Handbook of Clinical Anesthesia

Chapter 16

Hemostasis and Transfusion Medicine

Anesthesia providers may be involved in as many as 8.3 million donor unit exposures per year in the United States, so it is important that anesthesiologists understand the principles of transfusion medicine (Drummond JC, Petrovich CT, Lane TA: Hemotherapy and hemostasis. In Clinical Anesthesia. Edited by Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC. Philadelphia: Lippincott Williams and Wilkins, 2009, pp 369–410).

  1. Risks of Blood Product Administration

The three leading causes of transfusion-related death in the United States are transfusion-related acute lung injury (TRALI), ABO incompatibility, and sepsis caused by bacterial contamination.

  1. Infectious Risks Associated with Blood Product Administration(Tables 16-1 and 16-2)
  2. Non-Infectious Risks Associated with Blood Product Administration(Table 16-3)
  3. Immunologically mediated transfusion reactions can occur as a result of the presence of antibodies that are either constitutive (anti-A, anti-B) or that have been formed as a result of prior exposure to donor erythrocytes (RBCs), white blood cells (WBCs), platelets, or proteins.
  4. Acute hemolytic transfusion reactions against foreign RBCs often manifest as hemolysis of the donor RBCs, leading to acute renal failure, disseminated intravascular coagulation (DIC), and death. Hypotension, hemoglobinuria, and diffuse bleeding may be the only clues that a hemolytic transfusion reaction has occurred during anesthesia. If a

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reaction is suspected, the transfusion should be stopped and the identity of the patient and labeling of the blood rechecked. Management has three main objectives—maintenance of systemic blood pressure, preservation of renal function, and prevention of DIC.

Table 16-1 Infectious Risks Associated with Blood Product Administration

Hepatitis A, B, C, D, and E
Human T-cell lymphotropic viruses (HTLV-1, HTLV-2),
Human immunodeficiency viruses 1 and 2
Cytomegalovirus
West Nile virus
Parasitic diseases (malaria, Chagas' disease)
Bacterial contamination of blood components
Prion-related diseases (Creutzfeldt Jacob disease and variant Creutzfeldt Jacob disease)
Contaminating bacteria
Parasites (malaria)

Table 16-2 Estimates of the Rate (per Donor Exposure) of Transfusion-Transmitted Infectious Disease in North America

Disease

Rate

Hepatitis B (HBV)

1/269,000

Hepatitis C (HCV)

1/1,600,000

Human immunodeficiency virus (HIV)

1/1,780,000

Human T-cell lymphotrophic virus (HTLV)

1/2,900,000

West Nile virus (WNV)
Cytomegalovirus (CMV)

Indeterminate/very low

   Non-leukoreduced random donor

7%

   Leukoreduced random donor

2%–4%

   CMV seronegative donor

1%–2%

Epstein-Barr virus (EBV)
Bacterial sepsis

0.5%

   Platelets (apheresis, culture tested)

1/50,000

   Platelets (whole blood derived, surrogate tested)

1/33,000

Table 16-3 The Non-infectious Adverse Reactions Associated with Blood Product Administration

Adverse Reaction

Comment/Incidence

Immunologically Mediated Transfusion Reactions

Acute hemolytic transfusion reactions

Acute renal failure; 2% mortality

Delayed hemolytic transfusion reactions

Evidence by 7 to 14 days; one in 2000 to 2500 transfusions

Reactions to Donor Proteins

Minor allergic reactions

Urticarial reactions; 0.5% to 4% of all transfusions

Anaphylactoid reactions

Dyspnea, bronchospasm, angioedema, hypotension

WBC-Related Transfusion Reactions

Febrile reactions

Temperature increase within 4 hours

TRALI

Noncardiogenic pulmonary edema; ≤5% mortality

GVHD

Pancytopenia

TRIM

Inflammatory response induced by transfusion

Transfusion-Induced
   Inflammatory Response

Inflammatory response induced by transfusion

Leukoreduction

Decreased alloimmunization or platelet refractoriness, prevention of febrile reactions, reduction of CMV transmission, decreased inflammatory mediator

CMV = cytomegalovirus; DIC = disseminated intravascular coagulation; GVHD = graft-versus-host disease; TRALI = transfusion-related acute lung injury; TRIM = transfusion-related immunomodulation; WBC = white blood cell.

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  2. Delayed hemolytic transfusion reactions should be suspected when a low-grade fever accompanied by increased bilirubin and an unexplained decrease in hematocrit (Hct) occurs 7 to 14 days after a transfusion.
  3. Reactions to donor proteins (minor allergic reactions) cause urticarial reactions in 0.5% of all transfusions. Patients with mild symptoms can be treated with diphenhydramine. Infrequently, a more severe form of allergic reaction involving anaphylaxis occurs in which the patient experiences dyspnea,

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bronchospasm, hypotension, laryngeal edema, chest pain, and shock. (This may occur when patients with hereditary IgA deficiency who have been sensitized by previous transfusions or pregnancy are exposed to blood with “foreign” IgA protein.)

Table 16-4 Diagnostic Criteria for Transfusion-Related Acute Lung Injury

Acute onset of arterial hypoxemia (within 6 hours after transfusion)
Bilateral infiltrates on chest radiography
Absence of evidence of left atrial hypertension
Absence of other temporally related causes of acute lung injury

  1. WBC-related transfusion reactions(febrile reactions) may occur as a result of antibody attack on donor leukocytes. The febrile response occurs in about 1% of all RBC transfusions. Typically, the patient experiences a temperature increase of more than 1°C within 4 hours of a blood transfusion and defervesces within 48 hours.
  2. Transfusion-Related Acute Lung Injury(Table 16-4)
  3. Graft-versus-host disease (GVHD)occurs when viable donor lymphocytes are transfused into immunocompromised patients. The donor lymphocytes may become engrafted, proliferate, and establish an immune response against the recipient. GVHD typically progresses rapidly to pancytopenia, and the fatality rate is very high. GVHD has been reported only after the transfusion of cellular blood components. It has not occurred after transfusion of fresh-frozen plasma (FFP), cryoprecipitate, or frozen RBCs. Irradiation remains the only effective means of preventing GVHD.
  4. Transfusion-Related Immunomodulation.Alteration of immune function has been associated with allogenic transfusion. Transfused WBCs are thought to be the mediators of the immunity-attenuating effects. Transfusion also induces an inflammatory response in the recipient.
  5. Leukoreductionis application of techniques for leukocyte depletion of donor blood products based on the suspicion that transfused leukocytes are the mediators of the immunity-attenuating effects of transfusions.
  6. Other Non-Infectious Risks Associated with Transfusion(Table 16-5)

Table 16-5 Consequences of Massive Blood Transfusions

Hypothermia (slows coagulation and causes sequestration of platelets)
Volume overload
Dilutional coagulopathy (manifests as deficiencies of platelets and clotting factors)
Decreases in 2,3-diphosphoglycerate (2,3-DPG) (left shifting of the oxyhemoglobin dissociation curve)
Metabolic acidosis
Hyperkalemia
Citrate intoxication

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  1. Blood Products and Transfusion Thresholds
  2. Red Blood Cells.The contemporary transfusion trigger for general medical-surgical patients is a Hct of 21% and a hemoglobin (Hb) of 7.0 g/dL (Table 16-6). The Practice Guidelines for Blood Component Therapy developed by the American Society of Anesthesiologists state that “red blood cell transfusion is rarely indicated when the hemoglobin concentration is greater than 10 g/dL and is almost always indicated when it is less than 6 g/dL.” Ultimately, the decision to transfuse RBCs should be made based on the clinical judgment that the oxygen-carrying capacity of the blood must be increased.
  3. Compensatory Mechanisms During Anemia(Table 16-7)
  4. Isovolemic Anemia vs. Acute Blood Loss.With acute blood loss, hypovolemia induces stimulation of the sympathetic nervous system, leading to vasoconstriction and tachycardia. In chronically anemic patients, cardiac output increases as the Hb decreases to approximately 7 to 8 g/dL.
  5. Platelets(Table 16-8). One platelet unit typically increases the platelet count by 5 to 10,000/mL3. However, the increase must be verified by platelet count, especially in patients who may have been alloimmunized by frequent platelet administration.
  6. Fresh-Frozen Plasma(Table 16-9). Empiric administration of 2 U of FFP or thawed plasma with every 5 U of packed RBCs is commonly used when massive transfusion is anticipated or ongoing. Normal coagulation can be achieved with clotting factor levels of 20% to 30% of

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normal. (These levels can be achieved by administration of 10 to 15 mL/kg of FFP.)

Table 16-6 Conditions That May Decrease Tolerance for Anemia and Influence the Red Blood Cell Transfusion Threshold

Increased oxygen demand
   Hyperthermia
   Hyperthyroidism
   Sepsis
   Pregnancy
Limited ability to increase cardiac output
Coronary artery disease
   Myocardial dysfunction (infarction, cardiomyopathy)
   β-adrenergic blockade
   Inability to redistribute cardiac output
Low SVR states
   Sepsis
   Post-cardiopulmonary bypass
   Occlusive vascular disease (cerebral, coronary)
Left shift of the O2 Hb curve
   Alkalosis
   Hypothermia
Abnormal hemoglobins
   Presence of recently transfused Hb (decreased 2,3 DPG)
   HbS (sickle cell disease)
Acute anemia (limited 2,3-DPG compensation)
Impaired oxygenation
   Pulmonary disease
   High altitude
Ongoing or imminent blood loss
   Traumatic or surgical bleeding
   Placenta previa or accreta, abruption, uterine atony
   Clinical coagulopathy

Hb = hemoglobin; SVR = systemic vascular resistance.

  1. Cryoprecipitatecontains factor VIII, the von Willebrand factor (vWF), fibrinogen, fibronectin, and factor XIII (Table 16-10).

Table 16-7 Compensatory Mechanisms that Maintain Oxygen Delivery During Isovolemic Hemodilution

Increased cardiac output
Redistribution of cardiac output
Increased oxygen extraction
Changes in oxygen–hemoglobin affinity

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Table 16-8 Indications for the Administration of Platelets

Indication

Platelet Count (/mL3)

Non-bleeding patients without other abnormalities of hemostasis

10,000

Lumbar puncture, epidural anesthesia, central line placement, endoscopy with biopsy, liver biopsy or laparotomy in patients without other abnormalities of hemostasis

50,000

Intended procedures in which closed cavity bleeding might be especially hazardous (e.g., neurosurgery)

100,000

To maintain platelets during ongoing bleeding and transfusion

Not less than 50,000

To maintain platelets during DIC with ongoing bleeding

Not less than 50,000

DIC = disseminated intravascular coagulation.

III. Blood Conservation Strategies

(Table 16-11)

  1. Jehovah's Witnesses

Jehovah's Witnesses accept neither administration of homologous blood products nor readministration of autologous products that have left the circulation. (This is at the individual's personal discretion, and many Jehovah's

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Witnesses do accept procedures that maintain extracorporeal blood in continuity with the circulation.)

Table 16-9 Indications for Administration of Fresh-Frozen Plasma

Correction of multiple coagulation factor deficiencies (DIC with evidence of microvascular bleeding and PT or aPTT >1.5 times normal)
Correction of microvascular bleeding during massive transfusion (>1 blood volume) when PT and aPTT cannot be obtained in a timely manner
Urgent reversal of warfarin therapy (prothrombin complex concentrate [II, VII, IX, X] is an alternative)
Correction of single coagulation factor deficiencies for which specific concentrates are not available (e.g., factor V)

aPTT = activated partial thromboplastin time; DIC = disseminated intravascular coagulation; PT = prothrombin time.

Table 16-10 Indications for the Administration of Cryoprecipitate

Microvascular bleeding when there is a disproportionate decrease in fibrinogen (DIC and massive transfusion) with fibrinogen below 80 to 100 mg/dL (FFP is the first-line component for the factor depletion associated with massive transfusion)
Bleeding caused by uremia that is unresponsive to DDAVP
Presurgical prophylaxis or treatment of bleeding in patients with hemophilia A and vWD
Presurgical prophylaxis or treatment of bleeding in patients with congenital dysfibrinogenemias
Factor XIII deficiency

DIC = disseminated intravascular coagulation; FFP = fresh-frozen plasma; vWD = von Willebrand disease.

  1. Collection and Preparation of Blood Products for Transfusion
  2. RBCs for transfusion are first collected in bags containing citrate–phosphate–dextrose–adenine or citrate–phosphate– dextrose solution. The citrate chelates the calcium present in the blood and prevents coagulation. Packed RBCsare prepared by centrifugation (Hct ~70% to 75%; contains 50–70 mL of residual plasma in a total volume of 250–275 mL and has a shelf life of 35 days). The administration of 1 U of packed RBCs increases the Hb of a 70-kg adult by approximately 1g/dL and the Hct by approximately 3%.

Table 16-11 Blood Conservation Techniques

Preoperative autologous donation (hip replacement, scoliosis surgery)
Acute normovolemic hemodilution
Intraoperative blood salvage (cell savers, risk of air embolism)
Postoperative blood salvage
Pharmacologic agents
   Erythropoietin
   Blood substitutes (hemoglobin and non–hemoglobin-based oxygen-carrying solutions)
   DDAVP
   Antifibrinolytics

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Table 16-12 Major RBC Surface Antigen Incidence in the US population

Group

Whites (%)

Blacks (%)

O

45

49

A

40

27

B

11

20

AB

4

4

Rh (D)

85

92

  1. Compatibility testinginvolves three separate procedures.
  2. ABOand Rhesus Typing (Table 16-12)
  3. The antibody screen(indirect Coomb's test) is performed to identify recipient antibodies against RBC antigens. The likelihood that the antibody screen will miss a potentially dangerous antibody has been estimated to be no more than one in 10,000.
  4. The Cross-Match, in which donor RBCs are mixed with recipient serum, requires about 45 minutes and is carried out in three phases: the immediate, incubation, and antiglobulin phases.
  5. The immediate phase requires only 1 to 5 minutes and detects ABO incompatibilities. Determining the ABO blood group type and Rh status alone yields the probability that the transfusion will be compatible in 99.8% of instances.
  6. The second phase, the incubation phase, requires 30 to 45 minutes and detects antibodies primarily in the Rh system.
  7. The third phase (antiglobulin phase crossmatch or the indirect antiglobulin test) is performed only on blood yielding a positive antibody screen and takes 60 to 90 minutes.
  8. Type and screen ordersare used preoperatively for surgical cases in which it is unlikely that the blood will actually be transfused. The ABO, Rh status of the patient is determined, and the antibody screen is performed. If the antibody screen result is negative, type-specific uncrossmatched blood will result in a hemolytic reaction in fewer than 1 in 50,000 U.
  9. Emergency Transfusions(Table 16-13)
  10. Platelets
  11. One unit of platelets will increase the platelet count of a 70-kg recipient by 5 to 10,000/mL3.

Table 16-13 Preferred Order for Selecting Blood in the Absence of Compatibility Testing

Type-specific, partially crossmatched blood
Uncrossmatched blood (urgent situations when blood is needed before compatibility testing can be completed):
   Group O red blood cells until there is time to complete ABO and Rh testing
   Rh-negative blood is preferable if the patient's Rh type is unknown or if the patient is a woman of childbearing age
   Non–group O patients who have received group O red cells approximating one patient blood volume (10–12 U) during the period of acute blood loss should not be switched back to their own ABO group unless testing has been performed to confirm that significant titers of anti-A or anti-B antibodies are not present

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  2. Platelets bear both ABO and human leukocyte antigens. ABO compatibility is ideal (but not required) because incompatibility shortens the life span of the platelet. Platelets do not carry the Rh antigen.
  3. Platelets should be administered through a 170-µfilter.
  4. FFP and Thawed Plasma.Plasma is separated from the RBC component of whole blood by centrifugation. To preserve the two labile clotting factors (V and VIII), it is frozen promptly and thawed only immediately before administration. FFP must be ABO compatible.
  5. The Hemostatic Mechanism
  6. Normal “hemostasis” involves a series of physiologic checks and balances that ensure that blood remains in an invariably liquid state as it circulates throughout the body, but as soon as the vascular network is violated, it transforms rapidly to a solid state (coagulation). Coagulation must inevitably be complemented by processes for eliminating clot that is no longer needed for hemostasis (fibrinolysis).
  7. The Nomenclature of Coagulation(Table 16-14)
  8. The Coagulation Mechanism.The classical dual-cascade (intrinsic and extrinsic pathway) model of coagulation is now recognized to be an inadequate representation of in vivo coagulation (this fails to explain several clinical phenomena). Although the classical theories may

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provide a model for in vitro coagulation tests, they fail to incorporate the central role of cell-based surfaces in the in vivo coagulation process (which has three stages).

Table 16-14 Factor Nomenclature and Half-Lives

Factor

Synonyms

in vivo Half-Life (hr)

I

Fibrinogen

100–150

II

Prothrombin

50–80

III

Tissue thromboplastin, tissue factor

 

IV

Calcium ion

 

V

Proaccelerin, labile factor

24

VII

SPCA, stable factor

6

VIII

AHF

12

vWF

von Willebrand factor

24

IX

Christmas factor

24

X

Stuart Power factor, Stuart factor, autoprothrombin

25–60

XI

PTA

40–80

XII

Hageman factor

50–70

XIII

FSF

150

Prekallikrein

Fletcher factor

35

HMW kininogen

Fitzgerald, Flaujeac, or Williams factor; contact activation cofactor

150

AHF = antihemophilic factor; FSF = fibrin stabilizing factor; PTA = plasma thromboplastin antecedent; SPCA = serum prothrombin conversion accelerator.

 
  1. Activation of the coagulation process begins when a breach in the vascular endothelium exposes blood to the membrane-bound protein, tissue factor.
  2. Amplificationof coagulation includes activation of adjacent platelets and factors V, VIII, and IX. The net result of this amplification stage is the availability of activated platelets and activated factors V, VIII, and IX.
  3. Propagationis characterized by an explosive generation of thrombin.
  4. Additional Principles of Coagulation(Table 16-15)
  5. Fibrinolysisleads to the dissolution of fibrin clots and recanalizes vessels that have been occluded by thrombosis.

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Table 16-15 Characteristics of Coagulation

Most clotting factors circulate in an inactive form
Most clotting factors are synthesized by the liver
Factor VIII is a large two-molecule complex (vWF and coagulant factor VIII)
Absence of vWF causes two hemostatic abnormalities
 A defect in primary hemostasis because of a failure of platelet adhesion to the sites of vascular injury
 Clinical hemophilia A because of an absence of circulating factor VIII:C
Synthesis of the vWF occurs in endothelial cells and megakaryocytes. Four clotting factors are vitamin K dependent
 Clotting factors, II, VII, IX, and X require vitamin K for completion of their synthesis in the liver
 Warfarin administration displaces vitamin K, and the vitamin K–dependent factors are not carboxylated
 Factor VII has the shortest half-life and is the first clotting factor to disappear from the circulation when a patient prescribed warfarin begins to develop vitamin K deficiency
 Factors V and VIII (labile factors) have short storage half-lives (Massive transfusion with stored blood leads to a dilutional coagulopathy because of diminished activity of factors V and VI)

vWF = von Willebrand factor.

  1. The Formation of Plasmin. Fibrinolysis involves primarily the production of plasmin, an active fibrinolytic enzyme. Plasmin is formed by the conversion of plasminogen to plasmin. Plasminogen circulates, and when it comes into contact with fibrin, binds to it. After it is bound to the fibrin surface, plasminogen is converted to plasmin by tissue plasminogen activator. When plasmin is released into the bloodstream, it is immediately neutralized by α2-antiplasmin.
  2. Fibrin degradation products(FDPs), or fibrin split products (FSPs), are removed from the blood by the liver, kidney, and reticuloendothelial system. If the FDPs are produced at a rate that exceeds their normal clearance, they accumulate. In high concentrations, FDPs impair platelet function, inhibit thrombin, and prevent cross-linking of fibrin strands.
  3. Control of Coagulation: Checks and Balances.Coagulation must be precisely regulated to prevent uncontrolled

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clotting (i.e., DIC). The first line of defense is the intact vascular endothelium, which has antithrombotic properties. In addition, clotting factors circulate in an inactive form.

Table 16-16 Interpretation of Coagulation Tests

Platelet Count

Bleeding Time

aPTT

PT

TT

Fibrinogen

FDPs

Possible Causes

Examples

D

N or D

N

N

N

N

N

Decreased production, sequestration
Increased consumption
Tissue damage

Radiation, chemotherapy
Immune destruction
Heparin

N

I

N

N

N

N

N

Platelet destruction

Drugs (ASA, NSAIDs), uremia, mild von

N

I

I

N

N

N

N

Severe vWF deficiency

Willebrand's disease von Willebrand's disease

N

N

I

N

N

N

N

Factor deficiency
Factor inhibition
Antiphospholipid antibody

Hemophilia A or B
Low-dose heparin
Lupus anticoagulant

N

N

N

I

N

N

N

Factor VII deficiency

Early liver disease
Early vitamin K deficiency
Early Warfarin therapy

N

N

I

I

I

N

N

Multiple factor deficiencies

Late vitamin K deficiency
Late Warfarin deficiency
Heparin therapy*

D

I

I

I

I

I

D

Dilution of factors and platelets

Massive transfusion

D

I

I

I

I

D

I

Hypercoagulable state with or without decreased production of clotting factors

DIC†
Advanced liver disease

*Bleeding time may also be prolonged in association with a marked aPTT increase.

†DIC may be distinguished by the presence of D-dimers.
aPTT = activated plasma partial thromboplastin time; ASA = aspirin; D = decreased; DIC = disseminated intravascular coagulation; FDP = fibrin degradation product; I = increased; N = normal; NSAID = nonsteroidal antiinflammatory drug; PT = prothrombin time; TT = thrombin time; vWF = von Willebrand factor.

VII. Laboratory Evaluation of the Hemostatic Mechanism

  1. Laboratory Evaluation of Primary Hemostasis.
  2. Platelet count (which does not reflect platelet activity) is the first test ordered in the evaluation of primary hemostasis. Normal platelet counts range between 50,000 and 440,000/mL3, and counts below 150,000/mL3are defined as thrombocytopenia. Spontaneous bleeding is unlikely in patients with platelet counts above 10,000 to 20,000/mL3. With counts from 40,000 to 70,000/mL3, surgery-induced bleeding may be severe.
  3. Bleeding timeis an accepted clinical test of platelet function. Both poor platelet function and thrombocytopenia may prolong the bleeding time (normal range, 2–9 minutes). Even though bleeding time reliably becomes progressively prolonged as platelet count falls below 80,000/mL3, no convincing data confirm that bleeding time is a reliable predictor of the bleeding that will occur in association with surgical procedures.
  4. Laboratory Evaluation of Coagulation
  5. Prothrombin Time (PT) and the Partial Thromboplastin Time (PTT).In 1936, when Quick introduced the PT to clinical medicine, sufficient “thromboplastin” was used to yield a clotting time of approximately 12 seconds. Under these circumstances, even patients lacking factors VIII or IX showed normal clotting times. However, when “dilute” thromboplastin (or a “partial” thromboplastin) was used in lieu of the “12-second reagent,” individuals with hemophilia showed much longer clotting times than did healthy control subjects. The two different pathways could be tested individually simply by varying the amount and type of thromboplastin added to blood.
  6. Prothrombin timeevaluates the coagulation sequence initiated by tissue factor (TF) and leads to the formation of fibrin without the participation of factors VIII or IX (classical extrinsic pathway).

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  1. Normal PT is 10 to 12 seconds. PT is prolonged if deficiencies, abnormalities, or inhibitors of factors VII, X, V, II, or I are present.
  2. When prothrombin levels are only 10% of normal, the increase in PT may be only 2 seconds. PT is not prolonged until the fibrinogen level is below 100 mg/dL.
  3. A prolonged PT is most likely to represent a deficiency or abnormality of factor VII. Because factor VII has the shortest half-life of the clotting factors synthesized in the liver, it is the clotting factor that first becomes deficient with liver disease, vitamin K deficiency, or Warfarin therapy.
  4. International Normalized Ratio (INR).A difficulty with the PT test is that many different thromboplastin reagents are used. This results in wide variation in normal values, which makes comparison of PT results between laboratories difficult. The INR was introduced to circumvent this difficulty.
  5. Activated partial thromboplastin time(aPTT) assesses the function of the classical intrinsic (time to fibrin strand formation) and final common pathways. It entails the addition of a “partial thromboplastin” and calcium to citrated plasma.
  6. Normal aPTT values are between 25 and 35 seconds.
  7. The aPTT is most sensitive to deficiencies of factors VIII and IX, but as is the case with the PT, levels of these factors must be reduced to approximately 30% of normal values before the test is prolonged. Heparin prolongs the aPTT, but with high levels also prolongs PT. As with the PT, the level of fibrinogen must also be reduced to 100 mg/dL before the aPTT is prolonged.
  8. Activated clotting time(ACT) is similar to the aPTT in that it tests the ability of blood to clot in a test tube and it depends on factors that are all “intrinsic” to blood (the classical intrinsic pathway of coagulation).
  9. The automated ACT is widely used to monitor heparin therapy in the operating room. Normal values range from 90 to 120 seconds.
  10. The ACT is far less sensitive than the aPTT to factor deficiencies in the classical intrinsic coagulation pathway.

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  1. Thrombin time(TT) is a measure of the ability of thrombin to convert fibrinogen to fibrin. The TT is prolonged when an inadequate amount of fibrinogen (<100 mg/dL) is present or when the fibrinogen molecules that are present are abnormal (dysfibrinogenemia as in advanced liver disease). The normal TT is below 30 seconds.
  2. Reptilase Time. When the TT is prolonged, the reptilase time can be used to differentiate between the effects of heparin and FDPs. A prolonged TT and a normal reptilase time suggest the presence of heparin. Prolongation of both TT and reptilase time occur in the presence of FDPs or when fibrinogen level is low. The normal reptilase time is 14 to 21 seconds.
  3. The anti-Ax activity assayis used to monitor the effects of low-molecular-weight inhibitors and unfractionated heparin.
  4. Fibrinogen Level.Normal values are between 160 and 350 mg/dL (<100 mg/dL may be inadequate to produce a clot). Fibrinogen is rapidly depleted during DIC. A marked increase in fibrinogen may occur in response to stress, including surgery and trauma (hypercoagulable state).
  5. Evaluation of Fibrinolysis: FDP and D-Dimer.FDPs are increased in any state of accelerated fibrinolysis (e.g., advanced liver disease, cardiopulmonary bypass, administration of exogenous thrombolytics [streptokinase], DIC). D-dimer is specific to conditions in which extensive lysis of the cross-linked fibrin of mature thrombus is occurring, in particular DIC but also deep vein thrombosis and pulmonary embolism.
  6. The thromboelastogramprovides a measure of the mechanical properties of evolving clot as a function of time. A principal advantage of this test is that the processes it measures require the integrated action of all the elements of the hemostatic process: platelet aggregation, coagulation, and fibrinolysis.
  7. Interpretation of Tests of the Hemostatic Mechanism(Table 16-16)
  8. The most commonly ordered coagulation tests are the platelet count, PT, aPTT, and occasionally bleeding time. Coagulation defects that appear most often are revealed as abnormal values of PT or aPTT.
  9. When a greater disruption of the hemostatic mechanism is suspected, further tests, including fibrinogen,

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TT, and assays for fibrin degradation products and the D-dimer, may be ordered.

Table 16-17 Common Coagulation Profiles

Platelet count decreased (normal aPTT and PT)
   Decreased platelet production
   Consumption of platelets
   Sequestration of platelets
Prolonged BT (normal platelet count, aPTT, PT)
   Antiplatelet drug ingestion (NSAIDs, ASA)
   Uremia
   vWD
   Heparin
Prolonged PT (normal platelet count and aPTT)
   Vitamin K deficiency
   Warfarin administration
   Early liver dysfunction
   Factor VII deficiency
   Acquired coagulation factor inhibitors
Prolonged PT, aPTT, and TT (normal platelet count)
   Heparin
   Dysfibrinogenemia

aPTT = activated plasma partial thromboplastin time; ASA = aspirin; nonsteroidal antiinflammatory drug; PT = prothrombin time; TT = thrombin time; vWF = von Willebrand factor.

Table 16-18 Classification and Treatment of Disorders of Hemostasis

Classification
Abnormal bleeding
Abnormal clotting
Involve platelets
Involve clotting factors
Presence of absence of inhibitors (FDPs)
Hereditary
Acquired
Treatment
Hemostatic agents (platelets or clotting factors)
Pharmacologic agents (desmopressin, antiplatelet drugs, vitamin K, Warfarin, heparin, aprotinin, antifibrinolytic agents, protamine, fibrinolytics)

FDP = fibrin degradation product.

  1. Common Coagulation Profiles(Table 16-17). The interpretation of coagulation tests may be difficult because patients who develop a bleeding diathesis in the perioperative period may have more than one bleeding disorder (e.g., DIC and coagulopathy caused by massive transfusion) and may also have a surgical cause for bleeding.

VIII. Disorders of Hemostasis: Diagnosis and Treatment

The preoperative history is invaluable in the identification of disorders of hemostasis. Abnormalities of primary hemostasis, usually caused by reduced platelet number or function, are revealed by evidence of “superficial” (skin and mucosal) bleeding, including easy bruising, petechiae, prolonged bleeding from minor skin lacerations, recurrent epistaxis, and menorrhagia. Coagulation abnormalities are

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associated with “deep” bleeding events, including hemarthroses or hematomas after blunt trauma.

  1. Hereditary Disorders of Hemostasis(Table 16-19)
  2. Acquired Disorders of Hemostasis(Table 16-20)
  3. It is helpful to classify bleeding disorders according to which of the three hemostatic processes are involved:

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primary hemostasis (platelet disorders), coagulation (clotting factor disorders), fibrinolysis (production of inhibitors such as FDPs), or some combination of the three.

Table 16-19 Hereditary Disorders of Hemostasis

von Willebrand's disease
 Most common hereditary bleeding disorder (approximately 1% of the general population has the disorder, although it is overtly symptomatic in only about 10% of those afflicted)
 Result of abnormal synthesis of the vWF that is important for binding of platelets to sites of vascular injury and for coagulation
 Diagnosis is based on history (abnormal bleeding from mucosal surfaces)
 Platelet count, aPTT, and PT may be normal
 Treatment is DDAVP and factor concentrate
Hemophilia A (deficient or functionally defective factor VIII:C)
Hemophilia B (Christmas disease; deficiency or abnormality of factors IX)
Hemophilia C (deficiency or abnormality of factor XI)

aPTT = activated plasma partial thromboplastin time; PT = prothrombin time; vWF = von Willebrand factor.

Table 16-20 Acquired Disorders of Hemostasis

Acquired Disorders of Platelets
Thrombocytopenia
Uremia
Agents (inhibit platelet aggregation)
   COX inhibitors (aspirin is the prototype)
   COX-2 inhibitors reduce prostacyclin generation by vascular endothelial cells and tilt the natural balance toward platelet aggregation (increased rate of myocardial ischemic events)
   Dipyridamole
   ADP receptor antagonists (ticlopidine, clopidogrel)
   GP IIb/IIIa receptor antagonists (management of acute coronary syndromes)
   Herbal medications (ginkgo, ginseng, garlic, ginger) and vitamins (vitamin E)
Myeloproliferative and myelodysplastic syndromes
Acquired Disorders of Clotting Factors (including anticoagulant therapy)
Vitamin K deficiency (prolongation of PT)
Warfarin therapy (competes with vitamin K for the carboxylation binding sites; administered for prevention of DVT and PE and to patients with AF and patients with prosthetic heart valves)
Heparin Therapy (inhibits coagulation principally through its interaction with one of the body's natural anticoagulant proteins, antithrombin III)
LMWH
Heparin-induced thrombocytopenia or thrombosis (relatively uncommon with LMWH)
Heparin in cardiopulmonary bypass (protamine is titrated against ACT for heparin reversal)
Inhibitors of Xa (fondaparinux, idraparinux)
Acquired Combined Disorders of Platelets and Clotting Factors with Increased Fibrinolysis
Liver disease
Disseminated Intravascular Coagulation
Diagnosis (increased PT, aPTT, thrombocytopenia, decreased fibrinogen level, presence of FDPs and D-dimer)
Treatment should focus on management of the underlying condition (septicemia, evacuation of the uterus, correction of hypovolemia, acidosis, and hypoxemia)

ACT = activated clotting time; ADP = adenosine diphosphate; AF = atrial fibrillation; aPTT = activated plasma partial thromboplastin time; COX = cyclo-oxygenase; DVT = deep venous thrombosis; FDP = fibrin degradation product; GP = glycoprotein; LMWH = low-molecular-weight heparin; PE = pulmonary embolism; PT = prothrombin time.

  1. It is useful to use the results of coagulation tests to determine whether the clinical problem involves primary hemostasis (decreased platelet count, increased bleeding time), coagulation (prolonged PT and aPTT, decreased factor levels), fibrinolysis (increased FDPs, increased D-dimer) or some combination of the three.
  2. Heparin in Cardiopulmonary Bypass.A common practice is to maintain ACT at 480 to 500 seconds for the duration of bypass.
  3. Direct thrombin inhibitorsare used during cardiopulmonary bypass when heparin is contraindicated. With the exception of bivalirudin, there is no antidote.

Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.; Cahalan, Michael K.; Stock, M. Christine

Title: Handbook of Clinical Anesthesia, 6th Edition

Copyright ©2009 Lippincott Williams & Wilkins

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