Recommendations for the use of antithrombin concentrates and prothrombin complex concentrates

Antithrombin concentrates

Introduction

Antithrombin (AT) concentrates can be therapeutically useful in cases of primary and acquired AT deficiency; their use, to be reserved to clinical conditions in which low levels of functional AT are associated with a thrombotic imbalance in haemostasis, has yet to be supported by clear scientific evidence.

Notions of physiology

AT is a glycoprotein synthesised by the liver. Its molecular weight is 58,000 Da and it circulates in the plasma at a concentration of 150 mg/mL^1–3. Belonging to the family of serpins or inhibitors of serine proteases, it inhibits proteases. AT is the most potent naturally occurring inhibitor of coagulation and plays a fundamental role in maintaining haemostatic balance. Furthermore, it has anti-inflammatory and anti-aggregant properties mediated through the release of prostacyclins from endothelial cells³.

Normal values of AT activity in the plasma range from 80% to 120%. In normal conditions its biological half-life is 1.5–2.5 days; in conditions of acquired deficiency and in the presence of heparin, the half-life of AT can be notably shorter, being reduced to even a few hours.

Preparations of AT

AT concentrates, like all other plasma derivates, are prepared from pools of human plasma, made from at least 1,000 different donors⁴.

Various companies have been licensed to manufacture this product for clinical use. AT preparations undergo microbial inactivation by pasteurisation, sometimes followed by nanofiltration. Vials containing 500, 1,000, 1,500 and 2,000 UI are available.

Mechanism of action

AT is used as replacement therapy in conditions of acquired or inherited deficiency, in particular circumstances. Its anticoagulant activity is mainly due to the inhibition of thrombin, activated factor X (FXa) and, to a lesser degree, also other activated clotting factors (FIXa, FXIa, FXIIa)¹. The rate of formation of the thrombin-antithrombin complex is very greatly increased by heparan sulphate, present on the surface of endothelial cells. Subjects lacking AT have an increased risk of thrombosis, particularly in the presence of other thrombophilic conditions.

Congenital AT deficiency

The estimated prevalence is 1/2,000–5,000 in the general population and 2–3% in a selected population of patients with thrombotic events^1,5.

There are two different types of congenital deficiency of AT, which are inherited in an autosomal dominant manner:

• - TYPE I (quantitative defect), in which there are proportional decreases in the concentration and, therefore, functional activity of the AT.

• - TYPE II (qualitative defect), characterised by normal levels of protein, but a reduction in its functional activity.

Acquired AT deficiency

Various clinical conditions are associated with acquired AT deficiency^5,6:

1. Reduced production^7–12:

   • - acute and chronic liver disorders;
   • - premature neonates;
   • - treatment with L-asparaginase.
2. Increased excretion/loss^13,14:

   • - protein-losing enteropathy;
   • - nephrotic syndrome;
   • - burns.
3. Dilution⁵:

   • - massive transfusion;
   • - plasma exchange;
   • - extracorporeal circulation.
4. Increased consumption^3,15–23:

   • - disseminated intravascular coagulation (DIC);
   • - major surgery;
   • - heparin infusion;
   • - multiple trauma;
   • - severe sepsis/septic shock;
   • - severe thromboembolism;
   • - haemolytic-uraemic syndrome;
   • - pre-eclampsia.

Indications

The use of AT concentrates, to be reserved to clinical conditions in which low levels of functional AT are associated with a thrombotic imbalance in haemostasis, has yet to be supported by clear scientific evidence.

1. Patients with congenital AT deficiency

In the absence of symptoms or risk factors, congenital AT deficiency is not an indication for replacement therapy with AT concentrates, which should be reserved, on a temporary basis and in association with heparin therapy, to the following circumstances (Grade of Recommendation: 2C)^1,6:

• - prophylaxis of deep vein thrombosis and thromboembolism in high-risk conditions: major surgery, obstetric procedures (such as delivery or abortion), trauma, immobilisation;

• - treatment of ongoing thrombosis, until the indicated level of oral anticoagulation is reached. Patients with congenital AT deficiency and repeated episodes of thromboembolism must receive life-long oral anticoagulant therapy (Grade of Recommendation: 2C+)^1,6 (Table I).

Table I.

Indications for the use of antithrombin

Clinical conditions	Notes	GoR
Congenital antithrombin deficiency
Prophylaxis of deep vein thrombosis and thrombo-embolism in high-risk situations	For the entire time that the high-risk state is present	2C
Treatment of ongoing thrombosis	Until the indicated level of oral anticoagulation is reached	2C
	This latter must be maintained life-long in cases of repeated thromboembolism	2C+
Acquired antithrombin deficiency
Increased consumption (in DIC associated with severe sepsis)	Administration of high doses, not associated with heparin, may improve survival	2C+
- DIC associated with trauma, burns, pregnancy - neonates of mothers with AT deficiency or a family history of venous thromboembolism - ongoing thrombosis with low levels of AT and resistance to heparin - acute thromboembolism during treatment with L-asparaginase - extracorporeal circulation - thrombosis of the hepatic artery following orthotopic liver transplantation - veno-occlusive disease following bone marrow transplantation - chronic, not decompensated conditions of deficiency: acute or chronic liver disease, nephrotic syndrome, protein-losing enteropathy, pre-eclampsia, neonatal respiratory distress syndrome, multiple trauma and post-operatively in the absence of DIC.	There is little evidence of the efficacy of treatment with AT in these clinical circumstances

GoR: Grade of Recommendation

2. Patients with acquired AT deficiency

There is little evidence concerning treatment with AT in conditions of acquired deficiency; replacement therapy with AT may be useful, although the levels of evidence are not high, in DIC associated with severe sepsis, in which the use of high doses, not associated with heparin, could improve the survival of patients (Grade of Recommendation: 2C+)^{3,5,15–18,20–36}.

Further studies are needed on the use of AT concentrates in the case of^1,6:

• - DIC associated with trauma, burns, pregnancy;

• - neonates of mothers with AT deficiency or a family history of severe venous thromboembolism;

• - ongoing thrombosis with low levels of AT and resistance to heparin;

• - acute thromboembolism during treatment with Lasparaginase^9–12;

• - extracorporeal circulation;

• - thrombosis of the hepatic artery following orthotopic liver transplantation;

• - veno-occlusive disease following bone marrow transplantation^37,38;

Furthermore, the use of AT is not generally indicated (given the lack of proof of clinical efficacy), even when AT levels are considerably below normal, in the following conditions of chronic, not decompensated deficiency: acute or chronic liver disease, nephrotic syndrome, protein-losing enteropathy, pre-eclampsia, neonatal respiratory distress syndrome, multiple trauma and postoperatively in the absence of DIC (Table I).

Calculation of the dose of AT to administer

There is no evidence that higher than normal levels of AT provide greater protection than physiological levels, just as an overdose does not imply an increased risk of bleeding. Before starting replacement therapy with a specific concentrate, it is advisable to assay AT functional activity. Given that the administration of 1 UI/kg of body weight increases plasma AT activity by 1.5%, the dose to administered is calculated as follows:

The dose and timing of subsequent administrations are based on the results of monitoring plasma AT activity every 12–48 h.

Monitoring indices for clinical auditing

Use of AT treatment in the following conditions:

• - congenital AT deficiency in the absence of symptoms or risk factors and/or with AT values > 70%.

Side effects and adverse reactions

AT infusions are generally well tolerated; allergictype reactions are, however, possible.

The use of AT concentrates contemporaneously with heparin increases the risk of bleeding and careful clinical and laboratory monitoring is, therefore, necessary, particularly in patients at high haemorrhagic risk.

Recommendations

It is recommended that all the details of the product infused, including its batch number, are recorded in the clinical records.

Prothrombin complex concentrates

Introduction

Prothrombin complex concentrate (PCC) may be therapeutically useful for the acute and temporary correction of deficiencies of factors in the prothrombin complex. There are no randomised, controlled clinical trials providing clear evidence on the use of PCC, but only observational or retrospective studies, on the basis of which the following recommendations were formulated. Reference is also made to the guidelines from the Italian Association of Haemophilia Centres (AICE) and the Italian Federation of Anticoagulation Clinics (FCSA)^1–3.

Preparations of PCC

PCC contain factor II (FII), factor IX (FIX) and factor X (FX), with procoagulant effects, as well as naturally occurring and physiological inhibitors of coagulation such as protein C, protein S and traces of antithrombin, heparin and vitronectin⁴. PCC containing unactivated clotting factors and one concentrate of activated factors are available. PCC, like all other plasma derivates, are prepared from pools of human plasma, made from at least 1,000 different donors⁵.

Various companies have been licensed to manufacture PCC for clinical use. These products are subjected to viral inactivation, both by physical methods (heating or vapour) and chemical methods (use of solvent-detergent). Vials containing 200, 500 and 1,000 UI are available.

Indications

Congenital deficiencies

Unactivated PCC is used only in the case of documented isolated deficiencies of FII and FX, for the prophylaxis or treatment of bleeding (table II); if it is not available, fresh-frozen plasma (FFP) can be used as an alternative. Similarly, in cases of congenital deficiencies of FVII and FIX, PCC should only be used when the specific clotting factor is not available (Grade of Recommendation: 2C)^1,6–8.

Table II.

Indications for the use of PCC

Congenital deficiencies of clotting factors in the prothrombin complex	GoR
Deficiencies of factors II and X: for prophylaxis or treatment of bleeding. If PCC are not available, FFP can be used as an alternative.	2C
Haemophilia B and inherited factor VII deficiency: when the specific factor IX and VII concentrates are not available.
Haemophilia A with inhibitors, during bleeding episodes (activated PCC).
Acquired deficiencies of clotting factors in the prothrombin complex (Factors II, IX, X)	GoR
Bleeding episodes in the presence of deficiencies of one or more factors of the prothrombin complex.
Limitations to the use of FFP because of the risk of circulatory overload or the need for immediate haemostasis, in the following circumstances:
-severe liver disease with serious bleeding or in preparation for elective surgery carrying the risk of bleeding (liver transplantation);
-vitamin K deficiency in the presence of life-threatening bleeding;
-acquired haemophilia (activated PCC).	2C
-Excessive doses of dicoumarols or the need to suspend them in emergency conditions (acute haemorrhage, urgent surgery).	2C+

GoR: Grade of Recommendation

Activated PCC is a therapeutic option, together with recombinant activated factor VII (rFVIIa), for the treatment of bleeding episodes in patients with haemophilia A with inhibitors (Grade of Recommendation: 2C)^1,6,9.

The dose indicated for congenital deficiency of FII or FX is 20–30 UI/kg, depending on the severity, site and extension of the bleeding. Once the first dose has been administered, the level of the individual deficient factor must be monitored in order to be able to decide the subsequent maintenance dose, taking into consideration that the minimum level required for haemostasis is 20–30 UI/dL for FII and 10–15 UI/dL for FX.

Greater detail can be gained from the AICE guidelines or by referring to Centres with expertise in the management of disorders of haemostais¹ (Table II).

Acquired deficiencies

In patients with acquired deficiencies of factors in the prothrombin complex (due to severe liver disease, reduction due to loss or dilution) PCC can be administered, as a second choice alternative to FFP, taking into account that the risk of thrombosis is higher with PCC than with plasma^10–12.

The administration of PCC is indicated (Table II):

1. in patients with deficiency of one or more of the factors of the prothrombin complex, in the presence of bleeding (Grade of Recommendation: 2C)^7,8,13,14.

2. when there are limitations to the use of FFP because of the risk of circulatory overload or the need for immediate haemostasis, in the following circumstances:

   • - severe liver disease with serious bleeding or in preparation for elective surgery carrying the risk of bleeding (liver transplantation) (Grade of Recommendation: 2C)^13,14;
   • - vitamin K deficiency (due to antibiotic treatment, persistent diarrhoea, malabsorption, malnutrition), in the presence of life-threatening bleeding (Grade of Recommendation: 2C)^13,14.

3. to correct excessive use of dicoumarols or when suspending oral anticoagulant therapy in emergency circumstances (acute major haemorrhage, urgent surgery) (Grade of Recommendation: 2C+)^2,3,15–28.

   In the case of oral anticoagulant therapy, PCC may be the treatment of first choice, although depending on the cause, site and extent of the potential or actual bleeding, the use of other therapeutic strategies, such as vitamin K and/or FFP, should be considered.

   Although results from adequate clinical trials are not yet available, in life-threatening, extremely urgent situations, an infusion of rFVIIa can be considered as a replacement for PCC, when this latter is not available (as stated by the FCSA) (Grade of Recommendation: 2C)^2,3.

4. in acquired haemophilia, in which PCC containing activated clotting factors can be used (Grade of Recommendation: 2C)^9,29–33.

Posology and method of administration

The doses and duration of replacement therapy must be decided on the basis of the haemostatic imbalance, the site and extent of the bleeding, and the clinical situation^10,22,28.

Before PCC is administered – compatibly with the urgency of the clinical situation – tests of haemostasis should be performed (PT/INR, aPTT and, if possible, assays of the factors in the prothrombin complex), in order to decide the dose and duration of the treatment.

In the case of severe bleeding or major surgery, the average first dose to administer, as a bolus, is 20–25 UI/kg. The PT and INR must be evaluated 30–60’ after the administration of the PCC, in order to determine whether to continue with this treatment and, if so, at what dose.

Correction of excessive anticoagulation from oral anticoagulant therapy

In the case of major bleeding or surgery that cannot be postponed^2,3:

1. suspend the ongoing oral anticoagulant therapy;

2. measure the INR.

3. administer vitamin K intravenously at a dose of 10 mg/100 mL of physiological saline, slowly over about 30’.

4. infuse the following doses of PCC slowly, over about 10–15’:

   • - for INR < 2 administer 20 UI/kg;
   • - for INR between 2 – 4 administer 30 UI/kg;
   • - for INR > 4 administer 50 UI/kg.

5. measure the INR again at the end of the infusion and ensure that is < 1.5; if this is not the case, repeat the administration of PCC, according to the above scheme.

Alternatively, and particularly if PCC is not available, administer FFP at a starting dose of 15–20 mL/kg.

Monitoring indices for clinical auditing

Use of PCC treatment in the following conditions:

• - in the absence of major bleeding;

• - in patients on oral anticoagulation undergoing elective surgery with an INR < 1.5.

Contraindications, side effects and adverse reactions

DIC is a contraindication to the use of PCC¹⁰.

Possible side effects and adverse reactions are^10–12:

• - thromboembolic complications;

• - allergic and anaphylactic reactions;

• - fever;

• - development of inhibitors of the clotting factors present in the PCC.

As other blood derivatives, PCC can be considered safe from an infectious point of view, although with some query concerning the potential transmission of prions.

Recommendations

It is recommended that all the details of the product infused, including its batch number, are recorded in the clinical records.

Appendix A.