Women with congenital factor VII deficiency: clinical phenotype and treatment options from two international studies.

INTRODUCTION: A paucity of data exists on the incidence, diagnosis and treatment of bleeding in women with inherited factor VII (FVII) deficiency. AIM: Here we report results of a comprehensive analysis from two international registries of patients with inherited FVII deficiency, depicting the clinical picture of this disorder in women and describing any gender-related differences. METHODS: A comprehensive analysis of two fully compatible, international registries of patients with inherited FVII deficiency (International Registry of Factor VII deficiency, IRF7; Seven Treatment Evaluation Registry, STER) was performed. RESULTS: In our cohort (N = 449; 215 male, 234 female), the higher prevalence of mucocutaneous bleeds in females strongly predicted ensuing gynaecological bleeding (hazard ratio = 12.8, 95% CI 1.68-97.6, P = 0.014). Menorrhagia was the most prevalent type of bleeding (46.4% of patients), and was the presentation symptom in 12% of cases. Replacement therapies administered were also analysed. For surgical procedures (n = 50), a receiver operator characteristic analysis showed that the minimal first dose of rFVIIa to avoid postsurgical bleeding during the first 24 hours was 22 µg kg(-1) , and no less than two administrations. Prophylaxis was reported in 25 women with excellent or effective outcomes when performed with a total weekly rFVIIa dose of 90 µg kg(-1) (divided as three doses). CONCLUSION: Women with FVII deficiency have a bleeding disorder mainly characterized by mucocutaneous bleeds, which predicts an increased risk of ensuing gynaecological bleeding. Systematic replacement therapy or long-term prophylaxis with rFVIIa may reduce the impact of menorrhagia on the reproductive system, iron loss and may avoid unnecessary hysterectomies.

Patient characteristics that influence efficacy of prophylaxis with rFVIII-FS three times per week: a subgroup analysis of the LIPLONG study.

Prospective data on the efficacy of secondary prophylaxis in adults with haemophilia A are limited. To analyse bleeding outcomes in the sucrose-formulated recombinant factor VIII [rFVIII-FS (control)] arm of the LIPLONG study, a randomized, double-blind, 52-week trial was conducted in patients with severe haemophilia A receiving prophylaxis with the investigational product BAY 79-4980 or rFVIII-FS. The per-protocol population of previously treated patients with severe haemophilia A without a history of inhibitors (n = 68 males; mean age, 34.4 years) received 25 IU kg−1 rFVIII-FS three times per week for a median of 50.7 weeks. Annualized bleeding rates were assessed and analysed according to predefined target joint status at study start, prestudy treatment type (prophylaxis vs. on demand), age (<30 or ≥30 years), geographical region, bleeding frequency during the previous 6 months and physical activity status during the study using the Student t-test. The annualized median (range) number of bleeds was 2.2 (0.0­23) bleeds per year. The median (range) number of bleeds per year was significantly lower in patient subgroups without vs. with target joints [0.5 (0.0­17.1) vs. 4.2 (0.0­22.8); P = 0.02] and in those with ≤9 vs. >9 bleeds during the previous 6 months [1.1 (0.0­19.2) vs. 5.3 (0.0­22.8); P = 0.01]. Following randomization to prophylaxis with rFVIII-FS, bleeding frequency was effectively reduced. Absence of target joints and prestudy bleeding frequency were predictors of a low bleeding frequency during prophylaxis treatment.

Long-standing prophylactic therapy vs. episodic treatment in young people with severe haemophilia: a comparison of age-matched Danish and Russian patients.

Two distinctly different substitution principles are commonly used in haemophilia: treatment at bleeding episodes only referred to as on-demand treatment, and prophylactic factor administration. The aim of the cross-sectional study which was undertaken in young patients suffering severe haemophilia A was to challenge our hypothesis that on-demand treatment is inferior to prophylactic substitution in prevention of chronic joint disease at young age. The method involved an investigation of 40 patients from Russia (n = 27) and Denmark (n = 13) born between 1975 and 1990 with no history of inhibitors; Russian patients had exclusively received factor VIII on demand, while Danish patients were managed with prophylactic treatment during a mean period of 16 years since median age of 5 years. The study endpoints were clinical joint scores, Quality of Life scores and functional independence scores. Matched by identical age (±1 year) 13 Danish and 13 Russian patients were compared, while 14 age similar Russian patients served as controls. Demographic data among all groups were quite comparable. The results are that Russian patients presented with clinical joint scores at 27 ± 8.5 (mean ± SD) while matched Danish counterparts scored 3.8 ± 5.3 (mean ± SD), differences being highly significant. The number of joint bleeds in recent 5 years were 199.5 ± 135 (mean ± SD) vs. 8.1 ± 8.7 (mean ± SD). Likewise, Quality of Life and functional independence scores were significantly higher in patients on prophylaxis as compared to on-demand treatment. In conclusion, the study outcomes confirmed our hypothesis. Longer term prophylactic factor administration during childhood and adolescence prevents joint destruction.

Endothelial dysfunction, increased inflammation, and activated coagulation in HIV-infected patients improve after initiation of highly active antiretroviral therapy.

OBJECTIVES: Endothelial dysfunction and inflammation have been demonstrated to be markers of cardiovascular risk. We investigated the effects of HIV infection per se and the antiretroviral treatment prescribed on the levels of risk factors of cardiovascular disease. METHODS: This was a prospective study of 20 treatment-naïve, nonsmoking, HIV-positive patients examined before and after 3 months of treatment with a protease inhibitor (PI)-containing regimen followed by 3 months of treatment with nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing therapy. Parameters of inflammation, endothelial function and coagulation were examined. The results were compared with those for an age- and gender-matched, nonsmoking, healthy control group. RESULTS: Compared with controls, treatment-naïve HIV-infected patients exhibited endothelial dysfunction [flow-mediated dilation (FMD) 108 vs. 111% for HIV-infected vs. control groups, respectively; P < 0.05] and activation [von Willebrand factor 2.0 vs. 0.9 U/l; soluble intercellular adhesion molecule (sICAM) 313 vs. 211 ng/L, respectively; P < 0.01]. Inflammation [C-reactive protein (CRP) 24 vs. 8.6 nmol/L; fibrinogen 9.4 vs. 8.6 µmol/L, respectively; P < 0.05] and coagulation/fibrinolysis (D-dimers 0.55 vs. 0.23 µg/mL, respectively; P < 0.01) were increased. Initiating therapy resulted in normalization of FMD and a significant decrease in endothelial activation and CRP. CONCLUSION: Endothelial dysfunction together with increased inflammation and coagulation were more prevalent in untreated HIV-infected patients compared with controls. These cardiovascular risk factors improved with treatment, although not all parameters normalized after 6 months.

Progression of haemophilic arthropathy in children: a Lithuanian--Danish comparative study.

Recurrent bleeding into joints initiates a sequence of events leading to a progressive joint damage in people with severe haemophilia. This is a continuous process during childhood and adolescence, therefore joint abnormalities may be minimal on physical examination in very young children - even those receiving on-demand treatment. The aim of our study was to quantify the burden of arthropathy in Lithuanian patients who had been treated exclusively by on-demand substitution and compare their physical joint health with age-matched Danish patients who received prophylaxis from an early age. Boys, aged 4-17 years, with severe haemophilia and no signs of inhibitors were included in the study. Joint outcome based on the Haemophilia Joint Health Score (HJHS) was analysed in two different treatment groups and compared within the matched pairs. In total, 32 (16 in each treatment group) patients were enroled. A total of 192 joints were evaluated. Joint status according to treatment strategy was strikingly different: 27.4 for on-demand vs. 3.3 for prophylaxis (<0.001) group. Significance of the difference in joint status comparing different treatment strategies was equally strong both in younger (4-9 years) and older (10-17 years) patient groups: 2.2 vs. 12.5 (P = 0.0002) and 3.9 vs. 36.3 (P < 0.0001) respectively. The results further demonstrate the unequivocal effect of prophylaxis on joint status and give an insight into early and late manifestations of joint impairment based on the HJHS in haemophilia patients with treatment on-demand compared with joint changes that may develop over the time with the preventative treatment.

Platelet activation and aggregation: the importance of thrombin activity--a laboratory model.

This study introduces a new laboratory model of whole blood platelet aggregation stimulated by endogenously generated thrombin, and explores this aspect in haemophilia A in which impaired thrombin generation is a major hallmark. The method was established to measure platelet aggregation initiated by tissue factor evaluated by means of impedance aggregometry. Citrated whole blood from healthy volunteers and haemophilia A patients with the addition of inhibitors of the contact pathway and fibrin polymerization was evaluated. In healthy persons, a second wave of platelet aggregation was found to coincide with the thrombin burst and to be abolished by thrombin inhibitors. In this system, platelet aggregation in severe haemophilia A (n = 10) was found to be significantly decreased as compared with healthy individuals (912 ± 294 vs. 1917 ± 793 AU × min, P = 0.003), most probably due to the weak level of thrombin generation. For the first time, analysis of platelet aggregation as induced by endogenously generated thrombin was demonstrated. The new method makes it possible to explore the influence of the coagulation system on platelet function. In contrast to the general understanding, the data suggest that the impaired thrombin generation in haemophilia may affect platelet activation. Future studies will address whether our results may contribute to understanding differences in bleeding phenotypes and response to haemostatic substitution observed among patients.

Malignant disease in the haemophilic population: moving towards a management consensus?

The Malignancy in Haemophilia Workshop Group convened a consensus working group of haematologists and oncologists to review topics related to malignancy in haemophilia. The treatment of malignant disease in this population is increasingly relevant as both outcome and lifespan continue to improve. Although adequate guidance exists for control of spontaneous bleeding episodes and of haemostasis in general surgery, information for management of haemostasis in patients with various malignancies is sparse. To date, no clinical guidelines exist for management of complex bleeding problems, diagnosis, therapy and follow-up of malignancies in haemophilia. Furthermore, it remains unclear whether or not morbidity and mortality outcomes associated with malignancies are affected by haemophilia or by its treatment. Through presentation of five malignancies - prostate cancer, colorectal cancer, acute leukaemia, bladder cancer and hepatocellular carcinoma - important issues are highlighted, such as risk from bleeding as a symptom of malignancy; risks from invasive screenings and how these should be handled in haemophilic individuals; the implications of chemotherapy and treatment schedules, bone marrow suppression, radiotherapy, or surgery; and the likelihood of an interaction between treatment for haemophilia and malignancy outcomes. Ultimately, the aim is to establish consensus guidelines to direct and harmonize future treatment policy for malignant disease in the haemophilic population.

Virtual surgical analysis: long-term cone beam computed tomography stability assessment of segmental bimaxillary surgery.

The assessment of the stability of orthognathic surgery is often time-consuming, relies on manual re-identification of anatomical landmarks, and has been based on short-term follow-up. The purpose of this study was to propose and validate a semi-automated approach for three-dimensional (3D) assessment of the long-term stability of segmental bimaxillary surgery. The approach was developed and validated using cone beam computed tomography scans obtained at 2 weeks and 2 years postoperative. The stability of the surgical outcome was calculated as 3D translational and rotational differences between the short- and long-term postoperative positions of the individual bone segments. To evaluate reliability, intra-class correlation coefficients were calculated at a 95% confidence interval on measurements of two observers. Ten class II and III patients (six male, four female; mean age 24.4 years), who underwent a combined three-piece Le Fort I osteotomy, bilateral sagittal split osteotomy, and genioplasty, were included in the study. Intra- and inter-observer reliability were excellent (range 0.82-0.99). The range of the mean absolute difference of the intra- and inter-observer translational and rotational measurements were 0.14 mm (0.13)-0.44 mm (0.50) and 0.20° (0.16)-0.92° (0.78). The approach has excellent reliability for 3D assessment of long-term stability of segmental bimaxillary surgery.

Standardization of thromboelastography: a report from the TEG-ROTEM working group.

Laboratory evaluation of bleeding disorders has been performed with the standard clotting assays such as the PT and PTT for several decades. Our improved understanding of the process of blood coagulation has now revealed the important role played by the cellular elements such as platelets, monocytes and red blood cells. The need for a test that can assess clotting in a more 'global' manner, beyond the initiation of clot formation, has led to greater interest in assays such as thrombin generation and thromboelastography. Even though there are several publications using thromboelastography it remains a research tool as the methodology is not standardized. In an attempt to show reproducibility and consistency using thromboelastography, a group of investigators from different countries joined hands to form the TEG-ROTEM Working Group. Two studies were performed using PRP and FVIII deficient plasma and an intrinsic pathway activator. This article summarizes the results of the first international effort at standardization of thromboelastography. Both of the instruments using this technology (TEG(®) and ROTEM(®)) were used. Nine laboratories from countries around the globe participated in this effort. The results showed a significant inter-laboratory variance with CV's greater than 10%. Although these results were not satisfactory, this has been the first effort to standardize this methodology and significant work remains to be done to improve reliability and reproducibility. These studies were performed on PRP and the results may be more reliable when preformed on whole blood samples. We believe that it is important to continue this work so that we may investigate the usefulness and potential applications of thromboelastography in the evaluation of bleeding and thrombosis.

Previously unrecognized advanced liver disease unveiled by transient elastography in patients with Haemophilia and chronic hepatitis C.

Before the introduction of viral inactivation procedures and viral screening of plasma-products, haemophiliacs were at high risk of infection with HCV. Those who acquired HCV infection in the 1980s, and are still alive today, may have developed significant liver fibrosis or cirrhosis. However, liver biopsy has not routinely been utilized in the evaluation of haemophiliacs with HCV in Denmark. The aim of this study was to investigate the prevalence of significant fibrosis/cirrhosis among haemophiliacs as evaluated by transient elastography (TE). Cross-sectional investigation of adult patients with haemophilia A or B. TE with liver stiffness measurements (LSM) ≥ 8 kPa were repeated after 4-6 weeks. Significant fibrosis and cirrhosis was defined as measurements ≥ 8 kPa or ≥ 12 kPa respectively. Among 307 patients with haemophilia A or B registered at the two Haemophilia centres, 141(46%) participate in this study. Forty (28.4%) had chronic hepatitis C, 33 (23.4%) past hepatitis C and 68 (48.2%) had never been infected, at screening LSM ≥ 8 kPa were found in 45.7%, 24.7% and 4.6% respectively. Among patients with chronic hepatitis C significant fibrosis was confirmed in 17.1% and cirrhosis in 2.9% by repeated LSM ≥ 8 and ≥ 12 kPa respectively. The median TE-value in never HCV-infected haemophiliacs was comparable with what has been found in healthy non-haemophiliacs. In Danish haemophiliacs where liver biopsy has not routinely been used for assessing severity of liver fibrosis, LSM identified advanced liver disease in one-fifth of cases that had not been recognized during clinical follow-up.

Muscle bleeds in professional athletes--diagnosis, classification, treatment and potential impact in patients with haemophilia.

Muscle haematoma represents 10-25% of bleeds in patients with severe haemophilia. There is limited consensus on diagnostic or treatment strategies and little knowledge about the natural history of muscle haematoma and optimal treatment goals. The aim of this review was to perform a systematic description of the natural history of muscle haematoma in healthy athletes, focusing on diagnosis, classification and treatment options. Publications and educational textbooks on management of sports injuries were used as data source. Muscle haematomas occur following contusion, strain, or laceration and can be categorized as mild, moderate, or severe. Muscle haematoma may be inter- or intramuscular. In healthy athletes, the healing process takes 20-40 days. Optimal diagnosis includes history, physical examination (inspection, palpation, active and passive range of motion (ROM) test, muscle length test, isometric strength test, biomechanical examination, full spinal examination, peripheral nerve test and slump test), ultrasound, MRI or CT. Treatment is conducted based on: (i) super-acute stage, control of the bleeding and minimizing the size of the haematoma; (ii) acute stage, restoration of pain-free ROM; (iii) subacute stage, functional rehabilitation; and (iv) gradual return to normal activity. Treatment and preventive strategies include RICE (rest, ice, compression and elevation), protected mobilization, stretching and strengthening exercises, manual therapy (articular, neural and soft tissue mobilization and massage), correction of movement dysfunction, functional rehabilitation and electro-therapeutic interventions. The study reviews the natural history of muscle haematoma and state-of-the-art diagnosis and treatment in healthy athletes. Results may be useful to optimize diagnosis and treatment of muscle haematoma in patients with haemophilia.

Current practice in the management of muscle haematomas in patients with severe haemophilia.

Muscle haematomas (MH) represent 10-25% of all bleeds in patients with severe haemophilia. We performed a cross-sectional survey on current practice in the management of MH with participation from 22 consultants. The respondents reported 492 MH/year, corresponding an average of 25/centre, mostly associated with trauma. Iliopsoas (55%), calf (18%) and thigh (18%) bleeds were scored as most serious. Half of the respondents distinguished between contusion and strains, whereas the majority (68.2%) did not categorize bleedings as intra- or intermuscular, although 77.3% routinely used ultrasound. Half of the respondents used a standard protocol for the management of MH. Twenty of 22 (90.9%) respondents offered physiotherapy in the hospital following MH, with no clear consensus on timing and type of treatment. In a theoretical case, for a 70-kg patient with a soleus triceps haematoma, the average initial dose of factor VIII was 2730 U (range: 1750-4000) twice daily for 3-5 days. In a similar case of a patient with inhibitors, 31.8% reported first-line and only use of either recombinant factor VIIa (rFVIIa) or activated prothrombin complex concentrate (APCC), while 36.4% switched between bypassing agents. Using rFVIIa, the median dose was 100 µg/kg (range: 85-270) and with APCC, the median dose was 70 U kg(-1) (range: 50-100). The majority (68.2%) did not use antifibrinolytics. Resolution of pain (81.8% & 77.3%) was regarded as the key clinical marker of arrest of bleeding as compared with diminished swelling and improved range of motion. The survey outlines limited consensus in the management of MH in patients with haemophilia and highlights potential topics for future studies.

Utility of the Haemophilia Joint Health Score in study of episodically treated boys with severe haemophilia A and B in Lithuania.

Musculoskeletal outcome remains the major hallmark of haemophilia. The purpose of the study was to assess joint status using a new musculoskeletal assessment tool in children with haemophilia and describe the development of haemophilic arthropathy during childhood and puberty focussing on the age of remarkable changes. The prospective study involved Lithuanian patients aged 4-17 years with severe haemophilia A and B, no signs of inhibitors and treatment on-demand. Patients were subdivided into two groups according to actual age. Group I patients were 4-9 years and group II patients 10-17 years of age. The musculoskeletal status was measured using the Haemophilia Joint Health Score (HJHS). We report on 20 patients with a mean age of 11.5 years (SD 4.3, range 4-17.2 years). The mean HJHS score was 24.5 (SD 14.5, range 5-50). The most affected joints were ankles, followed by knees and elbows. Mean HJHS score in age group I (n = 7) was 11.6 (SD 6.5); in group II (n = 13) the score was significantly higher - mean 31.5 (SD 12.8) (P = 0.0002). Ankles, knees and elbows were significantly more impaired based on the HJHS scores in older patients as compared with younger ones. The HJHS appears to be a useful tool in evaluating musculoskeletal outcome of patients receiving treatment on-demand. Children > or =10 years of age had significantly higher HJHS scores as a sign of progressing haemophilic arthropathy. We conclude that the most aggravating development of haemophilic joint damage seems to occur from the age of 10 and onwards.

Clinical benefit of recombinant factor VIIa in management of bleeds and surgery in two brothers suffering from the Bernard-Soulier syndrome.

Bernard-Soulier syndrome (BSS) is a rare congenital bleeding disorder characterized by thrombocytopenia and giant platelets that display impaired or absent platelet agglutination with ristocetin. The disease is caused by mutations in genes controlling the expression of the platelet glycoprotein Ib-IX complex. The most severely affected patients suffer from profound muco-cutaneous bleeding tendency. Patients suffering from BSS may require platelet transfusion in prevention and management of severe bleeding. However, recent publications have suggested that recombinant factor VIIa (rFVIIa) infusion may support haemostasis in BSS. The present report describes two brothers who received treatment with rFVIIa together with tranexamic acid on a total of six occasions in management of haemostasis in minor surgery and for a serious spontaneous upper gastrointestinal tract bleed. Although platelet transfusion was omitted, haemostasis was regarded excellent in all of these treatment episodes.

Cardiac surgery in patients with haemophilia.

Today the populations of haemophilia patients in many countries have a higher life expectancy than previously known, and age-related disorders such as arterial disease are expected to become more prevalent, calling for surgical intervention. Cardiac surgery constitutes a major haemostatic challenge because of sternotomy, the need of total heparinization, extracorporal circulation, mild hypothermia and cardiac arrest. To evaluate our current experience and results with cardiac surgery in patients with haemophilia the present case series report on six patients with haemophilia A (Severe = 1, Moderate = 1, Mild = 4) undergoing cardiac surgery (coronary artery bypass grafting; CABG = 2, aortic valve replacement = 1, CABG + aortic valve replacement = 2, ventricular resection + mitral valve reconstruction = 1). The present paper provides detailed information on the haemostatic treatment regimens adopted (factor concentrate dosages, timing and duration) and postoperative thromboprophylaxis (dosing and duration of low molecular weight heparin). Moreover, we present data on concomitant disorders (hypertension, hypercholesterolaemia, atrial fibrillation and diabetes), left ventricle ejection fraction (30-60%), type of anaesthesia, total amount of heparin (34 500-53 500 IU) and duration of extracorporeal circulation (80-115 min). Clinical outcomes included: re-operation because of bleeding (none), transfusion requirements, peri- and postoperative blood loss and complications and postoperative development of inhibitors (none). Clinical outcomes were compared with a control group of patients (n = 5993) without haemophilia and we found no difference in postoperative morbidity. Adopting meticulously supervised haemostatic treatment regimens, we have successfully performed major cardiac surgery in patients with haemophilia A. The clinical outcome as well as the severity and incidence of postoperative complications were similar to patients without haemophilia.

Assay discrepancy in mild haemophilia A: entire population study in a National Haemophilia Centre.

Assay discrepancy in mild haemophilia, here defined by a significantly higher factor VIII (FVIII):C response by the one-stage procoagulant assay as compared with a two-stage enzymatic method, has repeatedly been reported in literature. The purpose of this study was to determine the overall prevalence of this phenomenon amongst mild haemophilia families from a population of 2.95 million inhabitants in the Western Danish region. Information was collected retrospectively through a thorough search of archives of the National Haemophilia Centre in Aarhus. We identified 109 patients with mild haemophilia A amongst whom 92 were eligible to enter the study. These represent a total of 53 unrelated families. Our data illustrate that this assay discrepancy pattern is found quite frequently amongst our mild haemophilia A families. While the ratio of FVIII:C chromogenic/FVIII:C clot values was quite consistent amongst patients belonging to same family pattern, ratios in the entire cohort of families ranged from 0.18 to 1.00. Selecting a cut-off level for the FVIII:C chromogenic/FVIII:C clot ratios at 0.7, 0.6 and 0.5, respectively, we found that 38 (72%), 27 (51%) and 19 (36%) of families, respectively, displayed this assay discrepancy. In 10 patients, the FVIII:C chromogenic level was inside the category of moderate haemophilia at >0.01-<0.05 IU mL(-1), pointing to a class-shift in the biochemical phenotype. In conclusion, our data illustrate a substantial prevalence of the assay discrepancy phenomenon amongst mild haemophilia A patients in our geographical area.

Consensus protocol for the use of recombinant activated factor VII [eptacog alfa (activated); NovoSeven] in elective orthopaedic surgery in haemophilic patients with inhibitors.

Patients with haemophilia complicated by inhibitors have a significant burden of joint disease, which is associated with a negative impact on their quality of life. Successful elective orthopaedic surgery can result in decreased bleed frequency into a new joint, less time spent in hospital, increased mobility and improved well being. This paper describes a new protocol for use of recombinant activated factor VII (rFVIIa) in elective orthopaedic surgery, based on a review of published data as well as the personal experience of a group of expert physicians. The protocol offers guidance on the planning of the surgery and preoperative testing as well as the bolus schedule for rFVIIa and advice on the concomitant use of antifibrinolytic agents and fibrin sealants. A total of 10 operations involving 13 procedures in eight patients in five comprehensive care centres have been undertaken until now using the protocol, which employs an initial bolus dose of rFVIIa in the range of 120-180 microg kg(-1) to cover surgery. The clinical experience reported here encompasses all cases of elective orthopaedic surgery using rFVIIa as initial treatment carried out in the UK and Republic of Ireland over the last 2 years. In all cases, there was good control of haemostasis during surgery and the final outcome was rated as 'excellent' or 'extremely satisfactory' by the reporting clinicians. Although the initial cost of product to cover surgery such as arthroplasty is high, it needs to be borne in mind that this may be offset in subsequent years by savings resulting from avoidance of bleeding episodes in the affected joint.

Recombinant factor VIIa and fibrinogen display additive effect during in vitro haemodilution with crystalloids.

BACKGROUND: Major blood loss requires fluid resuscitation for maintaining hemodynamic stability. Excessive volume infusions predispose to dilutional coagulopathy through loss, consumption and dilution of cells and proteins involved in haemostasis. Further treatment with fibrinogen concentrate and/or recombinant activated factor VII (rFVIIa) may be initiated, although the haemostatic effects in a situation with haemodilution are not fully detailed. The present study evaluates haemostatic effect of fibrinogen and rFVIIa and their combination in an in vitro model of haemodiluted whole blood with two commonly used crystalloids. METHODS: Eight healthy, male volunteers were enrolled. Outcome variables were clot initiation, propagation and strength assessed by thrombelastographic parameters: clotting time, clot formation time, maximum velocity, time until maximum velocity, maximum clot firmness evaluated at dilution levels of 0% (control), 10%, 30% and 50% with isotonic saline and Ringer's lactate in a model of tissue factor-activated whole blood. Fibrinogen and rFVIIa were additional final reaction concentrations, reflecting commonly used clinically therapeutic dosages. RESULTS: Dose-dependent coagulopathy developed following haemodilution with isotonic saline and Ringer's lactate, characterised by a prolonged clot initiation, reduced clot propagation and reduced clot strength. Fibrinogen improved clot strength and propagation phase while rFVIIa shortened clot initiation, both with a positive dose dependency. CONCLUSIONS: The combination of fibrinogen and rFVIIa displays an additive effect and improves overall in vitro whole blood clot formation in a model of in vitro crystalloid-induced haemodilution.