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PubMed2000

Testing of platelet deposition on polystyrene surface under flow conditions by the cone and plate(let) analyzer: role of platelet activation, fibrinogen and von Willebrand factor.

Recently, we described a method of testing platelet deposition on extracellular matrix under flow conditions. The method was used for assessment of platelet function in various platelet disorders, for monitoring of replacement and anti-platelet therapy. In the present study, we investigated platelet deposition on a polystyrene surface compared with that on extracellular matrix, under defined shear rates, using the original Cone and Plate(let) Analyzer. A correlation of adhesion rate (surface coverage) and aggregate formation (average size) of platelets from normal citrated blood between polystyrene and extracellular matrix was observed. Blocking of von Willebrand factor binding to glycoprotein Ib by a recombinant von Willebrand factor fragment substantially decreased platelet adhesion to both surfaces. Blocking of GPIIb-IIIa by Arg-Gly-Asp-Ser peptide prevented platelet adhesion to the polystyrene while an extensive adhesion of single platelets to extracellular matrix was observed. Furthermore, platelet adhesion to polystyrene but not to extracellular matrix was completely inhibited by platelet inactivation with prostaglandin E(1). Platelets from patients with severe von Willebrand disease yielded very low adhesion to both polystyrene and extracellular matrix. The addition of von Willebrand factor to the blood of these patients or pre-coating of polystyrene surface with von Willebrand factor restored the ability of platelets to adhere and aggregate on the surface. Platelets from patients with Glanzmann's thrombasthenia and afibrinogenemia adhered to extracellular matrix (with defective aggregate formation), while they failed to adhere to the polystyrene. Fibrinogen added to afibrinogenemia blood or pre-coating of the polystyrene with fibrinogen restored the ability of platelets to adhere and aggregate on the surface. In conclusion, the polystyrene surface, like extracellular matrix, can be used to assess platelet function disorders taking in account that platelet deposition on polystyrene under flow is absolutely dependent on platelet activation and on the presence of fibrinogen, von Willebrand factor, and their receptors.

Afibrinogenemia↗

PubMed2001

Embolized ischemic lesions of toes in an afibrinogenemic patient: possible relevance to in vivo circulating thrombin.

Fibrinogen plays a complex role in hemostasis, thrombosis, and vascular disease. Hyperfibrinogenemia is an independent vascular risk factor and dysfibrinogenemia can provoke thrombosis. Afibrinogenemia is usually responsible for hemorrhagic diathesis, and unexpected ischemic lesions are intriguing. We report the case of an afibrinogenemic patient, who at the age of 30 developed ischemic lesions of the feet related to severe stenosis of the iliac and hypogastric arteries. The biopsy of the iliac artery lesion showed an intense myointimal hyperplasia. We performed standard hemostatic analysis and analyzed the activation markers of platelets and coagulation factors and the kinetics of thrombin generation in the patient and in normal control plasmas treated or not with reptilase. Occlusive arterial lesions were attributed to a disruptive hematoma penetrating the vascular lumen. Thrombin concentration after calcium addition increase markedly in the afibrinogenemic patient and in defibrinated normal plasma, as compared to untreated normal plasma. Thrombin-antithrombin complexes (T-AT) were markedly enhanced while F1+2 prothrombin fragments stayed in the normal range. These results suggested activation of coagulation and in vivo circulating thrombin. Thrombin activates the platelets that secrete growth factors for smooth muscle cells and generate the intimal hyperplasia. Recurrent hemorrhage within the vessel wall might induce injury and local thrombin generation. Thrombin not trapped by the clot is available for platelet activation and smooth muscle cell migration and proliferation. The absence of a protective fibrin cap on the intima might account for intima vulnerability and embolization. Afibrinogenemia appears in this paradoxical situation as a vascular risk factor.

Adult↗

PubMed2006

The molecular basis of quantitative fibrinogen disorders.

Hereditary fibrinogen disorders include type I deficiencies (afibrinogenemia and hypofibrinogenemia, i.e. quantitative defects), with low or unmeasurable levels of immunoreactive protein; and type II deficiencies (dysfibrinogenemia and hypodysfibrinogenemia, i.e. qualitative defects), showing normal or altered antigen levels associated with reduced coagulant activity. While dysfibrinogenemias are in most cases autosomal dominant disorders, type I deficiencies are generally inherited as autosomal recessive traits. Patients affected by congenital afibrinogenemia or severe hypofibrinogenemia may experience bleeding manifestations varying from mild to severe. This review focuses on the genetic bases of type I fibrinogen deficiencies, which are invariantly represented by mutations within the three fibrinogen genes (FGA, FGB, and FGG) coding for the three polypeptide chains Aalpha, Bbeta, and gamma. From the inspection of the mutational spectrum of these disorders, some conclusions can be drawn: (i) genetic defects are scattered throughout the three fibrinogen genes, with only few sites appearing to represent relative mutational hot spots; (ii) several different types of genetic lesions and pathogenic mechanisms have been described in affected individuals (including gross deletions, point mutations causing premature termination codons, missense mutations affecting fibrinogen assembly/secretion, and uniparental isodisomy associated with a large deletion); (iii) the possibility to express recombinant fibrinogen mutants in eukaryotic cells is rapidly shedding light into the molecular mechanisms responsible for physiologic and pathologic properties of the molecule; (iv) though mutation analysis of the fibrinogen cluster does not yield precise information for predicting genotype/phenotype correlations, it still provides a valuable tool for diagnosis confirmation, identification of potential carriers, and prenatal diagnosis.

Adolescent↗

PubMed1998

Studies on the role of adhesive proteins in maintaining pregnancy.

UNLABELLED: It is well known that maternal fibrinogen (Fg) and factor X III are essential for maintaining early pregnancy. We studied their role by analysis of clinical reports and immunohistochemical investigation. METHODS: (1) We analyzed the pregnancy cases of congenital afibrinogenemia and congenital factor X III deficiency. (2) Immunohistochemical staining of Fg, subunit A of factor X III (X IIIA) and fibronectin (Fn) were performed in the human implantation site, placenta, and endometrial cells cultured in serum-free medium. RESULTS: (1) Afibrinogenemia needed to be administrated Fg from 4 weeks' gestation (4 wG), and factor X III deficiency needed factor X III concentrate from 5 wG, in order to prevent abortion. (2) Implantation tissues: Fg, cellular X IIIA and Fn were present at the decidual stroma around invasive cytotrophoblasts at 5 wG. X IIIA-positive cells coincided with LN-5-positive macrophages. Placenta: Fg, cellular X IIIA and Fn were present in the decidual layer. Endometrial culture cells: Fn was secreted by spindle-like shaped cells. X IIIA was secreted by round-shaped cells. CONCLUSION: Maternal Fg and factor X III are essential just after 4-5 wG, and in that period they and Fn are present abundantly in decidual stroma around invasive cytotrophoblasts. It is concluded that when cytotrophoblasts invade endometrium maternal Fg, factor X III and Fn are concerned with cytotrophoblasts' anchoring as adhesive proteins.

Abortion, Spontaneous↗

PubMed2006

Molecular basis of fibrinogen deficiency.

Inherited fibrinogen disorders can be classified into qualitative and quantitative anomalies: dysfibrinogenemia is characterised by normal circulating levels of fibrinogen with abnormal function; hypofibrinogenemia and afibrinogenemia are characterised by reduced or absent fibrinogen in circulation respectively,while hypodysfibrinogenemia is defined by reduced fibrinogen with reduced function. All are due to mutations in one of the three fibrinogen genes, FGA, FGB and FGG, which are clustered in a region of 50 kb on the long arm of human chromosome 4. The aim of this review is to illustrate the diverse molecular mechanisms by which mutations lead to fibrinogen deficiency, in particular in congenital afibrinogenemia.

Afibrinogenemia↗

PubMed1999

Deletion of the fibrinogen [correction of fibrogen] alpha-chain gene (FGA) causes congenital afibrogenemia.

Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by the complete absence of detectable fibrinogen. Uncontrolled bleeding after birth from the umbilical cord is common, and spontaneous intracerebral bleeding and splenic rupture can occur throughout life. Patients respond well to fibrinogen replacement therapy, either prophylactically or on demand. Because the half-life of infused fibrinogen is essentially normal, the genetic defect is assumed to be at the level of synthesis, but no responsible locus has been identified. Preliminary studies using Southern blotting suggested that no gross structural changes of the fibrinogen genes were present in patients. We report the identification of causative mutations in a nonconsanguineous Swiss family with congenital afibrinogenemia. The four affected male individuals (two brothers and their two first cousins) have homozygous deletions of approximately 11 kb of the fibrinogen alpha-chain gene (FGA). Haplotype data suggest that these deletions occurred separately, on three distinct ancestral chromosomes, implying that the FGA region of the fibrinogen locus is susceptible to deletion by a common mechanism. Furthermore, our results demonstrate that humans, like mice, may be born without the capacity to synthesize functional fibrinogen.

Afibrinogenemia↗

PubMed2002

Inhibition of thrombin generation in plasma by fibrin formation (Antithrombin I).

The adsorption of thrombin to fibrin during clotting defines "Antithrombin I" activity. We confirmed that thrombin generation in afibrinogenemic or in Reptilase defibrinated normal plasma was higher than in normal plasma. Repletion of these fibrinogen-deficient plasmas with fibrinogen 1 (gamma A/gamma A), whose fibrin has two "low affinity" non-substrate thrombin binding sites, resulted in moderately reduced thrombin generation by 29-37%. Repletion with fibrinogen 2 (gamma'/gamma A), which in addition to low affinity thrombin-binding sites in fibrin, has a "high affinity" non-substrate thrombin binding site in the carboxy-terminal region of its gamma' chain, was even more effective and reduced thrombin generation by 57-67%. Adding peptides that compete for thrombin binding to fibrin [S-Hir53-64 (hirugen) or gamma'414-427] caused a transient delay in the onset of otherwise robust thrombin generation, indicating that fibrin formation is necessary for full expression of Antithrombin I activity. Considered together, 1) the increased thrombin generation in afibrinogenemic or fibrinogen-depleted normal plasma that is mitigated by fibrinogen replacement; 2) evidence that prothrombin activation is increased in afibrinogenemia and normalized by fibrinogen replacement; 3) the severe thrombophilia that is associated with defective thrombin-binding in dysfibrinogenemias Naples I and New York I, and 4) the association of afibrinogenemia or hypofibrinogenemia with venous or arterial thromboembolism, indicate that Antithrombin I (fibrin) modulates thromboembolic potential by inhibiting thrombin generation in blood.

Afibrinogenemia↗

PubMed1990

Enhancing effect by heparin on shear-induced platelet aggregation.

We have recently developed a new device for continuously measuring SIPA. Using the device, we have investigated the effects of heparin on SIPA. Heparin itself enhanced SIPA in the absence of agonists in a dose-dependent manner, whereas heparinoids had minimal effects on SIPA. LMW heparin had less enhancing effect on SIPA than unfractionated heparin. Effects of heparin were also investigated using PRP from patients with congenital bleeding disorders, including Bernard-Soulier syndrome, type III von Willebrand's disease, afibrinogenemia and Glanzmann's thrombasthenia. Heparin's effects were observed only when PRP from patients with Bernard-Soulier syndrome and type III von Willebrand's disease was exposed to low shear stress and when PRP from a patient with afibrinogenemia was exposed to high shear stress. These results gave us insights into heparin's effects on platelet aggregation.

Afibrinogenemia↗

PubMed1987

[Role of dysfibrinogenemia and disorders of fibrinolysis in the pathogenesis of hemostatic pathology in liver cirrhosis].

A study of 93 patients with liver cirrhosis showed that the most important blood coagulation disorder in this pathology resulting in hypocoagulation, was not decreased synthesis and deficit of the prothrombin complex factors but disturbance of the final stage determined by afibrinogenemia. Considerable depression of XIIa-kallikrein-dependent fibrinolysis and marked increment of an antiplasmin level in the plasma were noted. Positive paracoagulation tests were revealed in 57% of the patients, and as other signs typical of the lingering DIC-syndrome were absent, they were interpreted as the "hypercoagulation syndrome" or "pre-DIC syndrome". The problem of possible relationship of development of both thromboses and hemorrhages with acquired afibrinogenemia in liver cirrhosis was discussed.

Adult↗

PubMed2002

Antithrombotic effect of Lonomia obliqua caterpillar bristle extract on experimental venous thrombosis.

The venom of Lonomia obliqua caterpillar may induce a hemorrhagic syndrome in humans, and blood incoagulability by afibrinogenemia when intravenously injected in laboratory animals. The possible antithrombotic and thrombolytic activities of L. obliqua caterpillar bristle extract (LOCBE) were evaluated in this study. The minimal intravenous dose of the extract necessary to induce afibrinogenemia and anticoagulation was 3.0 and 10.0 microg protein/kg body weight for rabbits and rats, respectively. In rabbits, this dose induced total blood incoagulability for at least 10 h and did not reduce the weight of preformed venous thrombi, in contrast to streptokinase (30,000 IU/kg). In rats, pretreatment with 5.0 and 10.0 microg/kg LOCBE prevented the formation of thrombi induced by venous stasis or by injury to the venous endothelium. The dose of 5.0 microg/kg LOCBE did not modify blood coagulation assay parameters but increased bleeding time and decreased plasma factor XIII concentration. When the extract was administered to rats at the dose of 10.0 microg/kg, the blood was totally incoagulable for 6 h. These data show that LOCBE was effective in preventing experimental venous thrombosis in rats, justifying further studies using purified fractions of the extract to clarify the mechanisms of this effect.

Animals↗

PubMed1980

Skeletal changes in congenital fibrinogen abnormalities.

We report an anatomico-radiologic study of humerus, femur, and tibia from a case of total congenital afibrinogenemia. Juxtatrabecular hemorrhages occur mainly in metaphyses and seem to be related to normal lines of stress. They may lead to the formation of intraosseous cysts and to a remodelling of bone trabeculae. The radiologic lesions in a second case, diagnosed as congenital dysfibrinogenemia, are similar to those found in Case 1 (femoral trabeculae remodelling) but also resemble some alterations described in hemophilia (pseudotumor of the right iliac bone). Anatomic study of the lesions in Case 2 was not possible. The significance of these observations could be better defined by a more extended skeletal study (radiologic and when feasible anatomic) of patients with congenital clotting defects and especially with inherited disorders of the fibrinogen molecule. It would also be worthwhile investigating manifest or latent hemostatic disorders (particularly at the fibrinogen level) in patients with solitary or aneurysmal bone cysts, and even with bone infarct or unexplained trabecular remodelling.

Adult↗

PubMed1998

Severe coagulopathy after a bite of a green bush viper (Atheris squamiger): case report and biochemical analysis of the venom.

A 34 year old male bitten by an adult Atheris squamiger snake developed symptoms of nausea, vomiting, diarrhea which were followed by drowsiness and impaired breathing. Local hemorrhage, edema and pain at the bite-site occurred, but no systemic bleeding or hemorrhagic diathesis developed. All clinical and laboratory parameters were in the normal range except for afibrinogenemia, thrombocytopenia and slight proteinuria. Replacement therapy (fibrinogen and platelet concentrates) and treatment of shock stabilized the patient within 2d and coagulation returned to normal. Atheris squamiger venom was subjected to biochemical and biological analysis. The LD50 of the venom was 5 mg/kg (mice, s.c.). It produced local hemorrhage corresponding to about 25% of the activity of puff adder venom (Bitis arietans). In vitro the venom had a fibrinogen-converting activity, it did not activate purified prothrombin but very likely contained a F V and Ca2+-dependent prothrombin activator. The venom exhibited strong platelet-aggregating activity, which was not inhibited by protease inhibitors and by EDTA or EGTA. The venom also aggregated acetylsalicylic acid treated platelets indicating, that the arachidonic acid pathway was not essential for activation. Rat serum rapidly inhibited the platelet-aggregating activity of the venom; human serum, however, had only a partial inhibitory effect. Preliminary experiments showed that platelet-aggregating activity may be separated from fibrinogen-converting activity by anion-exchange chromatography.

Adult↗

PubMed1982

Spontaneous intracranial bleeding in hemorrhagic diathesis.

Eight patients with spontaneous intracranial bleeding secondary to hemophilia A, afibrinogenemia, and thrombocytopenia are described. The clinical picture was that of increased intracranial pressure of gradual onset with variable signs and symptoms. Both the hemostatic defect and the intracranial bleeding were proved by laboratory investigations and CT scanning. Mortality was 75% (six of eight patients). The two remaining patients recovered completely following combined medical and surgical treatment, and are alive and well.

Adolescent↗

PubMed1989

[Defibrination syndrome after snake bites].

A defibrination syndrome developed in two men (aged 51, and 29 years old) within two hours of having been bitten by vipers Echis carinatus and Agkistrodon halys, respectively. In both the syndrome was characterized by afibrinogenemia with prolongation of the thrombin time, presence of fibrin monomers and split products of fibrinogen. Haemorrhagic signs included oral mucosa bleeding and macrohematuria. Specific serum was administered 9 and 16 hours, respectively, after the bite and achieved normalization of all clotting values within 48 hours.

Adult↗

PubMed2006

Inherited abnormalities of fibrinogen: 10-year clinical experience of an Italian group.

Inherited abnormalities of fibrinogen present a high variability in penetrance and expressivity, and clinical manifestations vary from severe bleeding or thrombosis to asymptomatic This variability makes clinical and genetic counseling more difficult. We report the experience of a clinical group working in specialist centers in Southern Italy on a series of consecutive patients presenting with congenital abnormalities of fibrinogen. Over 10 years, 18 patients were diagnosed to carry a congenital abnormality of fibrinogen. These patients and 26 first-degree relatives were investigated in-depth to fully characterize the nature of their abnormal fibrinogen levels. A gene mutation was identified in 15 patients (four afibrinogenemic patients, three hypofibrinogenemic patients, and eight dysfibrinogenemic patients). A new mutation was found in four of them: Aalpha Arg159Stop in one afibrinogenemic patient, Aalpha Arg104Cys in two hypofibrinogenemic patients, and Aalpha Pro270Thr in one dysfibrinogenemic patient. While all afibrinogenemic patients had clinically important bleeding, participants presenting with hypofibrinogenemia remained asymptomatic. In the presence of the synthesis of an abnormal molecule, the clinical phenotype was not strictly related to plasma fibrinogen levels but was associated with the molecular defect, most carriers remaining asymptomatic. Personal and family histories of bleeding and thrombosis are important for the clinical management of patients presenting with congenital abnormalities of fibrinogen. Biochemical and genetic investigations may be a useful guide for decision-making, providing additional steps in the assessment of the risk of patients presenting with low levels of a normal molecule (hypofibrinogenemia and afibrinogenemia) and with an abnormal molecule (dysfibrinogenemia), respectively.

Adolescent↗

PubMed1979

Inherited bleeding syndromes in Jordan.

This paper presents data on the occurrence and pattern of inherited bleeding syndromes (IBS) in Jordan, a hitherto unexplored problem. In 1978, during the first 12 months of a prospective study at a major medical center, 91 patients from 51 families were diagnosed as having IBS. All patients were referred because of moderate-to-severe bleeding diatheses; they included 52 hemophiliacs, 27 patients with von Willebrand's disease, 4 with hemophilia B (IX-deficit), 2 with afibrinogenemia, 1 with prothrombin deficiency, and 4 were thought to have platelet dysfunction. The clinical and laboratory features of the patients observed in Jordan do not seem to be significantly different from those of patients in Western Europe or North America.

Adolescent↗

PubMed2006

A novel fibrinogen Bbeta chain frameshift mutation in a patient with severe congenital hypofibrinogenaemia.

Congenital afibrinogenemia and severe hypofibrinogenemia are severe bleeding disorders characterized by either undetectable or very low levels of fibrinogen in patients' plasma and platelets. A majority of the reported cases are caused by mutations in the fibrinogen Aalpha chain. In this study, we identified a genetic defect in the fibrinogen Bbeta-chain (FGB) underlying severe hypofibrinogenemia. The propositus frequently displayed bleeding episodes with a prolonged blood-clotting time (thrombin time > 180 s, activated partial thromboplastin time > 300 s, prothrombin time > 120 s) and had a very low level of plasma fibrinogen (1.7-1.8 mg/dl). His parents had a consanguineous marriage, and their functional and immunological fibrinogen was approximately half of the normal level. The platelet fibrinogen level of the propositus could not be detected by western blotting, and his platelet aggregation was severely impaired. DNA screening of the whole fibrinogen gene revealed a homozygous GGGG-->GGG mutation at nucleotide 7,969-7,972 in his FGB gene. The propositus' parents are both heterozygous for this mutation. This mutation contributes to Gly419-->Val, and the 419-434 codons are frame shifted, and a stop codon is formed at codon 435. The predicted truncated Bbeta-chain is 27 amino acids shorter than the normal Bbeta-chain and a central beta-strand in the globular betaC domain is absent, which may lead to destabilization of the entire beta-domain. To the best of our knowledge, this is the first report of such a mutation which is associated with severe hypofibrinogenemia.

Adult↗

PubMed1996

Plasma fibrinogen inhibits platelets adhesion in flowing blood to immobilized fibrinogen.

The influence of variations in plasma fibrinogen concentration on platelet adhesion to immobilized fibrinogen was investigated in a parallel-plate perfusion chamber. At a shear rate of 1600 s-1 platelet adhesion decreased when increasing concentrations of purified fibrinogen were added to the plasma (IC50 = 1.5 +/- 0.2 g/L fibrinogen, n = 24). Washed platelets reconstituted in a human albumin solution with red blood cells were more sensitive for soluble fibrinogen (IC50 = 0.4 +/- 0.1 g/L, n = 5, P < .05). When platelet activation during circulation of the blood was minimized by using a single-passage perfusion system, an IC50 of 2.0 +/- 0.2 g/L was found (n = 9). To exclude the possibility that the inhibition of fibrinogen was caused by irreversible changes in the fibrinogen molecule during the purification procedure, normal plasma was mixed in different ratios with plasma from a patient with congenital afibrinogenemia. Under these conditions, the plasma fibrinogen IC50 was 1.5 +/- 1.1 g/L. Absence of endogenous fibrinogen in the platelets of the patient resulted in an IC50 of 1.2 +/- 0.5 g/L for plasma fibrinogen. These results demonstrate that increased plasma fibrinogen concentrations inhibit platelet adhesion to fibrinogen under flow.

Afibrinogenemia↗