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The following is the patient’s complete blood count (CBC):

What’s what: WBC, white blood cell count; Hb, hemoglobin; MCV, mean cell volume; MCHC, mean cellular hemoglobin concentration; RDW, red cell distribution width; platelets, PLT; Normal values: WBC 5-10 x 10⁹/L, RBC 4-6 x 10¹²/L, Hb 12-16 g/dL, Hct 35-47%, MCV 80-100 fL, MCHC 32-36 g/dL, RDW-SD < 45%, platelets (PLT) 150-450 x 10⁹/L

How would you describe the CBC?

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Normocytic, normochromic anemia, thrombocytopenia

The following are the patient’s coags:

What’s what: PT, prothrombin time; INR, international ratio; aPTT, activated partial thromboplastin time; Normal values: PT 9.1-12 seconds, aPTT 24-33 seconds.

How would you interpret these coagulation assays?

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Elevated prothrombin time and INR

Question 1: Based on the information provided, what is NOT appropriate in this patient’s transfusion order (more than one answer may apply)?

Explanation to question 1:

The correct answer is C (FFP dosage is incorrect).

This is a prophylactic FFP order in non-bleeding patient with abnormal standard coagulation tests pre-elective procedure. The order is correct: plasma products are indicated. Transfusion of plasma products is indicated in:¹

• Multiple factor deficiencies, such as in:
  • Massive transfusion
  • Fulminant liver disease
  • Warfarin reversal
• As a replacement fluid therapeutic plasma exchange for thrombotic thrombocytopenic purpura (TTP).
• In bleeding with INR >1.5 or disseminated intravascular coagulopathy.
• For correction of single factor deficiencies (factor V, factor XI, protein S deficiency, plasminogen activator inhibitor (PAI) deficiency, a2-antiplasmin deficiency) when concentrate or recombinant factor is unavailable.
• Patients with C1 esterase inhibitor deficiency (hereditary angioedema) when recombinant therapy is not available.

While the blood component order is correct, the dosage is not. Unlike RBCs and platelets, where transfusion of one unit is usually indicated followed by monitoring response, in the case of plasma transfusion, the starting dose is usually 2 units. One FFP unit is very rarely indicated because the impact on coagulopathy correction is usually negligible. Most society guidelines and reviews highlight the insufficient evidence regarding the optimal dosage; however, they generally recommend 10-20 mL/Kg [1-2].² 10 mL/kg for someone who is ~70Kg would be 700 mL ~ 2-3 FFP units of ~250 mL each.

One recommended formula to calculate the impact on INR after transfusion of one FFP unit is:³

• DeltaINR = PreINR- PostINR = 0.57 x PreINR-0.72

Alternatively, the use of tables for total and partial reversal was recommended.⁴ A total reversal is defined as achieving a goal INR of less than 1.5, while a partial reversal the goal INR is 2-3.  Based on these tables, 3 FFP units are needed for a total reversal starting with an initial INR or 3-4, such as this case.

RBCs and platelets are not indicated. Although this patient has normocytic normochromic anemia and mild thrombocytopenia, he should receive neither RBCs, nor platelets. In a non-bleeding patient, prophylactic transfusion of RBCs is not indicated unless the Hb threshold is below 7 or 8 g/dL (see Transfusion Medicine Case 1), while prophylactic transfusion of platelets is not indicated unless the platelet count falls under 10-20K/microL (in anticipation of Case 3).

Answer D is also not correct. It would be correct in a different setting, specifically in emergency or bleeding patients, not such as the one presented here. Four-factor prothrombin complex concentrate (4-factor PCC; K-centra) has been approved by the US Food and Drug Administration approval in 2013 for warfarin reversal in the setting of an acute major bleed or urgent surgical or invasive procedure. There are rising use of off-label indications, including traumatic and spontaneous bleeds outside the scope of a “major bleed”,⁵ or in patients at risk for fluid overload.

Question 2: When are plasma products NOT indicated:

Explanation to question 2:

The correct answer is D (All the above).

Mildly prolonged coagulation tests have limited clinical significance, and correction of these laboratory values is not indicated. Transfusion for patients with INR<1.7 does not reliably reduce the INR and exposes patients to unnecessary risk [7-8].⁶ Plasma products are not indicated for to correct abnormal lab tests resulting from vitamin K deficiency, unless urgent invasive procedures are planned, or if the patient is actively bleeding. Many hospitalized patients have inadequate vitamin K intake, are likely to become deficient, and may have a prolonged INR/PTT. Oral or intravenous vitamin K should be given in these cases. Coagulation factors usually return to hemostatic levels approximately 12 hours after vitamin K administration. Plasma products should also not be used for:

• Volume expansion
• As a nutritional or protein source
• When the coagulopathy can be corrected with specific therapy (vitamin K or factor concentrates)
• In immunoglobulin deficiencies

Question 3: Which of the following are correct (more than one answer may apply):

Explanation to question 3:

The correct answers are A, B and D.

The volume of plasma products is usually about 200-250 mL, however, units obtained via apheresis (“Jumbo”) may have higher volumes (500-600mL). Plasma products are acellular (contain no RBCs and no platelets). They contain all coagulation factors at 1 unit of coagulation factor activity/1 mL plasma.

Question 4: Transfusion of plasma should be guided by (more than one answer may apply):

Explanation to question 4:

Correct answers are A and B.

The decision to transfuse should not be based solely on the patient’s abnormal coagulation values, but on patient’s clinical condition as well as the risk and consequences of bleeding. Assessment of response to plasma therapy should be also guided by patient’s clinical status and coagulation studies knowing that satisfactory hemostasis may be achieved when coagulation factor levels are at least 30% of normal, and when fibrinogen level is above 100 mg/dL. Lower levels of fibrinogen (coagulation factor I) may explain bleeding; however, they neither indicate the need to transfuse plasma, nor are they used to monitor the response to plasma therapy. Hypo- or dysfibrinogenemia are indications for transfusion cryoprecipitate, not plasma (this will be discussed further in Case #4). Plasma contains fibrinogen but administration of 250 mL plasma unit leads to increase in fibrinogen levels only by 5-10 mg/dL.

Answer D is a little tricky. INR (international normalized ratio) is a formula (a ratio) developed to standardize reporting of PT results: INR=(PT_test/PT_normal)^ISI where PT_test is patient’s PT,  PT_normal is normal PT, and ISI is international sensitivity index. This calculation is meant to minimize the variability of PT results due to differences in sensitivity of thromboplastin reagents across laboratories. It serves as a therapeutic monitor for warfarin’s anticoagulant effect. Given its relation to PT, it is used clinically as a substitute for the PT value. In that sense, it can be used as a monitor for plasma therapy. However, this relationship (INR-PT) or rather the PT conversion in INR scale is valid only for patients on vitamin K antagonists (VKA). This is because PTs from patients on VKA are inserted in the calibration plot.  Therefore, “application of the INR scale to the PT measured for conditions other than oral VKA treatment is neither justified, nor secures harmonization of results”. INR should not be used as a diagnostic tool to predict bleeding risk or outside of VKA therapy”.⁷