Mild Bleeding Disorders Research Articles

Study of 18 functional hemostatic polymorphisms in mucocutaneous bleeding disorders

Hereditary disorders of primary hemostasis, characterized by mucocutaneous bleeding (MCB), are highly prevalent in children. Few cases are clearly monogenic, but the overwhelming majority are classified as mild bleeding disorders, with wide clinical and laboratory heterogeneity suggestive of complex polygenic diseases. In this framework, and by homology with venous thrombosis, some functional polymorphisms affecting the hemostatic system should be considered. We evaluated the role of 18 common hemostatic polymorphisms on the occurrence and severity of MCB in a case-control study including 269 patients and 286 matched controls consecutively recruited. FV Leiden was associated with milder bleeding severity, assessed by a standardized bleeding score (p = 0.013). Multivariate analysis revealed that three additional polymorphisms protected against MCB (F13 Leu34, OR = 0.66; 95% CI, 0.47-0.94; p = 0.024; VKORC1 1173T, OR = 0.59; 95% CI, 0.40-0.87; p = 0.009; and non-O blood group alleles, OR = 0.59; 95% CI, 0.41-0.86; p = 0.006). When combined, these polymorphisms showed an additive protection (OR = 0.24; 95% CI, 0.11-0.52), supporting the polygenic nature of MCB. Our data suggest that some common polymorphisms affecting hemostasis-related genes could protect from bleeding.

Inhibition of Factor XIa as a New Approach to Anticoagulation

The dose-limiting issue with available anticoagulant therapies is bleeding. Is there an approach that could provide antithrombotic protection with reduced bleeding? One hypothesis is that targeting proteases upstream from the common pathway provides a reduction in thrombin sufficient to impede occlusive thrombosis yet allows enough thrombin generation to support hemostasis. The impairment of intrinsic coagulation by selective inhibition of factor XI (FXI) leaves the extrinsic and common pathways of coagulation intact, making FXI a drug target. This concept is supported by the observation that human deficiency in FXI results in a mild bleeding disorder compared with other coagulation factor deficiencies, and that elevated levels of FXI are a risk factor for thromboembolic disease. Moreover, FXI knockout mice have reduced thrombosis with little effect on hemostasis. The results from genetic models have been supported by studies using neutralizing antibodies, peptide inhibitors, and small-molecule inhibitors. These agents impede thrombosis without affecting bleeding time in a variety of experimental animals, including primates. Together, these data strongly support FXIa inhibition as a viable method to increase the ratio of benefit to risk in an antithrombotic drug.

Diagnosis of mild bleeding disorders.

The precise diagnosis of a severe haemorrhagic disorder is usually not too problematic. However, physicians are most often faced with individuals consulting for mild haemorrhagic symptoms, particularly occurring after a surgical intervention. The problem here is to evaluate whether this person really has a bleeding disorder requiring special investigations and treatments, particularly if another invasive procedure is planned. The key point is to ask the appropriate questions to discriminate bleeding occurring in normal subjects from that occurring in patients with haemostatic disorders. Recently, bleeding questionnaires allowing the calculation of bleeding scores have been proposed. Although they have some limitations, they are of help to better define and quantify the bleeding symptoms and to guide in the choice of selecting laboratory testing. This review focuses on inherited and not on acquired bleeding disorders.

Diagnosis of mild bleeding disorders.

The precise diagnosis of a severe haemorrhagic disorder is usually not too problematic. However, physicians are most often faced with individuals consulting for mild haemorrhagic symptoms, particularly occurring after a surgical intervention. The problem here is to evaluate whether this person really has a bleeding disorder requiring special investigations and treatments, particularly if another invasive procedure is planned. The key point is to ask the appropriate questions to discriminate bleeding occurring in normal subjects from that occurring in patients with haemostatic disorders. Recently, bleeding questionnaires allowing the calculation of bleeding scores have been proposed. Although they have some limitations, they are of help to better define and quantify the bleeding symptoms and to guide in the choice of selecting laboratory testing. This review focuses on inherited and not on acquired bleeding disorders.

C1584: Effect on von Willebrand Factor Proteolysis and von Willebrand Factor Antigen Levels

The present review provides a clearer picture of the effect of C1584 on the level and properties of von Willebrand factor (VWF). The C1584 variant is associated with decreased VWF levels (especially in combination with blood group O) and VWF function, and with slightly enhanced VWF proteolysis, and there is evidence to support its association with enhanced VWF clearance. These properties help explain the enrichment for C1584 in mild type 1 VWD and the observed marked association of the variant and blood group O in this mild bleeding disorder. It has been proposed that the mildly enhanced VWF proteolysis associated with C1584 (and also with blood group O) may compromise clot formation, offering a further rationale for the enrichment of the variant in type 1 VWD. C1584 shows variable penetrance and this is still not fully understood. It reflects the interaction of C1584 with other variables, one of which is clearly blood group O. Genome-wide association studies aimed at identifying loci involved in the control of the VWF level may provide further insights into C1584 penetrance and, more generally, into mechanisms underlying type 1 VWD and also cardiovascular disease.

The Level of Laboratory Testing Required for Diagnosis or Exclusion of a Platelet Function Disorder Using Platelet Aggregation and Secretion Assays

The major advances from research on platelet molecular and cell biology, physiology, and pathophysiology over the past decades have not been adequately translated to clinical laboratory diagnosis. Hereditary platelet function disorders (PFDs) are at least as prevalent in the general population as von Willebrand disease (VWD) although PFDs tend not be as well recognized or evaluated. Clinical mucous and skin bleeding in patients with PFDs is prototypic of primary hemostasis disorders, and the bleeding pattern is not distinguishable from that of other primary hemostasis disorders such as VWD. However, different treatment needs, between these discrete disorders, make a precise diagnosis mandatory. Currently, clinicians receive reliable laboratory reports when testing patients with severe PFDs, such as Glanzmann thrombasthenia and Bernard-Soulier syndrome, due to the distinctive laboratory defects that these disorders present, together with the availability of differential diagnostic tests. This is not the case for the majority of PFDs generically classified as "platelet secretion disorders," which are a heterogeneous group of "mild bleeding disorders," for which there are not universally accepted diagnostic criteria. An important reason for robust diagnostic tests is the high proportion (more than 50% in some reports) of patients with unequivocal bleeding who have no precise diagnosis established after a complete laboratory workup. It is paradoxical that the current "gold standard" test for PFD diagnosis, light transmission aggregometry (LTA), has not been standardized after more than four decades of worldwide clinical use. This review describes current diagnostic assays for PFD in a clinical hemostasis laboratory, relating these with current knowledge on platelet function and pathophysiology. Special emphasis will be given to LTA and platelet secretion tests, as well as to the reasons why sensitive tests are needed to explore the lesser known participation of platelets in blood clotting and fibrinolytic processes.

Laboratory Assessment of Familial, Nonthrombocytopenic Mucocutaneous Bleeding: A Definitive Diagnosis Is Often Not Possible

Patients with inherited mucocutaneous bleeding (MCB) pose frequent and significant diagnostic challenges. Bleeding symptoms are frequent among the otherwise healthy population, and the clinical distinction between normal subjects and patients with genuine bleeding disorders is complex. Screening or global laboratory assays are nonspecific and have low sensitivity to detect mild bleeding disorders. Moreover, there are inherent difficulties in diagnosing von Willebrand disease and platelet function defects, the best-characterized and most frequent disorders of primary hemostasis. On the other hand, some patients with moderate to severe clotting factor deficiencies and those with increased fibrinolysis usually present with MCB. Finally, in a significant proportion of patients, the definitive diagnosis is not possible even after an extensive laboratory workup. This article reviews the clinical and laboratory approach to the diagnosis of patients presenting with MCB, the limitations of the available methodologies to evaluate the clinical significance of bleeding, and the diagnostic yield of global and specific hemostasis tests used to investigate these patients.

Mild bleeding disorders: review of 120 patients

Of 120 patients presenting with mild bleeding disorders, 63 were found to have a definite coagulopathy. The commonest disorders were haemophilia, Christmas disease and von Willebrand's disease (vWd), the latter being predominant. Diagnosis led to prophylactic treatment prior to surgery in 18 patients with prevention of excessive haemorrhage. Three patients who had received blood products developed hepatitis. DDAVP (desamino-cys-1-8-D-arginine vasopressin) is the treatment of choice in suitable mildly affected patients with haemophilia A and vWd. Examination of blood group distribution suggests an excess of group O among patients with bleeding disorders, especially those with vWd.

Relevance of quantitative assessment of bleeding in haemorrhagic disorders

In the last few years, there has been a growing interest in the diagnosis of mild bleeding disorders (MBD) to find reliable tools for the assessment of their inherent bleeding risk and minimum criteria for the definition of a clinically useful diagnosis. Unlike in more severe haemorrhagic disorders, in MBD, the bleeding history may overlap with that reported by normal people. This problem has required the development of strategies that could allow the assessment of bleeding symptoms from both a qualitative (presence or absence) and quantitative (bleeding severity) aspect. An example of high quality clinical research in bleeding disorders was given by the systematic approach used for the evaluation of menorrhagia. For this symptom, the most common in women with bleeding disorders, the use of pictorial charts provided many new insights. Dr Kadir will review its use in a clinical context. The assessment of the whole bleeding history requires first, the development of reproducible tools to collect symptoms and secondly, formulation of easily applicable criteria to convert the collected data into clinical information. Dr Tosetto will propose a bleeding questionnaire in which clinical criteria were developed and validated, and show how a summative, quantitative index of bleeding severity (the Bleeding Score) could be used in von Willebrand disease. Finally, Dr James will review the development of quantitative analysis in children, a particularly important and difficult application, but one that needs to be tackled urgently.

Four novel FXI gene mutations in three factor XI- deficient patients

Hereditary factor XI deficiency is a mild bleeding disorder, which is highly prevalent among Ashkenazi Jews, but has been reported in all populations. In Ashkenazi Jews, two factor XI gene mutations Glu 117X (type II) and Phe283Leu (type III) are particularly common. In other ethnic groups, factor XI deficiency is a rare bleeding disorder and is related to a variety of mutations throughout the factor XI gene. Three cases of quantitative factor XI deficiency in relation with four novel missense mutations are reported: a compound heterozygosity for two novel mutations (Ala 181 Val and Ala 412 Thr) with a severe factor XI deficiency and two missense mutations (His 388 Pro and Trp 407 Cys) in heterozygous patients with partial factor XI deficiency.

The Prevalence of Bleeding Disorders Among Healthy Pediatric Patients With Abnormal Preprocedural Coagulation Studies

We evaluated the prevalence of hemostatic disorders among pediatric patients with abnormal screening coagulation tests. We analyzed 48 consecutive referrals for abnormal prothrombin times, partial thromboplastin times, or closure times obtained as preprocedural screens. Patients were evaluated by uniform diagnostic testing. Seventeen patients (35%) had an isolated nonspecific inhibitor (NSI). Six patients (12.5%) presented with mildly low factor activity with a concomitant NSI. These deficiencies were of unclear clinical significance. One patient (2%) had a lupus anticoagulant. Only 9 patients (19%) had a possible or true mild bleeding disorder: 5 patients (10%) had isolated low von Willebrand factor levels, 2 patients (4%) had possible type I von Willebrand disease, and 2 (4%) had platelet aggregation disorders. In all patients, personal and family bleeding history had a positive predictive value of 45% for hemostatic disorders. The most common diagnosis among the patients referred to us for abnormal preoperative coagulation tests was a NSI, which is not associated with an increased risk of operative bleeding complications. Less than 20% had a possible or true mild bleeding disorder. Although certain bleeding disorders can be occult in children and are associated with perioperative bleeding risks, our study demonstrates the inherent limitations in making a laboratory diagnosis of a bleeding disorder in pediatric patients preoperatively. Our findings contribute to existing doubt about the usefulness of prothrombin times, partial thromboplastin times, and closure times to identify occult bleeding disorders in this population.

Bleeding Complications and Pregnancies in an Established Plasminogen Activator Inhibitor, Type-1 (PAI-1) Deficient Population.

In 1992, a young Amish girl with marked post-procedural bleeding was found to have a PAI-1 deficiency with a homozygous frame shift mutation in exon 4 of the PAI-1 gene that results in a non-functional protein. This mutation was tracked within the ancestors of this Amish community and two individuals were identified that likely introduced this gene into the community. In 1997, seven children (including the proband) from two families within the kindred were described with symptoms consistent with a mild bleeding disorder. Two further homozygous children, one from a third family within the kindred, have subsequently been identified. Presently, over 300 members of this kindred have been tested with nearly 100 identified heterozygotes, none of whom have experienced bleeding complications. The homozygotes all have had bleeding problems with injury a common cause. Five of the nine homozygotes have had head trauma, resulting in significant bleeding complications. ε-aminocaproic acid (EACA) initiated early controls bleeding. One child had a recurrence of his subdural hematoma when he discontinued the EACA upon discharge from the hospital. But the bleeding was subsequently controlled with reinstitution of EACA, and the child had a full recovery. Another common bleeding complication is menorrhagia with all homozygous females experiencing this symptom, and two even requiring red blood transfusions due to severe anemia. Currently, these women require concurrent EACA with onset of menses to control bleeding. Of interest PAI-1 and the plasminogen activation system have been shown to play an important role in embryo implantation, and it was unknown whether homozygous PAI-1 deficient women would be able to conceive and maintain a pregnancy. We now report 2 of these homozygous deficient females have become pregnant; one remains pregnant at 28 weeks gestation, and one delivered at 32 weeks. This child represents that first documented birth to a woman with complete PAI-1 deficiency. The mother experienced abnormal cervical bleeding beginning at 27 weeks requiring EACA therapy which was continued until delivery and for about 7 days post-partum without abnormal bleeding at delivery or in the post-partum period, and without ill effect on the fetus. This cohort is the largest group of PAI-1 deficient patients ever documented. The molecular defect is well defined so that it is simple to differentiate normals from heterozygotes and homozygotes. Continued follow-up will allow further understanding of the role of PAI-1 in human physiology.

FcγRIIa Is Required for Outside-In β3 Integrin Signaling in Human Platelets.

ITAMs (Immunoreceptor Tyrosine-based Activation Motifs) are signaling motifs that are found within the cytoplasmic domains of T and B cell antigen receptors, and in the Fc receptor γ (FcRγ) chain that is associated with Fc receptors for IgG and IgE and with the GPVI collagen receptor on platelets. ITAMs are also an intrinsic component of the cytoplasmic domain of the platelet and leukocyte low affinity receptor for IgG, FcγRIIa. When ITAM-bearing receptors are engaged or cross-linked, ITAM tyrosines undergo Src-dependent phosphorylation, providing a docking site for the protein-tyrosine kinase, Syk. Activation of Syk results in assembly of a multi-protein signaling complex containing the adaptor molecule SLP-76, ultimately resulting in the activation of phospholipase Cγ2 (PLCγ2), which via its lipase activity initiates a multitude of cellular activation responses. Recent studies in platelets and neutrophils have found that ITAM-mediated signaling cascades also play a novel and unexpected role in outside-in integrin signaling, as cells containing mutant forms of Syk, SLP-76, or PLCγ2 fail to become activated normally following integrin engagement. Furthermore, the FcRγ chain and DAP12 have been identified as ITAM-bearing subunits required for integrin signaling in neutrophils and macrophages, and we and others have reported that the GPVI/FcRγ chain complex can function as a weak integrin amplifier in human platelets. Nevertheless, the complement of ITAM-bearing receptors in platelets that are involved in integrin signaling in platelets is not known. To identify candidate receptors that might couple integrins to ITAM signaling, we initiated fibrinogen (Fg) binding to the integrin αIIbβ3 by1.activating the thrombin receptor, PAR1, on platelets in suspension, or2.by allowing platelets to spread directly on immobilized Fg.Interestingly, both forms of platelet activation initiated strong, ligand binding-dependent tyrosine phosphorylation of FcγRIIa, as well as downstream phosphorylation of Syk and PLCγ2. Importantly, prior addition of Fab fragments of the FcγRIIa blocking monoclonal antibody, IV.3, inhibited platelet spreading on immobilized Fg, as well as downstream tyrosine phosphorylation of FcγRIIa, Syk, and PLCγ2. Finally, platelets from a patient with a mild bleeding disorder whose platelets express only 30% of the normal level of FcγRIIa exhibit markedly reduced spreading on immobilized Fg. Taken together, these studies identify FcγRIIa as the major ITAM-bearing receptor in human platelets that supports outside-in integrin signaling.

Can blood flow assays help to identify clinically relevant differences in von Willebrand factor functionality in von Willebrand disease types 1-3?

Can blood flow assays help to identify clinically relevant differences in von Willebrand factor functionality in von Willebrand disease types 1-3?

Platelet glycoprotein VI‐related clinical defects

Human patients with defects associated with the platelet collagen receptor, glycoprotein (GP)VI, are rare and usually described as having a mild bleeding disorder. However, here we review clinical profiles of patients with familial or acquired GPVI defects, revealing the bleeding defect is often severe and associated with immune dysfunction. GPVI is a member of the immunoreceptor family, and co-expressed on platelets with Fc receptor gamma-chain (FcRgamma). Ligand binding to GPVI leads to activation of platelet integrins, in particular alpha(IIb)beta(3) that mediates platelet aggregation; and activation of endogenous platelet metalloproteinases resulting in ectodomain shedding and release of a soluble GPVI fragment. Increasing evidence supports the functional importance of GPVI/FcRgamma in thrombus formation at arterial shear rates, and expression levels of platelet GPVI may be a marker of thrombotic risk. Over the past 20 years, patients have been reported with GPVI-related defects involving: (i) an acquired deficiency, resulting from (a) anti-GPVI autoantibodies or (b) other causes; or (ii) a congenital deficiency, where (c) GPVI is not expressed or (d) is expressed in a dysfunctional form with defective signalling to alpha(IIb)beta(3). Clinical consequences of GPVI-related defects may be uniquely informative about the role of platelet GPVI in health and disease.

Hereditary Factor VII Deficiency in the Alaskan Klee Kai Dog

Background: Hereditary factor VII (FVII) deficiency is characterized as a mild bleeding disorder in Beagles, caused by a missense mutation in exon 5 of the FVII gene. An Alaskan Klee Kai dog with severe bleeding after trauma was diagnosed with FVII deficiency based on coagulation testing. Molecular analyses were undertaken to identify the genetic basis of the defect in this breed. Hypothesis: FVII deficiency in Alaskan Klee Kai dogs is caused by a mutation in the FVII gene. Animals: Eighteen client‐owned Alaskan Klee Kai. Methods: Coagulation screening tests and factor assays were performed to characterize the coagulopathy. All coding regions of the propositus' FVII gene were sequenced. Amplification of exon 5, sequencing, and Mnl I restriction digest experiments were performed to screen for a point mutation in the remaining 17 dogs. Results: FVII deficiency was diagnosed in 6 dogs with a median FVII activity (FVII:C) of 5% (reference range, 50–150%). All FVII‐deficient Alaskan Klee Kai were homozygous for the same mutation as FVII‐deficient Beagles (ie, a G to A transition), resulting in substitution of glycine 96 by glutamic acid. An overlap in the FVII: C values obtained from heterozygote and wild‐type dogs precluded accurate detection of carriers without genetic screening. Conclusions and Clinical Importance: FVII deficiency may be associated with a bleeding tendency and should be considered in Alaskan Klee Kai dogs with prolonged prothrombin times. Plasma FVII:C accurately identifies affected dogs, but deoxyribonucleic acid testing is required for identification of carriers.

Approach to the diagnosis and management of mild bleeding disorders.

Symptoms suggestive of the presence of a mild bleeding tendency are commonplace. Whilst the majority with such symptoms are healthy, it is important to identify those with bleeding disorders in order to manage symptoms, to minimize risk from invasive procedures and to avoid unnecessary exposure to blood products. Thorough clinical assessment remains the cornerstone of the diagnostic strategy for mild bleeding disorders, although the sensitivity and specificity of the clinical history and examination are limited. When clinical suspicion is aroused the use of a staged protocol of laboratory investigations is appropriate, but the limitations of currently available tests of primary hemostasis and blood coagulation must be recognized if diagnostic errors are to be avoided. Whilst there is considerable current interest in global assays of hemostasis and coagulation, none has yet been demonstrated conclusively to be more effective than the more standard approach. Iatrogenic bleeding has increasing prominence in clinical practise. The expanding use of anticoagulants and platelet inhibitor drugs has resulted in an increased proportion of the population being at risk of abnormal bleeding. Knowledge of the levels of risk associated with particular drugs and combinations, and the advantages and hazards of interruption of drug use for planned interventional procedures, are essential in order to reduce the incidence of iatrogenic bleeding. Prevention and treatment of hemorrhage in subjects with mild bleeding disorders includes the application of general measures, including attention to surgical technique, measures specific to the precise diagnosis, and less specific treatments that enhance hemostasis and coagulation or inhibit fibrinolysis. The last of these includes the widely prescribed drugs desmopressin, aprotinin, epsilon aminocaproic acid and tranexamic acid. Data are now available on their efficacy and safety in a range of clinical situations.

How to estimate bleeding risk in mild bleeding disorders.

The concept of mild bleeding disorders (MBD) has evolved in contrast to severe hemophilia A and B to indicate less severe disorders, characterized by the presence of more frequent and/or more prominent bleeding symptoms than in the normal population. These symptoms occur mostly after a recognizable challenge and do not lead to major discomfort or organ damage, even in the absence of specific medical intervention. However, it has become clear that, from the most severe to the mildest hemostatic disorders, there is a continuous spectrum of bleeding manifestations, which overlap with the occasional bleeding occurring in people without any identifiable hemostatic abnormality. By reviewing the principal hemorrhagic disorders we have tried to identify those entities that could fit a diagnosis of MBD and result, at the same time, in a net benefit for treatment or prophylaxis of patients rather than being simply accurate. This goal can usually be achieved by comparing the patient's phenotype with known nosological entities. However, limitations of this approach are evident, considering the paucity of clinical data and the biases of most published reports on the different disorders. In addition, in a partial deficiency of a clotting factor, a reliable relationship between the residual activity and bleeding severity is not invariably found. Molecular characterization of the defects is also generally useless. Accordingly, an accurate bleeding history in the propositus and his/her family remains of major importance. For this purpose, new standardized and possibly quantitative tools are being developed in several institutions. Innovative approaches, combining into a single probability phenotypic and genetic data, could possibly estimate better the bleeding risk in specific disorders.

Hereditary Factor VII Deficiency in the Alaskan Klee Kai Dog

Hereditary factor VII (FVII) deficiency is characterized as a mild bleeding disorder in Beagles, caused by a missense mutation in exon 5 of the FVII gene. An Alaskan Klee Kai dog with severe bleeding after trauma was diagnosed with FVII deficiency based on coagulation testing. Molecular analyses were undertaken to identify the genetic basis of the defect in this breed. FVII deficiency in Alaskan Klee Kai dogs is caused by a mutation in the FVII gene. Eighteen client-owned Alaskan Klee Kai. Coagulation screening tests and factor assays were performed to characterize the coagulopathy. All coding regions of the propositus' FVII gene were sequenced. Amplification of exon 5, sequencing, and Mnl I restriction digest experiments were performed to screen for a point mutation in the remaining 17 dogs. FVII deficiency was diagnosed in 6 dogs with a median FVII activity (FVII: C) of 5% (reference range, 50 150%). All FVII-deficient Alaskan Klee Kai were homozygous for the same mutation as FVII-deficient Beagles (ie, a G to A transition), resulting in substitution of glycine 96 by glutamic acid. An overlap in the FVII: C values obtained from heterozygote and wild-type dogs precluded accurate detection of carriers without genetic screening. FVII deficiency may be associated with a bleeding tendency and should be considered in Alaskan Klee Kai dogs with prolonged prothrombin times. Plasma FVII: C accurately identifies affected dogs, but deoxyribonucleic acid testing is required for identification of carriers.

Factor XI Deficiency Confers a Survival Advantage in a Murine Sepsis Model.

Bacterial sepsis is frequently accompanied by intravascular activation of coagulation and fibrinolysis, resulting in a coagulopathy with thrombotic, hemorrhagic, and inflammatory components (disseminated intravascular coagulation - DIC) that contributes significantly to morbidity and mortality. Recently, using vascular occlusion models, the plasma coagulation protease factor XI (FXI) has been shown to contribute to pathologic thrombus formation in primates, mice, and rabbits. These results are supported by epidemiologic studies in human populations that show an association between elevated plasma FXI levels and an increased risk for venous and arterial thrombosis. FXI has also been shown to contribute to the lethal consumptive coagulopathy in protein C deficient mice. To investigate the contribution of FXI to consumptive coagulopathy and mortality in sepsis, we compared wild type (WT) and FXI deficient (FXI−/−) mice in models of polymicrobial sepsis and endotoxemia. Polymicrobial sepsis was induced in WT and FXI−/− C57Bl/6 mice (n = 24 for each genotype) using an established model of cecal ligation and puncture (CLP). Overall survival was 21% for WT and 42% for FXI−/− mice (p < 0.01), with WT deaths occurring between days 2 and 4, and FXI−/− deaths between days 3 and 6. Average survival for mice succumbing to sepsis was 55 ± 10 hr for WT, and 88 ± 22 hr in FXI−/− mice (p < 0.01). 24 hrs after CLP, platelet count in WT and FXI−/− animals decreased 27 ± 13% and 13 ± 12% (p = 0.05), and leukocyte counts decreased by 64 ± 13% and 40 ± 23% (p < 0.01), respectively. Fibrinogen levels 24 hours post-CLP decreased slightly in WT mice (37 ± 34% from baseline), while increasing 212 % ± 74% in FXI−/− mice (p < 0.01). Mice were also challenged with intraperitoneal Escherichia coli endotoxin. Mortality 24 hrs after endotoxin administration was identical for WT and FXI−/− mice (n =15 for each dose) at doses of 50 mg/kg (mortality 80%) and 25 mg/kg (mortality 70%). Twelve hours after administering 25 mg/kg endotoxin, the mean platelet counts in WT animals decreased by an average of 60% (from 440 ± 159/mm3 at baseline to 175 ± 77/mm3, n = 10), and by 36% in FXI−/− animals (from 474 ± 218/mm3 to 303 ± 100/mm3). In summary, prognosis was better for FXI−/− mice in CLP-induced sepsis compared to WT mice, and the CLP and endotoxin data indicate that consumptive coagulopathy is less severe in the absence of FXI. The results suggest that therapeutic inhibition of FXIa activity could be beneficial in treating sepsis-related DIC. Humans with severe congenital FXI deficiency typically have, at most, a mild trauma-induced bleeding disorder. It is possible, therefore, that inhibition of FXIa in DIC may be associated with a lower risk of exacerbating bleeding when compared to anticoagulant therapies such as heparin or activated protein C.