Blood Products and Coagulation

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Chapter 54 Blood Products and Coagulation

George Kasotakis, MD , Hasan B. Alam, MD, FACS

1 What components of blood are available for transfusion?

Components available for transfusion include whole blood, packed red blood cells (PRBCs), fresh frozen plasma (FFP), platelets, factor concentrates, cryoprecipitate, and white cell preparations. Fresh whole blood is sometimes used by the military but is not typically available for civilian use.

2 What are PRBCs?

Red blood cells contain hemoglobin and serve as the primary oxygen-transporting agent to tissues. Red blood cells are obtained by centrifugation of whole blood to remove much of the plasma, or by apheresis (a procedure in which blood is drawn and separated into its components, with the unwanted ones being returned by transfusion to the donor). The resulting product is called PRBCs, because of its high hematocrit (65%-80%) concentration. The usual volume of 1 unit of PRBCs ranges between 225 and 350 mL, and its shelf life ranges from 21 to 42 days, depending on the type of anticoagulant-preservatives added. When transfused, 1 unit of PRBCs typically raises the hemoglobin by 1 mg/dL or the hematocrit by an average of three points.

3 What are the main red blood cell surface antigen systems?

An individual’s red cells may express A, B, both, or no surface antigens, which determine that individual’s blood type. Those who do not express an antigen will eventually develop antibodies against it. People carrying anti-A or anti-B antibodies cannot receive red blood cells with the corresponding surface antigens, or immunologic destruction of the transfused red cells may occur. Consequently, type O individuals are considered universal donors, whereas AB individuals may donate only to other AB recipients. Similar to the ABO system, a separate Rh surface antigen exists that may be either present (Rh+) or absent (Rh−) from the red cell plasma membrane. Individuals who are Rh negative will develop antibodies to the Rh factor when exposed to Rh+ blood. This is not a problem with the initial exposure, but hemolysis may occur with subsequent transfusions (Table 54-1).

Table 54-1 Compatible packed red blood cells donor-recipient combinations

4 What are blood typing, screening, and crossmatching?

Donor and recipient blood typing is a process that determines what ABO and Rh antigens are expressed on the red cell surface. Screening is a process that detects circulating antibodies to various other antigens that might interact with the donor blood components. Cross-matching involves directly mixing the recipient’s plasma with the donor’s red cells to ensure that hemolysis does not occur from undetected antibodies.

6 What is a febrile nonhemolytic reaction?

A febrile nonhemolytic reaction manifests as a mild to moderate temperature elevation (typically ≤ 2° F or < 1.1° C) during or shortly after a transfusion and in the absence of any other pyretic stimuli. Febrile reactions occur in fewer than 1% of all transfusions and are thought to arise from circulating molecules or cells either in the transfused product or generated by the recipient. Routine pretreatment with antihistamines and antipyretics may ameliorate symptoms. Patients having recurrent severe febrile reactions may benefit from leukocyte-reduced blood products.

7 What is a hemolytic reaction?

It is the immunologic destruction of the transfused cells due to incompatibility of the antigen on their surface with preexisting circulating antibodies in the recipient’s plasma. It may occur when as little as 10 mL of blood is infused and is associated with significant morbidity. Associated mortality may be as high as 35%. The most common cause of acute hemolytic reactions is transfusion of ABO- or Rh-incompatible blood, resulting from identification errors. Serologic incompatibility undetected during pretransfusion testing is much less common. Delayed hemolytic reactions can also occur in previously alloimmunized patients in whom antigens on the transfused product provoke anamnestic antibody production. This anamnestic response is usually most evident within 2 to 14 days after the transfusion.

8 What are the classic findings in a hemolytic transfusion reaction?

Fever (with or without chills), tachycardia, back or flank pain, chest pain, dyspnea, hypotension, and oliguria are frequently present. Disseminated intravascular coagulopathy (DIC) may become clinically evident in severe cases. Laboratory findings include hemoglobinuria and elevation of the indirect serum bilirubin and lactate dehydrogenase levels. The direct antiglobulin test is also positive.

9 How should a hemolytic transfusion reaction be managed?

When an acute hemolytic reaction is recognized, the transfusion must be stopped immediately. The blood bank should be notified and transfusion forms and labels rechecked. Postreaction blood samples need to be sent along with the remaining blood component. Treatment is supportive and includes administration of intravenous fluids, diuretics, inotropes, and close monitoring as needed. Delayed reactions are typically benign and require no treatment.

10 What are the infectious risks of transfusion?

The incidence of transmission of hepatitis C, human T-lymphotropic virus, and human immunodeficiency virus in the United States through a blood component transfusion is approximately 1:2,000,000 units transfused.

Hepatitis B is transmitted in 1:270,000 transfusions.

The risk of transfusion-related bacterial infections is much higher at 1:2000 units of platelets transfused (platelets carry a higher risk of contamination because they are stored at room temperature).

Transmission of other infectious agents (e.g., Babesia spp, variant Creutzfeldt-Jakob disease agent, West Nile virus) for which blood products are not routinely tested is possible, yet even rarer.

11 What is TRALI?

TRALI describes the acute onset of hypoxemia (within 6 hours) after a blood component transfusion and is the most common cause of transfusion-related death in the United States. In addition to hypoxemia, criteria for diagnosis include bilateral infiltrates on chest radiograph and exclusion of preexisting lung injury or circulatory overload. Postulated mechanisms include second-hit injuries to the lungs from lipid products in stored blood products, human neutrophil antibodies, and human leukocyte antigen antibodies. Treatment consists of aggressive pulmonary support, frequently requiring mechanical ventilation.

12 When should red cells be transfused to critically ill adults?

This has been one of the most hotly debated topics in critical care for the last decade. It appears that a restrictive transfusion strategy (hemoglobin level of 7 g/dL as transfusion trigger) is at least as effective as, and possibly superior to, a liberal transfusion strategy (hemoglobin trigger of 10 g/dL) with regard to overall mortality. It is also known from studies in populations with anemia who decline transfusions for religious reasons that perioperative mortality increases from zero to 9% as the hemoglobin levels drop below 7 g/dL. Patients with acute myocardial infarction and unstable angina are an exception, and higher transfusion triggers should be maintained for them. Other parameters, including patient age, chronic anemia or acute blood loss, and vasoocclusive disease should also be taken into consideration when individualizing transfusion triggers.

13 What are the most commonly used techniques of autologous transfusion?

Preoperative autologous blood donation (PABD). Blood is donated at frequent intervals (as often as every 3 days) starting 4 to 6 weeks before surgery and transfused after surgery as needed. Benefits include freedom from hemolytic, allergic, and febrile reactions, as well as alloimmunization and transfusion-related infections.

Acute normovolemic intraoperative hemodilution (ANH). This blood conservation technique entails the removal of blood (typically 500-1500 mL) from a patient immediately before surgery, with maintenance of normovolemia with crystalloids and/or colloids. Intraoperative blood loss leads to smaller hemoglobin losses due to hemodilution. The removed blood, which is anticoagulated and stored for up to 8 hours, is reinfused during or after surgery as needed.

Intraoperative blood salvage (Cell Saver) (IBS). Blood is aspirated from the surgical field, anticoagulated, and collected for centrifuging. Salvaged red cells are washed and reinfused to the patient as needed. Contraindications include bacteremia, gross operative field contamination, and cancer.

14 What else can be done to minimize blood loss and transfusion requirements?

Antifibrinolytic agents (ε-aminocaproic acid and tranexamic acid [TXA]) are synthetic lysine analogs that have been used extensively, mainly in cardiac surgery, to minimize blood loss and decrease transfusion requirements. They also appear to minimize blood loss and improve survival in trauma patients, and their use has been increasing in the field. (Aprotinin, an older-generation antifibrinolytic, was withdrawn from the market in 2008 when it was found to be associated with a higher risk for cardiovascular complications and death). A recent multiinstitutional large prospective randomized clinical trial has shown survival advantage in trauma patients treated early with TXA.

Recombinant erythropoietin, a normally endogenously produced hormone that stimulates erythropoiesis, was previously thought to decrease tranfusion requirements and possibly improve survival in the critically ill. However, recent evidence suggests that the benefit may be too small to outweigh risks (thrombotic events). This finding, in addition to the fact that it does not work quickly enough to have a role in the management of acute blood loss, has led to the abandonment of its routine use in modern intensive care units.

Recombinant human factor VIIa is licensed for use in patients with hemophilia but has gained momentum in recent years as a potent agent in controlling life-threatening hemorrhage, usually after trauma. However, significant complications (thromboembolic episodes), along with two prospective randomized trials in trauma patients that failed to show any clear benefits, have dampened enthusiasm for its use.

Desmopressin increases plasma levels of von Willebrand factor (vWF) and factor VIII and is licensed for use in von Willebrand disease and hemophilia A. It can also be used to control bleeding in patients with uremia.

Factor concentrates (fibrinogen concentrate [FC], prothrombin complex concentrate [PCC]) have emerged recently as potential adjuvant therapies in the management of the acute, massive bleeding with associated hypofibrinogenemia (the former) and emergent reversal of warfarin anticoagulation (the latter). FC contains fibrinogen at very high concentrations (even higher than cryoprecipitate), and PCCs are preparations containing near-physiologic concentrations of factors II, IX, and X and proteins C and S and variable levels of factor VII. FC has been approved for management of acute bleeding episodes in patients with congenital fibrinogen deficiency, but PCC, although its use in Europe and Canada is on the rise, is still undergoing phase III testing in the United States.

15 What are the characteristics of an ideal oxygen carrier?

Effective O₂ carrying capacity and delivery to the peripheral tissues

Favorable interaction with nitric oxide

Universal compatibility (crossmatching elimination)

Minimal side effects

Easy storage, long shelf life, immediate availability

16 What alternative oxygen carriers are available for use in the critically ill?

Two types of oxygen carriers are available as alternatives to PRBC transfusion: hemoglobin-based oxygen carrier and perfluorocarbons, but neither of them is currently commercially available. The former has been associated with adverse outcomes in human studies, whereas the latter is currently undergoing phase III testing in Europe.

17 What is FFP?

FFP is plasma obtained from single units of whole blood collected by apheresis. It is frozen and maintained at −18° to −30° C to preserve the labile coagulation factors. FFP contains all of the coagulation factors present in blood, along with antithrombin III and proteins C and S, at near-physiologic concentrations. It has a half life of approximately 1 year and has to be thawed before administration. It has to be matched for ABO system compatibility (Table 54-2) but not Rh compatibility.

Table 54-2 Compatible Fresh Frozen Plasma Donor-Recipient Combinations

18 List the indications for FFP

Coagulopathy due to a congenital or acquired deficiency of multiple factors (severe liver disease, DIC, dilutional or consumption coagulopathy)

Emergent reversal of warfarin effect or vitamin K deficiency

Massive transfusion protocol

Treatment of antithrombin III deficiency

19 What is cryoprecipitate?

Cryoprecipitate is the precipitate that remains when FFP is thawed slowly at 4° C. It is a concentrated preparation (10-15 mL) that contains virtually all of the factor VIII, XIII, fibrinogen, and vWF that are in the FFP (without the additional volume).

20 List the indications for cryoprecipitate

Fibrinogen repletion (levels <100 mg/dL) and a clinical need to avoid excessive transfusion volume (unable to give FFP)

Von Willebrand disease

Factor XIII deficiency

21 What is measured by prothrombin time (PT)? What is international normalized ratio (INR)?

PT is used to assess the extrinsic pathway of clotting, namely the activity of factor VII and the common pathway factors (fibrinogen and factors II, V, and X). It is prolonged in patients with liver disease, vitamin K deficiency, or circulating lupus anticoagulants or receiving warfarin therapy.

INR is a standardized method of reporting the PT, so that values from various laboratories can be directly comparable. It is most commonly used to monitor patients receiving oral warfarin therapy.

22 What is measured by partial thromboplastin time (PTT)?

PTT assesses the intrinsic coagulation pathway, which includes factors XII, XI, IX, and VIII, along with the common pathway factors (fibrinogen and factors II, V, and X). It is used to monitor heparin therapy.

23 How does warfarin work?

Warfarin (Coumadin) inhibits the conversion of vitamin K to its active form. This inhibition interferes with the hepatic synthesis of the vitamin K–dependent clotting factors (II, VII, IX, and X and proteins C and S). Warfarin therapy is routinely monitored by following the INR.

24 How does dabigatran work?

Dabigatran is an orally active direct thrombin inhibitor that has been recently approved for use in patients with nonvalvular atrial fibrillation. It has also been shown that it is at least as effective as warfarin for the treatment of acute venous thromboembolism and with a similar safety profile. Its main benefit is that it does not require laboratory monitoring, but its high cost is likely to prevent mass adoption.

25 How does heparin work?

Heparin binds to and activates antithrombin III, which in turn inhibits several coagulation enzymes, including thrombin and activated factors X, XII, XI, and IX. The biologic half-life of heparin is 30 to 60 minutes, and its effects are reversed within 2 to 4 hours after an infusion is stopped. If urgent reversal is required, protamine can be given intravenously. Heparin therapy is monitored by serial PTT measurements.

26 What is low-molecular-weight heparin (LMWH)?

LMWH is a fragment produced by the chemical breakdown of heparin. It exerts its anticoagulant effect by binding with antithrombin III and inhibiting several coagulation enzymes. LMWH principally inhibits activated factor X.

27 What are the major differences between standard heparin and LMWH?

LMWH has a longer half-life and thus can be administered once daily.

LMWH provides a more predictable anticoagulant response and thus can be administered without monitoring.

LMWH is as effective as heparin but produces fewer bleeding complications at equivalent antithrombotic doses.

28 What is damage control resuscitation?

The basic tenets of damage control resuscitation are as follows:

Avoid crystalloid resuscitation.

Aim for permissive hypotension whenever possible.

Prevent coagulopathy through early use of blood products.

Aggressively break the vicious cycle of acidosis, coagulopathy, and hypothermia.

A key component of this damage control approach is early hemorrhage control. Another core concept is that resuscitation fluids should resemble what the trauma patient loses—warm fresh whole blood. In civilian settings, fresh whole blood is not available for transfusion, and blood components in appropriate ratios should be used toward this goal. A number of studies suggest that FFP and platelets should be given early and in high ratios (e.g., PRBCs/FFP/platelets in a ratio of 1:1:1) in patients who require massive transfusion (>10 units PRBCs). A randomized trial is about to begin to identify the optimal ratio of component therapy.

Key Points Blood Products and Coagulation

1. Controlling the bleeding is more important than replacing the losses.

2. Blood products carry significant risks. Transfuse only when necessary.

3. Know the mechanism of warfarin and heparin anticoagulants and how they can be reversed.

4. Early use of blood component therapy can prevent development of coagulopathy in massively bleeding patients.

5. Excessive crystalloid resuscitation can worsen coagulopathy.

1 Alter H.J., Stramer S.L., Dodd R.Y. Emerging infectious diseases that threaten the blood supply. Semin Hematol. 2007;44:32–41.

2 Brown C.V., Foulkrod K.H., Sadler H.T., et al. Autologous blood transfusion during emergency trauma operations. Arch Surg. 2010;145:690–694.

3 Carless P.A., Henry D.A., Carson J.L., et al. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. 10, 2010. CD002042, 2010

4 Carson J.L., Noveck H., Berlin J.A., et al. Mortality and morbidity in patients with very low postoperative hemoglobin levels who decline blood transfusion. Transfusion. 2002;42:812–818.

5 CRASH-2 trial collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376:23–32.

6 Duchesne J.C., Hunt J.P., Wahl G., et al. Review of current blood transfusions strategies in a mature level I trauma center: were we wrong for the last 60 years? J Trauma. 2008;65:272–276.

7 Hauser C.J., Boffard K., Dutton R., et al. Results of the CONTROL trial: efficacy and safety of recombinant activated factor VII in the management of refractory traumatic hemorrhage. J Trauma. 2010;69:489–500.

8 Henry D.A., Carless P.A., Moxey A.J., et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 3, 2011. CD001886, 2011

9 Holcomb J.B., Wade C.E., Michalek J.E., et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg. 2008;248:447–458.

10 Inaba K., Lustenberger T., Rhee P., et al. The impact of platelet transfusion in massively transfused trauma patients. J Am Coll Surg. 2010;211:573–579.

11 Kennedy L.D., Case L.D., Hurd D.D., et al. A prospective, randomized, double-blind controlled trial of acetaminophen and diphenhydramine pretransfusion medication versus placebo for the prevention of transfusion reactions. Transfusion. 2008;48:2285–2291.

12 Levi M., Levy J.H., Andersen H.F., et al. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363:1791–1800.

13 Martí-Carvajal A.J., Solà I., González L.E., et al. Pharmacological interventions for the prevention of allergic and febrile non-haemolytic transfusion reactions. Cochrane Database Syst Rev. 6, 2010. CD007539, 2010

14 Roberts I., Shakur H., Ker K., et al. Antifibrinolytic drugs for acute traumatic injury. Cochrane Database Syst Rev. 1, 2011. CD004896, 2010

15 Schulman S., Kearon C., Kakkar A.K., et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342–2352.

16 Vanderlinde E.S., Heal J.M., Blumberg N. Autologous transfusion. BMJ. 2002;324:772–775.

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