Haemorrhagic events

Kavana h D, Hill ADK, Martin S, Power C, McDermott EW, O Higgins N, Murphy K. Life threatening haemorrhagic events associated with the administration of low-molecular-weight-heparin. Thromb Haemost (2004) 91, 833-4. 

Adverse events risks associated with the addition of bevacizumab to breast cancer chemotherapy were recently assessed in a review and meta-analysis that included five phase III clinical trials that used bevacizumab alone or in combination with chemotherapy [96 ]. Four adverse events, proteinuria, hypertension, l t ventricular dysfunction and haemorrhagic events, showed a statistically significant bevacisumab-associated risk while no significant risk was found for gastrointestinal perforation, vascular events, febrile neutropenia and fatal events. 

Alteplase has proven effective in the early treatment of patients with acute myocardial infarction (i.e. those treated within 12 h after the first symptoms occur). Significantly increased rates of patient survival (as measured 1 day and 30 days after the initial event) are noted when tPA is administered in favour of streptokinase, a standard therapy (see later). tPA has thus established itself as a first-line option in the management of acute myocardial infarction. A therapeutic dose of 90-100 mg (often administered by infusion over 90 min) results in a steady-state alteplase concentration of 3-4 mg l 1 during that period. However, the product is cleared rapidly by the liver, displaying a serum half-life of approximately 3 min. As is the case for most thrombolytic agents, the most significant risk associated with tPA administration is the possible induction of severe haemorrhage. 

Advances in Neurology 92 197-202 Mas JL, Arquizan C, Lamy C et al. (2001). Patent Foramen Ovale and Atrial Septal Aneurysm Study Group. Recurrent cerebrovascular events associated with patent foramen ovale atrial septal aneurysm or both. New England Journal of Medicine 345 1740-1746 Masuda J, Yutani C, Wald R et al. (1992). Histopathological analysis of the mechanisms of intracranial haemorrhage complicating infective endocarditis. Stroke 23 843-850 Matijevic N, Wu K (2006). Hypercoagulable states and strokes. Current Atherosclerosis Reports 8 324-329... 

The treatment of haemostasis disorders is indicated in cases of acute liver failure or when a necrotic episode occurs during the course of cirrhosis, even if no haemorrhagic complications have been observed. There are two reasons for this (I.) an elevated risk of haemorrhage must be anticipated in the event of acute liver dysfunction and (2.) extensive liver necrosis leads to the release of thromboplastic compounds, accompanied by a deterioration in the microcirculation and additional haemostatic disturbances. In this situation, an early and optimized correction of the coagulation and fibrinolysis parameters is thus essential, (l, 9-ll, 13,17) (s. tab. 19.2)... 

Haemorrhage-related lethality of 20-30% (and more) has to be expected in the event that acute liver failure leads to acute haemostasis disorders. The following courses of treatment are recommended ... 

There are a number of causes including (I.) well-known hepatotoxic factors (e.g. superimposed viral infection, alcohol consumption, hepatotoxic drugs, intoxication) and (2.) endogenous factors (e.g. sepsis, variceal bleeding, gastrointestinal haemorrhage, diarrhoea, hypoxia). Acute liver failure is frequently the result of a chain of damaging events, like a vicious circle. 

The ubiquitous occurrence of proteinases is accompanied by a similar distribution of fairly specific proteins that inhibit these enzymes. In normal health, there is a delicate balance between the levels of enzymes and their macromolecular inhibitors. This balance is particularly important in the blood-clotting clot-lysis scheme. Since the total volume of blood in the adult human body is only about 5 1, a massive response is required in the event of an injury that results in a rapid haemorrhage. Some positive feedback is present in the blood-clotting mechanism in order to achieve this rapid response, but clearly this must be sensitively controlled by endogenous inhibitors if a thrombosis is not to occur. 

In another study, the combination of adjusted dose fluindione (INR 2 to 2.6) plus aspirin 100 mg daily was assoeiated with a mueh higher incidence of haemorrhagic complications than fluindione alone (13.1% versus 1.2%). The overall balance of benefit to risk eould not be assessed because of the low incidence of the primary endpoint (isehaemie events). ... 

Acute myocardial infarction results in nearly all cases from thrombotic occlusion of the coronary artery at a point of atherosclerotic narrowing . Histological studies have demonstrated that the thrombus is largely composed of platelets at its point of attachment to the vessel walP°°, suggesting that platelet activation is the initiating event. In addition, the endothelium is frequently disrupted with haemorrhage from the lumen into the atherosclerotic plaque ° Thus, coronary thrombosis may result from platelet activation by exposed subendothelial collagen and subsequent formation of a fibrin clot. 

These infants with severe combined immunodeficiency are exquisitely susceptible to graft-versus-host disease which has been observed in them following administration of peripheral blood, fetal liver cells, or histoincom-patible bone marrow " The course of the reaction much resembles the disease of mice and is rapidly fatal in 10-14 days. It is characterized by fever, a maculopapular rash involving the volar surfaces, diarrhoea with protein-losing enteropathy and edema, haemolytic anaemia and thrombocytopenia. Haemorrhage into the gut or lung is usually the terminal event. Donor cells are most abundantly evident in the spleen and liver and less so in skin and kidney. Splenic enlargement resembles also the observation in mice and correlates with the severity of the reaction. 

Observational studies An open-label, dose-escalation study of albumin in subarachnoid haemorrhage that treated 47 adults reported 171 adverse events in 32 people [l ]. Only volume overload leading to acute heart failure or pulmonary oedema was attributed to albumin administration. Three severe adverse events, all pulmonary oedema, were thought to be possibly related to the albumin. 

Observational studies In a multicenter, observational retrospective review of 127 patients (80 male, mean age 51.7years) who had undergone at least ISmonths of treatment with alpha-l-antitrypsin therapy (Trypsone or Pro-lastin ), there were four serious adverse events that occurred during the treatment period one massive pulmonary thromboembolism, one myeloid leukaemia, one acute myocardial infarction and one haemorrhagic infarcHon but were judged not to be related to treatment. Seven of 11 nonserious adverse events were considered related to treatment including mild to moderate cutaneous symptoms (facial erythema, oedema/pruritus, rash), chills, fever and anxiety [31 ]. 

Observational studies In a multicenter case series, 25 women received recombinant Factor Vila for treatment of severe obstetric haemorrhage [123 ]. A total of 9 patients experienced 11 adverse events within 28days of rFVIIa exanthema (n= 1), fever (n=1), hypopituitarism (n= 1), acute myocardial infarction (n=1), ileus (n = 1), asymptomatic deep vein thrombosis (n=2), asymptomatic PE (n=2) and allergic reaction (n=2). 

---