Haemorrhage and thrombosis

Cutaneous reactions, apart from purpura and ecchymoses in those who are excessively anticoagulated, include hypersensitivity, rash and alopecia. Skin necrosis due to a mixture of haemorrhage and thrombosis occurs rarely where induction of warfarin therapy is over-abrupt and/or the patient has a genetically determined or acquired deficiency of the anticoagulant protein C or its cofactor protein S it can be very serious. 

Tocantins and Kazal Blood Coagulation Haemorrhage and Thrombosis 2nd Ed. Grune and Stratton, New Yoijc, 1961... 

Connolly AJ, Ishihara H, Kahn ML et al. (1996) Role of the thrombin receptor in development and evidence for a second receptor. Nature 381 516-519 Cui J, O Shea KS, Purkayastha A et al. (1996) Fatal haemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor V. Nature 384 66-68 Denis C, Methia N, Frenette PS et al. (1998) A mouse model of severe von Willebrand disease defects in hemostasis and thrombosis. Proc Nad Acad Sci USA 95 9524-9529 Dewerchin M, Liang Z, Moons L et al. (2000) Blood coagulation factor X deficiency causes partial embryonic lethality and fatal neonatal bleeding in mice. Thromb Haemost 83 185-190... 

Just as normal blood contains substances which act as anticoagulants so it contains others that act as antifibrinolytics, and the system for removing clots seems to be almost as complicated as that which is responsible for their formation. However, perched as the higher vertebrates are on a knife edge between death from haemorrhage and death from thrombosis it is not surprising to find such complex systems of checks and counterchecks. 

The prevention of excessive blood loss through breaches of the vascular barrier is important to maintain oxygen delivery and blood volume. A fall in blood volume would cause a drop in blood pressure and the metabolism of all of the major organs would be badly affected. Failures of the haemostatic mechanisms can lead to haemorrhage (bleeding disorders) or thrombosis (hypercoagulation disorders). 

Animals fed spoiled sweet clover were prone to fatal haemorrhages. The canse was traced to the presence of dicoumarol. This compound interferes with the effects of vitamin K in blood coagulation, the blood loses its ability to clot, and minor injnries can lead to severe internal bleeding. Synthetic dicoumarol has been nsed as an oral blood anticoagnlant in the treatment of thrombosis, where the risk of blood clots becomes life threatening. It has since been snperseded by warfarin, a synthetic development based on the natnral prodnct. 

Adverse effects include nausea, vomiting, headache, fever, abdominal pain, hyperglycemia leading to coma, hypersensitivity, renal damage, coagulation defects, thrombosis, CNS depression or hyperexcitability and acute haemorrhagic pancreatitis. 

Bara L, Planes A, Samama M-M Occurrence of thrombosis and haemorrhage, relationship with anti-Xa, anti-I la activities, and D-dimer plasma levels in patients receiving low molecular weight heparin, en-oxaparin or tinzaparin, to prevent deep vein thrombosis after hip surgery. Br. J. Haematol. (1999) 304 230-240. 

When these patients are discharged from hospital, prophylactic treatment with an oral anticoagulant is recommended to prevent recurrence of the thrombosis. Warfarin sodium, which antagonizes the effects of vitamin K, is used in prophylaxis and treatment of DVT and pulmonary embolism. It is usual to start with an induction dose of 10 mg daily for two days the dose can then be reduced. Patients need to be monitored as there is a risk of haemorrhage with oral anticoagulant drugs. 

H2-histamine receptor blockers alone or together. Hyperuricaemia, due to cell destruction, is prevented by allopurinol and iron and folate deficiency by replacement doses (due to the rapid response of the myeloproliferative erythron). Aspirin remains controversial. Low-dose aspirin (for antiplatelet action) may be used if the platelet coxmt remains high or thrombosis occurs despite the above treatment but is best avoided in patients with a history of haemorrhage. 

Complications Acute liver failure, arterioportal fistula formation, oesophageal varices (15) and pulmonary hypertension have been reported as complications. In most cases, the cause of death is anorexia with tumour cachexia, accompanied by signs of circulatory and renal failure. Occasionally, there is intraperitoneal haemorrhage, portal vein thrombosis (138,146) and tumour rupture with formation of haemorrhagic ascites. (121)... 

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. 

Changes in the complex phenomena represented by each of these terms will result in changes in the haemostatic efficiency. The significant values for K are and KJ, the critical thrombotic value and the critical haemorrhagic value. When the product of V.CjF reaches the value Kf at a certain point in the circulation, thrombosis will be initiated. When it falls to K, at a certain point in the circulation, haemorrhage will result. Anticoagulants chiefly (but not solely) affect C (the composition of the blood) to decrease haemostatic efficiency. The three factors, vessel wall, blood composition and blood flow are not completely independent. The vessel wall component is affected by blood composition and blood flow, and vice versa, and situations arise where thrombosis and haemorrhage can occur simultaneously in the circulation of the same individual. 

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. 

---