Hypofibrinogenemia Research Articles

Nonalcoholic fatty liver in patients with Laron syndrome and GH gene deletion – Preliminary report

Background There is little information on the relationship between growth hormone/insulin-like growth factor-I (GH/IGF-I) deficiency or IGF-I treatment on nonalcoholic fatty liver disease (NAFLD) a disorder linked to obesity and insulin resistance. Objective To find out whether the markedly obese patients with Laron syndrome (LS) and GH gene deletion have fatty livers. Subjects We studied 11 untreated adult patients with LS (5M, 6F), five girls with LS treated by IGF-I and five adult patients with GH gene deletion (3M, 3F), four previously treated by hGH in childhood. Methods Fatty liver was quantitatively evaluated by ultrasonography using a phase array US system (HITACHI 6500, Japan). Body adiposity was determined by DEXA, and insulin resistance was estimated by HOMA-IR using the fasting serum glucose and insulin values. Results Six out of 11 adult patients with LS, two out of the five IGF-I treated girls with LS and three out of five adult hGH gene deletion patients were found to have NAFLD (nonalcoholic fatty liver disease). Conclusion NAFLD is a frequent complication in untreated and treated congenital IGF-I deficiency. No correlation between NAFLD and age, sex, degree of obesity, blood lipids, or degree of insulin resistance was observed.

Use of serum insulin-like growth factor-I levels to predict psychiatric non-response to donepezil in patients with Alzheimer’s disease

Objective Insulin-like growth factor-I (IGF-I) deficiency may be involved in cognitive deficits seen with aging and in neurodegenerative diseases such as Alzheimer’s disease (AD). This study was aimed at investigating whether non-responder to donepezil could be predicted using decreased serum levels of IGF-I in AD patients. Design This study involved 106 elderly subjects: 50 patients with AD and 56 age-matched controls without dementia. In patients with AD, donepezil was given orally 3 mg/day for 4 weeks and 5 mg/day for another 12 weeks. AD patients were divided into responders and non-responders based on the changes in mini-mental state examination (MMSE) scores before and 16 weeks after treatment with donepezil. Serum levels of IGF-I and atherogenic biomarkers were determined. Results Before treatment with donepezil, there was a significant positive correlation between serum IGF-I levels and the MMSE scores in all subjects. Serum IGF-I levels and the MMSE scores were significantly lower in AD patients than in non-demented controls and were the lowest in non-responders to donepezil. Atherogenic biomarkers (LDL cholesterol, triglycerides, lipoprotein(a), lipid peroxide, apolipoprotein E, and glucose levels) did not differ significantly among these groups. On multiple logistic regression, non-responders to donepezil showed decreased serum IGF-I levels <110 ng/ml and MMSE scores <15 points before treatment. Conclusions These findings suggest that decreased levels of serum IGF-I combined with MMSE scores before treatment could predict non-responders to donepezil among AD patients, which may be a simple and practical method for selecting patients expected to show a response to treatment.

The interactive Factor H-atypical hemolytic uremic syndrome mutation database and website: update and integration of membrane cofactor protein and Factor I mutations with structural models

Atypical hemolytic uremic syndrome (aHUS) is a disease of hemolytic anemia, thrombocytopenia, and renal failure associated with defective alternative pathway (AP) complement control. Previously, we presented a database (www.FH-HUS.org) focusing on aHUS mutations in the Factor H gene (CFH). Here, new aHUS mutations are reported for the complement regulatory proteins Factor H (FH), Factor I (FI), and membrane cofactor protein (MCP). Additional mutations or polymorphisms within CFH have been associated with membranoproliferative glomerulonephritis (MPGN) and age-related macular degeneration (AMD). Accordingly, the database now includes substitutions that predispose to aHUS, MPGN, and AMD. For this, structural models for the domains in MCP and FI were developed using homology modeling. With this new database, patients with mutations in more than one gene can be displayed and interpreted in a coherent manner. The database also includes SNP polymorphisms in CFH, MCP, and IF. There are now a total of 167 genetic alterations, including 100 in CFH, 43 in MCP, and 24 in IF. The mutations characterize clinical outcomes that vary from several AMD-associated polymorphisms to those associated with aHUS, MPGN, or FI deficiency. A consensus short complement regulator (SCR) domain structure facilitated the interpretations of aHUS mutations. Specific locations within this consensus domain often correlate with the occurrence of clinical phenotypes. The AMD Tyr402His polymorphism is structurally located at a hotspot for several aHUS mutations. The database emphasizes the causative role of the alternative pathway of complement in disease and provides a repository of knowledge to assist future diagnosis and novel therapeutic approaches.

A Mutant Signal Transducer and Activator of Transcription 5b, Associated with Growth Hormone Insensitivity and Insulin-Like Growth Factor-I Deficiency, Cannot Function as a Signal Transducer or Transcription Factor

A natural missense mutation in the signal transducer and activator of transcription (STAT) 5b gene was recently identified in association with a female patient presenting with severe growth failure and immune dysfunction. The mutation results in an alanine to proline substitution at residue 630 (A630P) in the src-homology-2 domain, a region essential for docking of STATs to phospho-tyrosines on activated receptors, STAT dimerization, and stabilization of phospho-STAT-DNA interactions. The purpose of this study was to explore the molecular mechanisms underlying the GH insensitivity and IGF-I deficiency caused by the A630P-mutated STAT5b. In reconstitution experiments using HEK293 cells, both GH and interferon-gamma were unable to activate mutant STAT5b (A630P), as demonstrated by lack of immunodetectable phospho-tyrosyl-STAT5b (A630P) and inability to drive luciferase reporter activity. However, the Src family of nonreceptor kinases [constitutively active v-src and epithelial growth factor-induced c-src] tyrosine-phosphorylated STAT5b(A630P). The v-src-induced phospho-STAT5b(A630P) translocated to the nucleus but, unlike wild-type Stat5b, was unable to bind DNA. The A630P mutation disrupts the src-homology-2 architecture such that: 1) mutant STAT5b most likely cannot dock to phospho-tyrosines on ligand-activated receptors; and 2) stable interactions with DNA are prevented. Because STAT5b (A630P) is an inefficient signal transducer and transcription factor, the detrimental impact on signaling pathways important for normal growth and immunity explains, in part, the complex clinical phenotype of GH insensitivity and immune dysfunction.

Do deficiencies in growth hormone and insulin-like growth factor-1 (IGF-1) shorten or prolong longevity?

Present knowledge on the effects of growth hormone (GH) and insulin-like growth factor-I (IGF-I) deficiency on aging and lifespan are controversial. Studying untreated patients with either isolated GH deficiency due to GH gene deletion, patients with multiple pituitary hormone deficiency due to PROP-1 gene mutation and patients with isolated IGF-I deficiency due to deletions or mutations of the GH receptor gene (Laron syndrome); it was found, that these patients despite signs of early aging (wrinkled skin, obesity, insulin resistance and osteopenia) have a long life span reaching ages of 80–90 years. Animal models of genetic GH deficiencies such as Snell mice (Pit-1 gene mutations) the Ames mice (PROP-1 gene mutation) and the Laron mice (GH receptor gene knock-out) have a statistically significant higher longevity compared to normal controls. On the contrary, mice transgenic for GH and acromegalic patients secreting high amounts of GH have premature death. Those data raise the question whether pharmacological GH administration to adults is deleterious, in contrast to policies advocating such therapies.

Mammary gland branching morphogenesis is diminished in mice with a deficiency of insulin-like growth factor-I (IGF-I), but not in mice with a liver-specific deletion of IGF-I.

The development of the mouse mammary gland occurs postnatally. Hormonal activation of local growth factor pathways stimulates rapid elongation and branching of the rudimentary gland through the fatty stroma. Earlier studies showed that GH is required for mammary gland ductal morphogenesis and that IGF-I mediates this action of GH. In the present study we show that adult IGF-I(m/m) mutant mice exhibit a marked reduction in levels of mammary gland and liver igf1 transcripts compared with controls. Whole mounts of the adult IGF-I(m/m) mammary glands revealed ducts that extended to the limits of the fat pad; however, the number of bifurcation branch points in the ductal tree of the mutants was reduced by half compared with that of wild-type glands. In contrast, adult mutant mice with a liver-specific deletion of the igf1 gene obtained by Cre/loxP recombination strategy maintained the normal levels of mammary gland igf1 transcripts and did not exhibit a branching deficit in this organ. It was previously reported that this specific loss of liver IGF-I causes serum levels of IGF-I (endocrine) to decrease by approximately 75%, whereas the levels of tissue igf1 transcripts remain unchanged. On the basis of these findings, we propose that paracrine, not endocrine, IGF-I is important for mammary branching morphogenesis.

Effects of insulin-like growth factor-I deficiency and replacement therapy on the hematopoietic system in patients with Laron syndrome (primary growth hormone insensitivity).

Primary insulin-like growth factor-I (IGF-I) deficiencies, such as in Laron syndrome (LS), are a unique model in man to study the consequences resulting from defects in growth hormone (GH) signal transmission. To assess retrospectively the effect of IGF-I deficiency and its therapy on the various cells of the hematopoietic system as reflected by peripheral blood counts. Two groups of patients were studied. The first group consisted of 11 untreated patients with LS, seven males and four females, who were followed from childhood into adult age. Average age at the time of data analysis was 45.4 +/- 9.6 years. The second group included ten children with LS, six males and four females, who received IGF-I replacement therapy for an average period of 6 years, ranging in age from 0.9-11 years. The mean age at initiation of therapy was 6.9 +/- 4.28 years. Only the seven children treated for 5 years or more were included in the analysis. Data on blood counts were collected from the patients' charts. Blood samples were drawn at baseline, weekly during the first month, once a month during the first year, and once every 3 months thereafter. Statistical analysis of the change over time was performed using repeated measures ANOVA. Children with LS had red cell indices in the lower normal range and an elevated monocyte count. A statistically significant rise in red blood cell (RBC) indices was seen in children during IGF-I therapy: RBC rose from 4.66 x 10(6)/ml to 4.93 x 10(6)/ml (p = 0.011); hemoglobin from 11.55 g/dl to 13.01 g/dl (p < 0.001); hematocrit from 34.94% to 38.52% (p = 0.007), and mean corpuscular volume from 72.27 fl to 79.93 fl (p < 0.001). The platelet count diminished significantly during IGF-I therapy from 316 x 10(3)/ml to 219 x 10(3)/ml (p = 0.02), and the monocyte count from 0.74 x 10(3)/ml to 0.49 x 10(3)/ml (p < 0.001). The present investigation, the first of its kind in this syndrome, confirms that IGF-I has a strong stimulatory effect on erythropoiesis. In addition, IGF-I therapy had a reducing effect on monocytes and platelets, an effect not previously described. The mechanism by which IGF-I mediates these effects needs further elucidation.

Zinc and IGF-I Concentrations in Pregnant Women with Anemia before and after Supplementation with Iron and/or Zinc

Objective: The objective of our study was to investigate zinc (Zn) status and effects of Zn supplementation in relation to insulin-like growth factor-I (IGF-I) and iron deficiency anemia in pregnant women. The role of Zn and IGF-I in hematologic abnormalities has remained unclear.Methods: Thirty-eight Japanese women, when examined at the second trimester of pregnancy, had hemoglobin concentrations below 11.0 g/dL and 32 of 38 had normocytic erythrocytes. These 38 women were divided into three groups, and we compared the hematological status and serum IGF-I levels before and after iron (Group A) or Zn (Group B) or iron plus Zn (Group C) supplementation.Results: The concentrations of hemoglobin (Hb) did not change in groups A and B. In group C, Hb levels were significantly increased from 10.3±0.3 to 11.0±0.6 g/dL. Furthermore, numbers of RBC and reticulocytes also increased significantly. Concentrations of iron, IGF-I and total iron binding capacity (TIBC) were increased, and concentrations of erythropoietin were decreased, but not statistically. There were significant positive correlations between increases in IGF-I and increases in Hb and RBC in the Zn administered groups.Conclusion: Zn status to some extent can account for hematological abnormalities in pregnant women. Zn derived IGF-I has a role in the regulation of hematopoiesis in pregnant women.

Insulin-like growth factor-I deficiency caused by a partial deletion of the IGF-I gene: Effects of rhIGFmi therapy

Insulin-like growth factor-I (IGF-I) is one of the most important regulator of growth. IGF-I deficiency is associated with prenatal and post-natal growth failure and may arise primarily as a result of GH receptor/post-receptor abnormalities or defects in the synthesis and transport of IGF-I. We have previously reported a 17.2-year-old boy with severe growth retardation and undetectable serum levels of IGF-I caused by a partial deletion of the IGF-I gene. This short review will concentrate on results of a recent study which examined the effects of rhIGF-I therapy on the GH-IGF system of this patient. Similar to healthy individuals, this patient had normal IGFBP-3 but elevated ALS levels. IGF-I treatment has improved linear growth and insulin sensitivity in this patient by restoring IGF-I levels and by normalizing circulating GH, IGFBPs and insulin levels.

Perinatal Intracranial Hemorrhage as First Manifestation of Congenital Hypofibrinogenemia

We describe a new case of congenital hypofi brinogenemia revealed by the dramatic occurrence of a perinatal intracranial hemorrhage, which resulted in dif fuse multicystic encephalopathy with severe hydroceph alus. The family history was negative for hemorrhagic tendency, but the assessment of a complete coagulation study showed the presence of low fibrinogen coagulant and antigen plasma levels both in the patient and in her 5-year-old healthy sister. Because the hereditary trans mission of the disease is autosomal recessive, similar fi brinogen concentrations were expected in the two af fected sisters. However, the patient showed lower levels than the sister (14 mg/dl and 46 mg/dl, respectively): a different phenotypic expression of the disorder or the dif ferent age of the two sisters could provide some explana tion. Moreover, we emphasize the importance of neonatal coagulative screening for the diagnosis of such defects.

The 'dawn phenomenon' in adolescents with insulin dependent diabetes mellitus: possible contribution of insulin-like growth factor binding protein-1.

Insulin resistance increases during adolescence, and is exaggerated in patients with insulin dependent diabetes mellitus (IDDM). A relative deficiency of insulin-like growth factor-I (IGF-I) may contribute to this increased insulin requirement. Two mechanisms have been proposed: (a) increased GH secretion, caused by failure of IGF feedback control, leading to increased insulin resistance and (b) lack of insulin-like action of the IGFs which is reinforced by high plasma levels of IGFBP-1, an inhibitor of IGF action. The contribution of these two mechanisms to the 'dawn phenomenon' is assessed. The two possible mechanisms were studied during the dawn rise of glucose in pubertal adolescent patients with IDDM. Two overnight studies were performed in each subject. Patients remained on the same insulin regimen throughout. Twenty-two diabetic adolescent subjects, aged (mean +/- SEM) 14.0 +/- 0.4 years, duration of IDDM 7.9 +/- 0.8 years, were recruited. Pubertal status was: group 1 (breast stage 1-2; testicular volume < 4-8 ml) 3 male and 4 female, group 2 (breast stage 3; testicular volume 10-12 ml) 0 male 4 female, group 3 (breast stage 4-5; testicular volume 15-25 ml) 4 male and 7 female. Height standard deviation score (mean +/- SD) (-0.02 +/- 0.99) and daily insulin dose (50.4 +/- 3.1 U/day) did not change between studies. There were no differences in HbA1 (study A 11.26 +/- 0.45%, study B 11.09 +/- 0.42%). The subjects were admitted for the two studies 0.3 +/- 0.03 years apart. Blood samples were taken via an indwelling cannula every 20 minutes between 1900 and 0700 h. GH was assayed every 20 minutes, IGFBP-1, glucose and free insulin every hour and IGF-I at 0700 h. GH, IGFBP-1, IGF-I and free insulin were measured by radioimmunoassay. IGFBPs were also analysed by Western ligand blotting techniques. GH profiles were analysed by Pulsar and results compared by paired Student's t-test. The relations between the dawn rise in glucose and the changes in IGFBP-1, GH and free insulin were examined by multiple linear regression analysis. Serum IGFBP-1 levels rose overnight in the two studies (study A, from 9 +/- 1 at 2200 to 59 +/- 9 micrograms/l at 0700 h; study B, from 10 +/- 1 at 2100 to 64 +/- 14 micrograms/l at 0700 h) whilst insulin levels fell from 47 +/- 5 at 2200 to 16 +/- 2 mU/l at 0700 h (study A) and from 45 +/- 5 at 2000 to 14 +/- 2 mU/l at 0700 h (study B). Glucose levels fell from 16.0 +/- 1.0 to 9.3 +/- 0.9 mmol/l at 0400 h, and then rose to 11.9 +/- 1.1 mmol/l at 0700 h during study A, and from 13.4 +/- 1.3 to 10.1 +/- 1.1 mmol/l at 0400 h and then rose to 13.5 +/- 1.0 mmol/l at 0700 h during study B. There were no differences in GH secretion between studies (mean GH levels (mean +/- SD) (study A, 15.7 +/- 6.6 mU/l; study B, 16.2 +/- 7.1 mU/l; correlation within subjects between studies r = 0.77, P < 0.001), sum of GH peaks (study A, 189.9 +/- 90.3 mU/l; study B, 185.8 +/- 100.2 mU/l; r = 0.57, P = 0.006)). Mean GH levels varied with pubertal stage (group 1, 12.1 +/- 1.5 mU/l; group 2, 23.3 +/- 2.1 mU/l; group 3, 15.3 +/- 1.2 mU/l). Serum IGF-I levels were not different (study A, 203 +/- 12 micrograms/l; study B, 218 +/- 13 micrograms/l). REGRESSION ANALYSIS: The change in plasma glucose between 0200 and 0700 h in both studies related to free insulin, IGFBP-1 and the sum of the GH levels over the preceding hour (log glucose = 7.87 + 5.32 log IGFBP-1 (P = 0.0001) - 5.05 log free insulin (P = 0.0001) - 1.44 log GH (P = 0.004); R2 = 72%). Mean overnight GH levels did not predict the morning rise in plasma glucose. The morning rise of IGFBP-1 and plasma glucose appear to be related in this group of subjects with IDDM and this was a consistent finding in the two studies. This relation was additive to the effect of insulin deficiency.

Growth curves for Laron syndrome.

Growth curves for children with Laron syndrome were constructed on the basis of repeated measurements made throughout infancy, childhood, and puberty in 24 (10 boys, 14 girls) of the 41 patients with this syndrome investigated in our clinic. Growth retardation was already noted at birth, the birth length ranging from 42 to 46 cm in the 12/20 available measurements. The postnatal growth curves deviated sharply from the normal from infancy on. Both sexes showed no clear pubertal spurt. Girls completed their growth between the age of 16-19 years to a final mean (SD) height of 119 (8.5) cm whereas the boys continued growing beyond the age of 20 years, achieving a final height of 124 (8.5) cm. At all ages the upper to lower body segment ratio was more than 2 SD above the normal mean. These growth curves constitute a model not only for primary, hereditary insulin-like growth factor-I (IGF-I) deficiency (Laron syndrome) but also for untreated secondary IGF-I deficiencies such as growth hormone gene deletion and idiopathic congenital isolated growth hormone deficiency. They should also be useful in the follow up of children with Laron syndrome treated with biosynthetic recombinant IGF-I.

THE MOST EFFECTIVE DOSE OF STREPTOKINASE.

The usual dose of intravenous streptokinase for evolving MI is 1.5 million units; it was chosen based on studies showing a greater degree of hypofibrinogenemia with doses greater than 1 million units. The …

Ancrod: normalization of fibrinolytic enzyme abnormalities in patients with systemic lupus erythematosus and lupus nephritis.

Ancrod is a thrombinlike enzyme from Malayan pit viper (Agkistrodon rhodostoma) venom that has a selective enzyme substrate specificity for fibrinogen. Unlike thrombin, it splits only fibrinopeptide A from the fibrinogen molecule and does not activate factor XIII. Simultaneously with the occurrence of hypofibrinogenemia there is a reduction of plasma plasminogen and a rise in fibrin degradation products, suggesting secondary recruitment of the fibrinolytic enzyme system. Ancrod was given to 18 patients with systemic lupus erythematosus and glomerular and vascular microthrombi. Before treatment vascular plasminogen activator (VPA) was low or unmeasurable in 14, an inhibitor of urokinase-induced plasminogen activation (IPA) was elevated in 18, and an inhibitor of plasmin (PI) was elevated in five. Ancrod treatment resulted in prompt normalization of IPA levels in 13 patients; they were classified as fibrinolysis responders. In five patients IPA levels remained elevated throughout treatment with ancrod; they were classified as fibrinolysis nonresponders. In these five the PI level was elevated before treatment and decreased slowly toward the normal range during ancrod administration. The PI did not appear related to the nonspecific serine protease inhibitors, and was shown to be identical with alpha 2-antiplasmin. In the fibrinolysis responders serial histologic studies showed a striking decrease of disappearance of microvascular thrombosis; in the fibrinolysis nonresponders microvascular thrombosis persisted. The action of ancrod is discussed.

Brain injury disseminated intravascular coagulation and fibrinolysis syndrome in children.

Questions or comments regarding this article may be directed to the author at: Hermann Hospital, 1203 Ross Sterling Avenue, Houston, Texas 77030. Ms. Nelson is in the Staff Development Department at Hermann Hospital. Dr. Miner is in the Department of Surgery (Neurosurgery) at the University of Texas Medical School at Houston. The research described in this article was supported by NINCDS Grant #P01, NS14844–01A1.

Disseminated intravascular coagulation fibrinolytic syndrome following head injury in children: Frequency and prognostic implications

Eight-seven consecutive children with head injury were evaluated within two hours of injury by clinical examination, by computed tomographic brain images, and for systemic blood clotting disorders. All were treated by a standard regimen and survival rates calculated according to the initial neurologic abnormalities and pathology of the injury. Patients with the more severe neurologic abnormalities and those with more brain tissue destruction had poorer survival rates. However, 71% of all patients had one or more abnormal clotting tests and 32% had the disseminated intravascular coagulation and fibrinolysis syndrome by laboratory criteria. The mortality was over four times greater in those patients with DIC compared to those with normal clotting values. Our findings indicate that minor hemostatic abnormalities are the rule in head-injured children, that DIC occurs in nearly one-third of cases, and that DIC is associated with a marked increase in the mortality after brain injury: DIC may be a treatable secondary effect of head trauma that could decrease the mortality.

Blood Coagulation, Fibrinolysis and their Inhibitors Studies on Patients with Cancer

Fourteen parameters concerning coagulation, fibrinolysis and their inhibitors were measured in the 170 patients with various malignancies, including 68 cases of stomach cancer, 22 lung cancer, 21 colon and rectum cancer, 14 renal and urinary tract cancer, 9 primary hepatic cancer, 8 uterus and ovary cancer, 4 breast cancer and 19 others.Their parameters were platelet count, plasma fibrinogen level, prothrombin time, thrombotest, hepaplastintest, serial thrombin time, fibrinolytic split products, plasma plasminogen, ethanol gelation test, protamin sulfate test, cryofibrinogen, serum antithrombin III, serum α1 antitrypsin and serum α2 macroglobulin. Cases treated with anti-tumor agents were excluded in this study.Increased FDP in 52% (86 cases), prolonged serial thrombin time in 80%, positive paracoagulation tests and decreased antithrombin III were suggestive of increased activity of coagulation and fibrinolysis. The term of intravascular coagulation and fibrinolysis syndrome (ICF syndrome) was applied to the condition of increased FDP over 20μg/ml.And on the basis of fibrinogen (normal 200-400mg/dl) ICF syndrome was divided into 3 groups as following.Group I; hyperfibrinogenemiaPlatelet was increased, antithrombin III was decreased, plasminogen was normal or increased and paracoagulation tests tended to be positive. This conditions was defined as over compensated ICF syndrome, which was 16% (14 cases) of total ICF syndrome.Group II; normal fibrinogenemiaPlatelet was normal, antithrombin III was decreased, plasminogen was normal and paracoagulation test were less frequently positive. This condition was compensated ICF syndrome, which 59% (51 cases).Group III; hypofibrinogenemiaPlatelet was decreased, also antithrombin III and plasminogen were decreased. Paracoagulation tests were more frequently positive. This condition was defined as decompensated ICF syndrome, which was 25% (21 cases).Marked decrease of fibrinogen, platelet antithrombin III and plasminogen was observed in some patients in this group. DIC with bleeding tendency clinically observed belongs to this group.We concluded that it was significant to devide ICF syndrome due to malignancy into 3 groups on the basis of blood coagulation and fibrinnolysis for the management of patients with malignancy.

A purified procoagulant enzyme from the venom of the eastern diamondback rattlesnake (Crotalus adamanteus): in vivo and in vitro studies.

Abstract A procoagulant enzyme in the venom of the eastern diamondback rattlesnake, Crotalus adamanteus , has been isolated and purified. The enzyme acts directly on purified fibrinogen or fibrinogen in plasma, forming a friable fibrin clot. The enzyme does not activate factors of the extrinsic system, nor does it activate factor XIII. It also does not aggregate platelets and is not inhibited by heparin. Incubation with plasma produces insignificant changes in all coagulation factors except fibrinogen. The enzyme does not activate components of the fibrinolytic system, but is itself fibrinolytic at extremely high concentration. Infusion into dogs produces well tolerated hypofibrinogenemia lasting up to 8 hours. Post infusion, intense fibrinolysis is observed with high titers of nonclottable fibrinogen derivatives in the serum, some with an electrophoretic mobility similar to native fibrinogen. Following infusion declines in factors II, V, and VIII were noted by one stage assays, but may be artifactual due to high levels of fibrinogen derivatives in the test plasmas.

Clinical and laboratory studies on severe abruptio placentae

Presented are clinical observations and laboratory studies made on 141 cases of abruptio placentae so severe that the fetus died. In 38 per cent the fibrinogen concentration was below 150 mg. and in 28 per cent below 100 mg. per 100 ml. When hypofibrinogenemia developed it did so within 8 hours from the onset of symptoms of abruption. Intravascular coagulation best accounted for the coagulation defects. Fibrinogen was administered prior to laparotomy but most often was not necessary with vaginal delivery. Oxytocin to stimulate labor did not contribute to hypofibrino genemia but sometimes was followed by gross disruption of the uterus. Hypovolemia and renal ischemia caused oliguria but serious renal failure could be circumvented by appropriate administration of blood and other fluids. Continuous monitoring of urine flow served as an excellent indicator of the adequacy of the circulation. Shock was not out of proportion to total blood loss. “Obstetric shock” due to intravascular coagulation and vascular obstruction was not identified.