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PubMed1982

Fibrin deposition in the kidney and renal blood flow during intravascular coagulation in the rat: influence of the renin-angiotensin system.

1. Intravascular coagulation in the kidneys of rats was induced by intravenous infusion of thrombin and by inhibition of fibrinolysis with tranexamic acid under alpha-chloralose anaesthesia. The amount of fibrin in the kidneys was measured with radioactively labelled fibrinogen. Chronic saline loading and inhibition of angiotension II (ANG II) with saralasin reduced the fibrin deposition in the kidneys. Infusion of ANG II had the opposite effect. 2. Renal and aortic blood flows were measured by injection of radioactively labelled microspheres. After thrombin infusion the renal and aortic blood flows were reduced to about one-third of the pre-infusion values. Chronic saline loading diminished these changes, but saralasin had no effect. 3. Plasma renin activity (PRA), measured by radioimmunoassay, decreased by about 50% after thrombin infusion. 4. The reduction in PRA and the lack of effect of saralasin indicate that the renin-angiotensin system is not the mediator of the observed decrease in the renal blood flow. As saralasin reduced the amount of fibrin the mechanism regulating fibrin deposition appears to be independent of the mechanism that reduces the renal blood flow.

Angiotensin II↗
PubMed1997

Tumour cell u-PA as a cause of fibrinolytic bleeding in metastatic disease.

Tumour cells may express urokinase type plasminogen activator (u-PA). This may influence the invasive properties of the cells but has seldom been implicated in production of a systemic bleeding state. Two patients are described in whom severe bleeding occurred in association with disseminated malignancies. Thrombin generation was little disturbed and platelet numbers were insufficient to account for the bleeding. Florid plasmin generation was evident in the circulation and the fibrinolytic inhibitor tranexamic acid controlled the bleeding well. Free active u-PA was demonstrated in the circulation and u-PA antigen on the malignant cells which invaded the marrow of one of the patients. Tumour cell u-PA may occasionally be responsible for a bleeding state.

Blood Coagulation Disorders↗
PubMed1998

Norethisterone therapy for bleeding due to gastrointestinal telangiectases in Glanzmann's thrombasthenia.

We report a case of a patient with Glanzmann's thrombasthenia and anti-GPIIb/IIIa alloantibodies who developed life-threatening and intractable bleeding from gastrointestinal telangiectatic lesions. After a period of transfusion-dependent gastrointestinal bleeding despite tranexamic acid, oral iron, omeprazole and platelet transfusions, the use of oral norethisterone produced a significant improvement with a marked reduction in her transfusion requirements.

Adult↗
PubMed2000

Experimental study of the influence of endoleak size on pressure in the aneurysm sac and the consequences of thrombosis.

BACKGROUND: This was an experimental study of endovascular aortic surgery, looking at the relationship between the size of an endoleak, pressure in the aneurysm sac and the effect of thrombosis produced by coagulation. METHODS: In three pigs, 16 saccular aneurysms were connected to the aorta by various side branches with different diameters and lengths ('endoleaks'). Mean and pulse pressures were measured in the systemic circulation as well as in the aneurysm sac during the experiment. Duplex ultrasonography was used to determine whether the endoleak and the aneurysm were patent or thrombosed. Thrombosis was influenced by systemic tranexamic acid, fibrinogen in the aneurysm sac, Gelfoam in both endoleak and aneurysm sac, and by Histoacryl glue in the endoleak. RESULTS: With an open endoleak, the mean pressure in the aneurysm and the aorta was identical. Mean aneurysm pressure was lower with a thrombosed endoleak and was related to the diameter of the endoleak. Pulse pressure was recorded in the aneurysm sac when there was an open endoleak and a non-thrombosed aneurysm, and was related to the diameter of the open endoleak. Thrombosed endoleaks never produced pulse pressure in the aneurysm. If Histoacryl and Gelfoam induced thrombosis of the endoleak, the decrease in mean aneurysm pressure was identical to that resulting from the spontaneous thrombosis of endoleaks. CONCLUSION: An open endoleak results in systemic arterial pressure in the aneurysm sac. Pulse pressure is detected if the aneurysm is patent, but absent if there is complete or partial thrombosis of the aneurysm. Endoleak thrombosis, either spontaneous or by embolization, is accompanied by a decrease in mean pressure and the absence of pulse pressure in the aneurysm sac. The extent to which these experimental findings are comparable to the clinical situation represents a field of further research.

Aortic Dissection↗
PubMed1999

Efficacy of a high purity, chemically treated and nanofiltered factor IX concentrate for continuous infusion in haemophilia patients undergoing surgery.

We have evaluated the haemostatic efficacy of plasma derived, highly purified, solvent-detergent treated factor IX concentrate (Nanotiv), to which a nanofiltration step has recently been added to improve safety with regard to parvovirus B19, hepatitis A and other nonlipid enveloped viruses. Thirteen surgical procedures, including eight orthopaedic operations, were carried out using continuous infusion of Nanotiv in 10 haemophilia B patients (nine severe and one mild). Tranexamic acid was used for 11 of the 13 procedures. The mean factor IX levels on the day of surgery and postoperative days 1-3 were 0.77, 0.89, 0.80 and 0.73 IU mL(-1), respectively. The haemostatic effect was rated as normal or excellent and no blood transfusions were needed. One patient had thrombophlebitis twice at the infusion site. The remaining cases received heparin, 5 units per 100 IU of Nanotiv, and had neither superficial nor deep venous thromboembolic complications. The requirement for factor IX in the four joint replacement operations was 663 IU kg(-1) during the first 9 days, which compares favourably with previous materials. Thus, continuous infusion with this highly purified factor IX concentrate with improved viral safety is effective for surgery in haemophilia B.

Adolescent↗
PubMed2000

Proposal of a standard approach to dental extraction in haemophilia patients. A case-control study with good results.

We found no case-control studies on dental extraction in haemophilia patients in the literature even though the use of antifibrinolytic agents following a single infusion of factor VIII or IX has been accompanied by a lower number of bleeding complications in dental extractions. In this study we verified the incidence of bleeding complications after dental extraction in a group of 77 haemophilia patients. One hundred and eighty-four male patients requiring dental extraction represented the control group. All haemophilia patients received 20 mg kg-1 of tranexamic acid and a single infusion of factor VIII or IX to achieve a peak level about 30% of factor VIII or IX in vivo prior to dental extraction. Forty-five of 98 (45.9%) dental extractions in haemophilia patients and 110 of 239 (46%) dental extractions in the control group were surgical ones. We registered two bleeding complications in the group of haemophilia patients (one late bleeding and one haematoma in the site of the anaesthetic injection) and one (a late bleeding) in the control group. The difference of bleeding complications in the two groups of patients were not statistically significant (P=0.2; OR 0.2; CI 0.01-2.22). The protocol proposed in this study, characterized by the feasibility and the number of haemorrhagic complications not different from normal population, make dental extractions in haemophilia patients possible on an out-patient basis with a cost reduction for the community and minor discomfort for the patients.

Adult↗
PubMed2003

Continuous infusion.

There is evidence, albeit scientifically weak, for improved cost/benefit with administration of factor concentrates by continuous infusion when high-dose replacement is necessary, as several studies have shown a reduced requirement for the concentrate. There is evidence from only one study for fewer bleeding complications with continuous infusion. There is evidence from two studies that additional therapy with tranexamic acid reduces the risk of bleeding complications in patients receiving continuous infusion. Future studies should address the question of minimum steady-state levels required for haemostasis, comparisons with bolus injection using a randomized design and investigate the risk of inhibitor formation.

Blood Coagulation Disorders↗
PubMed1997

Type I hereditary angio-oedema. Variability of clinical presentation and course within two large kindreds.

OBJECTIVES: Hereditary angio-oedema (C1-inhibitor deficiency) is a disease with protean manifestations which is often misdiagnosed initially. The purpose of this study was to delineate the clinical spectrum and course of this potentially life-threatening disease. SETTING: Ten members of two unrelated affected kindreds were repeatedly hospitalized in our service with attacks of angio-oedema. Among the 271 members of the two kindreds 69 were identified who reported typical attacks. DESIGN AND SUBJECTS: Detailed information on the clinical course and laboratory data (C1-inhibitor concentration and activity, C4 concentration) were obtained from 59 of the 69 affected subjects. RESULTS: C1-inhibitor concentration and activity were low in all affected patients. The disease had become manifest by age 30 years in 98%. Most patients suffered from attacks of subcutaneous swellings and abdominal pain, and half of the patients have had attacks affecting the airways. The frequency of attacks ranged from less than one to over 26 per year. Forty-two per cent had to be hospitalized at least once. Four have died of acute airway obstruction. Thirty-eight attacks in 10 patients hospitalized in our service were all treated successfully with fresh frozen plasma or with C1-inhibitor concentrate. Trauma, stress, insect stings and foodstuff were triggering factors, but the majority of attacks occurred without an identifiable trigger. Oral contraceptives and pregnancy led to worsening of symptoms. Nonetheless, all 36 pregnancies reported were carried to term. Twenty-five patients were on continuous treatment with attenuated androgens or tranexamic acid, but only seven were free of attacks in the year preceding the survey. CONCLUSION: Hereditary angio-oedema is an autosomal dominant disease with great variability of clinical expression and severity, even within a single kindred. It often goes unrecognized over years, and it may lead to death if, in case of impending airway obstruction, specific therapy is not instituted.

Acute Disease↗
PubMed1994

Role of fibrinolysis in the formation of postoperative adhesions.

It has been hypothesized that peritoneal hypofibrinolysis is of importance in the formation of postoperative adhesions, but results from experiments with fibrinolytic modulators are conflicting. We tested this hypothesis in a controlled prospective study in rabbits, comparing the effects of fibrinolytic inhibition (tranexamic acid) to fibrinolysis enhancement by local instillation of gel containing tissue-type plasminogen activator. Adhesion formation was measured after 1 week in a strictly standardized way and is presented as a percentage of an induced lesion that was covered by adhesions. Fibrinolytic inhibition significantly increased adhesion formation, both to the parietal peritoneum (34.2%+/- 3.2%) compared with untreated control (19.7%+/- 3.3%, p < 0.01) and to the bowel (76.3%+/- 5.8%) compared with untreated control (51.2%+/- 8.7%, p < 0.05). Control gel significantly increased adhesions to the parietal peritoneum (35.6%+/- 4.6%) versus untreated control (19.7%+/- 3.3%, p < 0.05), whereas gel containing tissue-type plasminogen activator significantly reduced the amount of adhesions to the parietal peritoneum (4.9%+/- 1.7%) compared with untreated control (19.7%+/- 3.3%, p < 0.01) and abolished adhesion formation to the injured bowel. The fibrinolytic system thus seems to be intimately involved in the early formation of intraabdominal adhesions.

Journal Article↗
PubMedDate not supplied

Factor VIII concentrate prepared from blood donors stimulated by intranasal administration of a vasopressin analogue.

With an interval of eight weeks between collections, blood was drawn twice from 120 blood donors. At one of the donations, 0.25 ml of synthetic vasopressin, (DDAVP, 1300 micrograms/ml), was administered intranasally 60 minutes prior to collection of the blood. No drug was given at the other donation. The yield of factor VIII clotting activity (VIII:C) and factor VIII antigen (VIIIR:Ag) was compared in blood drawn from the treated and untreated donors. To prevent degradation of VIII:C by fibrinolysis, tranexamic acid was added to the plasma from treated donors immediately after separation from the red blood cells. Plasma from treated donors and the derived Cohn fraction I-O contained approximately twice as much VIII:C as plasma and fraction I-O from untreated control donors. The concentration of VIIIR: Ag was also increased in fraction I-O made from plasma from treated donors, however to a lesser degree. The in vivo properties of factor VIII concentrates made from each group of donors were studied. Half-life in plasma and recovery of VIII:C were identical. Thus, intranasal synthetic vasopressin may be used to increase the yield of VIII:C in production of factor VIII concentrates.

Administration, Intranasal↗
PubMed2004

Factor XI deficiency.

Factor XI (FXI) deficiency leads to an injury-related bleeding diathesis, which is notable for the variability in the bleeding tendency and the lack of a clear relationship between bleeding and FXI coagulant activity. Bleeding in this disorder occurs especially in areas of high fibrinolytic activity. Although a rare disorder, the frequency of FXI deficiency is high in certain populations, notably persons of Ashkenazi descent and the Basque population of Southern France. In these populations, five mutations of the FXI gene have been identified and a founder effect has been confirmed for three of these. This paper reviews the role of FXI in coagulation and documents factors known to modify the bleeding tendency. Treatment of surgical bleeding in patients with FXI deficiency is reviewed with emphasis on the combined use of recombinant activated factor VII (rFVIIa; NovoSeven(R), Novo Nordisk, Bagsvaerd, Denmark) and the antifibrinolytic agent, tranexamic acid.

Antifibrinolytic Agents↗
PubMed2005

von Willebrand disease and women's health.

In 1926 von Willebrand described a bleeder family in Aland; this condition became known as von Willebrand disease (VWD). von Willebrand noted that "the trait seemed especially to be seen among the women." Today, the use of a pictorial bleeding assessment chart (PBAC) has enabled the prevalence of VWD to be established among women presenting with menorrhagia, as well as the documentation of this symptom in women with known VWD and the assessment of treatment response in menorrhagia. Treatments for menorrhagia include tranexamic acid, desmopressin (DDAVP) administered either intranasally or subcutaneously, the oral contraceptive pill, the "Mirena" coil (Schering Oy, Turku, Finland), and endometrial ablation. Von Willebrand factor (VWF) shows strong cyclical variation, with peak values occurring in the luteal phase. Although increased in pregnancy, levels of VWF decline postnatally and the incidence of both primary and secondary postpartum hemorrhage is high (20% to 25%). Baseline VWF levels less than 15 IU/dL are unlikely to reach greater than 50 IU/dL in the third trimester, and therefore prophylaxis with DDAVP or VWF-containing concentrate to cover delivery should be considered.

Female↗
PubMed2005

Antifibrinolytic agents in cardiac surgery: current controversies.

Antifibrinolytic agents play a prominent role in adult cardiac surgery. This article is a review of the modern published experience of antifibrinolytic agent use in adult cardiac surgery. The use of tranexamic acid, epsilon-aminocaproic acid, and aprotinin is examined during primary cardiac surgery, deep hypothermic circulatory arrest, reoperative cardiac surgery, and off-pump coronary artery bypass surgery. In addition, the issues of vein graft patency and hypersensitivity reaction in the presence of antifibrinolytic agents are examined.

Antifibrinolytic Agents↗
PubMed2002

Impact of hematocrit value after coronary artery surgery on perioperative myocardial infarction rate.

BACKGROUND: The optimal hematocrit (HCT) value after coronary artery bypass grafting on cardiopulmonary bypass (CPB) has not yet been established. The purpose of our retrospective study was to investigate the association between HCr at the time of entry into the ICU and perioperative Ml rate. METHODS: We reviewed the charts of 500 consecutive coronary artery surgery patients with respect to biometric data, operative procedure, aprotinin or tranexamic acid use, perioperative drainage blood loss and transfusion requirements, perioperative Ml, ICU stay and hospital mortality. Perioperative Ml was defined as new Q-wave on ECG and CK-MB 250U/I. Patients were categorized into three groups depending on their HCr value at the time of entry into the ICU: low (HCTcu 27%): medium (HCr,cu 28% to 32%); high(HCTrcu > or =33%). RESULTS: Age, gender distribution, preoperative LV function, and previous Ml rate were similar between the three groups. Low HCT patients (n -133) received 3.1 +/- 1.0 (Mean + SD) grafts during 55 +/- 19 minutes aortic cross clamp time, 98 +/- 31 minutes on CPB (medium HCT: n = 257; 3.2 +/- 1.0 grafts, 51 +/- 20 min cross clamp time, 93 +/- 30 min CPB; p - 0.45 vs. low HCT; high HCT: n = 110: 3.3 +/- 1:0 grafts; 53 +/- 20 min cross clamp time; 104 +/- 38 min CPB; p = 0.02 vs. medium HCT). The perioperative Ml rate was 3.8% in the low, 4.3% in the medium, and 6.4% in the high-HCr group (p =0.59 ). Intraoperative red blood cell and fresh frozen plasma transfusions were similar between the groups. In the low-HCa group, 53.4% of the patients received aprotinin during the procedure (medium HCa: 65.4%; high HCT: 77.3%; p<0.001). Drainage blood loss during the first 24 hours on ICU was 834 +/- 453 ml in the low, 757 +/- 485 ml in the medium (p -0.44 vs. low), and 640 +/- 353 ml in the high-HCr group (p = 0.003 vs. low). Postoperative red blood cell and fresh frozen plasma transfusions were highest in the low-HCa group(p<0.001). ICU stay was similar between the groups. Hospital mortality was 0.75% in the low, 1.9% in the medium, and 4.5%in the high-HCa group (p = 0.12). CONCLUSIONS: In this retrospective analysis of 500 consecutive coronary artery surgery patients, we did not find any association between perioperative Ml rate and HCr value on entry into the ICU. These results do not support the recent suggestion that low HCT at the time of entry into the ICU protects against perioperative Ml.

Aged↗
PubMed2003

[Acquired hemophilia A as a cause of postoperative bleeding].

Acquired spontaneous hemophilia is a rare but potentially life-threatening disease, which poses a major challenge to intensive care medicine. We report a case in which the disease occurred postoperatively in a patient following uncomplicated lumbal discectomy. The clinical sequelae involved hemorrhagic shock (cHb 4.1 g/dl; hct 17 %; systolic BP 60 mmHg; HR 130/min; saO2 73 %) due to retroperitoneal hematoma eight days after neurosurgical intervention. While lesions of the retroperitoneal vessels were not found during emergent angiography and laparotomy, the laboratory results showed a slightly prolonged activated prothrombin time (aPTT; 47 s). However, application of fresh frozen plasma (FFP) even prolonged the aPTT (53 s). Analysis of clotting factors proved a deficiency of factor VIII with a reduced activity of about 20 %, which was resistant against therapy with desmopressin (DDAVP) and substitution of factor VIII. Thus, the plasma-mix-test was performed, showing complete inactivation of the factor VIII-activity of the pooled plasma. This evidenced the presence of acquired inhibitors against factor VIII. Hemostasis was successfully and immediately restored with the application of recombinant factor VIIa (rFVIIa), including boluses of 60 - 80 microg/kg every 6th - 8th hour (supplemented with tranexamic acid, 3 x 1 g/d), leading to a continuous infusion of 12 microg/kg per hour. With prednisolone (1 mg/kgBW/d) over the ensuing 8 weeks, the antibodies were sufficiently suppressed and no additional substitution of factor VIII was necessary to maintain normal hemostasis.

Blood Coagulation Tests↗
PubMed2004

[Excessive blood loss after abdominal hysterectomy -- use of recombinant factor VIIa].

MEDICAL HISTORY: A 38-yr-old woman suffered from excessive blood loss after elective removal of the uterus because of a leiomyoma. The surgical attempt to stop the bleeding failed. The laboratory evaluation before surgery showed normal coagulation parameters (aPTT 23.4 sec, TPZ > 100 %, platelet count 267 000/microl). DEVELOPMENT: Despite treatment with the plasminogen activator inhibitor Tranexamic Acid (2 x 500 mg) and 10 units of concentrated platelets as well as 31 units of fresh frozen plasma and 31 units of red blood cell concentrates the bleeding continued. Reaching an cumulative blood loss of 15 000 ml the patient developed ventricular fibrillation necessitating cardiac resuscitation including defibrillation and application of epinephrine 7 mg. At this point systolic blood pressure decreased from 90 to 70 mm Hg, the core temperature was 31,9 degrees C. After successful resuscitation (systolic blood-pressure 90 mm Hg after 15 min) the bleeding started again with a blood loss of 2000 ml requiring 3 units of fresh frozen plasma and 3 red cell concentrates Use of recombinant activated Factor VII (r.FVIIa): 6 mg (300 KiU) r.FVIIa have been applied (92 microg/kgKG [4.6 KiE/kg]). Within 10 minutes the bleeding stopped. More transfusions were not necessary. The patient left the intensive care unit 8 days after the operation without neurological deficit. CONCLUSION: The use of recombinant Factor VIIa may stop excessive haemorrhage, even if the cause is unknown.

Adult↗
PubMed2005

[Lethal sepsis and multi-organ failure after accidental injection of urine in a drug addict].

HISTORY AND ADMISSION FINDINGS: A 33-year-old drug addict injected accidentally into the femoral vein 5 ml urine (kept in the refrigerator for 1 week for unanticipated drug-screening) which she mis-took for methadone. Soon after injection she was found confused with shivering. On admission she had a blood pressure of 90/60 mmHg, heart rate of 120/min and fever of 40 degrees C. INVESTIGATIONS: Laboratory tests showed consumption coagulopathy (DIC) as well as leukopenia. Blood cultures were positive for E.coli and Klebsiella pneumoniae. Infection with hepatitis C and HIV was excluded. Echocardiography revealed good ventricular function without signs of endocarditis. DIAGNOSIS AND TREATMENT: The patient developed a fulminant Gram-negative sepsis with DIC and multi-organ failure. She was intubated and mechanically ventilated. Acute renal failure required haemodialysis and ultrafiltration. Septic shock was treated with fluids and high doses of vasopressors. DIC was effectively treated with tranexamic acid, PPSB complex and fresh frozen plasma. The further course was complicated by septic emboli to the myocardium, liver, kidney and spleen. Laparotomy because of an acute abdomen revealed perforation of terminal ileum (mainly due to ischemic bowel lesions) requiring partial resection. The patient was weaned on day 18 with an initially uneventful further course. On day 25 the patient had a cardiac arrest with at first successful resuscitation but electromechanical dissociation proved fatal on day 26. CONCLUSION: Although serious systemic inflammation associated with i. v.-injection in drug addicts is rare, one has to be aware of severe complications with septic emboli. To our knowledge it is the first published case of i. v.-injection of urine followed by sepsis and multi-organ failure. Aggressive interdisciplinary treatment is required.

Accidents↗
PubMed1996

New model for in vivo studies of pharmacological interventions with endogenous fibrinolysis: effects of thrombin inhibitors.

A new rat model for investigation of the interactions of thrombin inhibitors with endogenous fibrinolysis in vivo is described. The method utilizes the thrombin-like snake enzyme batroxobin, which mainly cleaves the fibrinopeptide A from fibrinogen and activates factor XIII only to a slight degree. Compared to thrombin-formed fibrin, batroxobin-formed fibrin is more readily lysed by plasmin, since it only cross-links fibrin to a minor extent. Radiolabeled fibrinogen (125I) was given intravenously to monitor the effects of batroxobin on fibrinogen and the effects of plasmin on the fibrin formed. Batroxobin was given intravenously in a dose that converted most fibrinogen to fibrin. Five to 10 minutes after batroxobin administration, 125I-activity in the blood decreased, indicating the disappearance of fibrinogen from the circulating blood. At the same time, the 125I activity as measured with a gamma counter increased over the lungs. The fibrin formed in the microvasculature of the lungs started an endogenous fibrinolysis. This could be seen as reappearance of the 125I activity in the blood from fibrin degradation products accompanied by a decrease in the 125I activity over the lungs. When the rats were given tranexamic acid, the endogenous fibrinolysis was markedly decreased, measured as 125I activity in the blood, over the lungs and in lung parenchyma samples. The thrombin inhibitor DuP 714, which apparently inhibits not only thrombin but also plasmin and tissue plasminogen activator, completely prevented the fibrinolytic phase. The selective thrombin inhibitor argatroban, on the other hand, led to shortened lysis time. It is concluded that the present method provides a convenient and accurate means of studying pharmacological interventions with endogenous fibrinolysis. The differential effects of selective and nonselective thrombin inhibitors on endogenous fibrinolysis at comparable levels of thrombin inhibition are clearly demonstrated.

Animals↗