Bleeding diathesis after aortic valve operation and ascending aorta replacement (AV–AA) is managed with fresh-frozen plasma (FFP) and platelet concentrates. The aim was to compare haemostatic effects of conventional transfusion management and FIBTEM (thromboelastometry test)-guided fibrinogen concentrate administration.
A blood products transfusion algorithm was developed using retrospective data from 42 elective patients (Group A). Two units of platelet concentrate were transfused after cardiopulmonary bypass, followed by 4 u of FFP if bleeding persisted, if platelet count was ≤100×103 µl−1 when removing the aortic clamp, and vice versa if platelet count was >100×103 µl−1. The trigger for each therapy step was ≥60 g blood absorbed from the mediastinal wound area by dry swabs in 5 min. Assignment to two prospective groups was neither randomized nor blinded; Group B (n=5) was treated according to the algorithm, Group C (n=10) received fibrinogen concentrate (Haemocomplettan® P/Riastap, CSL Behring, Marburg, Germany) before the algorithm-based therapy.
A mean of 5.7 (0.7) g fibrinogen concentrate decreased blood loss to below the transfusion trigger level in all Group C patients. Group C had reduced transfusion [mean 0.7 (range 0–4) u vs 8.5 (5.3) in Group A and 8.2 (2.3) in Group B] and reduced postoperative bleeding [366 (199) ml vs 793 (560) in Group A and 716 (219) in Group B].
In this pilot study, FIBTEM-guided fibrinogen concentrate administration was associated with reduced transfusion requirements and 24 h postoperative bleeding in patients undergoing AV–AA.
blood, coagulation; measurement techniques, thrombelastograph; surgery, cardiovascular; transfusion
The appropriate strategy for trauma-induced coagulopathy management is under debate. We report the treatment of major trauma using mainly coagulation factor concentrates.
This retrospective analysis included trauma patients who received ≥ 5 units of red blood cell concentrate within 24 hours. Coagulation management was guided by thromboelastometry (ROTEM®). Fibrinogen concentrate was given as first-line haemostatic therapy when maximum clot firmness (MCF) measured by FibTEM (fibrin-based test) was <10 mm. Prothrombin complex concentrate (PCC) was given in case of recent coumarin intake or clotting time measured by extrinsic activation test (EXTEM) >1.5 times normal. Lack of improvement in EXTEM MCF after fibrinogen concentrate administration was an indication for platelet concentrate. The observed mortality was compared with the mortality predicted by the trauma injury severity score (TRISS) and by the revised injury severity classification (RISC) score.
Of 131 patients included, 128 received fibrinogen concentrate as first-line therapy, 98 additionally received PCC, while 3 patients with recent coumarin intake received only PCC. Twelve patients received FFP and 29 received platelet concentrate. The observed mortality was 24.4%, lower than the TRISS mortality of 33.7% (P = 0.032) and the RISC mortality of 28.7% (P > 0.05). After excluding 17 patients with traumatic brain injury, the difference in mortality was 14% observed versus 27.8% predicted by TRISS (P = 0.0018) and 24.3% predicted by RISC (P = 0.014).
ROTEM®-guided haemostatic therapy, with fibrinogen concentrate as first-line haemostatic therapy and additional PCC, was goal-directed and fast. A favourable survival rate was observed. Prospective, randomized trials to investigate this therapeutic alternative further appear warranted.
Thromboelastometry (TEM)-guided haemostatic therapy with fibrinogen concentrate and prothrombin complex concentrate (PCC) in trauma patients may reduce the need for transfusion of red blood cells (RBC) or platelet concentrate, compared with fresh frozen plasma (FFP)-based haemostatic therapy.
This retrospective analysis compared patients from the Salzburg Trauma Centre (Salzburg, Austria) treated with fibrinogen concentrate and/or PCC, but no FFP (fibrinogen-PCC group, n = 80), and patients from the TraumaRegister DGU receiving ≥ 2 units of FFP, but no fibrinogen concentrate/PCC (FFP group, n = 601). Inclusion criteria were: age 18-70 years, base deficit at admission ≥2 mmol/L, injury severity score (ISS) ≥16, abbreviated injury scale for thorax and/or abdomen and/or extremity ≥3, and for head/neck < 5.
For haemostatic therapy in the emergency room and during surgery, the FFP group (ISS 35.5 ± 10.5) received a median of 6 units of FFP (range: 2, 51), while the fibrinogen-PCC group (ISS 35.2 ± 12.5) received medians of 6 g of fibrinogen concentrate (range: 0, 15) and 1200 U of PCC (range: 0, 6600). RBC transfusion was avoided in 29% of patients in the fibrinogen-PCC group compared with only 3% in the FFP group (P< 0.001). Transfusion of platelet concentrate was avoided in 91% of patients in the fibrinogen-PCC group, compared with 56% in the FFP group (P< 0.001). Mortality was comparable between groups: 7.5% in the fibrinogen-PCC group and 10.0% in the FFP group (P = 0.69).
TEM-guided haemostatic therapy with fibrinogen concentrate and PCC reduced the exposure of trauma patients to allogeneic blood products.
The kinetics of the depletion of plasma fibrinogen were studied in seven patients who received fibrinogen-131I 1 hr before an intravenous injection of the coagulating enzyme (CE) derived from the venom of the pit viper, Agkistrodon rhodostoma. Disappearance of the clottable radioactivity labeled fibrinogen from the circulation conformed to an exponential decay with an average half-life of 0.85 hr. The mean clearance rate for protein-bound radioactivity, composed of fibrinogen and it's split products, was 12% of the intravascular pool per hour. The breakdown products of fibrin produced by CE inhibited polymerization of fibrin in vitro.
Studies in five patients performed between the 3rd and 10th day following the administration of CE revealed that the absolute catabolic rates of fibrinogen were subnormal initially, but gradually increased as the fibrinogen concentration returned to normal.
In rabbits, after the administration of CE, regeneration of the fibrinogen pool was markedly prolonged. This delayed regeneration time was not influenced by an excess of antivenene, but rapid regeneration to pretreatment values of plasma fibrinogen was immediately initiated by stimulating fibrinogen synthesis with subcutaneous turpentine.
Postpartum haemorrhage (PPH) remains a leading cause of maternal mortality worldwide. In Denmark 2% of parturients receive blood transfusion. During the course of bleeding fibrinogen (coagulation factor I) may be depleted and fall to critically low levels, impairing haemostasis and thus worsening the ongoing bleeding. A plasma level of fibrinogen below 2 g/L in the early phase of postpartum haemorrhage is associated with subsequent development of severe haemorrhage. Use of fibrinogen concentrate allows high-dose substitution without the need for blood type crossmatch. So far no publications of randomised controlled trials involving acutely bleeding patients in the obstetrical setting have been published. This trial aims to investigate if early treatment with fibrinogen concentrate reduces the need for blood transfusion in women suffering severe PPH.
In this randomised placebo-controlled double-blind multicentre trial, parturients with primary PPH are eligible following vaginal delivery in case of: manual removal of placenta (blood loss ≥ 500 ml) or manual exploration of the uterus after the birth of placenta (blood loss ≥ 1000 ml). Caesarean sections are also eligible in case of perioperative blood loss ≥ 1000 ml. The exclusion criteria are known inherited haemostatic deficiencies, prepartum treatment with antithrombotics, pre-pregnancy weight <45 kg or refusal to receive blood transfusion. Following informed consent, patients are randomly allocated to either early treatment with 2 g fibrinogen concentrate or 100 ml isotonic saline (placebo). Haemostatic monitoring with standard laboratory coagulation tests and thromboelastography (TEG, functional fibrinogen and Rapid TEG) is performed during the initial 24 hours.
Primary outcome is the need for blood transfusion. To investigate a 33% reduction in the need for blood transfusion, a total of 245 patients will be included. Four university-affiliated public tertiary care hospitals will include patients during a two-year period. Adverse events including thrombosis are assessed in accordance with International Conference on Harmonisation (ICH) good clinical practice (GCP).
A widespread belief in the benefits of early fibrinogen substitution in cases of PPH has led to increased off-label use. The FIB-PPH trial is investigator-initiated and aims to provide an evidence-based platform for the recommendations of the early use of fibrinogen concentrate in PPH.
Postpartum haemorrhage; Haemostasis; Blood transfusion; Fibrinogen concentrate; Obstetrics; Thrombelastography; Coagulation
Fibrinogen concentrations were determined in normal plasma and in plasma from patients with high and low levels. There was a good correlation between the results of a rapid semi-quantitative fibrinogen titre technique and those of a quantitative assay of coagulable fibrinogen. In normal subjects fibrinogen levels were not significantly influenced by taking blood into epsilon aminocaproic acid (EACA) or by the addition of protamine to plasma. In patients with the defibrination syndrome in whom increased plasma fibrinolysis was not detected, fibrinogen levels were not affected by taking blood into EACA but considerably increased levels were observed after the addition of protamine to plasma. In patients undergoing thrombolytic therapy the fibrinogen levels measured were increased both in blood taken into EACA and in plasma containing protamine. It is suggested that EACA acted by preventing lysis in vitro whilst protamine counteracted abnormal fibrin polymerization. The pattern of results may be of diagnostic importance.
Haemostatic therapy in surgical and/or massive trauma patients typically involves transfusion of fresh frozen plasma (FFP). Purified human fibrinogen concentrate may offer an alternative to FFP in some instances. In this systematic review, we investigated the current evidence for the use of FFP and fibrinogen concentrate in the perioperative or massive trauma setting.
Studies reporting the outcome (blood loss, transfusion requirement, length of stay, survival and plasma fibrinogen level) of FFP or fibrinogen concentrate administration to patients in a perioperative or massive trauma setting were identified in electronic databases (1995 to 2010). Studies were included regardless of type, patient age, sample size or duration of patient follow-up. Studies of patients with congenital clotting factor deficiencies or other haematological disorders were excluded. Studies were assessed for eligibility, and data were extracted and tabulated.
Ninety-one eligible studies (70 FFP and 21 fibrinogen concentrate) reported outcomes of interest. Few were high-quality prospective studies. Evidence for the efficacy of FFP was inconsistent across all assessed outcomes. Overall, FFP showed a positive effect for 28% of outcomes and a negative effect for 22% of outcomes. There was limited evidence that FFP reduced mortality: 50% of outcomes associated FFP with reduced mortality (typically trauma and/or massive bleeding), and 20% were associated with increased mortality (typically surgical and/or nonmassive bleeding). Five studies reported the outcome of fibrinogen concentrate versus a comparator. The evidence was consistently positive (70% of all outcomes), with no negative effects reported (0% of all outcomes). Fibrinogen concentrate was compared directly with FFP in three high-quality studies and was found to be superior for > 50% of outcomes in terms of reducing blood loss, allogeneic transfusion requirements, length of intensive care unit and hospital stay and increasing plasma fibrinogen levels. We found no fibrinogen concentrate comparator studies in patients with haemorrhage due to massive trauma, although efficacy across all assessed outcomes was reported in a number of noncomparator trauma studies.
The weight of evidence does not appear to support the clinical effectiveness of FFP for surgical and/or massive trauma patients and suggests it can be detrimental. Perioperatively, fibrinogen concentrate was generally associated with improved outcome measures, although more high-quality, prospective studies are required before any definitive conclusions can be drawn.
Afibrinogenemia is a rare bleeding disorder with an estimated prevalence of 1:1,000,000. It is an autosomal recessive disease resulting from mutations in any of the 3 genes that encode the 3 polypeptide chains of fibrinogen and are located on the long arm of chromosome 4. Spontaneous bleeding, bleeding after minor trauma and excessive bleeding during interventional procedures are the principal manifestations. We review the management of afibrinogenemia. Replacement therapy is the mainstay of treatment of bleeding episodes in these patients and plasma-derived fibrinogen concentrate is the agent of choice. Cryoprecipitate and fresh frozen plasma are alternative treatments that should be used only when fibrinogen concentrate is not available. Secondary prophylactic treatment may be considered after life-threatening bleeding whereas primary prophylactic treatment is not currently recommended. We also discuss alternative treatment options and the management of surgery, pregnancy and thrombosis in these patients. The development of new tests to identify higher risk patients and of safer replacement therapy will improve the management of afibrinogenemia in the future.
afibrinogenemia; fibrinogen concentrate; cryoprecipitate; fresh frozen plasma; rare bleeding disorders
The fibrinogen beta-chain (FGB) -C148T polymorphism is linked with plasma fibrinogen concentration in the general population. We examined whether the -C148T polymorphism is associated with pre- and early postoperative levels of fibrinogen, C-reactive protein (CRP), and interleukin-6 (IL-6) in 243 consecutive patients undergoing coronary artery bypass grafting (CABG) surgery. Plasma inflammatory markers were measured prior to and 5–7 days after surgery. The -C148T polymorphism was analyzed with the restriction fragment-length polymorphism method. The genotype distribution was as follows: CC—142 (58%), CT—85 (35%), and TT—16 (7%). Carriers of the -148T allele had higher preoperative plasma fibrinogen (4.42 ± 0.14 vs. 4.07 ± 0.11 mg/L, p = 0.04) and CRP levels (7.49 ± 1.2 vs. 4.26 ± 1.0 mg/L, p = 0.04) compared with non-carriers; 5 to 7 days after CABG, patients carrying -148T allele had increased CRP (70.4 ± 5.0 vs. 51.6 ± 4.25 mg/L, p = 0.005) and IL-6 levels (22.34 ± 2.64 vs. 15.53 ± 2.28 pg/L, p = 0.05), but not fibrinogen, compared with the remaining subjects. In-hospital nonfatal stroke occurred more frequently in -148T allele carriers (4% vs. 0%, p = 0.02). No genotype-associated differences were found in the occurrence of postoperative myocardial infarction and death. Presence of the -148T allele has also been associated with longer intensive care stay and intubation time (p = 0.01). Multivariate analysis identified the CT+TT genotype as an independent predictor of pre- and postoperative CRP levels. The results indicate that the presence of the -148T FGB allele determines higher pre- and postoperative levels of inflammatory markers, which might be associated with in-hospital clinical outcomes.
CABG; -C148T FGB polymorphism; inflammation; CRP; fibrinogen; IL-6
Disseminated intravascular coagulation causes thrombotic tendency leading to multiple organ failure and occurs in a wide variety of diseases including malignancy. Disseminated intravascular coagulation is a latent complication in people with prostate cancer.
A 51-year-old Japanese man with advanced castration-resistant prostate cancer was admitted to our hospital because of extensive purpura and severe anemia. Prolonged plasma coagulation time, hypofibrinogenemia and normal platelet count suggested that a decrease in fibrinogen induced a bleeding tendency causing purpura. However, elevated plasma levels of thrombin-antithrombin complex, fibrin and/or fibrinogen degradation products and D-dimers, with positive fibrin monomer test, manifested disseminated intravascular coagulation and subsequent fibrinolysis. Plasma levels of thrombin-antithrombin complex, fibrin and/or fibrinogen degradation products and D-dimers decreased after administration of low-molecular-weight heparin. However, low fibrinogen and α2-antiplasmin levels were not improved and plasmin-antiplasmin complex did not decrease, which revealed excessive fibrinolysis complicated with disseminated intravascular coagulation. We suspected that prostate cancer cell-derived urokinase-type plasminogen activator caused excessive fibrinolysis. Administration of tranexamic acid for fibrinogenolysis was added together with high-dose anti-androgen therapy (fosfestrol) for prostate cancer. Thereafter, prostate-specific antigen and plasmin-antiplasmin complex decreased, followed by normalized fibrinogen and α2-antiplasmin levels, and the patient eventually recovered from the bleeding tendency. Immunohistochemical staining of the biopsied prostate tissue exhibited that the prostate cancer cells produced tissue factor, the coagulation initiator, and urokinase-type plasminogen activator.
This patient with rare complications of disseminated intravascular coagulation and excessive fibrinolysis is a warning case of potential coagulation disorder onset in patients with prostate cancer. We propose that combined administration of tranexamic acid and low-molecular-weight heparin together with high-dose anti-androgen therapy is a useful therapeutic option for patients with this complicated coagulation disorder.
Castration-resistant prostate cancer; Disseminated intravascular coagulation; Excessive fibrinolysis; Low-molecular-weight heparin; Tranexamic acid
Simultaneous studies of albumin and fibrinogen metabolism have been conducted using the carbonate-14C method before and after a 13 day course of prednisolone in eight patients with hepatocellular disease. Initially six patients were hypoalbuminemic. The mean plasma albumin and fibrinogen concentrations and albumin and fibrinogen synthetic rates were all lower than the corresponding values in a group of control subjects. Prednisolone therapy was associated with significant increases in the plasma concentration and synthetic rate of albumin but changes in the intravascular albumin pools were not significant. It is inferred that a low synthetic rate of albumin in a patient with liver disease does not necessarily represent the maximum capacity of the diseased liver to synthesize this protein. Changes in the plasma concentration, intravascular pool, and synthetic rate of fibrinogen were small and inconsistent. The data are compatible with a selective action of corticosteroids on hepatic protein metabolism and with the existence of different mechanisms for the control of albumin and fibrinogen synthesis.
To analyse the correlation between pre-treatment plasma fibrinogen levels and clinical–pathological parameters in patients with endometrial cancer and to assess the value of plasma fibrinogen as a prognostic parameter.
Within a retrospective multi-centre study, the records of 436 patients with endometrial cancer were reviewed and pre-treatment plasma fibrinogen levels were correlated with clinical–pathological parameters and patients' survival.
The mean (s.d.) pre-treatment plasma fibrinogen level was 388.9 (102.4) mg per 100 ml. Higher plasma fibrinogen levels were associated with advanced tumour stage (FIGO I vs II vs III and IV, P=0.002), unfavourable histological subtype (endometrioid vs non-endometrioid histology, P=0.03), and higher patients' age (⩽67 years vs >67 years, P=0.04), but not with higher histological grade (G1 vs G2 vs G3, P=0.2). In a multivariate analysis, tumour stage (P<0.001 and P<0.001), histological grade (P=0.009 and P=0.002), patients' age (P=0.001 and P<0.001), and pre-treatment plasma fibrinogen levels (P=0.04 and P=0.02) were associated with disease-free and overall survival, respectively.
Plasma fibrinogen levels can be used as an independent prognostic parameter for the disease-free and overall survival of patients with endometrial cancer.
fibrinogen; endometrial cancer; prognosis
The aim of the present study was to evaluate plasma total homocysteine (Hcys) and serum fibrinogen concentrations in subclinical hypothyroid (SH) and overt hypothyroid patients before and after L-thyroxine (LT4) replacement and to compare them in euthyroid subjects. Fifteen SH and 20 hypothyroid premenopausal women were recruited in the study. We measured fasting plasma levels of Hcys and serum levels of free thyroxine (fT4), free triiodothyronine (fT3), thyrotropin (TSH), folate, vitamin B12, fibrinogen, renal functions, and lipid profiles in patients with SH and overt hypothyroid patients before and after LT4 treatment. Eleven healthy women were included in the study as a control group. Pretreatment Hcys levels were similar in SH and control subjects, whereas mean fibrinogen level of SH patients was higher than that of control subjects (p<0.05). Baseline Hcys (p<0.01) and fibrinogen (p<0.001) levels of the overt hypothyroid patients were significantly higher than those of the healthy subjects, and the pretreatment Hcys levels decreased with LT4 treatment (p<0.001). In conclusion, our data support that SH is not associated with hyperhomocysteinemia and Hcys does not appear to contribute to the increased risk for atherosclerotic disease in patients with SH.
Hypothyroidism; Homocysteine and Fibrinogen
A 17 yr old female with a congenital bleeding disorder was found to suffer from dysfibrinogenemia. Whole blood and plasma coagulation times were delayed and thrombelastograms were grossly abnormal. Clottability of plasma fibrinogen by addition of thrombin was not demonstrated during the 30 min test period. Fibrinogen was revealed by turbidometric and immunologic techniques. Other coagulation factors were present in normal amounts and prothrombin activation was normal. Patient's plasma inhibited thrombin clotting times of normal plasma and purified normal fibrinogen. Fibrinolysis was not detected.
The plasma fibrinogen migrated normally on paper and cellulose acetate electrophoresis, but on immunoelectrophoresis it displayed a faster mobility than normal fibrinogen. On immunodiffusion the antigenic determinants were similar to those of normal fibrinogen. The patient's fibrinogen-antifibrinogen precipitins required longer to appear and the resultant precipitin was broader and hazier than those elicited with normal fibrinogen. These findings suggest the presence of two discrete populations of fibrinogen molecules.
Investigation of the family of the patient suggested that the defect has an autosomal dominant pattern of heredity. Immunologic comparisons of our patient's plasma and of her relatives with plasma of patients with “Fibrinogen Baltimore” and “Fibrinogen Cleveland” revealed certain differences in immunoelectrophoretic mobility as well as in immunodiffusion. In keeping with the nomenclatures of abnormal fibrinogens in the literature, we propose the term “Fibrinogen Detroit” for this fibrinogen.
Physicochemical properties of “Fibrinogen Detroit” were investigated also and compared with those of normal fibrinogen. Purified normal fibrinogen (clottability 96.7%) and “Fibrinogen Detroit” revealed homogeneity when studied by ultracentrifugation and immunoelectrophoresis. Native and cleaved “Fibrinogen Detroit” had the same sedimentation constants and molecular weights as the normal. In fresh samples. 3 moles of free SH groups/mole of fibrinogen were titrated in both. Determination of the amino acid composition revealed a decreased content of lysine, glucosamine, and galactosamine in abnormal fibrinogen. Total carbohydrates, protein-bound hexoses, sialic acid, and hexosamine were decreased in the abnormal fibrinogen.
In an investigation with Doctors Blombäck a specific molecular defect was revealed in the N-terminal disulfide knot of the alpha (A) chain in which the arginine at the 19th position was replaced by serine. It is believed that the substitution of a strongly basic amino acid with a neutral hydroxy acid may result in considerable conformational changes in the N-terminal disulfide knot of fibrinogen which might affect the “active site” for polymerization. The lower carbohydrate content observed in “Fibrinogen Detroit” may have been the result of a change in primary and tertiary structure of the protein.
Twenty-two patients with acute hepatic failure were studied to determine the incidence and magnitude of intravascular coagulation and fibrinolysis and their relation to the severity of bleeding and prognosis. The mean platelet count, Thrombotest, plasminogen activator, and plasminogen were reduced; the reduction in fibrinogen was not statistically significant. Fibrin/fibrinogen degradation products were only moderately increased. Hepatic fibrin deposition was not extensive, being present in 11 of 22 hepatic sections, more in areas of confluent necrosis than in the sinusoids. The combination of increased fibrin/fibrinogen degradation products with decreased plasminogen activator, plasminogen, and thrombocytopenia is consistent with a diagnosis of intravascular coagulation and secondary local fibrinolysis. However, neither of these processes was severe. Severity of bleeding was related only to plasminogen levels and prognosis only to Thrombotest levels. There was no relation between hepatic histological and haematological findings. Heparin therapy is not indicated in the routine management of acute hepatic failure, as intravascular coagulation is not severe and heparin may itself cause massive bleeding.
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 ∼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.
The rate of clotting and the rate of development and degree of turbidity after addition of thrombin to plasma or purified fibrinogen from a patient with fibrinogen Baltimore was delayed when compared with normal, especially in the presence of low concentrations of thrombin. Optimal coagulation and development of translucent, rather than opaque, clots occurred at a lower pH with the abnormal fibrinogen than with normal. Development of turbidity during clotting of the abnormal plasma or fibrinogen was less than normal at each pH tested, but was maximal in both at approximately pH 6.4. The physical quality of clots formed from fibrinogen Baltimore was abnormal, as demonstrated by a decreased amplitude on thromboelastography. The morphologic appearance of fibrin strands formed from fibrinogen Baltimore by thrombin at pH 7.4 was abnormal when examined by phase contrast or electron microscopy, but those formed by thrombin at pH 6.4 or by thrombin and calcium chloride were similar to, though less compact, than normal fibrin. The periodicity of fibrin formed from fibrinogen Baltimore was similar to normal and was 231-233 Å.
A study of the release of the fibrinopeptides from the patient's fibrinogen and its chromatographic subfractions verified the existence of both a normally behaving and a defective form of fibrinogen in the patient's plasma. The defective form differed from normal in three functionally different ways: (a) the rate of release of fibrinopeptides A and AP was slower than normal; (b) no visible clot formation accompanied either partial or complete release of the fibrinopeptides from the defective form in 0.3 M NaCl at pH 7.4; and (c) the defective component possessed a high proportion of phosphorylated, relative to nonphosphorylated, fibrinopeptide A, while the coagulable component contained very little of the phosphorylated peptide (AP). The high phosphate content of the defective component did not appear to be the cause of the abnormality, but may be the result of an associated metabolic or genetic phenomenon.
Massive bleeding and transfusion of packed red blood cells (PRBC), fresh frozen plasma (FFP) and platelets are associated with increased morbidity, mortality and costs.
Patients and Methods
We analysed the transfusion requirements after implementation of point-of-care (POC) coagulation management algorithms based on early, calculated, goal-directed therapy with fibrinogen concentrate and prothrombin complex concentrate (PCC) in different perioperative settings (trauma surgery, visceral and transplant surgery (VTS), cardiovascular surgery (CVS) and general and surgical intensive care medicine) at 3 different hospitals (AUVA Trauma Centre Salzburg, University Hospital Innsbruck and University Hospital Essen) in 2 different countries (Austria and Germany).
In all institutions, the implementation of POC coagulation management algorithms was associated with a reduction in the transfusion requirements for FFP by about 90% (Salzburg 94%, Innsbruck 88% and Essen 93%). Furthermore, PRBC transfusion was reduced by 8.4–62%. The incidence of intraoperative massive transfusion (≥10 U PRBC) could be more than halved in VTS and CVS (2.56 vs. 0.88%; p < 0.0001 and 2.50 vs. 1.06%; p = 0.0007, respectively). Platelet transfusion could be reduced by 21–72%, except in CVS where it increased by 115% due to a 5-fold increase in patients with dual antiplatelet therapy (2.7 vs. 13.7%; p < 0.0001).
The implementation of perioperative POC coagulation management algorithms based on early, calculated, goal-directed therapy with fibrinogen concentrate and PCC is associated with a reduction in the transfusion requirements for FFP, PRBC and platelets as well as with a reduced incidence of massive transfusion. Thus, the limited blood resources can be used more efficiently.
Thromboelastometry; Transfusion algorithms; Fibrinogen concentrate; Prothrombin complex concentrate; Transfusion-associated adverse events; Pharmacoeconomics
Platelet counts, fibrinogen levels, thrombotest, thromboplastin generation screening test, thrombin ratio, and titre of circulating fibrin degradation products, were measured in 30 infants with Rh isoimmunization, of whom 5 had a bleeding tendency clinically, and 8 had laboratory evidence of disturbed haemostasis.
At necropsy intravascular fibrin deposits were found in the tissues of 3 out of 4 babies who died with haemorrhage.
An additional retrospective survey indicated that haemorrhage had been a major factor in causing death in 10 out of 18 newborn babies who died with rhesus isoimmunization in the period 1967-69.
Sites of haemorrhage at necropsy were mainly intracranial (subarachnoid and intracerebral) and intrapulmonary, with microscopical evidence of intravascular fibrin deposits in 5 cases.
It is concluded that disseminated intravascular coagulation is a major cause of haemostatic failure in babies with rhesus isoimmunization, but that disturbed hepatic synthesis of coagulation factors may also play a part.
Babies at risk from haemostatic failure are those with cord Hb below 7 g/100 ml. It is suggested that a platelet count should be performed as an initial investigation on all such infants.
Hyperfibrinogenemia is a common problem associated with various carcinomas, and is accompanied by hypercoagulablity. In advanced non-small-cell lung cancer (NSCLC) it remains unclear whether or not chemotherapy-induced changes in fibrinogen level relate to chemotherapeutic response and prognosis. The purposes of this study were to: 1) analyze the association between chemotherapy-induced changes in plasma fibrinogen level and the chemotherapeutic response after the first two courses of standard first-line platinum-based chemotherapy; and 2) evaluate the prognostic significance of the basal plasma fibrinogen level in patients with advanced NSCLC.
In this retrospective study, the data from 160 patients with advanced NSCLC were collected. The association between the changes in fibrinogen and the response to chemotherapy, or between the pre-and post-chemotherapy fibrinogen levels and patient clinical characteristics, were analyzed using SPSS software. In addition, the prognostic value of pre-chemotherapy fibrinogen levels was assessed.
The median pre-chemotherapy plasma fibrinogen level was 4.4 g/L. Pre-chemotherapy plasma fibrinogen levels correlated significantly with gender (p = 0.041). Post-chemotherapy plasma fibrinogen levels correlated with gender (p = 0.023), age (p = 0.018), ECOG (p = 0.002) and tumor response (p = 0.049). Plasma fibrinogen levels markedly decreased after chemotherapy in 98 (61.25 %) patients with pre-chemotherapy hyperfibrinogenemia (p = 0.008); and in this population there was a significant link between the decrease in fibrinogen level, and initial partial response (PR; p = 0.017) and stable disease (SD; p = 0.031). Univariate and multivariate analysis revealed that higher levels of fibrinogen (≥4.4 g/L) and ECOG 1 were positively associated with shorter overall survival (OS). CEA and CA125 also decreased significantly (p =0.015, p =0.000) in DCR group after chemotherapy.
This study showed that the reduction in plasma fibrinogen levels induced by chemotherapy might be as a promising biomarker as CEA and CA125 for evaluating the efficacy of chemotherapy in advanced NSCLC. In addition, basal plasma fibrinogen levels could be used as an independent prognostic parameter for the OS of patients with advanced NSCLC.
Hyperfibrinogenemia; Biomarker; NSCLC
Objective—To evaluate laboratory markers of defibrination early after thrombolytic therapy and to determine their relation to residual stenosis and left ventricular ejection fraction measured angiographically before discharge from hospital.
Design—Prospective analysis of defibrination after streptokinase measured by fibrinogen assay and thrombin time to provide a comparison of these coagulation variables for predicting angiographic responses to treatment in patients with acute myocardial infarction.
Setting—The coronary care unit of a district general hospital.
Patients—44 patients with acute myocardial infarction treated by streptokinase infusion, all of whom underwent paired blood sampling before and one hour after streptokinase and cardiac catheterisation at a median of six (interquartile range 3–9) days later.
Main outcome measures—Assay of thrombin time and plasma fibrinogen concentrations one hour after streptokinase infusion. Relations between these coagulation variables and residual stenosis in the infarct related coronary artery and left ventricular ejection fraction. Separate analyses are presented for all patients (n = 44) and those with patency of the infarct related artery (n = 35).
Results—Streptokinase infusion produced profound defibrination in every patient as shown by changes in thrombin time and circulating fibrinogen. Thrombin time after streptokinase infusion correlated significantly with both residual stenosis (r = −0·43, p < 0·005) and left ventricular ejection fraction (r = 0·38, p < 0·02). The importance of these correlations was emphasised by the interquartile group comparison which showed that a thrombin time ≥49 seconds predicted a residual stenosis of 74% and an ejection fraction of 65%, compared with 90% and 49% for a thrombin time ≤31 seconds (p < 0·01). When the analysis was restricted to patients with patency of the infarct related artery, the correlation between thrombin time and residual stenosis remained significant and group comparisons continued to show that patients in the highest quartile range had more widely patent arteries and better preservation of ejection fraction. Analysis of the fibrinogen data, on the other hand, showed insignificant or only marginally significant correlations with these angiographic variables.
Conclusions—Early after streptokinase infusion for acute myocardial infarction, the level of defibrination measured by thrombin time has an important influence on residual coronary stenosis and left ventricular ejection fraction at discharge from hospital, values above 49 seconds being associated with the best angiographic result.
Cardiac rehabilitation is an accepted therapeutic intervention in patients after myocardial infarction or coronary revascularisation. The effects of cardiac rehabilitation programmes, whether home based or hospital based, on haemostatic indices (as reflected by fibrinogen, plasma viscosity, fibrin D‐dimer (an index of thrombogenesis), von Willebrand factor (vWf, an index of endothelial damage/dysfunction), soluble P‐selectin (an index of platelet activation)), vasomotor function (using flow‐mediated dilatation (FMD)) and ambulatory blood pressure (ABP) in patients with coronary heart disease are unknown.
81 patients (66 men, mean (SD) 59 (11) years) after myocardial infarction or coronary revascularisation were randomised to comprehensive hospital‐based (n = 40) or home‐based (n = 41) cardiac rehabilitation. Plasma levels of vWf, D‐dimer, fibrinogen, soluble P‐selectin and plasma viscosity, as well as FMD and 24‐h ABP, were measured at baseline and after 3 months of cardiac rehabilitation.
In patients who completed cardiac rehabilitation, levels of vWf, fibrinogen and D‐dimer were significantly lower and FMD improved (all p⩽0.001), whereas levels were unchanged in controls. Significant reductions were also observed in 24‐h mean systolic blood pressure, diastolic blood pressure and mean aortic pressure after completion of cardiac rehabilitation (all p<0.05). No significant differences were observed between the hospital‐based and home‐based cardiac rehabilitation programmes on these indices.
Cardiac rehabilitation improves haemostasis, endothelial function and ABP in patients with coronary heart disease, with no significant differences between home‐based and hospital‐based cardiac rehabilitation programmes. These effects may contribute to the beneficial effects of cardiac rehabilitation programmes on CV outcomes.
The plasma fibrinogen concentration is directly related to blood viscosity, which in turn is inversely related to blood flow. The way in which the plasma fibrinogen level affects the clinical status of patients with peripheral vascular disease is discussed with reference to both retrospective and prospective studies of patients undergoing major arterial surgery. Animal experiments are described in which the effect of reducing the plasma fibrinogen level with oral clofibrate and parenteral Arvin (ancrod) on the patency of Dacron arterial grafts was studied.
Heparin therapy in 114 patients was controlled by daily blood tests—the whole blood coagulation time, kaolin-activated partial thromboplastin time of plasma, and plasma heparin assay. Bleeding episodes occurred in 7 out of 92 patients (7·6%) who had normal haemostatic mechanisms before therapy and in 11 out of 22 patients (50%) with defective haemostasis, mostly due to intravascular coagulation or renal failure. The dose of heparin ranged from 20,000 to 60,000 units in each 24-hour period. In some patients bleeding was related to overdosage, but in others the laboratory tests indicated satisfactory or suboptimal dosage at the time of bleeding. Though there were positive correlations between the results of the three tests, these were not close, and no one test was preferable. Hence laboratory control of heparin therapy is unsatisfactory and patients may bleed despite careful control of the dose by all three methods.
The role of fibrinogen as a cofactor for platelet aggregation was examined by measuring the binding of 125I-labeled human fibrinogen to gel-filtered human platelets both before and after platelet stimulation by ADP and epinephrine. Platelet stimulation by ADP resulted in the rapid, reversible binding of fibrinogen to receptors on the platelet surface. Fibrinogen binding increased as the concentration of ADP was increased from 0.1 to 2 microM, reaching a plateau at higher ADP concentrations. Binding occurred only after platelet stimulation and in the presence of divalent cations. However, fibrinogen binding did not occur to ADP-stimulated platelets from three patients with Glanzmann's thrombasthenia. Analysis of fibrinogen binding as a function of increasing fibrinogen concentration demonstrated that maximal platelet stimulation exposed approximately or equal to 45,000 binding sites per platelet with a dissociation constant of 80--170 nM. These fibrinogen binding parameters were essentially the same whether ADP or epinephrine was the platelet-stimulating agent. Thus, these studies demonstrate that platelet stimulation by ADP and epinephrine exposes a limited number of fibrinogen receptors on the platelet surface. Furthermore, these data suggest that the fibrinogen molecules bound to the platelet as a consequence of platelet stimulation are directly involved in the platelet aggregation response.