Version July 2004, 3/16/09, 4/28/09, 7/7/09

5 Blood Transfusion Guidelines and Utilization Review

See also the University of Michigan Hospitals and Health Centers Adult Blood Transfusion Clinical Guidelines approved bny ECCA March 24, 2009.

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Transfusion decisions should be based on clinical assessment of the patient and laboratory test results. There are no absolute indications and few contraindications to blood transfusion. These guidelines are intended as an aid in decision making.

Red Blood Cells

Red blood cells (RBC) are indicated for increasing the oxygen carrying capacity in anemia patients. In addition, RBC transfusion can increase intravascular volume and improve platelet function, particularly in uremic patients. Considerations in ordering RBC transfusion include:

• Cause of anemia. In chronic anemia physiologic compensations may ameliorate some of the symptoms of anemia whereas in acute blood loss there may not be time for compensations to take place. Patients with hemoglobinopathies may have greater transfusion requirements. Hemolysis may be due to a transfusion reaction.
• Degree of anemia as measured by hemoglobin or hematocrit. Note that in acute blood loss without volume replacement, there may not be a change in the hemoglobin level.
• Prior hemoglobin level. The amount of blood loss after volume replacement can be estimated from the following table.

Weight Kg	estimated blood volume	pre hematocrit	post hematocrit	percent of red cell mass lost	estimated blood volume lost
60	4200	35	30	14%	600
	3500	30	25	17%	583
	3500	25	20	20%	700
70	4900	35	30	14%	700
	4900	30	25	17%	817
	4900	25	20	20%	980
80	5600	35	30	14%	800
	5600	30	25	17%	933
	5600	25	20	20%	1120

 

• Underlying cardiac or pulmonary disease. Oxygen delivery to tissues is dependent on hemoglobin, oxygenation, and cardiac output.
• Expectation of continued blood loss. If blood loss in ongoing or likely then transfusion may be indicated at a high hemoglobin level then when there in no expectation of further blood loss.
• Expectation for hemoglobin recovery.

 

General indications for RBC transfusion include:

• Symptomatic anemia in an euvolemic patient. Symptoms of anemia should be differentiated form cardiovascular or pulmonary disease. In the bleeding patient, replacement of intravascular volume is the first priority.
• Acute blood loss of 15% of estimated blood volume. Blood volume can be estimated as 70ml/kg (ideal body weight) in an adult. Note that a standard blood donation is 500ml or 10% of a typical adult blood volume. Many adults without significant cardiac or pulmonary disease can tolerate this degree of blood loss acutely without adverse effects.
• Preoperative hemoglobin less than 9g/dl with expected blood loss of greater then 500 mL.
• Hemoglobin less than 7 g/dL in a critically ill patient.
• Hemoglobin less than 10 g/dL (hematocrit less than 30%) in acute myocardial infarction. Note that transfusion at hematocrit of 33% or greater has been associated with increased mortality in myocardial infarction.
• Hemoglobin less than 8g/dL in a patient on a chronic transfusion regimen.
• Hemoglobin less than 10g/dL in a patient with uremic bleeding. Maintaining a hemoglobin above 10 g/dL (hematocrit above 30%) can improve platelet function in uremia.

 

RBC dosage

One unit of RBC can be expected to result in a hemoglobin increase of 1 g/dl or hematocrit increase of 3% in a typical adult. One unit of RBC can replace a blood loss of 500 ml.

Monitoring RBC transfusion effectiveness

The patient should be assessed and post-transfusion hemoglobin measured to monitor the effectiveness of transfusion. Lack of clinical benefit may indicate ongoing blood loss or cardiac or pulmonary disease. The Blood Bank house officer should be consulted if a patient has an inadequate response to transfusion and other causes are excluded. Causes of a less than expected hemoglobin response include:

• Increased blood volume due to infusion of crystalloid or colloid solutions.
• Incomplete transfusion of RBC
• Ongoing bleeding
• Hemolysis. A hemolytic transfusion reaction should be considered in this case.
• Transfusion of RBC units near outdate. The post-transfusion survival of RBC decreases with storage time.

 

Platelets

Platelets are indicated for the prevention or control of bleeding due to thrombocytopenia or platelet dysfunction. Platelets may be provided as pooled whole-blood derived platelet concentrates ("random donor" platelets) and as apheresis platelet concentrates ("single donor" platelets). For most patients these products are equally effective. Apheresis platelets are indicated for patients with immune refractoriness when crossmatched or HLA matched platelets have better post-transfusion survival.

Considerations in ordering platelet transfusions include:

• Current platelet count
• Cause of thromobocytopenia. Consumptive processes such as DIC, bleeding, and GVHD will shorten post-transfusion platelet survival.
• Underlying disease, such as uremia, that may affect platelet function.
• Recent medications that affect platelet function.
• Body size. Patient with body surface area greater than 2m² may require larger platelet dose.
• Spleen size. Splenomegaly for any reason will significantly decrease that effectiveness of platelet transfusions. Splenectomized patients may have larger post-transfusion platelet increments than individuals with normal spleens.
• Underlying conditions that may increase risk of critical hemorrhage.
• Alloimmunization to platelet or HLA antigens.

General indications for platelet transfusion include:

• Microvascular bleeding due to thrombocytopenia or platelet dysfunction. Microvascular hemorrhage may manifest as mucosal bleeding, bleeding as wound and IV sites, pleural or peritoneal hemorrhage, or visceral hemorrhage. Brisk bleeding from an anatomic lesion, such as a wound or ulcer, without evidence of microvascular hemorrhage elsewhere is usually not due to thrombocytopenia, and usually will not respond to platelet transfusion.
• Thrombocytopenia with significant risk of hemorrhage. Randomized trials indicate that a threshold transfusion for prophylactic platelet transfusion of 10,000/ml is appropriate for many patients with chemotherapy induced thrombocytopenia. A higher threshold may be appropriate for neonates, and patients with high fever, hyperleukocytosis, rapid fall in platelet count, coagulopathy (such as DIC). A threshold of 20,000/ml may be appropriate for patients with mucosal solid tumors (such as bladder or bowel) undergoing aggressive chemotherapy or patients with necrotic solid tumors. A higher threshold, such as 100,000/ml, may be appropriate for patients at risk of hemorrhage into critical organs, such as brain or eye.
• Surgical or invasive procedures in thrombocytopenic patients. Several consensus conference statements indicate that a platelet count of 50,000/ml is sufficient to perform major invasive procedures with safety, in the absence of other coagulation abnormalities. Bone marrow aspiration, central line insertion, lumbar puncture, gastrointestinal endoscopy, bronchoscopy, and bronchalveolar lavage can usually be safely performed when the platelet count is at least 20,000/ml. Liver biopsy and transbronchial biopsy can usually be safely performed when the platelet count is at least 50,000/ml.

Platelet dosage

Transfusion of one platelet pool and one unit of apheresis platelets will typically increase the platelet count of an adult by 20,000 – 40,000/microL. Alternatively, transfusion of one unit per 10 kg body weight will typically increase the platelet count by 10,000/ml. Platelets should be transfused immediately before or during invasive procedure for maximally effectiveness. In a patient with normal splenic function, approximately 40% of transfused platelets will be sequestered in the spleen. This proportion is increased in splenomegaly.

 

Monitoring platelet transfusion effectiveness

A post-transfusion platelet count should be obtained 10 minutes to 1 hour after transfusion for best assessment of transfusion effectiveness. Platelet counts obtained later may not allow for differentiation between immune and non-immune causes of platelet transfusion refractoriness. The corrected count increment (CCI) is usually the best assessment of transfusion effectiveness. A one-hour CCI greater than 5,000 is typically considered a satisfactory response. The Blood Bank house officer should be consulted when platelet transfusion refractoriness is suspected.

Causes of an inadequate response to platelet transfusion include:

• Insufficient dosage
• Incomplete transfusion
• Transfusion of platelet concentrates near outdate.
• Immune refractoriness. ABO antigens are weakly expressed on platelets and usually are not an important consideration in platelet transfusions. However, some patient may benefit from ABO matched platelet transfusions. Antibodies to platelet specific antigens are rare causes of transfusion refractoriness. HLA antibodies may cause transfusion refractoriness. HLA antigens are expressed on platelets and HLA antibodies are common in multiply transfused patients and parous women. Patients with immune refractoriness may benefit from crossmatched or HLA matched platelets.
• Splenomegaly
• Consumption. Bleeding, intravascular coagulation, intravascular platelet activation, GVHD, or sepsis may decrease platelet survival.
• Medications. Drugs that may impair platelet function or decrease platelet survival include:

Heparin	Fibrinolytic agents
Platelet function inhibitors	Nitroglycerin, insosorbide, nitroprusside
Non-steroidal anti-inflammatory drugs	Beta blockers
Antibiotics including beta lactams, nitrofurantions, and vancomycin	Calcium channel blockers
Antifungals, particularly amphotericin	Quinidine
Dipyriamole	Phenothiazines and tricyclic antidepressants
Local and general anesthetic agents	Radiographic contrast agents
Biological such as anti-thymocyte globulin and abciximab

If refractoriness is suspected, the Blood Bank house officer should be consulted. Generally, three one-hour post-transfusion platelet counts with poor increments are necessary to establish refractoriness. Blood samples for platelet crossmatch should be sent to the Blood Bank and for HLA antibodiesshould be set to the Tissue Typing laboratory. The determination of immune refractoriness and selection of platelet components will depend on these results. Additional studies for platelet specific antibodies or HLA typing of the recipient may be requested by the Blood Bank.

Contraindication to platelet transfusion

Platelet transfusion is contraindicated in thrombotic thrombocytopenic purpura (TTP) and heparin-induced thrombocytopenic (HIT). Serious adverse events have occurred with platelet transfusion in these settings. Platelet transfusion is relatively contraindicated in immune thrombocytopenic purpura (ITP) or post-transfusion purpura (PTP) because the survival of transfused platelets is extremely brief.

 

Fresh Frozen Plasma

Plasma is provided as Fresh Frozen plasma (FFP) or Liquid Plasma ("single donor" plasma). FFP is plasma within 24 hours of thawing. After 24 hours, thawed plasma may be relabeled as liquid plasma and stored at 4°C for up to 5 days. Liquid Plasma has essentially the same coagulation factor content as FFP and may be used interchangeably for most patients. Plasma may be transfused for replacement of any plasma protein deficiency, usually coagulation factor deficiency.

General indications for plasma transfusion include:

• Coagulation factor deficiency. Concentrates are available for Factor VIII and Factor IX, and are preferable to plasma patients with these deficiencies.
• Consumptive coagulopathy such as DIC
• Dilutional coagulopathy due to massive transfusion.
• Coagulopathy of liver disease. The coagulopathy of chronic liver disease is multifactorial and plasma transfusion can only address decreased factor synthesis. In general, prophylactic plasma transfusion in liver disease is futile. Plasma transfusion may be indicated for microvascular hemorrhage in a patient with liver disease. In general, invasive procedures including liver biopsy, endoscopy, central line insertion, and tooth extraction may be safely performed with the PT and aPTT are within 1.5 times the mean reference range.
• Microangiopathic hemolytic anemia including TTP, hemolytic uremic syndrome (HUS), and HELLP syndrome.
• Reversal of warfarin anticoagulation. Vitamin K is preferable if reversal in not urgent. Factor XI Complex Concentrate contains vitamin K dependent factors and may be preferable for rapid reversal, especially if intravascular volume restriction is important.

Plasma dosage

A dose of 10 ml/kg will typically provide sufficient coagulation factors to achieve hemostasis. Factor levels in donor plasma are variable, but can be assumed to be approximately 1 U/ml. Post-transfusion recovery of transfused factors may be less than expected due to extravascular distribution or consumption.
The following table may be useful as a guide to coagulation factor replacement.

Factor	Plasma Concentration Required for Hemostasis (U/ml)	Half-Life of Transfused Factor	Recovery in Blood (as % of Amount Transfused)
I (fibrinogen)	100-150 mg/dL	3-6 days	50%
II	0.4	2-5 days	40-80%
V	0.1 – 0.25	15-36 hours	80%
VII	0.05 – 0.2	2-7 hours	70-80%
VIII	0.1 – 0.40	8-12 hours	60-80%
IX	0.1 – 0.4	18-24 hours	40-50%
X	0.1 – 0.2	1.5-2 days	50%
XI	0.15 – 0.3	3-4 days	90-100%
XIII	0.1 – 0.5	6-10 days	5-100%
vWF	0.25 – 0.5	3-5 hours	¾

 

Monitoring plasma transfusion effectiveness

Plasma transfusion should be monitored with specific factor levels or PT and aPTT measurements within 4 hours of transfusion. Causes of an inadequate response to plasma transfusion include:

• Insufficient dosage
• Incomplete transfusion
• Active bleeding or consumptive coagulopathy
• Coagulation factor inhibitor
• Heparin administration
• Liver disease

Cryoprecipitate

Cryoprecipitated antihemophilic factor (CAF or "cryo") is a concentrate of Factor VIII, von Willebrand’s factor, fibrinogen, and Factor XIII. Each unit contains a minimum of 80 U of Factor VIII and typically 250 mg of fibrinogen. Cryoprecipitate is generally indicated for:

• Factor VIII deficiency when Factor VIII concentrate is not available.
• Von Willebrand’s disease. Intermediate purity human-source Factor VIII concentrates are a preferred source of von Willebrand’s factor.
• Hypofibrinogenemia
• Factor XIII deficiency
• Topical fibrin adhesive
• Uremic bleeding. Some evidence suggests that cryoprecipitate transfusion can decrease bleeding due to uremic platelet dysfunction.

Cryoprecipitate is not a significant source of other coagulation factors, and cannot be used as an alternative to plasma.

Cryoprecipitate dosage

For Factor VIII replacement, the dose can be calculated assuming 80 U per bag. Current methods of manufacturing typically yield higher Factor VIII content. Contact the Blood Bank for current information of Factor VIII levels. For fibrinogen replacement, the dose can be calculated assuming 250 mg per bag. For other indications, cryoprecipitate is usually given as 1 unit per 10 kg, or a pool of 10 units for an adult. For topical fibrin adhesive, typically 25 – 50 ml are ordered.

Monitoring cryoprecipitate transfusion

Clinical response is usually the best assessment of cryoprecipitate transfusion effectiveness. Factor VIII activity, fibrinogen, or von Willebrand’s factor activity should be measured 1 hour after transfusion. Lack of expected benefit may be due to:

• Inadequate dosage
• Incomplete transfusion
• Presence of a Factor VIII inhibitor
• Bleeding
• Intravascular coagulation

Massive Transfusion

Massive transfusion is defined as the replacement of one blood volume within 24 hours. This is approximately equivalent to transfusion of 10 units of Red Blood Cells in an adult. Coagulopathy due to thrombocytopenia, factor consumption, or factor dilution may occur in massive transfusion. Optimal management should be based on frequent clinical assessment and laboratory monitoring. Consideration should be paid to:

• Maintenance on intravascular volume
• Avoidance of hypothermia
• Normalization of acid/base status
• Pre-existing hematological or coagulation disorders
• Maintenance of normal ionized calcium levels
• Expectation for on-going blood loss

Patient assessment should include:

• Examination of mucus membranes, IV sites, and wounds for microvascular bleeding
• CBC with platelet count
• PT, aPTT, and fibrinogen
• Serum calcium and ionized calcium

Assessments should be repeated frequently (typically after each 5-10 units of red cells transfused). No single transfusion protocol is applicable for all massively transfused patients, but general guidelines include:

• The first priority is maintaining intravascular volume and oxygen carrying capacity. Red cells should be transfused first with a target hemoglobin of at least 10 g/dl.
• Coagulation factor dilution is usually not significant until one blood volume has been replaced. Factor deficiency may occur earlier with liver disease, DIC, or poor tissue perfusion. Plasma, 10 ml/kg, should be given if
• PT (INR) or aPTT >1.5 time control, or
• 10 units of red cells have been given and coagulation tests are not available, or
• microvascular bleeding continues after platelet transfusion
• Thrombocytopenia is usually not significant until two blood volumes have been replaced. Thrombocytopenia may occur earlier with splenomegaly, DIC, or extensive crush or burn injuries. Platelet dysfunction may be present in hypothermia, acidosis, or due to drug effects. In general, platelet transfusion during rapid hemorrhage is not effective due to rapid depletion. Platelets, 1 pool or 1 apheresis unit, should be given if:
• Microvascular bleeding is present, or
• 20 units of red cells have been given and a platelet count is not available, or
• Platelet count < 50,000/ml
• Cryoprecipitate may be useful if the fibrinogen is less than 100 mg/dl. However, cryoprecipitate does not contain other coagulation factors (except factor VIII and von Willebrand’s factor). Plasma is usually a preferable source of coagulation factors.

 

Mediastinal bleeding following cardiac surgery

Excessive bleeding after cardiac surgery may be due to heparin, coagulation factor deficiency, thrombocytopenia, surgical factors, or underlying coagulopathy. Evaluation of the postoperative patient should include:

• Assessment of chest tube output
• Examination of IV sites and wounds for microvascular bleeding
• CBC with platelet count
• Heparin level (factor Xa inhibition)
• PT, aPTT, and fibrinogen

Surgical bleeding is generally indicated by:

• Chest tube output > 1000 ml in the first hour
• Chest tube output > 300 ml/hr for the first two hours
• Chest tube output >150 ml/hr after the first two hours
• Abrupt increase in chest tube output > 300 ml/hr
• Widening of the cardiac silhouette on chest x-ray

An elevated heparin level, typically with prolongation of the aPTT, indicates that unneutralized heparin is present, in which case protamine is generally indicated. Coagulopathy may be indicated by:

• Presence of microvascular bleeding
• Chest tube output of 50-150 ml/hr
• Fibrinogen < 100 mg/dl
• PT or aPTT greater than 1.5 times normal with normal heparin (Xa inhibition) level
• Platelet count less than 50,000/ml

A low fibrinogen may be due to fibrinolysis, in which case e-aminocaproic acid may be indicated. Elevated PT or aPTT after heparin neutralization is usually an indication for plasma transfusion, 10 ml/kg. Microvascular bleeding or elevated chest tube output with platelet count < 50,000/ml is usually an indication for transfusion of 1 platelet pool or 1 apheresis platelet unit.

 

Liver disease

Factors contributing to bleeding in liver disease include:

• Portal hypertension with varices
• Splenomegaly with thrombocytopenia
• Reduced factor synthesis
• Vitamin K deficiency
• Presence of circulating activated coagulation factor inhibitors
• Presence of circulating fibrin degradation products
• Acquired dysfibrinogenemia
• Uremic platelet dysfunction due to hepatorenal syndrome. Evaluation of the bleeding patient with liver disease should include:
• Localization of the bleeding site
• CBC with platelet count
• PT, aPTT, factor V activity, fibrinogen antigen, clotable fibrinogen. General guidelines for transfusion therapy:
• Bleeding from a discrete anatomic site such as esophageal varices requires direct intervention and cannot be control with transfusion alone.
• Most patients with chronic liver disease, without vitamin K deficiency, has coagulation factor levels within the hemostatic range. Factor V activity greater than 30% generally indicates sufficient hepatic synthetic capacity.
• Fibrinogen antigen in excess of clotable fibrinogen indicates the presence of dysfibinogenemia. Plasma transfusion usually cannot overcome the effect of a dysfibinogenemia.
• The primary goal of transfusion should be maintenance of adequate intravascular volume and oxygen carrying capacity. A target hemoglobin range of 8 to 10 g/dl is typical.
• The goal of plasma transfusion is to provide sufficient coagulation factor replacement to prevent microvascular hemorrhage. Plasma transfusion is generally indicated after 5 units of red cells have been transfused. A larger plasma dose, typically 20 ml/kg, is generally indicated. Plasma transfusion even at large doses will rarely cause a significant correction of the PT and aPTT.
• Evidence of microvascular bleeding is an indication for platelet transfusion. However, platelet transfusion is often ineffective in liver disease due to hypersplenism, the effects of fibrin degradation products or dysfibinogen on platelet function, of the effect of uremia. Platelet transfusion will rarely result in a significant increase in platelet count.
• Invasive procedures such as central line placement, paracentesis, and liver biopsy can be preformed without increased risk of bleeding complications when the PT and aPTT are within 1.5 time control and the platelet count is greater than 50,000/ml.
• There is no evidence that prophylactic transfusion of platelets or plasma in liver disease will decrease the risk of bleeding.

 

Utilization Review

Blood transfusion practices at the University of Michigan Hospitals and Health Centers are reviewed by the Transfusion Committee of the Medical Staff. The purpose of a utilization review is to improve the processes involved in the ordering, distribution, handling, dispensing and administration of blood components and to monitor the effects of transfusion practices. Conducting such audits is an accreditation requirement of the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO).

The review criteria are approved by the Transfusion Committee, and the chairs of the clinical departments. These criteria reflect a consensus as to the generally accepted rationale for the use of blood components based published clinical trials, consensus statements, and guidelines produced by national organizations. However, it must be noted that review criteria do not necessarily constitute indications, or triggers, for transfusion and that specific clinical situations may dictate transfusion practices that differ from the review criteria. The Transfusion Committee recognizes that all transfusion decisions are clinical judgments that cannot necessarily be reduced to predefined indications.

Utilization reviews are generally focused on procedures and patient care units with high use, patients requiring special products, or transfusion situations at increased risk of adverse outcomes. Elements of utilization review include:

• Documentation of clinical indication for transfusion
• Pertinent laboratory testing including CBC, platelet count, PT, aPTT, and fibrinogen level
• Ordering and dosage of blood components
• Evaluation of transfusion outcome

References

• Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetisir E. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340(6):409-17.
• British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of platelet transfusions. Br J Haematol. 2003;122(1):10-23.
• Sacher RA, Kickler TS, Schiffer CA, Sherman LA, Bracey AW, Shulman IA; College of American Pathologists.Transfusion Medicine Resource Committee. Management of patients refractory to platelet transfusionArch Pathol Lab Med. 2003;127(4):409-14.
• Expert Working Group. Guidelines for red blood cell and plasma transfusion for adults and children. CMAJ 1997;156(11 Suppl):S1-S24.
• Murphy MF, Wallington TB, Kelsey P, Boulton F, Bruce M, Cohen H, Duguid J, Knowles SM, Poole G, Williamson LM; British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the clinical use of red cell transfusions. Br J Haematol. 2001 Apr;113(1):24-31.
• Schiffer CA, Anderson KC, Bennett CL, Bernstein S, Elting LS, Goldsmith M, Goldstein M, Hume H, McCullough JJ, McIntyre RE, Powell BL, Rainey JM, Rowley SD, Rebulla P, Troner MB, Wagnon AH; American Society of Clinical Oncology. Platelet transfusion for patients with cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001;19(5):1519-38.
• Hellstern P. Muntean W. Schramm W. Seifried E. Solheim BG. Practical guidelines for the clinical use of plasma. Thromb Res 2002; 107 Suppl 1:S53-7
• Practice Guidelines for blood component therapy: A report by the American Society of Anesthesiologists Task Force on Blood Component Therapy.
  Anesthesiology. 1996 Mar;84(3):732-47.
• Guidelines for Blood Utilization Review. Bethesda MD; American Association of Blood Bank. 2001.

Version July 2004