Study, a prospective study designed to assess risk factors for the development of atherosclerotic diseases, baseline measurements of factor VIII and von Willebrand factor (vWF) were performed to determine their relationship to the development of atherosclerosis. We herein report the associations of factor VIII and vWF with constitutional, lifestyle, and biochemical factors. Factor VIII and vWF were strongly correlated with each other (r = 0.73), and, therefore, had similar associations with risk factors. Mean levels of both factors were higher in women than in men, in blacks than in whites, and increased with age. In univariate analysis, both were positively associated with diabetes, body mass index, waist-to-hip ratio, serum insulin, and plasma triglycerides. Both were negatively associated with alcohol intake, educational level, physical activity (with some exceptions), and HDL-cholesterol. No correlations were observed between factor VIII or vWF and plasma LDL-cholesterol or lipoprotein(a). Although factor VIII was negatively associated with smoking in both sexes, vWF was not associated with smoking status. Most of these associations were confirmed in multivariate analysis. The strongest associations observed were of factor VIII and vWF with race and diabetes. In multivariate analysis, blacks had factor VIII and vWF levels 15 to 18 percentage points higher than whites, and diabetics had factor VIII and vWF levels 11 to 18 percentage points higher than non-diabetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Associations of fish intake and dietary n-3 polyunsaturated fatty acids with a hypocoagulable profile. The Atherosclerosis Risk in Communities (ARIC) Study.

Recent epidemiological evidence indicates that the hemostatic profile is an important predictor of cardiovascular disease, yet its dietary determinants are not well established. An important question is whether dietary fatty acid intake influences blood levels of coagulation proteins. We examined potential dietary determinants of six hemostatic factors--fibrinogen, factor VII, factor (vWF), protein C, and antithrombin III--in four population-based samples totaling over 15,000 participants, blacks and whites, in the Atherosclerosis Risk in Communities (ARIC) Study. Usual dietary intake was assessed by a food frequency questionnaire. Cross-sectional associations were explored using multiple linear regression analysis, adjusting for gender, race, age, body mass index, smoking status, alcohol use, diabetes, and field center. Dietary intake of n-3 polyunsaturated fatty acids (PUFAs) showed negative associations with fibrinogen, factor VIII, and vWF (blacks and whites) and a positive association with protein C (whites only). Fish intake, the major source of dietary n-3 PUFAs, was similarly related to the hemostatic profile: a 1 serving per day greater fish intake was associated with the following predicted differences (95% confidence interval): fibrinogen, -2.9 mg/dL (-6.3, 0.5); factor VIII, -3.3% (-5.4, -1.3); vWF, -2.7% (-5.2, -0.1) (blacks and whites); and protein C, +0.07 microgram/mL (0.03, 0.11) (whites only). Other nutrients or foods were variably associated with the hemostatic factors. These population-based associations, although cross-sectional, suggest that increases in n-3 PUFA intake from fish may modify the blood levels of several coagulation factors.

Association of coagulation factors and inhibitors with carotid artery atherosclerosis. Early results of the Atherosclerosis Risk in Communities (ARIC) Study.

Several population studies have shown that plasma levels of fibrinogen and factor VII are significantly associated with ischemic cardiovascular events. However, there is little information regarding the association of hemostatic factors with early atherosclerosis. To evaluate this, we compared the plasma concentrations of several coagulation proteins (fibrinogen, factor VII, factor VIII, von Willebrand factor, protein C, and antithrombin III) between 385 case patients, defined by high-resolution B-mode ultrasonography as having carotid arterial wall thickening, and 385 age-, race-, and sex-matched control subjects. These case patients and control subjects were selected from participants in a prospective population investigation, the Atherosclerosis Risk in Communities (ARIC) Study, who were examined between May 1987 and May 1989. Plasma fibrinogen, factor VII, protein C, and antithrombin III levels were significantly higher in case patients than in control subjects (P < 0.05). Factor VIII and von Willebrand factor were not different. These findings were supported by quartile distribution and univariate analysis. However, only fibrinogen remained significantly associated with carotid atherosclerosis on multivariate analysis taking other atherosclerosis risk factors into consideration. A one standard deviation increase in fibrinogen (67 mg/dL) was associated with a 1.6-fold increase in the odds of carotid atherosclerosis univariately (P < 0.001) and with a 1.3-fold increase in the odds multivariately (P = 0.010). Further analysis revealed that the association of fibrinogen with carotid atherosclerosis was somewhat stronger in cigarette smokers than in nonsmokers. This early case-control analysis of the ARIC Study demonstrates a significant association between plasma fibrinogen concentration and early atherosclerosis in the carotid arteries. In the context of published findings from population studies, our results indicate that plasma fibrinogen concentrations may be a useful marker for identifying individuals at high risk of developing arterial thrombotic disorders.

Relations between hemostasis variables and cardiovascular risk factors in middle-aged adults. Atherosclerosis Risk in Communities (ARIC) Study Investigators.

The relations between hemostatic variables and cardiovascular risk factors were examined in a biracial population sample of middle-aged adults. Fibrinogen, factor VII, factor VIII, von Willebrand factor, protein C, and antithrombin III levels varied considerably by age, sex, and race. Hemostatic variables also were associated with several life-style and biochemical risk factors. For the most part, higher levels of the risk factors were associated with higher levels of the hemostatic variables. The findings point to potential confounders that warrant consideration in cardiovascular disease studies, and/or mechanisms by which cardiovascular risk is conferred. They also suggest that modification of the cardiovascular risk factors may have the potential to alter the risk of thrombosis.

Porphyria cutanea tarda in association with human immunodeficiency virus infection in a hemophiliac.

A case of porphyria cutanea tarda in a human immunodeficiency virus-infected patient with hemophilia is reported. Onset of skin manifestations of porphyria cutanea tarda coincided with deterioration of immune function. However, acquired immunodeficiency syndrome has not yet developed with a follow-up interval of 39 months. Treatment with zidovudine and topical steroids has resulted in significant improvement in the skin lesions. The clinical features of 11 other reported cases of human immunodeficiency virus-associated porphyria cutanea tarda are reviewed. The data suggest that a true association exists between human immunodeficiency virus infection and porphyria cutanea tarda, with onset of clinical signs of porphyria cutanea tarda coincident with declining immunologic function.

Distributions of hemostatic variables in blacks and whites: population reference values from the Atherosclerosis Risk in Communities (ARIC) Study.

The Atherosclerosis Risk in Communities Study measured hemostatic variables in nearly 16,000 men and women, aged 45 to 64 years, from four US communities. This report, based on the first 12,681 participants, presents distributions of fibrinogen concentration, factor VII activity, factor VIII activity, von Willebrand factor antigen, protein C antigen, antithrombin III activity, and activated partial thromboplastin time. Many of the hemostatic variables differed between blacks and whites, and by sex and age. For example, compared to whites, blacks had higher mean values of fibrinogen, factor VIII, von Willebrand factor, and antithrombin III, and lower mean values of protein C. Some seasonal fluctuations in hemostatic variables were noted; most notably, mean values of factor VII were lowest and protein C were highest in subjects examined in the summer compared to those examined during the other seasons. These results provide population-based reference values on blacks and whites for those interested in the relation of hemostasis to disease.

Population correlates of plasma fibrinogen and factor VII, putative cardiovascular risk factors.

Recent prospective investigations have reported that higher plasma fibrinogen concentrations and higher factor VII coagulant activity are associated with greater risk of cardiovascular disease. To discover what characteristics may influence fibrinogen and factor VII, we analyzed data from the Atherosclerosis Risk in Communities Study obtained from over 12,000 men and women, aged 45-64 years, from four communities in December 1986 to June 1989. Fibrinogen was higher in blacks than whites and in women than men; in general, it increased with age, smoking, body size, diabetes, fasting serum insulin, LDL cholesterol, lipoprotein(a), leukocyte count, and menopause, and it decreased with ethanol intake, physical activity, HDL cholesterol, and female hormone use. Factor VII was higher in women than men and, in women, increased with age; in both sexes, it increased with body size, triglycerides, LDL cholesterol, and HDL cholesterol, and it decreased with ethanol intake. These findings indicate that elevations in fibrinogen and factor VII may be modifiable through appropriate lifestyle changes.

Prothrombotic hemostatic abnormalities in patients with refractory malignant lymphoma presenting for autologous stem cell transplantation.

Forty-six patients with refractory malignant lymphoma (Hodgkin's and non-Hodgkin's) admitted for autologous marrow or peripheral blood stem cell transplantation (ASCT) were evaluated for the presence of hemostatic abnormalities known to be associated with a hypercoagulable state in other patient populations. All patients had received numerous chemotherapeutic agents in the past and often radiation therapy as well. Hemostatic abnormalities were found to be common in these patients. The most frequent finding was hyperfibrinogenemia, present in 35% of patients. Decreased protein C activity was present in 32% of patients. Protein C antigen was low in only one individual and protein S was normal or increased in all patients. Low levels of antithrombin III were present in 16%. Plasminogen activator inhibitor was elevated in 20%. Anticardiolipin antibodies were present in 29% of patients; other evidence of a lupus anticoagulant was present in only eight patients. The frequency of each hemostatic abnormality was similar for patients with Hodgkin's disease (HD) and those with non-Hodgkin's lymphoma (NHL) despite the fact that significantly more patients with HD had received irradiation and/or previous splenectomy than patients with NHL. We conclude that multiple prothrombotic abnormalities of hemostasis are present in patients with refractory lymphoma referred for ASCT. Whether these are the result of lymphoma or the result of therapy cannot be determined from this study.

Vitronectin in bronchoalveolar lavage fluid is increased in patients with interstitial lung disease.

Vitronectin, also known as S-protein, is a 75,000-dalton serum glycoprotein that has a variety of functions, including the capacity to interact with the terminal components of the complement cascade, the coagulation system, and cell surfaces. By virtue of its ability to interact with cells, vitronectin is capable of mediating cell-spreading and adhesion and may also influence cell differentiation and cell growth. To investigate the possibility that vitronectin might contribute to the pathogenesis of interstitial lung disease, vitronectin was measured in bronchoalveolar lavage fluid from patients with sarcoidosis, idiopathic pulmonary fibrosis, and, for comparison, normal volunteers. Vitronectin was detected in lavage fluid and serum of all study subjects. Increased lavage fluid concentrations were found in patients with interstitial lung disease when compared with normal subjects (p less than 0.005), and glucocorticoid-treated patients with interstitial lung disease had lower vitronectin levels than did untreated patients. Furthermore, on SDS-PAGE and Western blot analysis lavage fluid vitronectin comigrated with serum vitronectin, suggesting similar molecular size. Thus, vitronectin is a normal constituent of the epithelial lining fluid, and lavage fluid vitronectin is similar to serum vitronectin. The increase of vitronectin concentrations in the epithelial lining fluid of patients with interstitial lung disease suggests that vitronectin may contribute to the pathogenesis of interstitial lung disease.

Clinical significance of hematologic parameters in non-Hodgkin's lymphoma at diagnosis.

Three hundred seventeen patients with non-Hodgkin's lymphoma (NHL) (54 low grade, 180 intermediate grade, 76 high grade, and seven unclassified) treated with chemotherapy were evaluated for the presence of hematologic abnormalities at diagnostic staging. Anemia was present in 42%, leukopenia in 6%, thrombocytopenia in 13%, leukocytosis in 26%, and thrombocytosis in 14% at presentation. The presence of bone marrow involvement by lymphoma was more likely to be associated with leukopenia and thrombocytopenia than the absence of bone marrow involvement. Although anemia was slightly more common in patients with bone marrow lymphoma than in those without marrow lymphoma, the difference was not statistically significant. Hematologic parameters were similar for patients with B-cell or T-cell lymphoma. Evidence of bone marrow failure with multiple cytopenias was present in 26 patients (8%). Leukoerythroblastosis was present in 2%. Circulating lymphoma was present in 9.5%. Anemic patients had a shorter survival time than nonanemic patients, whether bone marrow was involved by lymphoma or not. Survival was not affected by the presence of leukopenia or mild leukocytosis, but, in patients without marrow lymphoma, leukocytosis with a leukocyte count greater than 20 x 10(9)/l was associated with short survival length. Thrombocytopenia was associated with short survival time only in patients with bone marrow involvement by lymphoma. Patients with multiple cytopenias or leukoerythroblastosis had short survival times, but the presence of circulating lymphoma did not alter survival when compared with other patients with bone marrow involvement by lymphoma. These data suggest that hematologic evaluation at the time of diagnostic staging of NHL provides useful prognostic information that may have therapeutic implications.

Catheter-related thrombosis in patients with refractory lymphoma undergoing autologous stem cell transplantation.

Long-term indwelling central venous catheters have eased the administration of drugs, blood products, and hyperalimentation to patients with cancer. However, their use is associated with thrombotic complications. We report here on the thrombotic complications prospectively observed in 46 patients with refractory lymphoma (22 Hodgkin's disease, 24 non-Hodgkin's lymphoma) who had placement of one or more catheters in preparation for autologous stem cell transplantation (ASCT). Thrombosis of 26 catheters in 19 patients was observed. Specific abnormalities of hemostasis were equally common in patients who developed thrombosis and in those who did not. Thrombotic complications were more common in patients with Hodgkin's disease (13/22) than in patients with non-Hodgkin's lymphoma (6/24, p = 0.04). Although more patients with Hodgkin's disease had received prior splenectomy and/or irradiation to the area involved by thrombosis than patients with non-Hodgkin's lymphoma, the incidence of splenectomy and irradiation was similar for patients with Hodgkin's disease who developed thrombosis and those who did not. Therefore, although the etiology remains unexplained, patients with Hodgkin's disease undergoing intensive chemotherapy and ASCT appear to have a higher incidence of catheter-related thrombosis than patients with non-Hodgkin's lymphoma undergoing similar therapy.

Thrombospondin as a Marker for Leukemic Megakaryoblasts.

Four cases of acute leukemia are reported in which the blast cells were reactive with a monoclonal antibody to the platelet alpha granule glycoprotein thrombospondin (TSP). Blasts in all four cases were also terminal deoxynucleotidyl transferase (TdT)-positive. Two cases demonstrated the presence of the Philadelphia chromosome, t(9;22). The only cells in normal bone marrow which reacted with antibody to TSP were megakaryocytes. Blasts in nine cases of acute myelogenous leukemia, six cases of acute lymphocytic leukemia, four cases of undifferentiated leukemia, and three cases of myelodysplastic syndrome were negative for TSP. Thus, TSP is useful in the identification of normal megakaryocytes and a subset of acute leukemia cells. The presence of both TSP and TdT in the leukemic blasts of our four patients suggests evolution from a pluripotent stem cell capable of multi-lineage differentiation.

Disseminated intravascular coagulation and hemorrhage in hemophilia B following elective surgery.

Two patients with hemophilia B are described in whom disseminated intravascular coagulation (DIC) developed following infusion of repeated doses of Factor IX concentrate in the perioperative period. In both cases the surgery was elective, Factor IX survival studies had been done to assure proper dosing, and Factor IX levels were monitored daily. Neither patient had clinically significant liver disease. The DIC manifested itself as excessive blood loss from surgical drains without documented thrombosis and was accompanied by prolonged coagulation times, increased fibrin split products and decreased fibrinogen and platelets. In both patients the process was quickly reversed with administration of fresh frozen plasma, cryoprecipitate, and the addition of heparin to the Factor IX concentrate. These cases highlight the difficulty in managing patients with hemophilia B undergoing surgical procedures due to the potential thrombogenicity of the currently available concentrates, and the importance of differentiating the bleeding associated with DIC from underdosing with Factor IX. Furthermore, the potential complications associated with the presently available Factor IX concentrates stress the need for the development of purer, safer Factor IX concentrates.

Bone marrow involvement by non-Hodgkin's lymphoma: the clinical significance of morphologic discordance between the lymph node and bone marrow. Nebraska Lymphoma Study Group.

Bone marrow specimens from 317 patients with non-Hodgkin's lymphoma (NHL) obtained at initial staging were evaluated for the presence of lymphoma or benign lymphoid aggregates. Thirty-two percent (102 patients) had lymphoma in their bone marrow, and 9% had benign lymphoid aggregates. Bone marrow lymphoma was present in 39% of low-grade, 36% of intermediate-grade, and 18% of high-grade lymphomas. The bone marrow was involved in 25% of patients with diffuse large-cell or immunoblastic NHL (ie, diffuse histiocytic lymphoma of Rappaport). Bone marrow involvement did not affect survival of patients with low-grade NHL, but survival was significantly shorter (P = .03) for patients with intermediate- and high-grade NHL with bone marrow involvement. Bone marrow involvement was equally common in B-cell and T-cell NHL (31% v 32%). However, patients with T-cell NHL and bone marrow involvement had shorter survival than B-cell NHL with marrow involvement (P = .02) or T-cell NHL without marrow involvement (P = .05). A high incidence of morphologic discordance between lymph node and bone marrow was observed (ie, 40%), always with a more aggressive subtype in the lymph node than in the bone marrow. Presence of large-cell lymphoma in the bone marrow predicted for short survival. Survival for patients with small-cell lymphoma in their bone marrow did not differ significantly from patients with negative bone marrows. We conclude that bone marrow involvement in large-cell NHL, especially in those of T-cell origin, portends a poor prognosis. However, the subgroup of patients with an aggressive histologic subtype of NHL in a lymph node biopsy and small-cell NHL in the bone marrow do not have a poorer outlook than those without bone marrow involvement.

Low protein S in essential thrombocythemia with thrombosis.

Patients with essential thrombocythemia (ET) are at increased risk for large-vessel and microvascular thrombosis, presumably because of abnormal platelet number and function. To determine if another hemostatic abnormality might contribute to this thrombotic risk, we investigated protein C and protein S and the fibrinolytic system in four patients with ET. The patients segregated into two distinct groups. The first group consisted of two patients with moderate thrombocytosis who were without thrombotic symptoms and who had normal protein S and protein C and normal fibrinolysis. The second group consisted of two patients with mild to moderate thrombocytosis and thrombosis. Both these latter two patients had abnormalities in protein S. The first patient had only 31% free protein S and 67% total protein S, with normal protein C and normal fibrinolysis. Following treatment, vasoocclusive symptoms resolved and platelet count decreased, but protein S remained low (28% free protein S). The second patient in this group had only 35% total protein S at initial study. Other hemostatic abnormalities were also present. Following treatment, symptoms resolved and protein S returned to normal. Based on this limited series, it appears that, in some patients with ET, thrombotic phenomena may be due to the presence of a second hemostatic abnormality in addition to the high platelet count and abnormal platelet function. This abnormality may be acquired as part of the disease process. Some of these abnormalities may be corrected following treatment.

Prothrombotic abnormalities in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is known to be associated with a thrombotic tendency, which is often attributed to thrombocytosis, elevated fibrinogen, or decreased antithrombin III. We prospectively studied eight patients with IBD, seven of whom had little or no disease activity, to determine if they had any laboratory abnormality known to be associated with an increased risk of thrombosis. Abnormalities in fibrinolysis were noted in five patients: four with high plasminogen activator inhibitor levels and one with poor release of tissue plasminogen activator following venous occlusion. Circulating immune complexes were present in the sera of five patients. Fibrinogen was mildly elevated in one patient, and two patients had mild thrombocytosis. Decreased levels of antithrombin III, protein C, or protein S were not observed. There appears to be a high incidence of abnormalities in fibrinolysis in inactive IBD, which may contribute to the high frequency of thrombosis seen in IBD. The presence of circulating immune complexes may contribute to vascular injury and thrombosis.

Concomitant chronic lymphocytic leukemia, acute myeloid leukemia, and thrombosis with protein C deficiency. Case report and review of the literature.

A patient is reported who presented simultaneously with two distinct forms of leukemia: chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). The diagnosis of CLL was supported by the presence of lymphocytosis, lymphadenopathy, and splenomegaly with mature B-cell markers on the population of lymphoid cells in the bone marrow. AML was documented by the presence of circulating blast cells and 50% blasts with myeloid markers and Auer rods in the bone marrow. A complete remission from both forms of leukemia was obtained after treatment for the AML. The patient also experienced the temporal occurrence of venous thrombosis for the first time at the age of 69 years, shortly before the diagnosis of leukemia. Protein C deficiency was documented and may have been hereditary as suggested by the strong family history of thrombosis or alternatively may have been the consequence of one of the leukemias.