dxy

Although plasma exchange with FFP is undoubtedly effective, the optimal regimen has not been determined, but the current recommendation is for at least 1?0 plasma volume exchange daily until at least 2 d after remission is achieved (de?ned as normal neurology, platelet count over 150 ? 109/l, normal lactate dehydrogenase levels and rising haemoglobin concentration).

Recommendation
Single volume daily plasma exchange should ideally be begun at presentation (grade A recommendation, level Ib evidence) and preferably within 24 h of presentation (grade C recommendation, level IV). Daily plasma exchange should continue for a minimum of 2 d after remission is obtained (grade C recommendation, level IV evidence).

10.6. Reversal of warfarin effect (see BCSH, 1990b; BCSH, 1998; Baglin, 1998; Makris & Watson, 2001)

Warfarin achieves its anticoagulant effect by inhibiting the vitamin K-facilitated carboxylation of FII, FVII, FIX and FX. It thereby causes a functional de?ciency of these procoagulants as well as of the anticoagulants proteins C and S. Warfarin’s anticoagulant effects may be indicated by prolongation of the PT standardized by the international normalized ratio (INR). Target INRs for different thrombotic indications are given in BCSH (1998).

Over-anticoagulation from excessive effects of warfarin can be reversed by a range of measures. From the most mild to the most severe circumstances these are: withdrawing warfarin, giving vitamin K orally or parenterally (e.g. 5 mg by slow intravenous injection; grade B recommendation, level III evidence); transfusing FFP, or transfusing PCC (FII, FVII, FIX and FX, or separate infusions of FII, FIX and FX concentrate and FVII concentrate). PCC (50 units/kg) is preferred to FFP. Details have been previously published (BCSH, 1998; Makris & Watson, 2001). Makris et al (1997) showed that FFP contains insuf?cient concentration of the vitamin K factors (especially FIX) to reverse warfarin, supporting the ?nding that FFP is not the optimal treatment. The BCSH guidelines on oral anticoagulation (BCSH, 1998) only recommend FFP (15 ml/kg) if there is major bleeding in a patient on warfarin if PCC is not available. Simultaneous administration of intravenous vitamin K (5 mg) is also recommended, although they comment that levels of individual factors will typically remain less than 20%.

Recommendation
Fresh-frozen plasma should never be used for the reversal of warfarin anticoagulation when there is no evidence of severe bleeding (grade B recommendation, level IIa evidence).

10.7. Vitamin K policies in ICUs

Many patients in ICU have an inadequate vitamin K intake, particularly as parenteral nutrition for the seriously ill usually has a restricted lipid component. This can lead to a prolonged PT, which is usually correctable by oral or injected vitamin K; the vitamin K intake should be sustained. FFP is not the treatment of choice for correcting inadequate vitamin K intake, even if clotting times are prolonged and an invasive procedure such as liver biopsy is being contemplated.

Recommendation
Intensive care unit patients should routinely receive vitamin K; 10 mg thrice weekly for adults and 0?3 mg per kg for children (grade B recommendation, level IIa evidence).

10.8. Liver disease

A variety of abnormalities of coagulation is seen in patients with liver disease. The magnitude of haemostatic abnormalities correlates with the degree of parenchymal damage. Reduced clotting factor synthesis, re?ected in a prolonged PT, may predispose to bleeding, which may be exacerbated by dys?brinogenaemia, thrombocytopenia and increased ?brinolysis. However, bleeding seldom occurs without a precipitating factor such as surgery, liver biopsy, or variceal rupture.

Fresh-frozen plasma is still advocated by some for the prevention of bleeding in patients with liver disease and a prolonged PT, although complete normalization of the haemostatic defect does not always occur (Williamson et al, 1999). Routine use of FFP in these circumstances is therefore questionable. Platelet count and function, as well as vascular integrity, may be more important in these circumstances. Although PCCs have been shown to suf?ciently correct abnormal clotting in liver disease (Green et al, 1975; Mannucci et al, 1976), their use, even of the more recently available and less thrombogenic preparations, is not recommended in view of the high risk of DIC. For similar reasons, it may also be advisable to avoid giving SDFFP in this situation in view of the relative depletion of protein S.

Many liver units will only undertake liver biopsy if the PT is no more than 4 s longer than the upper limit of the normal range. There is no evidence to substantiate this. Other tests, such as the APTT and thrombin time, do not normally help the decision-making. The response to FFP in liver disease is unpredictable. If FFP is given, repeat coagulation tests should be conducted as soon as the infusion is completed if it is to inform future decision-making. The merits of different infusion regimens, such as 5 ml/kg/h versus intermittent boluses, have not been addressed. These are areas that need more research. More work needs to be conducted to establish the role, if any, of FFP in patients with liver disease to correct the bleeding tendency prior to biopsy.

Recommendation
Available evidence suggests that patients with liver disease and a PT more than 4 s longer than control are unlikely to bene?t from FFP (grade C recommendation, level IV evidence).

10.9. Surgical bleeding

There is much debate about managing extensive bleeding arising during or after surgery. Goodnough (1999) described a wide variation in use of blood components, including FFP. Recent advances in understanding coagulation has also led to a re-appraisal of traditional clotting tests (PT, APTT, TT) and of near-patient tests such as the thromboelastogram (TEG)(Shore-Lesserson et al, 1999).

10.9.1. Coronary artery bypass graft (CABG) surgery. 
Patients undergoing CABG surgery are heavily heparinized to counteract the thrombogenicity of the bypass circuit, receiving 25 000–30 000 units of heparin. Their blood clotting is usually monitored by the activated clotting time (ACT), and at the end of surgery the heparin is reversed by protamine. Excessive postoperative bleeding may require more protamine (Bull et al, 1975). In the past, blood transfusion requirements have been high, but with improved facilities and techniques, the use of blood products has declined and many patients undergoing ‘?rst-time’ procedures now require no transfusion. Recently developed ‘near-patient’ coagulation testing devices have enabled surgeons and anaesthetists to manage non-surgical causes without transfusing blood products. These devices include the TEG, which is used in several UK Cardiac Centres; the Sonoclot (Hett et al, 1995); Plateletworks (Lakkis et al, 2001); and the Platelet Function Analyser 100 (Wuillemin et al, 2002). The use of pharmacological agents (such as tranexamic acid and aprotonin), used either prophylactically or to curtail established bleeding when excessive fibrinolysis is suspected, have been accompanied by further reduction of blood product use (Horrow et al, 1990; Hunt, 1991; Laupacis et al, 1997; Peters & Noble, 1998).

10.9.2. Massive transfusion. 
This may be de?ned as the replacement of a patient’s total blood volume with stored blood in less than 24 h, although alternative de?nitions allowing more anticipation (such as 50% blood volume loss within 3 h, or a loss of 150 ml/min) may be a more useful clinical guide (Stainsby et al, 2000). Earlier guidelines and reports stated that early adequate resuscitation from shock is most important in preventing coagulopathy, although prophylactic replacement regimes neither prevent the process nor reduce transfusion requirements (Harke & Rahman, 1980; Mannucci et al, 1982; Ciavarella et al, 1987; Carson et al, 1988; Hewitt & Machin, 1990). Like most of these reports, the last BCSH guidelines on the management of extensive bleeding (BCSH, 1988) were prepared when most transfused red cell components were either ‘packed cells’ or ‘whole blood’. These contained 150–300 ml of donated plasma, while current UK preparation, with the exception of red cells for exchange transfusion, are resuspended in additive solutions and contain only about 30 ml residual plasma. BCSH (1988) stated that coagulation factor depletion is ‘not a frequent occurrence’ in massive blood loss in the absence of DIC which, when it occurs, is ‘a likely consequence of delayed resuscitation’. They referred to the use of FFP in this situation guardedly, stating that, although in theory abnormal PT or APPT should indicate treatment with FFP, there is ‘still a paucity of objective clinical evidence that it is of any bene?t’. This situation has not substantially changed. Ciavarella et al (1987) found that using replacement formulae to guide the use of blood products, including FFP, in massive bleeding was no more effective than basing replacement policies on timely clotting tests and clinical signs. They also stated that platelet counts correlate highly with microvascular bleeding and recommend platelet transfusion if this falls below 50 ? 109/l. More recently Hiippala et al (1995) found that clinically signi?cant ?brinogen de?ciency develops after a loss of about 150% of the blood volume – earlier than any other haemostatic abnormality – when plasma-poor red cell concentrates are used in replacing major blood loss; and Stainsby and Burrowes-King (2001) stated that ‘use of FFP in massive transfusion (and cardiac surgery) should be guided by tests of coagulation, and if a rapid turn-around cannot be achieved near-patients tests merit consideration’.
In their ‘Commentary’ on massive blood loss (which gives a ‘template guideline’), Stainsby et al (2000) recommended that, if bleeding continues after large volumes of (crystalloidresuspended) red cells and platelets have been transfused, FFP and cryoprecipitate may be given so that the PT and APTT ratios are shortened to within 1?5, and a ?brinogen concentration of at least 1?0 g/l in plasma obtained.