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PubMed1999

Recurrent spontaneous intracerebral hemorrhage in a congenitally afibrinogenemic patient: diagnostic pitfalls and therapeutic options.

BACKGROUND: Coagulation disorders can cause intracerebral bleeding that may be difficult to detect since subsequent aberrant clot formation may mask early detection. This is an important pitfall because, when diagnosed early, bleeding in these patients is treatable. CASE DESCRIPTION: A patient with congenital afibrinogenemia presented with recurrent hemiparesis. Spontaneous intracerebral hemorrhage was diagnosed, despite an initial negative CT scan. Diagnosis, therapy, and complications of therapy are discussed. CONCLUSIONS: Intracerebral hemorrhage must be strongly suspected in any patient with a coagulation disorder presenting with matching clinical symptoms. Therapy must be installed immediately, before additional investigations, and should be continued even when initial neuroimaging is negative.

Afibrinogenemia↗

PubMed1989

Uptake of plasma fibrinogen into the alpha granules of human megakaryocytes and platelets.

The origin of platelet alpha-granule fibrinogen (Fg), whether from endogeneous synthesis or exogeneous derivation, remains unknown. Although Fg biosynthesis by megakaryocytes (MK) has been suggested, recent studies have demonstrated that certain alpha-granular proteins originate primarily from plasma. To study the origin of alpha-granule Fg, platelet-associated Fg was measured by ELISA and Western blotting, and localized by immunofluorescence and immunoelectron microscopy in a patient with symptomatic congenital afibrinogenemia before and after replacement therapy with cryoprecipitate. alpha-Granule Fg was detected in the majority of platelets as early as 24 h postinfusion, suggesting that direct platelet uptake was occurring. Platelet Fg reached a maximum value of 42.5% of normal values at 3 d postinfusion and was localized in the alpha-granules, while plasma levels followed a typical half-life profile. Significant alpha-granule Fg was still detectable at 13 d postinfusion, with plasma Fg virtually absent. Studies on cultured CFU-MKs from the patient also confirmed that MKs can incorporate exogeneous Fg into alpha-granules. These results indicate that platelet alpha-granule Fg can be derived from the circulating plasma pool and that Fg uptake can occur in both platelets and MKs.

Adult↗

PubMed1991

The role of von Willebrand factor and fibrinogen in platelet aggregation under varying shear stress.

Exposure of platelets to shear stress leads to aggregation in the absence of exogenous agonists. We have now found that different adhesive proteins and platelet membrane glycoproteins are involved in aggregation depending on the shear stress conditions and the concentration of divalent cations in the medium. When blood is collected with trisodium citrate as anticoagulant, which causes a decrease in the levels of external ionized calcium ([Ca2+]o), platelet aggregation can be induced under low shear force (12 dyn/cm2) and is mediated by fibrinogen binding to the glycoprotein IIb-IIIa complex. Aggregates formed under these conditions are not stable, and when shear force is increased to 68 dyn/cm2, disaggregation results. By contrast, platelets from blood collected with hirudin as anticoagulant, wherein [Ca2+]o is within normal plasma levels, do not undergo low shear-induced aggregation; however, after exposure to a shear force above 80 dyn/cm2, aggregation is observed but only when von Willebrand factor is present and can interact with both its platelet binding sites, glycoprotein Ib-IX and glycoprotein IIb-IIIa. Fibrinogen is not involved in high shear-induced aggregation which, in fact, occurs normally in patients with severe afibrinogenemia. Thus, von Willebrand factor in the absence of exogenous agonists can mediate platelet aggregation in experimental conditions that may mimic the hemorheological situation of partially occluded arteries. This pathway of platelet aggregation involving only one adhesive ligand and two membrane adhesion receptors may play a relevant role in thrombogenesis.

Afibrinogenemia↗

PubMed2002

Distinct and concerted functions of von Willebrand factor and fibrinogen in mural thrombus growth under high shear flow.

Using a perfusion chamber and confocal laser scanning microscopy, we analyzed the interplay of von Willebrand factor (VWF) and fibrinogen during thrombus growth on a collagen surface under physiologic high shear rate conditions. During initial thrombogenesis, platelet thrombi were constructed totally by VWF, not by fibrinogen. Fibrinogen accumulated predominantly inside the growing thrombi as a function of time, whereas the thrombus surfaces directly exposed to flow were occupied constantly by VWF throughout the observation period. In perfusion of afibrinogenemia (AF) blood lacking both plasma and platelet fibrinogen, the final height and volume of thrombi were significantly reduced compared with controls, albeit the area of surface coverage was normal. The impaired thrombus growth in AF was only partially corrected by the addition of purified fibrinogen to AF blood, whereas the addition of purified VWF to blood of severe von Willebrand disease (VWD) completely normalized the defective thrombus growth in this disease. Thus, the initial 2-dimensional thrombus expansion involves only VWF, whereas the time-dependent accumulation of fibrinogen, released from activated platelets, acts as a core adhesive ligand, increasing thrombus strength and height and resulting in 3-dimensional thrombus development against rapid blood flow.

Afibrinogenemia↗

PubMed2005

Maternal fibrinogen is necessary for embryonic development.

Fibrinogen (Fg) is a precursor of fibrin, which is one of the main components of blood clots generated during the hemostatic response. Beyond its important role in hemostasis, Fg is involving in several physiologic and pathophysiologic states, such as infection, wound healing, the progression of certain types of tumors, and the severity of atherosclerosis. In addition, Fg has a critical role in maintaining pregnancy. Ovulation, fertilization, and implantation of the fertilized egg to the uterine wall can occur in afibrinogenemic women. However, all pregnancies in these patients resulted in spontaneous miscarriage. Fg supplemental therapy allows the patients to sustain the pregnancy. Mice with a total fibrinogen deficiency (FG-/-) reproduce the human experience. Despite of successes with fibrinogen supplementation, "paradoxical thrombosis" sometimes occurs, wherein supplemental therapies cause catastrophic thrombosis, such as pulmonary and mesenteric venous thrombosis. In these therapies, syncytial knots, hyaline membrane, and multiple recent infarctions with abruptio placenta were also observed. These findings indicate that the dosage regimen of Fg in afibrinogenemia-related pregnancies needs to be optimized according to other coagulation markers, such as thrombin-antithrombin complex (TAT) concentration, which represents the extent of thrombin formation. In addition, baseline thrombin assays would be helpful to predict the potential for paradoxical thrombosis during the supplemental therapy offered during pregnancy.

Adult↗

PubMed1978

Reaction of blood with artificial surfaces of hemodialyzers. Studies of human blood with platelet defects or coagulation factor deficiencies.

Heparinized human blood was exposed to the dialysis membranes of commercially available pediatric size hemodialyzers in an in vitro flow circuit. Bloods from normal subjects and from patients with various blood coagulation and platelet function deficiencies were tested in this model system. In most cases, there was a heavy linear deposit of leukocytes on the dialysis membrane overlying support structures. In other areas, the cellular deposit was less uniform and consisted of single platelets, platelet aggregates, leukocytes, and occasional fibrocellular microthrombi. The number of adherent platelets was smaller in tests with blood from patients with congenital afibrinogenemia, factor XII deficiency, severe von Willebrand's disease, and thrombasthenia then in tests with blood from normal subjects or hemophilic patients. Hence, fibrinogen, factor XII, the von Willebrand factor, and a normal platelet plasma membrane appear necessary for adhesion of platelets to dialysis membranes.

Afibrinogenemia↗

PubMed2006

Fibrinogen Mumbai: intracellular retention due to a novel G434D mutation in the Bbeta-chain gene.

BACKGROUND AND OBJECTIVES: Afibrinogenemia and hypofibrinogenemia are rare inherited coagulation disorders characterized by hemorrhagic manifestations of variable entity and by plasma fibrinogen deficiency. So far, 57 mutations have been associated with these disorders, and 18 of these are missense mutations. The aim of this study was to characterize the molecular mechanism underlying severe hypofibrinogenemia in a proband from India. DESIGN AND METHODS: The mutational screening was accomplished by DNA sequencing of the three fibrinogen genes. The mutant protein was expressed in COS-1 cells, and intracellular and secreted mutant fibrinogen was analyzed by means of pulse-chase experiments. RESULTS: A novel homozygous G-->A transition in exon 8 (nucleotide position 8017) was found in the proband's fibrinogen Bbeta-chain gene. The resulting G434D missense mutation (fibrinogen Mumbai) involves a highly conserved amino acid residue, located in the C-terminal globular D domain. In vitro expression experiments demonstrated intracellular retention of the mutant fibrinogen and marked reduction of its secretion. INTERPRETATION AND CONCLUSIONS: The G434D substitution causes severe hypofibrinogenemia by impairing fibrinogen secretion. Expression data confirm the importance of Bbeta-chain D domain folding in the intracellular processing of fibrinogen.

Adult↗

PubMed1990

[A family with von Willebrand disease and hypofibrinogenemia].

A family with two complex disorders of hemostasis, von Willebrand disease (vWD) and hypofibrinogenemia was reported. The probands were 21- and 16-year-old full brothers suffering from serious bleeding tendencies from childhood. The elder brother had a subarachnoid hemorrhage at the age of 15. The younger brother had repeated episodes of gastrointestinal bleedings since he was 10 years of age. Coagulation studies revealed that both of them had almost the same hemostatic abnormalities, i.e. severe vWD, 9 to 12% of plasma vWF levels, and mild hypofibrinogenemia, 125 to 130 mg/dl of plasma fibrinogen levels. Multimeric compositions of their vWF were normal, and functional assay for fibrinogen concentration yielded essentially the same values as did immunologic assay. These results indicated that they had two complex disorders, extreme type I vWD and heterozygous state of afibrinogenemia resulting in serious bleeding tendency. Family study showed that these two hemostatic disorders were paternal inheritance, and it was strongly postulated that vWD and hypofibrinogenemia might be highly-combined hemostatic disorders.

Adolescent↗

PubMed1977

Inherited bleeding syndromes in Iraq.

This paper presents data on the occurence and pattern of inherited bleeding syndromes (IBS) in Iraq, a hitherto unexplored problem. During the first fourteen months of a prospective on-going study at a major university center, 116 patients from 62 families were diagnosed as having IBS. All patients were referred because of moderate to severe bleeding diatheses. They included 62 haemophiliacs 32 patients with von Willebrand's disease (VWD), 9 with Christmas disease (CD), 6 with afibrinogenemia, 1 with prothrombin deficiency, and 6 were thought to have platelet dysfunction. 32 other bleeders (16 hemophiliacs, 14 VWD, and 2 CD) were also recognized among the pedigrees studied but were not available for full investigations. The clinical and laboratory features of the patients observed in Iraq do not seem to be significantly different from those of patients in Western Europe or North America. Although the absolute incidence and relative distribution of these disorders in the entire population cannot yet be determined, the rate of occurence per segment population is likely to be high, most likely due to the high rate of consanguinity and large number of births per family, phenomena still prevalent in this country.

Adolescent↗

PubMed1984

Studies of the origin of platelet-associated fibrinogen.

Platelet membranes and whole platelet preparations were examined by crossed immunoelectrophoresis in normal individuals, in a patient with congenital afibrinogenemia, and in two unrelated patients with Glanzmann's thrombasthenia (types I and II) to study the origin of platelet-associated fibrinogen. Results indicate: (1) platelet and plasma fibrinogen are probably derived from the same gene product, (2) platelet fibrinogen is not derived from the surrounding plasma milieu, (3) under basal conditions, platelet fibrinogen is located only within the alpha-granules and not on the platelet surface, (4) addition of trypsin to fibrinogen uncovers either a neoantigen or a hidden pool of platelet fibrinogen in the alpha-granules, (5) platelets from two patients with Glanzmann's thrombasthenia contain near-normal quantities of fibrinogen.

Afibrinogenemia↗

PubMed1984

Congenital hemorrhagic disorders in Jordan.

The results of a three year prospective study of inherited bleeding syndromes in Jordan is presented. There were 112 patients from 64 families. Of these there were 42 patients with hemophilia A, 23 with Glanzmann's thrombasthenia, 22 with von Willebrand's disease, 11 with Christmas disease, 6 with hypofibrinogenemia, 3 with afibrinogenemia, 2 with factor XIII deficiency, 2 with storage pool disease and 1 with factor XI deficiency. The pattern of inherited bleeding syndromes in Jordan is different from that seen in Europe and U.S.A. in that Glanzmann's thrombasthenia is very common. High proportion of hemophiliacs were severe. Arthropathy was common. A significant number of bleeders had fatal hemorrhage. In a high proportion of patients, no family history of bleeding was found.

Adolescent↗

PubMed1982

Distribution of plasma fibronectin (cold-insoluble globulin) and components of the factor VIII complex after heparin-induced precipitation of plasma.

Factor VIII procoagulant (VIII:C) activity, factor VIII coagulant antigen (VIII:CAg), von Willebrand ristocetin cofactor (VIIIR:RC) activity, factor VIII-related antigen (VIIIR:Ag), and plasma fibronectin (CIg; cold-insoluble globulin) were measured in the heparin precipitable fraction (HPF) and heparin supernatant fraction (HS) of normal human plasma. Following heparin induced precipitation, most measurable VIII:C activity (77% +/- 24%) was recovered in the HS. Although there was little VIII:C activity (less than 1%) in the HPF, 20% +/- 6.5% VIII:CAg was present as well as CIg (81% +/- 5.6%). VIIIR:RC activity (72% +/- 12%), and VIIIR:Ag (34 +/- 5.2%). As assessed by Na dodecyl SO4 glyoxyl agarose electrophoresis, the multimeric forms of plasma VIIIR:Ag could be resolved into a series of bands. Larger multimers tended to precipitate with the HPF whereas the smaller multimers tended to remain supernatant. Plasma from a subject with congenital afibrinogenemia was also studied. Although the afibrinogenemic HPF contained CIg, neither VIIIR:RC activity nor VIIIR:Ag was precipitated. However, both were present in the HPF from afibrinogenemic plasma to which fibrinogen had been added, suggesting that they are incorporated in this precipitate because of an affinity for fibrinogen. The ability of heparin to induce precipitation of CIg while leaving most VIII:C activity in the supernatant plasma may be useful in the preparation of procoagulant-rich plasma subfractions, since VIII:C can subsequently be recovered in good yield by cryoprecipitation.

Afibrinogenemia↗

PubMed1980

Platelet interaction with bacteria. V. Ultrastructure of congenital afibrinogenemic platelets.

Platelets from a patient with congenital afibrinogenemia (CA) were tested in their native plasma for reactivity in vitro to Staphylococcus aureus 502A. Previous studies of the interactions between normal human platelets and this organism have shown rapid irreversible aggregation responses in which the bacteria were regularly trapped between aggregating platelets. Engulfment of microbes by single normal platelets in a process akin to phagocytosis was a very rare occurrence. In contrast, CA platelets showed a delayed aggregation response to contact with this microorganism. The CA platelets were also much more sensitive to the concentration of bacteria than were normal platelets. Electron microscopy showed that individual CA platelets often engulfed the stimulatory organism rather than participating in aggregation. Postfixation staining with a colloidal tracer, lanthanum nitrate, indicated that the bacteria were sequestered in the open canalicular system of the CA platelets in a manner analogous to that previously observed with latex particles. Restoration of normal levels of human fibrinogen to the CA platelet-rich plasma corrected the delay in aggregation but did not eliminate the frequent engulfment of bacteria by the CA platelets. These findings indicate that fibrinogen is an important, although not essential, cofactor in the response of human platelets to contact with this common bacterial pathogen.

Afibrinogenemia↗

PubMed1994

Reduced thrombus formation in native blood of homozygous factor VII-deficient patients at high arterial wall shear rate.

Inhibition of thrombin formation in flowing native blood reduces thrombus formation on subendothelium, dacron, or collagen fibrils at arterial wall shear rates of 450 to 650 s-1. In the present study, we have investigated the role of low levels of factor VII (FVII) in thrombus formation on collagen fibrils at arterial wall shear rates of 650 s-1 (coronary arteries), 2,600 s-1 (mildly stenosed arteries), and 10,510 s-1 (severely stenosed arteries) in parallel-plate perfusion chambers. In the perfusion chamber with the highest wall shear rate, thrombus formation took place at the apex of an eccentric stenosis, which reduced the cross-sectional area of the blood flow channel by 80%, thus simulating thrombus formation at an atherosclerotic plaque rupture. Native blood from 21 healthy volunteers and 12 homozygous FVII-deficient patients was drawn by a pump directly from an antecubital vein over a surface of fibrillar collagen positioned in the respective perfusion chambers. The patients had FVII coagulant activities ranging from 1.3% to 4.5% and FVII antigen levels of 16% to 23% of normal. Immunoaffinity purification of the patients' FVII followed by electrophoresis (sodium dodecyl sulfate-polyacrylamide gel electrophoresis [SDS-PAGE]) and immunoblotting showed a protein with similar molecular mass as normal FVII. In the perfusion studies, a reduction in thrombus volume of 54% of normal (P < .007) at 10,510 s-1 was observed. The deposition of fibrin on the thrombogenic surface and the plasma level of fibrinopeptide A (FPA) in blood samples collected distal to the perfusion chamber were concomitantly reduced (P < .002 and P < .04, respectively). The plasma FPA level was also reduced at 2,600 s-1 (P < .04), but not at 650 s-1. However, at the lower shear conditions, the thrombus volume and the fibrin deposition were within the ranges observed in normal blood. The platelet-collagen adhesion was not affected at any of the three shear conditions. Thus, low plasma levels of FVII result in significantly less formation of thrombin and fibrin in and around growing platelet masses at high shear condition. This may weaken the thrombus stability and reduce platelet recruitment, thereby lowering thrombus volume. In support of this theory, one patient with afibrinogenemia had an 83% reduction in thrombus volume at this high shear condition.

Afibrinogenemia↗

PubMed1993

[Unexpectedly prolonged thrombin time].

The thrombin time assay is able to detect abnormalities of the terminal phase of plasmatic coagulation. The differential diagnosis of thrombin time prolongation includes (1) inhibition of the added thrombin by exogenous heparin or endogenous heparin-like anticoagulant, seldom by acquired antibovine thrombin antibodies, (2) qualitative fibrinogen disorders (congenital and acquired dysfibrinogemia, (3) quantitative fibrinogen disorders (hypo- and afibrinogenemia), and (4) delayed fibrin polymerization due to fibrin/fibrinogen degradation products, paraproteins or seldom acquired antibodies against fibrinogen.

Adult↗

PubMed1977

[A family with hereditary hypofibrinogenemia].

A family with congenital hypofibrinogenemia (fibrinogen levels of 60-90 mg%) has been studied. Out of 19 members tested, 11 exhibit this trait, which follows a strictly autosomal-dominant pattern of inheritance. Congenital hypofibrinogenemia appears to be a separate entity which can be distinguished from heterozygous individuals of congenital afibrinogenemia and from congenital dysfibrinogenemia. A bleeding tendency of clinical significance is observed only during major surgery or after severe injury.

Adolescent↗

PubMed2003

Acute abdomen as first symptom of acute leukemia.

CASE REPORT: The authors presented a rare case of acute abdomen syndrome caused by the rupture of the corpus rubrum as the first symptom in a 35-years-old woman with the acute lymphatic leukemia. During the laparotomy is notice diffuse bleeding from under skin blood vessels and muscles. The blood was electrocoagulated and was sewn with catgut sutures. The right ruptured corpus rubrum was found from which fresh blood was leaking. The right ovary was carefully resected and sutured, and each ligature was bleeding. At the beginning of the surgery laboratory analysis results arrived which showed a high leukocytosis (28.0 x 10(9)/l) with sever thrombocytopenia (10 x 10(9)/l) and afibrinogenemia (0.1 g/l) with anemia (1.9 x 10(12)/l erythrocyte, haematocrit 0.24), which indicated leukemia with disseminated intravascular coagulopathy (antithrombin III levels 0.9 g/l, D-dimers 1989 micro g/l). RESULT. A year later she died with the picture of severe disseminated intravascular coagulopathy, agranulocytosis and septic condition with multiorganic failure.

Abdomen, Acute↗

PubMed1987

Pulmonary fibrin deposition and increased microvascular permeability to protein following fibrin microembolism in dogs: a structure-function relationship.

The effects of fibrin microembolism were examined using an infusion of a prothrombin activator (Echis carinatus venom, ECV; 30 min, 0.5 NIH thrombin equivalent units/kg) in acute mongrel dogs prepared with a pulmonary lymph cannula (n = 6, 12.3-21.5 kg). Lymph flow increased approximately 2.5-fold after 1-1.5 hr of elevated left atrial pressure (Pla = 20 cm H2O; 26 +/- 7 to 63 +/- 16 microliter/min, P less than 0.01) and the plasma to lymph protein concentration ratio (CP/CL) declined from 0.66 +/- .04 to 0.54 +/- .16 (P less than 0.01, x +/- SE). After Pla was reduced to control levels, the initiation of fibrin microembolism was associated with an approximate 2.7-fold elevation of lymph flow (62 +/- 8 microliters/min, P less than 0.01) and the CP/CL was not changed (0.56 +/- 0.04, P = ns). When Pla was increased following microembolism, lymph flow more than doubled to 117 +/- 24 microliter/min (P less than 0.01) and the CP/CL remained unaltered (0.56 +/- 0.03, P = ns). These changes were associated with afibrinogenemia and the appearance of fibrin degradation products (FDP) in plasma (150 +/- 50 micrograms/ml) and lymph (80 micrograms/ml) in three of the animals tested. No consistent pattern was seen in the CL/CP of separate endogenous plasma proteins after each intervention. These data support the view that pulmonary fibrin microembolism without inhibition of the fibrinolytic system was associated with an early increased pulmonary microvascular permeability to protein. In a separate group of similarly prepared animals (n = 8, 13-21.5 kg) without a lymph catheter, scanning electron microscopic observations showed branching fibrin microemboli to partially occlude some pulmonary arterioles. Mixed thrombus formations in larger precapillary blood vessels were also seen. Ultrastructural observations revealed the deposition of fibrin strands (periodicity = 220-230 A) within the pulmonary capillaries. Some of these deposits were overlaid by lamellar pseudopodia from endothelial cells and the fibrin appeared to be within these cells. Although plasmalemmal vesicles seemed to be more numerous in the endothelial cells with adjacent fibrin deposits, no gaps or breaks were seen in the densely stained interendothelial cell junctions and/or the endothelial cell membrane of the affected lung capillaries. Activated neutrophils and platelets were more numerous in the pulmonary capillaries following EVC. These data suggest that the presence of FDP and/or fibrin deposits within the pulmonary microvasculature may influence the early functional integrity of pulmonary endothelial cells at sites of fibrin accumulation.

Animals↗