Management of Acute Coagulopathy of Trauma-Shock

According to the American Society of Anesthesiologists surgical practice guidelines, RBC transfusions are required when the hemoglobin is less than 6.0 g/dL and are contraindicated when the hemoglobin is greater than 10.0 g/dL.¹³ For hemoglobin concentrations between 6.0 and 10.0 g/dL, the decision to transfuse is based upon the acuity of the patient’s condition as determined by physical evidence of blood loss; current blood loss rate; blood pressure; arterial blood gas values, especially pH and oxygen saturation; urine output; and laboratory evidence for coagulopathy, provided there is time for specimens to be collected and laboratory assays completed.

During surgery, coagulopathy is assessed based on microvascular bleeding, which is evaluated by measuring the volume of blood filling suction canisters, surgical sponges, and surgical drains. Platelet concentrate is ordered when the platelet count is less than 50,000/mcL unless the surgeon anticipates limited blood loss. Platelet concentrate therapy is generally ineffective when the patient is known to have immune thrombocytopenic purpura, thrombotic thrombocytopenic purpura, or heparin-induced thrombocytopenia. In patients with these conditions, therapeutic platelets are rapidly consumed, and their administration may therefore be contraindicated, although they may provide temporary rescue. Platelet concentrate is never ordered when the platelet count is greater than 100,000/mcL. Platelet administration may be necessary when the platelet count is between 50,000 and 100,000/mcL provided there is bleeding into a confined space such as the brain or eye; if the patient is taking aspirin or clopidogrel; if there is a known platelet disorder such as a release defect, Glanzmann thrombasthenia, or Bernard-Soulier syndrome (see Chapter 43); or if the surgery involves cardiopulmonary bypass, which suppresses platelet activity.

Use of Frozen Plasma in Acute Coagulopathy of Trauma-Shock

FP is thawed, warmed to 37° C, and transfused when there is microvascular bleeding and the PT is prolonged to greater than 1.5 times the mean of the PT reference interval or if the PTT is prolonged to greater than 2 times the mean of the PTT reference interval. FP is also transfused when the patient is known to have a preexisting single coagulation factor deficiency such as factor VIII deficiency and no factor concentrate is available, when there has been significant volume replacement with colloid plasma expanders and RBCs, and when hemorrhage is caused by warfarin overdose (see Chapter 46).

FP is used only to treat coagulopathy and should not be used as a blood volume expander. The dosage is 10 to 15 mL/kg in continuous infusion. Theoretically, FP should be transfused until 30% coagulation factor activity has been reached for all factors; however, the actual volume administered is limited by the risk of transfusion-associated circulatory overload (TACO).

Although many refer to frozen plasma as “fresh frozen plasma,“ this term no longer applies, because most FP is prepared up to 24 hours after the time of collection rather than within 8 hours, as was the traditional practice.¹⁴ High-volume trauma centers such as combat facilities may maintain a small inventory of thawed FP ready for administration. Thawed FP may be stored at 1° C to 6° C for up to 5 days subsequent to thawing. The activity of von Willebrand factor (VWF) and coagulation factors V and VIII decline to approximately 60% after 5 days of refrigerator storage; however, the product may still be transfused.¹⁵

Administration of cryoprecipitate is indicated when there is microvascular bleeding and the fibrinogen concentration is less than 100 mg/dL. A 15- to 20-mL unit of cryoprecipitate provides 150 to 250 mg of fibrinogen, and the risk of TACO is lower than that with FP or plasma expanders. Often dosages of RBCs, platelets, FP, and cryoprecipitate are estimated in the absence of laboratory monitoring when the patient’s condition is emergent.

Most trauma center transfusion service directors require surgeons and emergency department physicians to transfuse 1 unit of FP for every 4 units of RBCs, although there is battlefield evidence that a ratio of 1 unit of FP per single unit of RBCs may lead to more favorable mortality statistics.¹⁶ The latter approach places a strain on the FP supply, however.

Potential adverse effects of FP administration are transfusion-related acute lung injury (TRALI) and TACO. The effects of TRALI and TACO both can lead to potentially fatal acute adult respiratory distress syndrome. FP therapy may also cause anaphylaxis, thrombosis, and multiple organ failure.

Use of Activated Prothrombin Complex Concentrate, Recombinant Activated Factor VII, and Tranexamic Acid in Acute Coagulopathy of Trauma-Shock

When administration of RBCs, platelets, cryoprecipitate, and FP fails to achieve hemostasis, activated prothrombin complex concentrate (FEIBA [factor eight inhibitor bypassing activity], Baxter Healthcare Corp., Deerfield, Ill.; Autoplex T, Nabi Biopharmaceuticals, Inc., Boca Raton, Fla.), recombinant activated coagulation factor VII (NovoSeven), or the antifibrinolytic drug tranexamic acid (Cyklokapron) may be employed. Autoplex T or FEIBA may be used at a dosage of 50 units/kg every 12 hours not to exceed 200 units/kg in 24 hours. The dose-response relationship of FEIBA is variable, and because FEIBA contains activated coagulation factors it raises the risk of disseminated intravascular coagulation (DIC). NovoSeven has been cleared by the Food and Drug Administration (FDA) for use in treating hemophilia A or B when factor VIII or factor IX inhibitors are present, respectively; its application in the treatment of ACOTS is off label. A NovoSeven dosage of 30 mcg/kg is instantly effective in stopping microvascular hemorrhage in nonhemophilic trauma victims, and NovoSeven does not cause DIC.17,18 However, one study found a possible link between off-label NovoSeven use and arterial and venous thrombosis in patients with existing thrombotic risk factors.¹⁹ Cyklokapron may be used at a loading dose of 1 g administered over 10 minutes followed by infusion of 1 g over 8 hours. First approved in 1986 to prevent bleeding in hemophilic patients who are about to undergo invasive procedures, Cyklokapron is effective for ACOTS, but this is an off-label use.

No laboratory tests are available to monitor the concentrations of Autoplex T, FEIBA, NovoSeven, or Cyklokapron. Laboratory directors characteristically advise surgeons to monitor the effectiveness of all ACOTS therapy indirectly by checking for the correction of platelet count, PT, and PTT to within their respective reference intervals. Platelet aggregometry may be used to establish platelet function efficacy, and coagulation factor assays are valuable as follow-up assays to PT and PTT to determine if the target activity of 30% has been met. Once the condition of patients with ACOTS has been stabilized, additional hemostasis-related therapy is seldom required.

Procoagulant Deficiency in Liver Disease

The liver produces nearly all of the plasma coagulation factors and regulatory proteins. Hepatitis, cirrhosis, obstructive jaundice, cancer, poisoning, and congenital disorders of bilirubin metabolism may suppress the synthetic function of hepatocytes, reducing either the concentrations or activities of the plasma coagulation factors to below hemostatic levels (less than 30% of normal).

Liver disease predominantly alters the production of the vitamin K–dependent factors II (prothrombin), VII, IX, and X and control proteins C, S, and Z. In liver disease, these seven factors are produced in their des-γ-carboxyl forms, which cannot participate in coagulation (see Chapter 40). At the onset of liver disease, factor VII, which has the shortest plasma half-life at 6 hours, is the first coagulation factor to exhibit decreased activity. Because the PT is particularly sensitive to factor VII activity, it is characteristically prolonged in mild liver disease, serving as a sensitive early marker.²⁰ Vitamin K deficiency caused by dietary insufficiency independent of liver disease produces a similar effect on the PT (see the case study in this chapter).

Declining coagulation factor V activity is a more specific marker of liver disease than deficient factor II, VII, IX or X because factor V is non–vitamin K dependent and is not affected by dietary vitamin K deficiency. The factor V activity assay, performed in conjunction with the factor VII assay, may be used to distinguish liver disease from vitamin K deficiency.²¹

Fibrinogen is an acute phase reactant that is frequently elevated in early or mild liver disease. Moderately and severely diseased liver produces fibrinogen that is coated with excessive sialic acid, a condition called dysfibrinogenemia in which the fibrinogen functions poorly. Dysfibrinogenemia causes generalized soft tissue bleeding associated with a prolonged thrombin time and an exceptionally prolonged reptilase clotting time.²² In end-stage liver disease, the fibrinogen level may fall to less than 100 mg/dL, which is a mark of liver failure.²³

VWF and factors VIII and XIII are acute phase reactants that may be unaffected or elevated in mild to moderate liver disease.24,25 In contrast to the other coagulation factors, VWF is produced from endothelial cells and megakaryocytes and is stored in endothelial cells and platelets.

Platelet Abnormalities in Liver Disease

Moderate thrombocytopenia occurs in a third of patients with liver disease. Platelet counts of less than 150,000/mcL may result from sequestration and shortened platelet survival associated with portal hypertension and resultant hepatosplenomegaly. In alcoholism-related hepatic cirrhosis, acute alcohol toxicity also suppresses platelet production. Platelet aggregation and secretion properties are often suppressed; this is reflected in reduced platelet aggregometry and lumiaggregometry results. Occasionally platelets are hyperreactive. Aggregometry may be used to predict bleeding and thrombosis risk.²⁶

Disseminated Intravascular Coagulation in Liver Disease

Chronic or compensated DIC (see Chapter 42) is a significant complication of liver disease that is caused by decreased liver production of regulatory antithrombin, protein C, or protein S and by the release of activated procoagulants from degenerating liver cells. In addition, the failing liver cannot clear activated coagulation factors that are regularly produced by abdominal organs and transported through the portal circulation. In primary or metastatic liver cancer, hepatocytes also may produce procoagulant substances that trigger chronic DIC, leading to ischemic complications.

In acute, uncompensated DIC, the PT, PTT, and thrombin time are prolonged; the fibrinogen level is reduced to less than 100 mg/dL; and fibrin degradation products, including D-dimers, are significantly increased.²⁷ If the DIC is chronic and compensated, the only elevated test result may be the D-dimer assay value, a hallmark of unregulated coagulation and fibrinolysis.²⁸ Although DIC can be resolved only by removing its underlying cause, its hemostatic deficiencies may be temporarily corrected by administering RBCs, FP, platelet concentrates, activated protein C, or antithrombin concentrates.^29,30

Hemostasis Laboratory Tests in Liver Disease

The PT, PTT, thrombin time, fibrinogen concentration, platelet count, and D-dimer concentration are useful in characterizing the hemostatic abnormalities in liver disease (Table 41-2). Factor V and VII assays may be used in combination to differentiate liver disease from vitamin K deficiency. Both factors are decreased in liver disease, but only factor VII is decreased in vitamin K deficiency.

Plasminogen deficiency, a shortened euglobulin lysis time, and an elevated D-dimer confirm systemic fibrinolysis. The reptilase time occasionally may be useful to confirm dysfibrinogenemia. This test duplicates the thrombin time test except that venom of the reptile Bothrops atrox (common lancehead viper) is substituted for thrombin reagent. The Bothrops venom triggers fibrin polymerization by cleaving fibrinopeptide A, but not fibrinopeptide B, from the fibrinogen molecule. The subsequent polymerization is slowed by structural defects, which prolong the interval from reagent addition to clot formation. The reptilase time test is unaffected by standard unfractionated heparin therapy and can be used to assess fibrinogen function even when there is heparin in the sample.

Hemostatic Treatment to Resolve Liver Disease–Related Hemorrhage

Oral or intravenous vitamin K therapy may correct the bleeding associated with des-γ-carboxyl factors II (prothrombin), VII, IX, and X, although the therapeutic effect of vitamin K is short-lived compared to its effect in dietary vitamin K deficiency because of the liver’s impaired synthetic ability. In severe liver disease, FP transfusion provides all of the coagulation factors in hemostatic concentrations, although VWF and factors V and VIII may be reduced. Owing to the small concentration and short half-life of factor VII, FP is unlikely to return the PT to within the reference interval.

A unit of FP consists of 200 to 280 mL. The typical adult FP dose for liver disease is 2 units, but the dose varies widely depending on the indication and the ability of the patient’s cardiac and renal system to rapidly excrete excess fluid. TACO is likely to occur when 30 mL/kg has been administered, but it may occur with even smaller volumes in patients with compromised cardiac or kidney function.

If the fibrinogen level is less than 50 mg/dL, spontaneous bleeding is imminent, and cryoprecipitate is preferred for its smaller volume and high fibrinogen concentration, 150 to 250 mg in a 15- to 20-mL unit. FP and cryoprecipitate present a theoretical risk of virus transmission, as do other untreated single-donor biologic blood products. Allergic transfusion reactions are more common with plasma-containing products. Other therapeutic options for patients with liver disease–related bleeding are platelet concentrates, prothrombin complex concentrate, activated protein C (Xigris, Eli Lilly and Co., Indianapolis, Ind.), antithrombin concentrate (Thrombate III, Telacris Biotherapeutics, Inc., Research Triangle Park, N.C.), NovoSeven, and Cyklokapron.

Nephrotic Syndrome and Hemorrhage

Nephrotic syndrome is a state of increased glomerular permeability associated with a variety of conditions, such as chronic glomerulonephritis, diabetic glomerulosclerosis, systemic lupus erythematosus, amyloidosis, and renal vein thrombosis.³⁹ In nephrotic syndrome, low-molecular-weight proteins are lost through the glomerulus into the glomerular filtrate and the urine. Coagulation factors II (prothrombin), VII, IX, X and XII have been detected in the urine, as have the coagulation regulatory proteins antithrombin and protein C. In 25% of cases, loss of regulatory proteins takes precedence over loss of procoagulants and leads to a tendency toward venous thrombosis.⁴⁰

Hemorrhagic Disease of the Newborn Caused by Vitamin K Deficiency

Because of their sterile intestines and the minimal concentration of vitamin K in human milk, newborns are constitutionally vitamin K deficient.⁴¹ Hemorrhagic disease of the newborn was common in the United States before routine administration of vitamin K to infants was legislated in the 1960s, and it still occurs in developing countries. The activity levels of factors II (prothrombin), VII, IX, and X are lower in normal newborns than in adults, and premature infants have even lower concentrations of these factors.⁴² Breastfeeding prolongs the deficiency, because passively acquired maternal antibodies delay the establishment of gut flora.

Vitamin K Antagonists

The γ-carboxylation cycle of coagulation factors is interrupted by coumarin-type oral anticoagulants such as warfarin that disrupt the vitamin K epoxide reductase and vitamin K quinone reductase reactions (Figure 41-1). In deficient γ-carboxylation, the liver releases dysfunctional des-γ-carboxyl factors II (prothrombin), VII, IX, and X, and proteins C, S, and Z; these inactive forms are called proteins in vitamin K antagonism (PIVKA). Therapeutic overdose or the accidental or felonious administration of warfarin-containing rat poisons may result in moderate to severe hemorrhage because of the lack of functional factors. The effect of brodifacoum or “superwarfarin,“ often used as a rodenticide, lasts for weeks to months, and treatment of poisoning with this substance requires repeated administration of vitamin K with follow-up PT monitoring.⁴³ Warfarin overdose is the single most common reason for hemorrhage-associated emergency department visits.

Detection of Vitamin K Deficiency or Proteins in Vitamin K Antagonism

Clinical suspicion of vitamin K deficiency is supported by a prolonged PT with or without a prolonged PTT. In PT and PTT mixing studies, if pooled platelet-free normal plasma (NP; Cryocheck, Precision BioLogic, Inc., Dartmouth, Nova Scotia) is combined with patient plasma, the mixture yields normal (corrected) PT and PTT results, which indicates that factor deficiencies were the cause of the prolonged screening test times. Specific single-factor assays always detect low factor VII because of its short half-life, followed in turn by decreases in factors IX, X, and II (prothrombin).

The standard therapy for vitamin K deficiency is oral—or, in an emergency, intravenous—vitamin K. Because synthesis of functional factors requires at least 3 hours, in the case of severe bleeding, FP, Autoplex T, FEIBA, or NovoSeven may be administered. There is no direct laboratory assay for FP, Autoplex T, FEIBA, or NovoSeven, but the patient’s recovery may be monitored indirectly using the PT, with an attempt made to restore the INR to the therapeutic range of 2.0 to 3.0.

Clot-Based Studies in Acquired Hemophilia

PT, PTT, and thrombin time are recommended tests for any patient with sudden onset of anatomic hemorrhage resembling acquired hemophilia. In the presence of a factor VIII inhibitor, which is the most common type, the PTT should be prolonged, whereas the PT and thrombin time are expected to be normal. A factor assay should reveal factor VIII activity to be less than 30% and often undetectable.

The presence of the inhibitor is confirmed with clot-based mixing studies. The PTT prolongation may be corrected initially by the addition of NP to the test specimen in a 1:1 ratio, but PTT again becomes prolonged after incubation of the 1:1 NP–patient plasma mixture at 37° C for 1 to 2 hours. The return of the lack of correction after incubation occurs because factor VIII autoantibodies are frequently of the immunoglobulin G4 isotype, which is time and temperature dependent. Consequently, the inhibitor effect may be evident only after the patient’s inhibitor is allowed to interact with the factor VIII in the NP for 1 to 2 hours at 37° C before testing. A few high-avidity inhibitors may cause immediate prolongation of the PTT; in this case an incubated mixing study is unnecessary.

The in vitro kinetics of factor VIII neutralization by inhibitor are nonlinear. Although there is early rapid loss of factor VIII activity, residual activity remains, which indicates that the reaction has reached equilibrium. This is called type II kinetics (Figure 41-2). In contrast, alloantibodies to factor VIII, which develop in 20% to 25% of patients with severe hemophilia in response to factor VIII therapy, exhibit type I kinetics. In the latter, there is linear in vitro neutralization of factor VIII activity over 1 to 2 hours, which results in complete inactivation. In type I kinetics in vitro measurement is relatively accurate, whereas in type II kinetics the titration of inhibitor activity is semiquantitative.⁴⁶