utilization of plasma and plasma derivatives in the perioperative period. irene sadek medical...

Utilization of Plasma and Plasma derivatives in the perioperative period.

Irene SadekMedical Director

Blood Transfusion ServicesCapital Health

Utilization of Plasma and Plasma derivatives in the perioperative period.Plasma productsPlasma dosage and volumeNational and local utilization of plasma Effect on coagulation tests Inappropriate plasma transfusionsUse of Octaplex

Plasma transfusion• Although plasma transfusion guideline exists,

there is little evidence to guide the current use of Frozen Plasma.

• Over 200,000 units of frozen plasma are transfused in Canada annually.

• A large number of Frozen Plasma transfusions is considered inappropriate

• The pattern of practice for Frozen Plasma transfusions is highly variable.

Plasma transfusionThese unnecessary transfusions have

important effects on patients and the health care system. Patients experience adverse transfusion

reactionsFrozen Plasma, a valuable and scarce resource

is used up.Not enough Canadian plasma to manufacture

plasma derivatives products, e.g IVIg.

Plasma productsApheresis plasma 500 ml Aphresis plasma 250 mlFresh frozen plasma Frozen plasma BC frozen plasma

FFP vs BC FP Protein Function (ABO matched, n=20)

0.50 - 1.50 U0.1880.870.1421.03Factor IX

0.50 - 1.50 U0.2500.910.3151.26Factor VIII

0.50 - 1.50 U0.2070.900.2301.09Factor VII

0.50 - 1.50 U0.1921.060.1891.15Factor V

0.50 - 1.50 U0.1230.950.1371.12Factor II

0.50 - 1.50 U0.1510.940.1611.11Factor XI

0.50 - 1.50 U0.1641.070.1641.24Factor X

NL RangeStd DevMeanStd DevMean

FP produced from BC 20-24 hrs after

collection

FFP produced within 8 hours of collection

6

Note: small data sample size may not be reflective of current performance.

FFP vs BC FP Protein Function (ABO matched, n=20)

---------0.0840.960.0841.01Alpha 2

Antiplasmin

>0.50 U0.3771.130.4051.24Von Willebrand

>0.65 U0.1801.030.4721.15Protein S2.00 - 5.00 g/L1.9453.920.4813.01Fibrinogen

>0.70 U0.1221.050.2231.19Protein C>0.75 U0.0531.010.0780.97Antithrombin

NL RangeStd DevMeanStd DevMean

Produced from BC 20-24 hrs after collection

FFP Produced within 8 hours of collection

7

Note: small data sample size may not be reflective of current performance.

National Plasma utilization

Plasma Equivalent Units (Incl CSP) Issued by Province - Fiscal Years 2004/05 to 2009/10(per 1,000 population)

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2004/05 9.6534445 12.047168 3.937636 10.814499 7.2420213 8.1254471 10.590404 8.8997096 8.143532 10.836294 6.8083639 0.4530744 3.4813084 0.7094595

2005/06 9.8566394 12.234974 4.2402315 11.905983 7.9808332 7.966965 10.476467 9.3757452 8.2383838 9.8692352 8.5033566 1.1254019 2.7166276 0.6333333

2006/07 10.081285 10.233379 3.673913 10.973158 9.2218366 8.2225853 10.737094 8.5880356 9.0217722 9.9994066 9.2176469 1.6025641 1.9811321 0.3947368

2007/08 9.9091999 11.277898 3.3405483 11.373515 10.380101 8.5979379 10.412999 9.242437 8.0078243 10.72654 8.2752323 1.1612903 1.1267606 0.1286174

2008/09 9.828057 10.220516 3.7982833 10.953853 10.248896 8.6385394 9.6759997 11.400662 10.599409 11.60386 8.2138945 3.141994 4.665127 0.477707

2009/10 8.8331854 9.9213682 3.769559 10.323576 7.7513687 8.862092 8.6416167 9.7173842 10.80518 10.352236 7.5156134 2.1428571 2.8504673 0.4716981

Canada (Excl

Quebec)

Newfoundland and Labrador

Prince Edward Island

Nova Scotia

New Brunswic

kQuebec Ontario Manitoba

Saskatchewan

AlbertaBritish

ColumbiaYukon

Territory

Northwest Territorie

sNunavut

Guideline for plasma transfusionMany guidelines published by national

organizations or professional organizations over the past 20 years.

The guidelines are uniformly, non-evidence-based, or lack sufficient detail to be useful to guide practice in many clinical situations.

Typical recommendations such as those put forth by a Canadian Expert Working Group in 1997 include only very general recommendations.

British Committee for Standards in Haematology, Blood Transfusion Task Force

The British Society for Haematology, 126, 11–28, 2004

Canadian Recommendations regarding plasma transfusionCMAJ 1997

Underlying condition

Clinical setting Coagulation parameter

Level of Evidence

Vit K deficiency or warfarin therapy

Active bleedingBefore emergency surgical or invasive procedure

Significantly increased PT, INR, or PTT

III

Liver disease Active bleedingBefore emergency surgical or invasive procedure (except percutaneous liver biopsy, paracenthesis and thoracocentesis)

Significantly increased PT, INR, or PTT

II

Massive transfusion Micro vascular bleeding Significantly increased or unknown PT, INR, or PTT

II

Acute DIC with treatable triggering condition

Active bleeding Significantly increased PT, INR, or PTT

II

TTP and HUS plasmapheresis I

Acquired deficiencies of a single coagulation factor

DDAVP or appropriate factor concentrate, unavailable or inneffective.Serious bleedingBefore emergency surgical or invasive procedure

III

British Committee for Standards in Haematology, Blood Transfusion Task ForceThe British Society for Haematology, 126, 11–28, 2004

Microvascular bleeding with prolonged PT or aPTT.

Continued bleeding and lab evidence of coagulopathy during massive transfusion.

Urgent reversal of warfarin to stop bleeding or prior to surgery.

Acquired or congenital factor deficiencies of V or XI in bleeding patients or prior to surgery or an invasive procedure.

Deficiency of antithrombin III, heparin cofactor II, protein C, or protein S when specific factor concentrate is not available.

Plasma exchange for TTP or HUS.

What is a prolonged PT and PTTThe PT and aPTT begin to prolong out of the normal range

when coagulation factor levels fall below about 30-50% of normal.

Prolongation of the PT or aPTT up to about 1.5 times the midpoint of the normal range, which corresponds to coagulation factor levels of 20-30%, is not usually associated with spontaneous hemorrhage and does not increase the risk of bleeding during routine invasive procedures.

However, the risk of bleeding is greater if the platelet count is decreased, platelet function is abnormal, the patient has massive trauma or is undergoing extensive surgery.

Indication for plasma transfusionFFP should be used to correct multiple

coagulation factor deficiencies in bleeding patients or patients at risk of

bleeding requiring an invasive procedure. Coagulation parameters:

INR >1.5 and/or PTT > 1.5 times the midpoint or of the normal range.

Specific coagulation factor assay with < 30% activity.

What do INR and PTT results mean in relation to factor levels

Effect of coagulation factor percentage on PT/INR

• Paradoxic effect of multiple mild coagulation factor deficiencies on the prothrombin time and activated partial thromboplastin time. Burns et al. Am J Clin Pathol. 1993 Aug;100(2):94-8

– The PT begins to lengthen when individual factor levels fall below 25%.

– The APTT becomes prolonged when the levels of • Factor V fall below 45%; • the levels of Factors II and XI fall below 40%; and • the levels of Factors I, V, VII, VIII, IX, and XII fall below

25% of normal. • Coagulation assays have variable sensitivity to

different factors.

More than one factor deficiency Burns et al. Am J Clin Pathol. 1993 Aug;100(2):94-8

When plasma samples containing 50% activity of a single factor and 100% of all other factors were prepared by mixing the congenitally deficient plasma samples with the normal pool, the resulting mixtures had normal PT and APTT values.

However, when two of these 50% factor-deficient plasmas were combined so that the mixture contained 75% activity of two coagulation factors and 100% of all other factors, the resulting PT and APTT were prolonged over the clotting times of either 50% factor-deficient plasma.

More than one factor deficiencySimilar findings were obtained in patients with mild

factor reductions caused by warfarin treatment.

These data indicate that prolongations of the PT and APTT in disorders of coagulation

affecting multiple factors represent less of a reduction in factor levels than is generally appreciated.

This may explain the poor clinical correlation between abnormalities in these test results and clinical bleeding in acquired disorders of hemostasis.

200 consecutive liver transplantsTwo groups:

Low INR <1.5High INR >1.5

Coagulation parameters were not corrected in the absence of uncontrollable bleeding.

Plasma dosageThe goal of FFP transfusion is to

increase the plasma level of each coagulation factor above 30%.

Usually, 10 to 15 mL of FFP per kg body weight is required to treat bleeding due to multiple factor deficiencies.

This dose corresponds to 750-1200 ml in an adult.

The PT and PTT should be rechecked before subsequent units are transfused.

If the PT and PTT remain prolonged, more FFP is indicated.

Effect of plasma transfusions on factor levels.• Plasma – Dosage

– Volume of 1 Unit Plasma: 200-250 mL– 1 mL plasma contains 1 u coagulation factors– 1 Unit contains 220 u coagulation factors– Factor recovery with transfusion = 40%– 1 Unit provides ~80 u coagulation factors– 70 kg X .05 = plasma volume of 35 dL (3.5 L)

80 u = 2.3 u/dL = 2.3% (of normal 100 u/dL) 35 dL

• In a 70 kg Patient:1 Unit Plasma increases most factors ~2.5%4 Units Plasma increase most factors ~10%

Appropriate utilizationRequests for FFP are the most frequent

inappropriate orders received by the blood bank.

Reported percentages of inappropriate FFP orders vary from institution to institution and range from 10% to 83%.

The most frequent reason for these inappropriate orderaccounting for at least a third of them, is for

correction of a prolonged INR in the absence of bleeding.

This prophylactic correction of minor laboratory coagulation abnormalities continues in the absence of evidence of its benefit.

Inappropriate use of plasmaCrit Care Med. 2007 Jul;35(7):1655-9.Fresh frozen plasma transfusion in

critically ill patients. Lauzier F et al

73 (32.4%) were consistent with guidelines, 45 (20.0%) were inconsistent but appropriate, 107 (47.6%) were inappropriate

Toward Rational Fresh Frozen Plasma TransfusionThe Effect of Plasma Transfusion on Coagulation Test Results

Lorne L. Holland, Am J Clin Pathol 2006;126:133-139

Effect of fresh-frozen plasma transfusion on prothrombin time and bleeding in patients with mild coagulation abnormalities.Dzik et al • Transfusion. 46(8):1279-1285, August 2006

• All patients transfused with FFP for – a pretransfusion prothrombin time (PT)

between 13.1 and 17 seconds (international normalized ratio [INR], 1.1-1.85)

– and with a follow-up PT-INR within 8 hours of transfusion were included.

– Of 1091 units of FFP transfused, follow-up coagulation values within 8 hours were available for 121 patients (324 units).

Effect of fresh-frozen plasma transfusion on prothrombin time and bleeding in patients with mild coagulation abnormalities.Dzik et al

• RESULTS: – Transfusion of FFP resulted in

• normalization of PT-INR values in 0.8 percent of patients • decreased the PT-INR value halfway to normalization in

15.0 percent of patients • Median decrease in PT was 0.20 seconds (median decrease

in INR, 0.07). • Pretransfusion PT-INR, partial thromboplastin time,

platelet count, and creatinine values had no correlation with red blood cell loss.

• CONCLUSION: – It is concluded that transfusion of FFP for mild

abnormalities of coagulation values results in partial normalization of PT in a minority of patients and fails to correct the PT in 99 percent of patients.

Fresh-frozen plasma transfusion in patientswith mild coagulation abnormalities at alarge Canadian transfusion center. Cheng et alTransfusion vol 47, 2006

722 plasma transfusion episodes mean number of units transfused per episode

was 1.07(range, 1-6). The mean pretransfusion international

normalized ratio (INR) was 2.04, A significant number (452/722 [62.6%]) were

being transfused for an INR between 0.9 and 1.8 (Fig. 1).

Fresh-frozen plasma transfusion in patientswith mild coagulation abnormalities at alarge Canadian transfusion center. Cheng et al

CDHA study about plasma transfusions Cheng et al

199 plasma transfusion episodes involving 62 patients, some being transfused on

multiple occasions. 16/199(8%) were for plasmapheresis, the majority 183/199(92%) were transfused for other

indications. Of these 183 transfusion instances,

The average dose of plasma was 567ml, or 1.2 units. Pre-transfusion coagulation studies were ordered 4.6

hours pre-transfusion, with mean INR, PT, and PTT being 2.0, 28 seconds and 40

seconds respectively. Post-transfusion studies were ordered 3.9 hours after

transfusion, in 168/183(92%) of cases, with a mean change in INR, PT, and PTT of -0.4, -7.7s, and -

3.7s respectively. There was a significant number of plasma transfusions,

91/183(50%) occurring in the population with INR<1.7.

CDHA study about plasma transfusionsCheng et al

Those transfused with 1 unit of plasma (500 ml) experienced a mean change of

INR= - 0.44, PT= -8.4 sec, PTT = -4.15sec. Those receiving 2 units

had changes of INR =-0.168, PT= -2.96sec, PTT= 0.14sec

In the subgroup 91/183(50%) with INR<1.7; their INR = 1.4, PT = 17.3 sec, and PTT 33 sec a mean change of these coagulation values post-

transfusion were INR= 0.000, PT= -0.02seconds, and PTT =-3.35sec.

Appropriateness of Frozen plasma

Appropriateness of Frozen Plasma Use in CanadaPrincipal Investigator:Alan T. Tinmouth et al

Start Jan 24Review all transfusions for 2 months.

PLASMA DERIVATIVES

octaplex®:

A product in good haemostatic balance, i.e. balanced potencies of prothrombin complex factors

FII, FVII, FIX and FX – ideal ratio 1:1:1:1 (low target level, but short half-life for FVII)

Therapeutic levels of PC, PS (and PZ)

(Traces of) ATIII in combination with heparin

Low proteolytic activity (e.g. FSAP) and FVIIa

Potent product with no thrombogenic tendency

octaplex®: Manufacturing process

Cryoprecipitate-poor plasma

Heparin and pH adjustment

Ion Exchange Chromatography

S/D Virus inactivation

Ion exchange chromatography

Virus removal: Nanofiltration

Diafiltration

Ultrafiltration

Heparin and pH adjustment

Sterile filtration, filling

Lyophilisation

OCTAPLEX

octaplex® use and indication In Canada, octaplex® is licensed for:

Treatment of bleeding and perioperative prophylaxis of bleeding in acquired deficiency of the prothrombin complex coagulation factors

(such as deficiency caused by treatment with vitamin K antagonists, or in case of overdose of vitamin K antagonists, when rapid correction of the deficiency is required)

Dosing recommendations

Initial INR 2.0 - 2.5 2.5 - 3.0 3.0 - 3.5 >3.5

Approximate dose* (mL octaplex® / kg body weight)

0.9 - 1.3 1.3 - 1.6 1.6 - 1.9 >1.9

The dose will depend on the INR before treatment and the targeted INR. In the following table approximate doses (mL / kg body weight of the reconstituted product) required for normalisation of INR (≤1.2 within 1 hour) at different initial INR levels are given.

For example:

Recommended dose of octaplex for a 70 kg patient with starting INR of 2.5:

1.3 mL x 70 kg = 91 mL octaplex

91 mL octaplex / 20 mL per vial = 4.55 vials octaplex (2275 IU octaplex)

One vial of octaplex is 20 mL and contains 500 IU FIX

Dosing recommendations

Administration:

octaplex® should administered IV. The infusion should start at a speed of 1ml/min, followed by 2-3ml/min, using an aseptic technique.

Precaution: pulse should taken before and during injection. If increase occurs, reduce the injection speed or stop administration.

For example:

Recommended dose of octaplex for a 70 kg patient with starting INR of 2.5:

1.3 mL x 70 kg = 91 mL octaplex

91 mL octaplex / 20 mL per vial = 4.55 vials octaplex (2275 IU octaplex)

Dosage: less than the manufacturer’s recommended dose

Adult patients:40 mL octaplex (1000 IU Factor IX activity*) and

10 mg Vitamin K IV*[Others have - Double the dose if INR>3 or

weight>90 kg, adopted weight based dosing or adopted weight based/ INR based dosing.

Administration: Run over 15 min/1,000 IU

• Contains a small amount of heparin therefore should not be given to patients with HIT or with known allergies to heparin

• Should not be given to patients with a hypersensitivity to any ingredient in the product

• Relative contraindications, due to high risk of thrombotic complications, include acute coronary syndrome, DIC, severe liver disease, and liver transplant

• octaplex® should not be used in massive transfusion cases.

• octaplex® should not be used in coagulopathy associated with liver dysfunction.

• octaplex® should not be used in patients with recent history of thrombosis, myocardial infarction, recent ischemic stroke or Disseminated Intravascular Coagulation (DIC).

OCTAPLEX, CDHA experience.Al-Mohamadi et al.Retrospective data on 50 patients received

OCTAPLEX between Feb and December 2009. . - - 38 met NAC criteria

22 presented with bleeding16 prophylactic (taken to surgery)

- 12 did not meet NAC criteria 8 with bleeding4 prophylactic (taken to surgery)

OCTAPLEX, CDHA experience.

Patients

N=38

INR

Pre-octaplex

INR

Post-octaplex

Bleeding

N=22

3.9 1.6

Pre-op

N=16

3.3 1.6

OCTAPLEX, CDHA experience.• One dose of 40ml reasonably corrected

INR in the vast majority of patients.

• Moreover, this single dose was enough to stop the bleeding in all patients except one patient who was on non steroidal anti-inflammatory drugs presenting with massive upper GI bleeding.

OCTAPLEX, CDHA experience.INR

Pre-octaplex

INR

Post- octaplex

<2

N=6

<1.5

2-4

N=21

1.67

4-6

N=7

1.61

>6

N=4

2.2

Patients divided by two post-octaplex targetsINR of 1.6 and INR of 1.7INR: 4-642%

post INR 1.6 or less

85%post INR 1.7 or

less

INR: 2-452%

post INR 1.6 or less

68%post INR 1.7 or

less

OctaplexOctaplex utilization is monitored closely

Provincial guidelines are in place

Approval process

Acceptable use of octaplex at CDHA

Dose per capita comparison.

PlasmaPlasma utilization is high.

50-60 % of plasma transfusions are for INR<1.7.

Need for plasma transfusion guidelines???

Physician education?? Approriate utilization Adverse events to plasma transfusion...

Questions or advice?

utilization of plasma and plasma derivatives in the perioperative period. irene sadek medical...

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