Hemostasis, Surgical Bleeding, and Transfusion

Biology of Hemostasis

• Hemostasis is a complex process that limits blood loss from an injured vessel.
• Four major physiologic events:
  • Vascular constriction
  • Platelet plug formation
  • Fibrin formation
  • Fibrinolysis
• These events are interrelated and occur in a continuum.

Vascular Constriction

• Initial response to vessel injury, more pronounced in vessels with medial smooth muscles.
• Dependent on local contraction of smooth muscle.
• Linked to platelet plug formation.
• Thromboxane A2 (TXA2):
  • Produced locally at the injury site.
  • Released from platelet membranes via arachidonic acid.
  • TXA2 is a potent constrictor of smooth muscle.
• Endothelin:
  • Synthesized by injured endothelium.
  • A potent vasoconstrictor.
• Serotonin (5-HT):
  • Released during platelet aggregation.
  • A potent vasoconstrictor.
• Bradykinin and fibrinopeptides:
  • Involved in the coagulation schema.
  • Capable of contracting vascular smooth muscle.
• Extent of vasoconstriction varies with the degree of vessel injury.
  • Small artery with a lateral incision may remain open due to physical forces.
  • A completely transected vessel may contract to the extent that bleeding ceases spontaneously.

Platelet Function

• Platelets are anucleate fragments of megakaryocytes.
• Normal circulating number: 150,000 to 400,000/μL.
• Up to 30% may be sequestered in the spleen.
• Life span: 7 to 10 days; removed by the spleen if not consumed in a clotting reaction.
• Role in hemostasis:
  • Forming a hemostatic plug
  • Contributing to thrombin formation
• Platelets do not normally adhere to each other or the vessel wall; they form a plug when vascular disruption occurs.
• Injury to the intimal layer exposes subendothelial collagen, to which platelets adhere.
• von Willebrand factor (vWF) is required.
  • A protein in the subendothelium.
  • Lacking in patients with von Willebrand’s disease.
  • vWF binds to glycoprotein (GP) I/IX/V on the platelet membrane.
• Following adhesion, platelets initiate a release reaction, recruiting other platelets.
• Primary hemostasis: Up to this point.
• Platelet aggregation is reversible and not associated with secretion.
• Heparin does not interfere with this reaction.
• Adenosine diphosphate (ADP) and serotonin are principal mediators in platelet aggregation.
• Arachidonic acid is converted to prostaglandin G2 (PGG2) and then to prostaglandin H2 (PGH2) by cyclooxygenase.
• PGH2 is converted to TXA2, which has potent vasoconstriction and platelet aggregation effects.
• Arachidonic acid may be converted to prostacyclin (PGI2) in adjacent endothelial cells.
  • PGI2 is a vasodilator that inhibits platelet aggregation.
• Platelet cyclooxygenase:
  • Irreversibly inhibited by aspirin
  • Reversibly blocked by nonsteroidal anti-inflammatory agents
  • Not affected by cyclooxygenase-2 (COX-2) inhibitors
• Second wave of platelet aggregation:
  • A release reaction occurs.
  • Substances discharged: ADP, Ca^{2+}, serotonin, TXA2, and α-granule proteins.
• Fibrinogen is a required cofactor, acting as a bridge for the GP IIb/IIIa receptor on activated platelets.
• Thrombospondin stabilizes fibrinogen binding and strengthens platelet-platelet interactions.
• Platelet factor 4 (PF4) and α-thromboglobulin are secreted during the release reaction; PF4 is a potent heparin antagonist.
• The second wave of platelet aggregation is inhibited by aspirin and nonsteroidal anti-inflammatory drugs, by cyclic adenosine monophosphate (cAMP), and by nitric oxide.
• Alterations occur in phospholipids of the platelet membrane, allowing calcium and clotting factors to bind to the platelet surface, forming enzymatically active complexes.
• The altered lipoprotein surface (platelet factor 3) catalyzes:
  • Conversion of prothrombin (factor II) to thrombin (factor IIa) by activated factor X (Xa) in the presence of factor V and calcium
  • Reaction by which activated factor IX (IXa), factor VIII, and calcium activate factor X
• Platelets may also play a role in the initial activation of factors XI and XII.

Coagulation

• Hemostasis involves a complex interplay between platelets, the endothelium, and multiple coagulation factors.
• Coagulation cascade:
  • Intrinsic pathway (factors VIII, IX, X, XI, XII)
  • Extrinsic pathway (factor VII)
  • Common pathway (Fibrin formation)
• The intrinsic pathway begins with the activation of factor XII that subsequently activates factors XI, IX, and VIII. In this pathway, each of the primary factors is “intrinsic” to the circulating plasma, whereby no surface is required to initiate the process.
• In the extrinsic pathway, tissue factor (TF) is released or exposed on the surface of the endothelium, binding to circulating factor VII, facilitating its activation to VIIa.
• Each of these pathways continues on to a common sequence that begins with the activation of factor X to Xa.
• Xa (with the help of factor Va) converts factor II (prothrombin) to thrombin and then factor I (fibrinogen) to fibrin.
• Clot formation occurs after fibrin monomers are cross-linked to polymers with the assistance of factor XIII.
• Elevated activated partial thromboplastin time (aPTT) is associated with abnormal function of the intrinsic arm of the cascade (VIII, IX, X, XI, XII).
• Prothrombin time (PT) is associated with the extrinsic arm (VII).
• Vitamin K deficiency or warfarin use affects factors II, VII, IX, and X.
• Cell-based model of hemostasis:
  • Initiation: TF exposure following subendothelial injury; TF binds to VIIa, and this complex catalyzes the activation of factor X to Xa and IX to IXa, which in turn activates factor V to Va. Generates small amounts of thrombin.
  • Amplification: Platelets adhere to extracellular matrix components and become activated upon exposure to thrombin and other stimuli.
  • Propagation: “Tenase” (factor VIIIa/IXa) and prothrombinase (factor Va/Xa) complexes assemble on the surfaces of activated platelets, resulting in large-scale generation of thrombin ("thrombin burst") and fibrin.
• Factor VIIIa combines with IXa to form the intrinsic factor complex.
  • Factor IXa is responsible for the bulk of the conversion of factor X to Xa.
  • This complex (VIIIa-IXa) is 50 times more effective at catalyzing factor X activation than is the extrinsic (TF-VIIa) complex and five to six orders of magnitude more effective than factor IXa alone.
• Thrombin converts fibrinogen into fibrin and fibrinopeptides A and B.
• Removal of fibrinopeptide A permits end-to-end polymerization of the fibrin molecules.
• Cleavage of fibrinopeptide B allows side-to-side polymerization of the fibrin clot.
• This latter step is facilitated by thrombin-activatable fibrinolysis inhibitor (TAFI), which acts to stabilize the resultant clot.
• Feedback inhibition on the coagulation cascade deactivates the enzyme complexes leading to thrombin formation.
• Thrombomodulin (TM):
  • Presented by the endothelium serves as a “thrombin sink”.
• TM forms a complex with thrombin, rendering it no longer available to cleave fibrinogen, then activates protein C (APC) and reduces further thrombin generation by inhibiting factors V and VIII.
• Tissue plasminogen activator (tPA) is released from the endothelium following injury, cleaving plasminogen to initiate fibrinolysis.
• APC consumes plasminogen activator inhibitor-1 (PAI-1), leading to increased tPA activity and fibrinolysis.
• Tissue factor pathway inhibitor (TFPI) is released, blocking the TF-VIIa complex and reducing the production of factors Xa and IXa.
• Antithrombin III (AT-III) neutralizes all of the procoagulant serine proteases and also inhibits the TF-VIIa complex.
• APC forms a complex with its cofactor, protein S, on a phospholipid surface, cleaving factors Va and VIIIa so that they are no longer able to participate in the formation of TF-VIIa or prothrombinase complexes.
• Factor V Leiden:
  • Factor V is resistant to cleavage by APC, thereby remaining active as a procoagulant.
  • Patients are predisposed to venous thromboembolic events.

Fibrinolysis

• Fibrin clot breakdown (lysis) allows restoration of blood flow during the healing process following injury and begins when clot formation has initiated.
• Fibrin polymers are degraded by plasmin, a serine protease derived from the proenzyme plasminogen.
• Plasminogen is converted to plasmin by one of several plasminogen activators, including tPA.
• Plasmin degrades the fibrin mesh, producing circulating fragments termed fibrin degradation products (FDPs), cleared by other proteases or by the kidney and liver.
• Fibrinolysis is directed by circulating kinases, tissue activators, and kallikrein present in vascular endothelium.
• tPA:
  • Synthesized by endothelial cells and released on thrombin stimulation.
• Bradykinin:
  • A potent endothelial-dependent vasodilator.
  • Cleaved from high molecular weight kininogen by kallikrein and enhances the release of tPA.
• tPA and plasminogen bind to fibrin as it forms, and this trimolecular complex cleaves fibrin very efficiently.
• After plasmin is generated, it cleaves fibrin somewhat less efficiently.
• tPA activates plasminogen more efficiently when it is bound to fibrin, so that plasmin is formed selectively on the clot.
• Plasmin is inhibited by α2-antiplasmin (
  • A protein that is cross-linked to fibrin by factor XIII, which helps to ensure that clot lysis does not occur too quickly.
• Any circulating plasmin is also inhibited by α2-antiplasmin and circulating tPA or urokinase.
• Clot lysis yields FDPs including E-nodules and D-dimers.
• These smaller fragments interfere with normal platelet aggregation, and the larger fragments may be incorporated into the clot in lieu of normal fibrin monomers.
• This may result in an unstable clot as seen in cases of severe coagulopathy such as hyperfibrinolysis associated with trauma-induced coagulopathy or disseminated intravascular coagulopathy.
• The presence of D-dimers in the circulation may serve as a marker of thrombosis or other conditions in which a significant activation of the fibrinolytic system is present.
• TAFI removes lysine residues from fibrin that are essential for binding plasminogen.

Congenital Factor Deficiencies

Coagulation Factor Deficiencies

• Inherited deficiencies of all coagulation factors are seen.
• Three most frequent:
  • Factor VIII deficiency (hemophilia A or von Willebrand’s disease)
  • Factor IX deficiency (hemophilia B or Christmas disease)
  • Factor XI deficiency
• Hemophilia A and hemophilia B: inherited as sex-linked recessive disorders; males are affected almost exclusively.
• Clinical severity of hemophilia A and hemophilia B depends on the measurable level of factor VIII or factor IX in the patient’s plasma.
  • Plasma factor levels less than 1% of normal: severe disease
  • Factor levels between 1% and 5%: moderately severe disease
  • Levels between 5% and 30%: mild disease
• Severe hemophilia: spontaneous bleeds, frequently into joints, leading to crippling arthropathies, intracranial bleeding, intramuscular hematomas, retroperitoneal hematomas, and gastrointestinal, genitourinary, and retropharyngeal bleeding.
• Moderately severe hemophilia: less spontaneous bleeding but likely to bleed severely after trauma or surgery.
• Mild hemophilia: no spontaneous bleeding; minor bleeding after major trauma or surgery.
• Platelet function is normal in hemophiliacs; patients may not bleed immediately after injury or minor surgery.
• Diagnosis of hemophilia may not be made until after their first minor procedure (e.g., tooth extraction or tonsillectomy).
• Treatment of patients with hemophilia A or B: factor VIII or factor IX concentrate, respectively.
• Recombinant factor VIII is strongly recommended for patients not treated previously and is generally recommended for patients who are both human immunodeficiency virus (HIV) and hepatitis C virus (HCV) seronegative.
• For factor IX replacement, the preferred products are recombinant or high-purity factor IX.
• Activity levels should be restored to:
  • 30% to 40% for mild hemorrhage
  • 50% for severe bleeding
  • 80% to 100% for life-threatening bleeding
• Up to 20% of hemophiliacs with factor VIII deficiency develop inhibitors that can neutralize FVIII.
• For patients with low titers, inhibitors can be overcome with higher doses of factor VIII.
• For patients with high titer inhibitors, alternate treatments should be used and may include porcine factor VIII, prothrombin complex concentrates, activated prothrombin complex concentrates, or recombinant factor VIIa.
• For patients undergoing elective surgical procedures, a multidisciplinary approach with preoperative planning and replacement is recommended.
• von Willebrand’s Disease:
  • Most common congenital bleeding disorder causing a quantitative or qualitative defect in vWF, a large glycoprotein responsible for carrying factor VIII and platelet adhesion,
  • Important for normal platelet adhesion to exposed subendothelium and for aggregation under high shear conditions.
    • Patients have bleeding that is characteristic of platelet disorders, such as easy bruising and mucosal bleeding. Menorrhagia is common in women.
    • vWD is classified into three types.
      • Type I partial quantitative deficiency
      • Type II is a qualitative defect
      • Type III is total deficiency
        For bleeding, type I patients usually respond well to desmopressin (DDAVP). Type II patients may respond, depending on the particular defect. Type III patients are usually unresponsive. These patients may require vWF concentrates.
• Factor XI Deficiency:
  • Factor XI deficiency, an autosomal recessive inherited condition sometimes referred to as hemophilia C, is more prevalent in the Ashkenazi Jewish population but found in all races. Spontaneous bleeding is rare, but bleeding may occur after surgery, trauma, or invasive procedures.
  • Treatment of patients with factor XI deficiency who present with bleeding or in whom surgery is planned and who are known to have bled previously is with fresh frozen plasma (FFP). Each milliliter of plasma contains 1 unit of factor XI activity, so the volume needed depends on the patient’s baseline level, the desired level, and the plasma volume. Antifibrinolytics may be useful in patients with menorrhagia. Factor VIIa is recommended for patients with anti-factor XI antibodies, although thrombosis has been reported. There has been renewed interest in factor XI inhibitors as antithrombotic agents because patients with factor XI deficiency generally have only minimal bleeding risk unless a severe deficiency is present and seem to be pro- tected from thrombosis.
• Deficiency of Factors II (Prothrombin), V, and X:
  • Inherited deficiencies of factors II, V, and X are rare. Thesedeficiencies are inherited as autosomal recessive. Significant bleeding in homozygotes with less than 1% of normal activity is encountered. Bleeding with any of these deficiencies istreated with FFP. Similar to factor XI, FFP contains one unit of activity of each per milliliter. However, factor V activity isdecreased because of its inherent instability. The half-life of prothrombin (factor II) long about 72 hours, and only about 25% of a normal level is needed for hemostasis. Prothrombin complex concentrates can be used to treat deficiencies of prothrombin or factor X. Daily infusions of FFP areused to treat bleeding in factor V deficiency, with a goal of 20%to 25% activity. Factor V deficiency may be coinherited withfactor VIII deficiency. Treatment of bleeding in individuals withthe combined deficiency requires factor VIII concentrate andFFP. Some patients with factor V deficiency are also lackingthe factor V normally present in platelets and may need plateletransfusions as well as FFP
• Factor VII Deficiency: Inherited factor VII deficiency is a rare autosomal recessive disorder. Clinical bleeding can vary widely and does not always correlate with the level of FVII coagulant activity in plasma. Bleeding is uncommon unless thelevel is less than 3%. The most common bleeding manifestations involve easy bruising and mucosal bleeding, particularly epistaxis or oral mucosal bleeding. Postoperative bleeding isalso common, reported in 30% of surgical procedures. Treatment is with FFP or recombinant factor VIIa. The half-life ofrecombinant factor VIIa is only approximately 2 hours, but excellent hemostasis can be achieved with frequent infusions. The half-life of factor VII in FFP is up to 4 hours
• Factor XIII Deficiency:
  • Congenital factor XIII (FXIII) deficiency, originally recognized by Duckert in 1960, is a rare autosomal recessive disease usually associated with a severe bleeding diathesis. The male-to-female ratio is 1:1. Although acquired FXIII deficiency has been described in association with hepatic failure, inflammatory bowel disease, and myeloid leukemia, the only significant association with bleeding in children is the inherited deficiency. Bleeding is typically delayed because clots form normally but are susceptible to fibrinolysis. Umbilical stump bleeding is characteristic, and there is a high risk of intracranial bleeding. Spontaneous abortion is usual in women with factor XIII deficiency unless they receive replacement therapy. Replacement can be accomplished with FFP, cryoprecipitate, or a factor XIII concentrate. Levels of 1% to 2% are usually adequate for hemostasis.

Platelet Functional Defects

• Inherited platelet functional defects include abnormalities of platelet surface proteins, abnormalities of platelet granules, and enzyme defects. The major surface protein abnormalities are thrombasthenia and Bernard-Soulier syndrome
• Thrombasthenia (Glanzmann thrombasthenia): a rare genetic platelet disorder, inherited in an autosomal recessive pattern, in which the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) complex is either lacking or present but dysfunctional. This defect leads to faulty platelet aggregation and subsequent bleeding, treated with platelet transfusions.
• Bernard-Soulier syndrome: caused by a defect in the GP Ib/IX/V receptor for vWF, which is necessary for platelet adhesion to the subendothelium. Transfusion of normal platelets is required for bleeding in these patients.
• Storage pool disease:
  • The most common intrinsic platelet defect.
  • Involves loss of dense granules (storage sites for ADP, adenosine triphosphate [ATP], Ca^{2+}, and inorganic phosphate) and α-granules.
  • Dense granule deficiency is the most prevalent of these.
  • It may be an isolated defect or occur with partial albinism in Hermansky-Pudlak syndrome.
  • Bleeding is variable, depending on the severity of the granule defect.
  • Bleeding is caused by the decreased release of ADP from these platelets.
  • A few patients have been reported who have decreased numbers of both dense and α-granules; they have a more severe bleeding disorder.
  • Patients with mild bleeding as a consequence of a form of storage pool disease can be treated with DDAVP.
  • It is likely that the high levels of vWF in the plasma after DDAVP somehow compensate for the intrinsic platelet defect.
  • With more severe bleeding, platelet transfusion is required.

Acquired Hemostatic Defects

Platelet Abnormalities

• Acquired platelet abnormalities are much more common than acquired defects and may be quantitative or qualitative, although some patients have both types of defects.
  • Quantitative defects may result from failure of production, shortened survival, or sequestration.
  • Failure of production is generally a result of bone marrow disorders such as leukemia, myelodysplastic syndrome, severe vitamin B12 or folate deficiency, chemotherapeutic drugs, radiation, acute ethanol intoxication, or viral infection.
    If a quantitative abnormality exists and treatment is indicated either due to symptoms or the need for an invasive procedure, platelet transfusion is utilized.
  • Shortened platelet survival is seen in immune thrombocytopenia, disseminated intravascular coagulation, or disorders characterized by platelet thrombi such as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome
  • Immune thrombocytopenia may be idiopathic or associated with other autoimmune disorders or low-grade B-cell malignancies, and it may also be secondary to viral infections (including HIV) or drugs. Secondary immune thrombocytopenia often presents with a very low platelet count, petechiae and purpura, and epistaxis. Large platelets are seen on peripheral smear. Initial treatment consists of corticosteroids, intravenous gamma globulin, or anti-D immunoglobulin in patients who are Rh positive. Both gamma globulin and anti-D immunoglobulin are rapidin onset. Platelet transfusions are not usually needed unless central nervous system bleeding or active bleeding from other sitesoccurs. Survival of the transfused platelets is usually short."
    • Drug-induced immune thrombocytopenia may simply entail withdrawal of the offending drug, but corticosteroids, gamma globulin, and anti-D immunoglobulin may hasten recovery of the count
  • Heparin-induced thrombocytopenia (HIT):
    • A form of drug-induced immune thrombocytopenia.
    • An immunologic event during which antibodies against platelet factor 4 (PF4) formed during exposure to heparin affect platelet activation and endothelial function with resultant thrombocytopenia and intravascular thrombosis.
    • The platelet count typically begins to fall 5 to 7 days after heparin has been started, but if it is a reexposure, the decrease in count may occur within 1 to 2 days.
    • HIT should be suspected if the platelet count falls to less than 100,000 or if it drops by 50% from baseline in a patient receiving heparin.
    • Is more common with full-dose unfractionated heparin, it can also occur with prophylactic doses or with low molecular weight heparins.
    • Laboratory testing should include an anti–platelet factor 4–heparin enzyme-linked immunosorbent assay (ELISA).
    • The initial treatment is to stop heparin and begin an alternative anticoagulant; Alternative anticoagulants are primarily thrombin inhibitors.
  • Thrombotic thrombocytopenic purpura (TTP):
    • Large vWF molecules interact with platelets, leading to activation, results from inhibition of a metalloproteinase enzyme, ADAM-S13, which cleaves the large vWF molecules.
    • Classically characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, and renal and neurologic signs or symptoms.
    • Plasma exchange with replacement of FFP is the treatment for acute TTP
  • Hemolytic uremic syndrome (HUS):
    • often occurs secondary to infection by Escherichia coli 0157:H7 or other Shiga toxin-producing bacteria.
    • HUS is usually associated with some degree of renal failure, with many patients requiring renal replacement therapy. Neurologic symptoms are less frequent.
  • Sequestration:
    • another important cause of thrombocytopenia and usually involves trapping of platelets in an enlargedspleen typically related to portal hypertension, sarcoid, lymphoma, or Gaucher’s disease.The total body platelet mass is essentially normal in patients with hypersplenism, but a much larger fraction of the plateletsis sequestered in the enlarged spleen. Platelet survival is mildly decreased. Bleeding is less than anticipatedfrom the count because sequestered platelets can be mobilized tosome extent and enter the circulation. Platelet transfusion doesnot increase the platelet count as much as it would in a normalperson because the transfused platelets are similarly sequesteredin the spleen. Splenectomy is not indicated to correct the thrombocytopenia of hypersplenism caused by portal hypertension.
• Thrombocytopenia and platelet dysfunction are the most common abnormalities of hemostasis that result in bleeding in the surgical patient. The patient may have a reduced platelet count as a result of a variety of disease processes, as discussed earlier. In these circumstances, the marrow usually demonstrates a normal or increased number of megakaryocytes. By contrast, when thrombocytopenia occurs in patients with leukemia or uremia and in patients on cytotoxic therapy, there are generally a reduced number of megakaryocytes in the marrow. Thrombocytopenia also occurs in surgical patients as a resultof massive blood loss with product replacement deficient inplatelets. Thrombocytopenia may also be induced by heparin administration during cardiac and vascular cases, as in the case of HIT, or may be associated with thrombotic and hemorrhagic complications. When thrombocytopenia is present in a patient for whom an elective operation is being considered, management is contingent upon the extent and cause of platelet reduction and extent of platelet dysfunction.
• Early platelet administration has now become part of massive transfusion protocols.Platelets are also administered preoperatively to rapidly increase the platelet count in surgicalpatients with underlying thrombocytopenia or platelet dysfunction. One unit of platelet concentrate contains approximately 5.5 Imes 10^{10} platelets and would be expected to increase the circulating platelet count by about 10,000/μL in the average 70-kgperson. Fever, infection, hepatosplenomegaly, and the pres-ence of antiplatelet alloantibodies decrease the effectiveness ofplatelet transfusions. In patients who are refractory to standardplatelet transfusion, the use of human leukocyte antigen (HLA)-compatible platelets coupled with special processors has proved effective.

Qualitative Platelet Defects

• Impaired platelet function often accompanies thrombocytopenia but may also occur in the presence of a normal platelet count.
• 80% of overall clot strength is related to platelet function.
• Life span of platelets ranges from 7 to 10 days, placing them at increased risk for impairment by medical disorders and prescription and over-the-counter medications.
• Impairment of ADP-stimulated aggregation occurs with massive transfusion of blood products.
• Uremia may be associated with increased bleeding time and impaired aggregation.
• Defective aggregation and platelet dysfunction are also seen in patients with severe trauma, thrombocythemia, polycythemia vera, and myelofibrosis.
• The general recommendation is that approximately 5 to 7 days should pass from the time the drug is stopped until an elective procedure is performed
• Other disorders associated with abnormal platelet function include uremia, myeloproliferative disorders, monoclonal gammopathies, and liver disease.

Acquired Hypofibrinogenemia

*Acquired HypofibrinogenemiaDisseminated Intravascular Coagulation (DIC). DIC isan acquired syndrome characterized by systemic activation ofcoagulation pathways that result in excessive thrombin generation and the diffuse formation of microthrombi. This disturb-ance ultimately leads to consumption and depletion of plateletsand coagulation factors with the resultant classic picture of dif-fuse bleeding. Fibrin thrombi developing in the microcirculationmay cause microvascular ischemia and subsequent end-organfailure if severe. There are many different conditions that pre-dispose a patient to DIC, and the presence of an underlyingcondition is required for the diagnosis. For example, injuries resulting in embolization of materials such as brain matter, bone marrow, or amniotic fluid can act as potent thromboplastins that activate the DIC cascade. Additional etiologies include malignancy, organ injury such as severe pancreatitis, liver failure, certain vascular abnormalities (such as large aneurysms), snakebites, illicit drugs, transfusion reactions, transplant rejection, and sepsis. In fact, DIC frequently accompanies sepsis and may be associated with multiple organ failure. The important interplay between sepsis and coagulation abnormalities was demonstrated by Dhainaut et al who showed that activated protein C was effective in septic patients with DIC, though this has subsequently been disproven.29 The diagnosis of DIC is made based on an inciting etiology with associated thrombocytopenia, prolongation of the prothrombin time, a low fibrino-gen level, and elevated fibrin markers FDPs, D-dimer, solublefibrin monomers. A scoring system developed by the Interna-tional Society for Thrombosis and Hemostasis has been shownto have high sensitivity and specificity for diagnosing DIC as well as a strong correlation between an increasing DIC scoreand mortality, especially in patients with infections.
The most important facets of treatment are relieving the patient’s causative primary medical or surgical problem and maintaining adequate perfusion. If there is active bleeding,hemostatic factors should be replaced with FFP, which is usuallysufficient to correct the hypofibrinogenemia, although cryopre-cipitate, fibrinogen concentrates, or platelet concentrates may also be needed. Given the formation of microthrombi in DIC,heparin therapy has also been proposed. Heparin may be indi-cated in cases where thrombosis predominates, such as arterialor venous thromboembolism and severe purpura fulminans.Primary Fibrinolysis Other than due to trauma, an acquiredhypofibrinogenic state in the surgical patient can be a result ofpathologic fibrinolysis. This may occur in patients followingprostate resection when urokinase is released during surgicalmanipulation of the prostate or in patients undergoing extracor-poreal bypass. The severity of fibrinolytic bleeding is dependenton the concentration of breakdown products in the circula-tion. Antifibrinolytic agents, such as ε-aminocaproic acid andtranexamic acid, interfere with fibrinolysis by inhibiting plas-minogen activation.

Myeloproliferative Diseases

• Polycythemia, or an excess of red blood cells, places surgicalpatients at risk. Spontaneous thrombosis is a complication ofpolycythemia vera, a myeloproliferative neoplasm, and can beexplained in part by increased blood viscosity, increased plate-let count, and an increased tendency toward stasis. Paradoxi-cally, a significant tendency toward spontaneous hemorrhagealso is noted in these patients. Thrombocytosis can be reducedby the administration of low-dose aspirin, phlebotomy, andhydroxyurea.

Coagulopathy of Liver Disease

• The liver plays a key role in hemostasis because it is responsible for the synthesis of many of the coagulation factors. Patients with liver disease, therefore, have decreased productionof several key nonendothelial cell-derived coagulation factorsas well as natural anticoagulant proteins, causing a disturbancein the balance between procoagulant and anticoagulant path-ways. This disturbance in coagulation mechanisms causes acomplex paradigm of both increased bleeding risk and increasedthrombotic risk. The most common coagulation abnormalities associated with liver dysfunction are thrombocytopenia and impaired humoral coagulation function manifested as prolonga-tion of the prothrombin time and international normalized ratioINR. The etiology of thrombocytopenia in patients with liverdisease is typically related to hypersplenism, reduced produc-tion of thrombopoietin, and immune-mediated destruction ofplatelets. The total body platelet mass is often normal in patients with hypersplenism, but a much larger fraction of the platelets is sequestered in the enlarged spleen. Bleeding may be less thananticipated because sequestered platelets can be mobilized tosome extent and enter the circulation. Thrombopoietin, the pri-mary stimulus for thrombopoiesis, may be responsible for somecases of thrombocytopenia in cirrhotic patients, although its role is not well delineated. Finally, immune-mediated thrombocyto-penia may also occur in cirrhotics, especially those with hepatitisc and primary biliary cirrhosis. In addition to thrombocytope-nia, these patients also exhibit platelet dysfunction via defectiveinteractions between platelets and the endothelium, and possibly due to uremia and changes in endothelial function in the settingof concomitant renal insufficiency. Hypocoagulopathy is fur-ther exacerbated with low platelet counts because platelets help facilitate thrombin generation by assembling coagulation factors on their surfaces. In conditions mimicking intravascular flow,low hematocrit and low platelet counts contributed to decreasedadhesion of platelets to endothelial cells, although increasedvWF, a common finding in cirrhotic patients, may offset this change in patients with cirrhosis. Hypercoagulability of liver disease has recently gained increased attention, with more evidence demonstrating the increased incidence of thromboem-bolism despite thrombocytopenia and a hypocoagulable state on conventional blood tests. This is attributed to decreased production of liver-synthesized proteins C and S, antithrombin, and plasminogen levels, as well as elevated levels of endothe-lial-derived vWF and factor VIII, a potent driver of thrombin generation. Given the concomitant hypo- and hypercoagu-lable features seen in patients with liver disease, conventionalcoagulation tests may be difficult to interpret, and whole bloodfunctional tests such as thromboelastography TEG or ROTEMmay be more informative of the status of clot formation andstability in cirrhotic patients. Small studies have indicated that TEG provides a better assessment of bleeding risk than standard tests of hemostasis in patients with liver disease; however, no large studies have directly tested this, and future larger trials are needed.
  Before instituting any therapy to ameliorate thrombocy- topenia, the actual need for correction should be strongly con- sidered. In general, correction based solely on a low plateletcount should be discouraged. Most often, treatment should be withheld for invasive procedures and surgery. When required, platelet transfusions are the mainstay of therapy; however, the effect typically lasts only several hours. Risks associated with transfusions in general and the development of antiplate-let antibodies in a patient population likely to need recurrentcorrection should be considered. A less well-accepted option is splenectomy or splenic embolization to reduce hypersplenism. In addition to the risks associated with these techniques, reduced splenic blood flow can reduce portal vein flow with subsequent portal vein thrombosis. Results are mixed following insertion of a transjugular intrahepatic portosystemic shunt TIPS. Therefore, treatment of thrombocytopenia should not be the primary indication for a TIPS procedure.Decreased production or increased destruction of coagula- tion factors as well as vitamin K deficiency can all contribute to a prolonged PT and INR in patients with liver disease. As liver dysfunction worsens, so does the liver’s synthetic func-tion, which results in decreased production of coagulation fac-tors. Additionally, laboratory abnormalities may mimic those of DIC. Elevated D-dimers have been reported to increase the risk of variceal bleeding. The absorption of vitamin K is dependenton bile production. Therefore, liver patients with impaired bile production and cholestatic disease may be at risk for vitamin K deficiency. Similar to thrombocytopenia, correction of coagulopathy should be reserved for treatment of active bleeding and prophy-laxis for invasive procedures and surgery. Treatment of coagu-lopathy caused by liver disease is usually done with FFP, butbecause the coagulopathy is usually not a result of decreased levels of factor V, complete correction is not usually possible. If the fibrinogen is less than 200 mg/dL, administration of cryo- precipitate may be helpful. Cryoprecipitate is also a source of factor VIII for the rare patient with a low factor VIII level.Coagulopathy of TraumaTraditional teaching regarding trauma-related coagulopathy attributed its development to acidosis, hypothermia, and dilution of coagulation factors. Recent data, however, have shown thatover one-third of severely injured patients have laboratory-based evidence of coagulopathy at the time of admission a phenotype called trauma-induced coagulopathy TIC. TIC is independent of traditional atrogenic causes of posttraumatic coagulopathy such as hemodilution is precipitated by tissue injury and/or hemorrhagic shock and is associated with significantly higher risk of mortality, especially in the first 24 hours after injury. Furthermore, TIC is a separate and distinct process from disseminated intravascular coagulopathy with its own specific components of hemostatic failure. As shown in Fig. 4-5, several non–mutually exclusive mechanisms have been proposed as the etiology of TIC, including activated protein C-mediated clotting factor deactivation, endothelial injury and “auto-heparinization” due to shedding of endothelial heparin sulfate and chondroitin sulfate into the circulation, platelet dysfunction, and hyperfibrinolysis. Hemorrhagic shock was previously thought to be an essential component of TIC, but isolated traumatic brain injury and pulmonary contusions have been shown to induce laboratory-defined TIC in the absence of shock, possibly due to a high pro-portion of endothelium in these organs. Traumatic brain in jurymay also induce TIC via a consumptive mechanism by the release of large amounts of tissue factor into the circulation.
  However, the relationship between laboratory-based coag