Endometrial haemostasis and menstruation

Under normal physiological circumstances menstruation is a highly regulated, complex process that is under strict hormonal control. During normal menstruation, progesterone withdrawal initiates menstruation. The cessation of menstrual bleeding is achieved by endometrial haemostasis via platelet aggregation, fibrin deposition and thrombus formation. Local endocrine, immunological and haemostatic factors interact at a molecular level to control endometrial haemostasis. Tissue factor and thrombin play a key role locally in the cessation of menstrual bleeding through instigation of the coagulation factors. On the other hand, fibrinolysis prevents clot organisation within the uterine cavity while plasminogen activator inhibitors (PAI) and thrombin-activatable fibrinolysis inhibitors control plasminogen activators and plasmin activity. Abnormalities of uterine bleeding can result from imbalance of the haemostatic factors. The most common abnormality of uterine bleeding is heavy menstrual bleeding (HMB). Modern research has shown that an undiagnosed bleeding disorder, in particular von Willebrand disease (VWD) and platelet function disorders, can be an underlying cause of HMB. This has led to a change in the approach to the management of HMB. While full haemostatic assessment is not required for all women presenting with HMB, menstrual score and bleeding score can help to discriminate women who are more likely to have a bleeding disorder and benefit from laboratory haemostatic evaluation. Haemostatic agents (tranexamic acid and DDAVP) enhance systemic and endometrial haemostasis and are effective in reducing menstrual blood loss in women with or without bleeding disorders. Further research is required to enhance our understanding of the complex interactions of haemostatic factors in general, and specifically within the endometrium. This will lead to the development of more targeted interventions for the management of abnormal uterine bleeding in the future.     

A new, ideal technique to monitor thrombolytic therapy

In an earlier article we have reported a technique which allows the measurement of haemostasis from whole blood by the "tube bleeding" principle. The technique is now progressed by using non-anticoagulated blood and therefore clotting-time is also measured. We report here that the technique allows a simple thrombolytic assay to perform from the same blood sample used for haemostasis measurement by detecting the length of time until the haemostatic plugs crack or are expelled. Evidence is presented that this "spontaneous" expulsion is mainly due to thrombolysis. Generation of thrombin during haemostasis is indicated by the inhibitory effect of hirudin. 125I-fibrinogen accumulates (28-fold) in the haemostatic plugs. Plasminogen activators (streptokinase and urokinase) reduce while inactivation of plasminogen by specific antibody greatly prolongs the expulsion-time. The effect of cytochalasin B shows that the retraction of the haemostatic plug is not a decisive factor of the expulsion. As the technique allows the simultaneous measurement of haemostasis, thrombolysis and clotting, it seems ideal for monitoring thrombolytic therapy.     

Comparative effects of proteinase inhibitors, plasminogen antiactivators, heparin and acetylsalicylic acid on the experimental disseminated intravascular coagulation induced by thormbin

In an experimental study in the rabbit, the modifications of some haemostasis parameters (platelet count, platelet retention and aggregation, platelet factors 3 and 4, platelet and plasma plasmin inhibiting activities, fibrinogen and other plasma factor levels, FDP), and histological findings are compared in both the normal animal and the animal with disseminated intravascular coagulation (DIC) induced by thrombin perfusion after administration of fibrinolytic inhibitors (plasminogen antiactivators and proteinase inhibitors). In the normal animal, the administration of fibrinolytic inhibitors is followed by haemostatic changes similar to those found in thrombophilic states. The modifications are more pronounced with plasminogen antiactivators than with proteinase inhibitors. In the animal with DIC, the administration of fibrinolytic inhibitors enhances the haemostatic and the biological disorders produced by thrombin perfusion. The effect of the plasminogen antiactivators is even more evident. The preventive administration of heparin reduces or abolishes the biological and histological disorders induced by thrombin; its beneficial effect is considerably reduced when thrombin is combined with fibrinolytic inhibitors. The administration of acetylsalicylic acid appears to be ineffective for the prevention of haemostatic and histological changes induced by thrombin perfusion.     

Safety,pharmacokinetics and efficacy of factor VIIa formulated with PEGylated liposomes in haemophilia A patients with inhibitors to factor VIII – an open label,exploratory, cross‐over,phase I/II study

Summary. Recombinant activated factor VIIa (FVIIa) is a bypassing agent used to treat bleeding episodes in haemophilia patients with inhibitors to factor VIII (FVIII) and factor IX. The pharmacological effect of FVIIa is short‐lived and therefore with the recommended dose of 90 μg kg^?1, a bleeding episode is treated with multiple injections. A long‐acting form of FVIIa that can ensure adequate haemostasis with a single infusion, without increasing the thrombotic risk, would therefore be beneficial. PEGylated liposomes (PEGLip) have been shown to bind FVIIa and to improve haemostatic efficacy in preclinical experiments. In the present phase I/II clinical trial, we assessed the safety and efficacy of PEGLip‐formulated FVIIa in severe haemophilia A patients (FVIII ≤ 1%) with inhibitors to FVIII. Each patient received one prophylactic infusion of standard FVIIa and one prophylactic infusion of PEGLip‐formulated FVIIa. The order of the infusions was randomized and the two infusions were separated by a ten‐day washout period. Efficacy assessed by thromboelastography revealed that PEGLip‐FVIIa induced significantly shorter clotting times and produced higher clot firmnesses than standard FVIIa. Thrombin generation assays showed that PEGLip‐FVIIa induced faster thrombin generation and higher peak levels of thrombin than standard FVIIa. These effects lasted up to 5 h postinfusion. Measurements of D‐dimer, prothrombin fragment 1 + 2 and fibrinogen showed no significant differences between the PEGLip‐FVIIa and standard FVIIa treatments. PEGLip‐FVIIa therefore showed improved haemostatic efficacy without increased risk of thrombosis and may be further developed for the treatment for bleeding episodes in haemophilia patients with inhibitors.     

Shear-induced in-vitro haemostasis/thrombosis tests: the benefit of using native blood.

The historical development of in-vitro bleeding time tests, using solely shear forces to initiate haemostatic plug formation, in the absence of the vessel wall or its components, is described. Techniques that have no potential for routine use in clinical practice, such as flow chambers and cone-and-plate viscometers, are excluded. The problems related to the use of citrated blood in platelet function tests are discussed. In light of the pivotal role of thrombin and platelet-dependent thrombin generation in haemostasis/thrombosis, the advantage and clinical benefits of testing unadulterated native blood is discussed.     

Generalized Proteolysis in a Young Woman with Weber-Christian Disease (Nodular Nonsuppurative Panniculitis)

A patient with Weber-Christian disease (syn. nodular nonsuppurative panniculitis) is reported. The generalized cellular destruction in this patient resulted in liberation of proteolytic enzymes into the circulation, which led to multiple haemostatic disturbances with haemorrhagic diathesis. The most prominent haemostatic defects were thrombocytopenia with a normal life span of isologous platelets, high levels of AHF-related antigen, hypofibrinogenaemia with short fibrinogen survival, low levels of Factor XIII (fibrin stabilizing factor = FSF) and increased amounts of fibrin/fibrinogen degradation products (FDP). Proteolytic enzymes, other than thrombin and plasmin which especially degrade Factor XIII and fibrinogen, derived from destroyed cells (probably leukocytes) seem to have been involved in the pathogenesis of the bleeding disorder in this patient.     

Fibrin glue

Fibrin glue is a topical biological adhesive, the effect of which imitates the final stages of coagulation. The glue consists of a solution of concentrated human fibrinogen which is activated by the addition of bovine thrombin and calcium chloride. The resultant clot aids haemostasis and tissue sealing and is completely absorbed during wound healing without foreign body reaction or extensive fibrosis. The fibrinogen component of fibrin glue can be produced from fresh frozen plasma obtained from single unit donations thereby reducing the risks of transfusion transmitted infections encountered by exposure to pools from large numbers of donors. Methods involving precipitation of fibrinogen by cryoprecipitation, polyethylene glycol or ammonium sulphate have been described and evaluated. The risk of transmission of infection can be further reduced by using plasma from 'accredited donors' who are plasma donors regularly tested for ALT and markers of viral infection or by use of fibrinogen prepared in advance of surgery from autologous blood. The second component, a mixture of thrombin and CaCl2, is quantitatively and qualitatively well defined and commercially available (Armour Pharmaceutical Co., Thrombinar (bovine thrombin]. Thrombin is applied to the operation site simultaneously and in equal volume to the fibrinogen but from a separate syringe. In the UK a commercial heat treated fibrin glue prepared from pooled plasma is available on a doctor/named patient basis (Tisseel, Immuno, Vienna). The haemostatic and adhesive properties of fibrin glue can be employed in virtually every surgical specialty. The usefulness of the glue is particularly well documented in the fields of cardiovascular surgery, ENT and neurosurgery.(ABSTRACT TRUNCATED AT 250 WORDS)     

History and evolution of dorsal onlay urethroplasty for bulbar urethral stricture repair using skin or buccal mucosal grafts

OBJECTIVES. To illustrate the history and the evolution over time of bulbar dorsal onlay urethroplasty, comparing outcomes when using buccal mucosa or skin grafts. MATERIALS AND METHODS. Ninety-four patients underwent bulbar urethral reconstruction using two dorsal onlay techniques, namely augmented anastomotic urethroplasty and dorsal onlay graft urethroplasty. Preoperative evaluation included clinical history, physical examination, urine culture, residual urine measurement, uroflowmetry and urethrography. Thirty-four patients underwent augmented anastomotic urethroplasty using penile skin (10 cases) or buccal mucosa (24 cases) grafts. Sixty patients underwent dorsal onlay graft urethroplasty using penile skin (38 cases) or buccal mucosa (22 cases) grafts. Forty-eight out of 94 patients received skin grafts and 46 buccal mucosal grafts. RESULTS. Sixty-four (68%) out of 94 cases were successful, whereas 30 (32%) failed. The 34 augmented anastomotic urethroplasties provided successful outcomes in 24 cases (70.6%), but poor outcomes in 10 (29.4%) cases. The 60 dorsal onlay graft urethroplasty proved to be successful in 42 cases (70%), failing in 18 (30%) cases. Twenty-eight (58.3%) out of 48 penile skin grafts were successful and 20 (41.7%) failed. Thirty-six (78.3%) out of 46 buccal mucosa grafts were successful and 10 (21.7%) failed. The 30 failed cases were then treated with internal urethrotomy in 14 cases (46.7%), perineal urethrostomy in 8 cases (26.7%), two-stage repair in 4 cases (13.3%), and one-stage repair in 4 cases (13.3%). CONCLUSIONS. The dorsal onlay technique used for bulbar urethral stricture repair has changed over time. In our experience, the buccal mucosa seems to be the best substitute graft material for bulbar urethroplasty using dorsal approach.     

Reinfusion of aspirated pericardial blood during CPB. Part II. Laparotomy sponges are hazardous parts of the CPB circuit?

Usually, cotton laparotomy sponges are discarded when they become blood soaked. During bypass surgery, however, they are often wrung out into the pericardial sac and the contents of the sac are aspirated into the cardiopulmonary bypass (CPB) circuit. After cardiopulmonary bypass, many patients give evidence of mental confusion, excessive bleeding, and systemic inflammatory response syndrome (SIRS). We believe that a possible cause is reinfusion of blood that has been activated by contact with laparotomy sponges and contains fibrin microemboli and thrombin. Thrombin production, soluble fibrin (SF) development, and fibrinogen disappearance were measured, over time, in model systems composed of increasing amounts (0-10-20 microL) of tissue factor (TF) in 4 ml of anticoagulated blood distributed through the interstices of a 49-cm(2) laparotomy sponge. Clotting occurred in all of the sponges. Clotting was accelerated by the presence of TF. Without TF, clotting occurred in an average of 28 min (range 17-39). With 10 and 20 microl TF, clotting occurred in 20 (range 11-27) and 13 (range 10-16) min, respectively. Thrombin at a level of approximately 16 NIHU/ml whole blood was present in several donors for 10-20 min after clotting was complete. If 120 ml of blood was to be wrung from a full-sized laparotomy sponge at this point in time, it could contain as much as 2000 units of thrombin.     

Fibrin sealant in preclinical and clinical studies.

Fibrin sealant, now commercially available in the United States, is a virally inactivated preparation of highly purified human fibrinogen and human thrombin that includes aprotinin to reduce fibrinolysis. Although the product is relatively expensive, cost can be justified when the sealant is used to produce localized hemostasis in surgery in which bleeding cannot be controlled by sutures. Fibrin sealant can also be justified as an alternative to factor concentrates in patients with coagulopathies who have a localized site of bleeding. Newer formulations of fibrinogen and thrombin in a freeze-dried form applied as a bandage may be useful in immediate, on-site treatment of trauma victims in either a civilian or military setting.     

Generalized proteolysis in a young woman with Weber-Christian disease (nodular nonsuppurative panniculitis).

A patient with Weber-Christian disease (syn. nodular nonsuppurative panniculitis) is reported. The generalized cellular destruction in this patient resulted in liberation of proteolytic enzymes into the circulation, which led to multiple haemostatic disturbances with haemorrhagic diathesis. The most prominent haemostatic defects were thrombocytopenia with a normal life span of isologous platelets, high levels of AHF-related antigen, hypofibronigenaemia with short fibrinogen survival, low levels of Factor XIII (fibrin stabilizing factor = FSF) and increased amounts of fibrin/fibrinogen degradation products (FDP). Proteolytic enzymes, other than thrombin and plasmin which especially degrade Factor XIII and fibrongen, derived from destroyed cells (probably leukocytes) seem to have been involved in the pathogenesis of the bleeding disorder in this patient.     

Evaluation and Treatment of Urethral Stricture Disease

Any process causing trauma to the urethral tissue or underlying corpus spongiosum can lead to urethral stricture disease. The traditional treatment algorithm for urethral strictures, also known as the reconstructive ladder, begins with minimally invasive interventions, including urethral dilation and endoscopic urethrotomy. Inevitably, endoscopic incision and dilation fails, resulting in stricture recurrence. After the expenditure of valuable time and resources, physician and patient frustration finally leads to tertiary center referral with reconstructive urologic expertise. With dramatic advances in urethral surgery, many experts are abandoning the once-favored reconstructive ladder. In light of the excellent success rates for urethroplasty, the controversy continues, as reconstructive specialists now support open surgical treatment over endoscopic management for most urethral strictures.     

Increased activation of protein C, but lower plasma levels of free, activated protein C in uraemic patients: relationship with systemic inflammation and haemostatic activation

Chronic renal failure (CRF) courses with both systemic inflammatory reaction and haemostatic activation. We explored the relationship of these processes with plasma levels of free, activated protein C (APC) and complexes of APC with its inhibitors in patients with CRF under conservative treatment. Plasma concentrations of inflammatory cytokines [tumour necrosis factor alpha (TNFalpha) and interleukin 8], acute-phase proteins (C-reactive protein, fibrinogen, alpha1-anti-trypsin and von Willebrand factor), and markers of haemostatic activation (thrombin-anti-thrombin complexes, plasmin-anti-plasmin complexes, and fibrin and fibrinogen degradation products) were higher in patients than in controls. Inflammatory and haemostatic markers were significantly and positively correlated. Total plasma APC and APC:alpha1-anti-trypsin (alpha1AT) complexes were 44% and 75% higher in patients than in controls (P = 0.0001), whereas free APC was 20% lower (P < 0.015). No significant difference was observed in APC:protein C inhibitor (PCI) complexes between both groups. The free/total APC ratio was significantly lower in patients than in controls (P < 0.0001). Total plasma APC and APC:alpha1AT were positively correlated with activation markers of haemostasis and acute-phase proteins, whereas free APC was inversely correlated with plasma levels of creatinine, acute-phase proteins and fibrin degradation products (FnDP). Systemic inflammation and activation of haemostasis are interrelated processes in CRF. APC generation was increased in response to elevated thrombin production, but the inflammatory reaction, associated with increased synthesis of alpha1AT, reduced its anticoagulant effect. Lower free plasma APC in CRF may be pathogenically associated with atherothrombosis, a major cause of death in this disease.     

Fibrinolysis and Haemostasis

Summary: Platelet function has been examined in humans during periods of enhanced fibrinolysis induced by streptokinase or occurring spontaneously. The degree of lytic activity has been assessed by thrombin times, fibrinogen levels and measurement of fibrin degradation pro-ducts in the serum. The bleeding time was usually normal although there was a tendency for prolongation during the course of prolonged lysis or in the presence of profound hypofibrinogenaemia. Platelet adhesiveness to glass beads and aggregation with adenosine di-phosphate and collagen were usually normal even in the presence of markedly elevated levels of degradation products. Platelet aggregation with thrombin was impaired and the abnormality could be corrected by increasing thrombin concentrations. The results suggest that the major haemostatic defect during enhanced lysis results from the anti-thrombin action of degradation products and that there is little decrease in platelet aggregation as long as fibrinogen levels are not excessively reduced.     

The value of rotation thromboelastometry to monitor disturbed perioperative haemostasis and bleeding risk in patients with cardiopulmonary bypass

Rotation thromboelastometry (ROTEM) performed on whole-blood samples provides information on the contribution of fibrinogen and platelets to clot formation. Such measurements are believed superior to classical plasma coagulation measurements as a means of monitoring disturbed haemostasis. On-pump cardiac surgery is associated with high bleeding risk. The study objective was to obtain information on the frequency of abnormal values of ROTEM variables and to assess their value in estimating bleeding risk in such patients. We studied 150 patients undergoing elective on-pump cardiac surgery. We found a significant surgery-induced decrease in haemostatic potential, with more abnormal ROTEM values in intrinsically activated coagulation (up to 50%) than in extrinsically activated coagulation (up to 27%) or the maximum clot firmness in FIBTEM (10%), a test measuring the contribution of fibrinogen. All ROTEM variables tend to normalize within 14-18 h postoperatively. Best positive predictive values and specificity for a postoperative blood loss above 600 ml were found for the clot formation time in extrinsically activated coagulation (71%/94%) and the maximum clot firmness in FIBTEM (73%/95%); these values were superior to the activated partial thromboplastin time or prothrombin time (56%/72% and 43%/5%, respectively). There was no relation between preoperative or early postoperative ROTEM values and intraoperative bleeding. ROTEM recorded a benefit of administration of platelet concentrates or fresh-frozen plasma, particularly when given postoperatively, on haemostasis. In contrast, intraoperative administration of red blood cells impaired haemostasis. ROTEM can provide a more detailed diagnostic basis enabling a focused therapy to cardiac surgery patients with high bleeding risk.     

Microparticles adhere to collagen type I, fibrinogen, von Willebrand factor and surface immobilised platelets at physiological shear rates

Microparticles (MPs), shed during the storage of platelets, support blood coagulation and could be helpful in restoring the haemostatic system in thrombocytopenic patients. The mechanisms by which MPs support haemostasis under flow conditions were investigated. Fluorescent-labelled MPs were perfused at shear rates of 100 and 1000/s over surfaces coated with collagen, fibrinogen, von Willebrand factor (VWF) or surface-adherent platelets. Adhesion was monitored in real-time by fluorescence microscopy. In addition, thrombin-antithrombin (TAT) complex formation was measured in flowing thrombocytopenic blood. MPs attained the capacity to firmly adhere to collagen, VWF, fibrinogen and surface-adherent platelets at high and low shear rate. Antibodies against glycoprotein Ibalpha and alpha(IIb)beta(3) were used to demonstrate the specificities of these interactions. The addition of MPs to thrombocytopenic blood did not affect platelet adhesion. TAT complex formation was increased in the presence of MPs in capillaries coated with fibrinogen, but not on collagen fibres. We confirmed that MPs adhere to a damaged vascular bed in vivo after infusion in denuded arteries in a mouse model. MPs have platelet-like adhering properties and accelerate thrombin generation. These properties strongly support the notion that MPs can be beneficial in maintaining normal haemostasis when platelet function is impaired or reduced, as in thrombocytopenic patients.     

Targeting platelet receptor function in thrombus formation: The risk of bleeding

In this review, we presume that the process of thrombus formation, as assessed in whole blood flow studies and in experimental (murine) thrombosis studies, reflects the platelet responses in human haemostasis and thrombosis. Following this concept, we give an up-to-date overview of the main platelet receptors and signalling pathways that contribute to thrombus formation and are used as targets in (pre)clinical intervention studies to prevent cardiovascular disease. Discussed are receptors for thrombin, thromboxane, ADP, ATP, prostaglandins, von Willebrand factor, collagen, CLEC-2 ligand, fibrinogen and laminin. Sketched are the consequences of receptor deficiency or blockage for haemostasis and thrombosis in mouse and man. Recording of bleeding due to (congenital) platelet dysfunction or (acquired) antiplatelet treatment occurs according to different protocols, while common laboratory methods are used to determine platelet function.     

Clinical approach to the patient with unexpected bleeding

Bleeding can be considered unexpected if it is disproportionate to the intensity of the haemostatic stress in a patient with no known haemorrhagic disorder or if it occurs in a patient in whom a bleeding disorder has been characterized but is adequately treated. A thorough history usually allows the clinician to predict reasonably accurately whether the patient is likely to have a systemic haemostatic defect (and if so whether it is congenital or acquired), or whether the bleeding likely has a purely anatomical basis. The nature of bleeding is instructive with respect to preliminary categorization. Thus, mucocutaneous bleeding suggests defects of primary haemostasis (disordered platelet-vascular interactions). Bleeding into deeper structures is more suggestive of coagulation defects leading to impaired fibrin clot formation, and delayed bleeding after primary haemostasis is characteristic of hyperfibrinolysis. Localized bleeding suggests an anatomical cause, although an underlying haemostatic defect may coexist. Where bleeding is so acutely threatening as to require urgent intervention, diagnosis and treatment must proceed simultaneously. In the case of minor haemorrhage (not threatening to life or limb) it may be preferable to defer therapy while the nature of the bleeding disorder is methodically investigated. Initial laboratory evaluation is guided by the preliminary clinical impression. The amount of blood loss can be inferred from the haematocrit or haemoglobin concentration, and the platelet count will quickly identify cases in which thrombocytopenia is the likely cause of bleeding. In the latter instance, examination of the red cell morphology, leucocyte differential, and mean platelet volume may allow the aetiological mechanism to be presumptively identified as hypoproliferative or consumptive. With regard to coagulation testing, the activated PTT, prothrombin time, and thrombin time usually constitute an adequate battery of screening tests, unless the clinical picture is sufficiently distinctive to indicate the immediate need for more focused testing. In any event, sufficient blood should be taken to allow more detailed studies to be done based on the results of these screening tests. These results will direct the need for further assays, such as specific clotting factor activity levels, von Willebrand factor assays, tests for coagulation inhibitors, platelet function assays, and markers of primary or secondary fibrinolytic activity.     

Surgical wound healing in bleeding disorders

Animal experiments have shown that a number of bleeding disorders may affect wound healing (WH), including haemophilia B, deficiency of factor XIII and abnormalities of fibrinogen. Therefore, normal healing requires adequate haemostatic function for the appropriate time frame (up to 4 weeks in the clean and uncontaminated wound). Many factors may affect WH, including impaired haemostasis, diabetes, poor nutrition, insufficient oxygenation, infection, smoking, alcoholism, old age, stress and obesity. The gold standard for the correct care of surgical wounds in patients with bleeding disorders includes wound dressing and comprehensive standard care (haemostasis, nutritional support, treatment of co-morbidities, offloading, reperfusion therapy and compression). Although complications of surgical wounds healing in patients with bleeding disorders are uncommon, a low level of the deficient factor for an insufficient period of time could cause WH complications such as haematomas, infection, and skin necrosis and dehiscence. Clinical experience and animal experiments appear to indicate that, to get a satisfactory healing of surgical wounds and avoid potential complications of WH, a good level of haemostasis is necessary for 2-3 weeks after surgery. However, many treaters would regard this recommendation at odds with (i.e. more aggressive than) current standards. Unfortunately no additional clinical evidence for this recommendation can be provided.     

Algorithm for approach to therapy

The management of unexpected bleeding must be directed at the specific abnormality identified, as there is no universally effective and safe procoagulant product. Where practical, a purely pharmaceutical approach obviates the residual risks of exposure to plasma‐derived products. Desmopressin is often effective in bleeding due to mild haemophilia A, Type I von Willebrand's disease and some platelet function disorders. Where replacement therapy is necessary, it should be as specific as possible, preferably using purified components singly or in combination. Recombinant proteins provide the greatest margin of safety, but it must be borne in mind that these are biologicals, and that they may contain human and animal plasma‐derived proteins. Where specific replacement is unavailable or impractical, plasma or crudely fractionated plasma derivatives may be used. In the case of inhibitor antibodies to factor VIII, high dose human factor VIII or porcine factor VIII may be used. Where replacement therapy is impossible due to a high inhibitory titre, it may be necessary to bypass the specific haemostatic defect using activated prothrombin complex concentrates or recombinant activated factor VIIa. The latter product is being studied in patients with various disorders of platelet function, and in the more global haemostatic failure that accompanies end‐stage liver disease. Ancillary methods are often of great value in securing haemostasis. These may be derived from pharmacological or biological sources, and their sites of action may be systemic or topical. Examples include antifibrinolytic lysine analogues, corticosteroids where inflammation accompanies bleeding, and the topical application of fibrin sealants or thrombin. Simple physical measures such as pressure, ice, or splinting are also valuable adjunctive measures. Finally, it must be emphasized that the ultimate control of bleeding often depends upon effective management of the inciting cause, such as eliminating the trigger for DIC, or suppressing the causative antibody of ITP. These principles will be presented using a practical algorithmic approach. The initial question when considering treatment should be whether or not the patient is acutely unstable. Instability may be due to one of two causes: the volume of blood loss leading to a compromised cardio‐vascular status, or the site of the bleed. The relevance of the site of the bleed is independent of the volume of blood loss, so for example, a closed bleed into CNS will cause critical functional compromise even though the volume of bleeding may be minimal. Similarly bleeding into a compartment, such as into a forearm or a calf will cause critical functional compromise irrespective of the volume of bleeding.