1-4 Hemostasis, Surgical Bleeding and Transfusion

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Surgery

Hemostasis, Surgical Bleeding, and Hemostasis, Surgical Bleeding, and Transfusion Transfusion DR. Bibera DR. Bibera July 5, 2012 July 5, 2012 1-41-4 

 _{a complex process whose function is to limit blood lossa complex process whose function is to limit blood loss}

from an injured vessel from an injured vessel



 _{4 major physiologic events4 major physiologic events} o

o vascular constrictionvascular constriction o

o platelet plug formationplatelet plug formation o

o fibrin formationfibrin formation o

o fibrinolysisfibrinolysis

Vascular Constriction Vascular Constriction



 _{is the initial response to vessel injury, moreis the initial response to vessel injury, more}

pronounced in vessels with medial smooth muscles pronounced in vessels with medial smooth muscles dependent on local contraction of smooth muscle

dependent on local contraction of smooth muscle



 _{subsequently linked to platelet plug formationsubsequently linked to platelet plug formation} 

 _{potent potent vasoconstrictorvasoconstrictors:s:} o

o Thromboxane A2Thromboxane A2  (TXA2) is produced locally at  (TXA2) is produced locally at

the site of injury via the release of arachidonic acid the site of injury via the release of arachidonic acid from platelet membranes

from platelet membranes

o

o EndothelinEndothelinsynthesized by injured endotheliumsynthesized by injured endothelium

and serotonin (5-hydroxytryptamine) released and serotonin (5-hydroxytryptamine) released during platelet

during platelet aggregationaggregation

o

o BradykininBradykinin and and FibrinopeptidesFibrinopeptides 

 _{the extent of vasoconstriction varies with the degree ofthe extent of vasoconstriction varies with the degree of}

vessel injury vessel injury

Platelet Function Platelet Function



 _{platelets are anucleate fragments of megakaryocytes,platelets are anucleate fragments of megakaryocytes,}

normal circulating number of platelets ranges between normal circulating number of platelets ranges between 150,000 and 400,000/ L

150,000 and 400,000/ L



 _{up to 30% may be sequestered in the up to 30% may be sequestered in the spleenspleen} 

 _{if not consumed in a clotting reaction, platelets areif not consumed in a clotting reaction, platelets are}

normally removed by the spleen and have an average normally removed by the spleen and have an average life span of

life span of 7 to 107 to 10 days days



 _{platelets play an integral role in hemostasis by formingplatelets play an integral role in hemostasis by forming}

a hemostatic plug and by contributing to thrombin a hemostatic plug and by contributing to thrombin formation

formation



 _{injury to the intimal layer in the vascular wall exposesinjury to the intimal layer in the vascular wall exposes}

subendothelial collagen to which platelets adhere, subendothelial collagen to which platelets adhere, which requires

which requires von Willebrand's factor (vWF)von Willebrand's factor (vWF) binds to glycoprotein I/IX/V on the platelet binds to glycoprotein I/IX/V on the platelet membrane

membrane



 _{after adhesion, platelets initiate a release reaction thatafter adhesion, platelets initiate a release reaction that}

recruits other platelets from the circulating blood to recruits other platelets from the circulating blood to seal the disrupted vessel. Up to this point, this process seal the disrupted vessel. Up to this point, this process is known as

is known as primary hemostasisprimary hemostasis



 _{platelet aggregation is reversible and is not associatedplatelet aggregation is reversible and is not associated}

with secretion with secretion

o

o heparin does not interfere with this reactionheparin does not interfere with this reaction o

o adenosine diphosphate (adenosine diphosphate (ADPADP) and) and serotoninserotonin  are  are

the principal mediators in platelet aggregation the principal mediators in platelet aggregation



 _{arachidonic acid releasedarachidonic acid released}  _{converted by COX to  converted by COX to}

prostaglandin G2 (PGG2)

prostaglandin G2 (PGG2) _{prostaglandin H2 (PGH2)prostaglandin H2 (PGH2)} 

_{converted to TXA2converted to TXA2} 

 _{effects:Arachidonic acideffects:Arachidonic acid}   _{shuttled to adjacent  shuttled to adjacent}

endothelial cells

endothelial cells _{converted to prostacyclin (PGI2 )converted to prostacyclin (PGI2 )} 

_{vasodilation and acts to inhibit vasodilation and acts to inhibit platelet aggregationplatelet aggregation} 

 _{platelet COX isplatelet COX is} o

o irreversibly inhibited by aspirinirreversibly inhibited by aspirin o

o reversibly blocked by NSAIDsreversibly blocked by NSAIDs o

o but is not affected by COX-2 inhibitorbut is not affected by COX-2 inhibitor 

 _{in the second wave of platelet aggregation, a releasein the second wave of platelet aggregation, a release}

reaction occurs in which several substances, including reaction occurs in which several substances, including ADP, Ca2+,serotonin, TXA2, and -granule proteins are ADP, Ca2+,serotonin, TXA2, and -granule proteins are discharged

discharged



 _{fibrinogenfibrinogen is a required cofactor, acting  is a required cofactor, acting as a bridgeas a bridge}

for the glycoprotein IIb/IIIa receptor on the activated for the glycoprotein IIb/IIIa receptor on the activated platelets

platelets



_{its release causes compaction of the plateletsinto aits release causes compaction of the plateletsinto a}

plug, a process that is

plug, a process that is irreversibleirreversible



 _{thrombospondinthrombospondin , secreted by the granule, stabilizes, secreted by the granule, stabilizes}

fibrinogen binding to the activated platelet surface and fibrinogen binding to the activated platelet surface and strengthens the platelet-platelet interactions.

strengthens the platelet-platelet interactions.



 _{platelet factor 4platelet factor 4  (PF4), potent heparin antagonist,  (PF4), potent heparin antagonist,}

and thromboglobulin also are secreted during the and thromboglobulin also are secreted during the release reaction

release reaction



 _{the second wave of platelet aggregation is inhibited bythe second wave of platelet aggregation is inhibited by}

aspirin and NSAIDs, by (cAMP), and by nit

aspirin and NSAIDs, by (cAMP), and by nit ric oxideric oxide



 _{alterations occur in the phospholipids of the plateletalterations occur in the phospholipids of the platelet}

membrane that allow Ca2+ and clotting factors

membrane that allow Ca2+ and clotting factors  _bind bind

to the platelet surface

to the platelet surface _{enzymatically enzymatically activeactive}

complexes complexes BIOLOGY OF HOMEOSTASIS

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o the altered lipoprotein surface (sometimes referred

to as platelet factor 3) catalyzes reactions that are involved in:

- conversion of prothrombin to thrombin by activated factor X (Xa) in the presence of factor V and Ca2+

- is also involved in the reaction by which activated factor IX (IXa), factor VIII, and Ca2+ activate factor X

Coagulation

 _{the coagulation cascade has 2 intersecting pathways:} o Intrinsic pathway

- begins with factor XII and through a cascade of reactions activates factors XI, IX, and VII in sequence  _{fibrin clot formation, intrinsic to the}

circulating plasma and no surface is required to initiate the process

o Extrinsic pathway

- requires exposure of tissue factor on the surface of the injured vessel wall to initiate the cascade beginning with factor VII

 _{the two arms of the coagulation cascade merge to a}

common pathway at factor X

_{activation sequence of factors II (prothrombin) and I}

(fibrinogen)

 _{clot formation occurs after proteolytic conversion of}

fibrinogen to fibrin

 _{an elevated activated partial thromboplastin}

time(aPTT) _{abnormal function Intrinsic pathway}  _{an elevated prothrombin time (PT)} _abnormal

extrinsic pathway

 _{vitamin K deficiency and warfarin use affect factors II,}

VII, IX, and X

 _{fibrinogen levels of <50 mg/dL causes prolongation of}

the PT and aPTT

 _{primary pathway for coagulation is initiated by}

 _{theexposure of subendothelial tissue factor when}

vessel surface is injured

 _{propagation of the clotting reaction then ensues with a}

sequence of enzymatic reactions, which involves a proteolytic enzyme

_{cleavage of a proenzyme and a phospholipid surface} _{generates the next enzyme in a cascade manner}

o each reaction requires a helper protein  (i.e.

Factor VIIa binds to tissue factor, and tissue factor-VIIa complex catalyzes the activation of factor X to factor Xa)

o the reaction takes place on the phospholipid

surface of activated platelets

o this complex is four orders of magnitude more

active at converting factor X  than is factor VIIa alone and also activates factor IX to factor IXa

o factor Xa, together with factor Va and Ca2+ and

phospholipid, comprises the prothrombinase complex that converts prothrombin to thrombin

o thrombin has multiple functions in the clotting

process, including conversion of fibrinogen to fibrin and activation of factors V, VII, VIII, XI,and XIII, as well as activation of platelets

o factor VIIIa combines with factor IXa to form the

intrinsic factor complex (VIIIa-IXa),  which is responsible for the bulk of the conversion of factor X to Xa_{50x more effective at catalyzing factor X}

activation than is extrinsic (tissue factor-VIIa) complex, five to six orders of magnitude more effective than is factor IXa alone

o the prothrombinase is significantly more effective

at catalyzing its substrate than is factor Xa alone

o once formed, thrombin leaves the membrane

surface _{converts fibrinogen by two cleavage}

steps into fibrin and 2 small peptides termed fibrinopeptides A and B

o removal of fibrinopeptide A permits end-to-end

polymerization of the fibrin

o cleavage of fibrinopeptide B allows side-to-side

polymerization of the fibrin clot, facilitated by thrombin-activatable fibrinolysis inhibitor(TAFI)

 _{the coagulation system is exquisitely regulated.}

Feedback inhibition on the coagulation cascade

deactivates the enzyme complexes leading to thrombin formation

 _{exists at upstream, intermediate, and downstream}

portions of the coagulation cascade to "turn off" thrombin formation once the procoagulantsequence is initially activated

Coagulation Factors Tested

by the PT and the aPTT

PT aPTT

VII XII

X High molecular weight

kininogen V Prekallikrein II (prothrombin) XI Fibrinogen IX VIII X V II Fibrinogen  _{Based on 3 mechanisms:}

o mechanisms of fibrinolysis allow for breakdown of

the fibrin clot and subsequent repair of vessel with deposition of connective tissue

o tissue factor pathway inhibitor (TFPI)  blocks

the extrinsic tissue factor–VIIa complex

_{eliminating this production of factors Xa and IXa}

- Antithrombin III  effectively neutralizes all of the procoagulant serine proteases and weakly inhibits the tissue factor–VIIa complex

o mechanism of inhibition of thrombin formation is

the protein C system

- thrombin binds to thrombomodulin and activates protein C to activated protein C  (APC), which then forms a complex with its cofactor, protein S, on a phospholipid surface

_{cleaves factors Va and VIIIa}

_{no longer able to participate in the formation of}

tissue factor–VIIa or prothrombinasecomplexe - also activates TAFI, which removes the terminal

lysine on the fibrin molecule  _{clot more}

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- factor V Leide, gene mutation, that is resistant to cleavage by APC _{predisposed to venous}

thromboembolic events

 _{degradation of fibrin clot is accomplished by plasmin, a}

serine protease derived from the proenzyme plasminogen

 _{tissue plasminogen activator (tPA) is made by the}  _{endothelium and is the main circulating form of this}

family of enzymes

o is selective for fibrin-bound plasminogen so that

endogenous fibrinolytic activity occurs predominately at the site of clot

o urokinase plasminogen activator (uPA), also

produced by endothelial cells, as well as by urothelium, is not selective for fibrin-bound plasminogen

Fibrinolysis

 _{fibrin clot undergoes clot lysis, which permits}

restoration of blood flow

 _{fibrinolysis is initiated at the same time as the clotting}

mechanismunder the influence of circulating kinases, tissue activators, and kallikrein

 _{plasmin- main enzyme degrades the fibrin mesh at}

various places

 _{plasminogen may be converted by one of several}

plasminogen activators, including tPA and uPA

 _{bradykinin, a potent endothelium-dependent}

vasodilator cleaved from high molecular weight kininogen by kallikrein, causes contraction of nonvascular smooth muscle, increases vascular permeability, and enhances release of tPA

 _{plasminogen activation may be initiated by activation}

of factor XII

 _{the tPA activates plasminogen more efficiently when it}

is bound to fibrin, so that plasmin is formed selectively on the clot

o plasmin is inhibited by 2-antiplasmin, a protein

that is cross-linked to fibrin by factor XIII, which helps to ensure that clot lysis does not occur too quickly

o any circulating plasmin also is inhibited by

2-antiplasmin and circulating tPA or urokinase

 _{clot lysis yields fibrin degradation products, including}

E-nodules and D-dimers

o the smaller fragments interfere with normal

platelet aggregation and the larger fragments may

be incorporated into the clot in lieu of normal fibrin monomers _{unstable clot.}

o D-dimers in the circulationmarker of thrombosis

or other conditions in which a significant activation of the fibrinolytic system is present

Most frequent inherited factor deficiencies

 factor VIII deficiency (hemophilia A and von

Willebrand's disease)

 factor IX deficiency (hemophilia B or Christmas

disease)

 factor XI deficiency

Factor VIII And Factor IX Hemophilia

 sex-linked recessive disorders

 Severity of both hemophilia A and hemophilia B

depends on the level of factor VIII or factor IX in the patient's plasma

Disease factor levels:

<1% normal: Severe Disease

1 - 5%: moderately severe disease 5 - 30%: mild disease

MANIFESTATIONS:

 Intracranial bleeding, retropharyngeal bleeding, and

bleeding from the tongue or lingual frenulum may be life-threatening

 Moderately severe hemophilia: less spontaneous

bleeding but are likely to bleed severely after trauma or surgery

 Retroperitoneal hematomas

 Mild hemophiliacs: do not bleed spontaneously and

have mild bleeding after major trauma or surgery

 May not bleed immediately after an injury or minor

surgery but will begin to bleed several hours later because of normal platelet function

TREATMENT:

 Factor VIII (hemo A) or factor IX (hemo B) concentrate  Recombinant factor VIII recommended for HIV and

hepa C virus (HCV)-seronegative

 For factor IX replacement :recommended tx are

recombinant or high purity factor IX

 Intermediate purity factor IX (prothrombin complex)

concentrates (not use: risk of thrombosis)

 1-deamino-D-argininevasopressin (DDAVP,

desmopressin): induces the release of vWF from endothelial cells, raising the levels of vWF and associated factor VIII

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useful adjunct to factor VIII or IX or DDAVP especially for oral and urinary tract bleeding

Patients with high titer inhibitors is not possible to achieve adequate factor VIII levels with factor VIII preparations

Alternatives:

 Porcine factor VIII

 Prothrombin complex concentrates

 Recombinant factor VIIa (most effective, given every 2

hrs, expensive)

Von Willebrand’s Disease

 Disorder with low factor VIII  Autosomal dominant disorder

 Primary defect: low level of the vWF, a large

glycoprotein with two functions

1. Serve as a carrier for factor VIII

2. Necessary for normal platelet adhesion and normal aggregation under high shear conditions Three types:

a) Type I (partial quantitative deficiency) b) Type II (qualitative defect)

c) Type III (total deficiency) MANIFESTATIONS:

 Menorrhagia is common in women with vWD

 Easy bruising and mucosal bleeding (platelet disorder)

TREATMENT:

 Intermediate purity factor VIII concentrates

(Humate-P: contains vWF and factor VIII)

 DDAVP: raises endogenous vWF levels by release of

the factor from endothelial cells - EACA (Amicar) is a useful adjunct

 In general, type I patients respond well to DDAVP,

type II patients may respond, depending on the particular defect and type III patients usually do not respond.

Factor XI Deficiency

 Hemophilia C

 Prevalent in the Ashkenazi Jewish population

(heterozygote frequency about 1:8)

 Mild bleeding disorder, autosomal recessive trait

MANIFESTATIONS:

 Spontaneous bleeding is rare, but may occur after

surgery or trauma TREATMENT:

 Fresh-frozen plasma (FFP) infusion  Factor XI concentrates

 DDAVP: useful in prevention of surgical bleeding

Deficiencies Of Factors II (Prothrombin), V & X

 Rare inherited deficiencies  autosomal recessive traits

 Significant bleeding in homozygotes with <1% of

normal activity

 Half-life of prothrombin (factor II) is approximately 72

hours

 Half-life of factor X is approximately 48 hours

 Factor V deficiency may be coinherited with factor VIII

deficiency TREATMENT:

 FFP. Contains 1 unit of activity of each (factors X and

II) per milliliter. However, factor V activity is decreased because of its inherent instability.

 Half-life of factor II is long (approximately 72 hours)

and only 25% of the normal level is needed for hemostasis, single infusion of FFP is sufficient.

 Prothrombin complex concentrates can be used to

treat deficiencies of prothrombin or factor X.

 Treatment of bleeding in combined deficiency (factor V

and factor VIII deficiency) requires factor VIII concentrate and FFP.

 Some factor V deficient pt also lacks factor V normally

present in platelets and may need platelet transfusions as well as FFP

Factor VII Deficiency

 Rare disorder

 Bleeding is uncommon unless the level is less than 3%

TREATMENT:

 FFP or with recombinant factor VIIa

 Half-life of recombinant factor VIIa is approximately 2

hours

 Half-life of factor VII in FFP is approximately 4 hours

Factor XIII Deficiency

 Rare, autosomal recessive trait

MANIFESTATIONS:

 Bleeding is delayed because clots form normally but

are susceptible to fibrinolysis

 Umbilical stump bleeding

 high risk of intracranial bleeding

 Spontaneous abortion is usual in women unless they

receive replacement therapy

 Half-life of factor XIII is approximately 9 to 14 days

TREATMENT:

 Replacement with FFP, cryoprecipitate, or a factor XIII

concentrate

 Levels of 1 - 2% : adequate for hemostasis

Inherited Defects

 Rare defects

 Abnormalities of platelet surface proteins, platelet

granules, and enzyme defects

 Major surface protein abnormalities are

thrombasthenia and Bernard-Soulier syndrome THROMBASTHENIA (GLANZMANN'S DISEASE)

 Caused by an absence of functional glycoprotein IIb

IIIa, the receptor for fibrinogen and also a receptor for vWF

 Because platelets must bind fibrinogen or vWF to

expose the ADP receptor so they can bind ADP and PLATELET FUNCTIONAL DEFECTS

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aggregate

 Treatment: platelet transfusions

BERNARD-SOULIER SYNDROME

 Caused by a defect in the GP Ib/IX/V receptor for vWF

-necessary for platelet adhesion

 Treatment: Platelet transfusion

STORAGE POOL DISEASE

 Most common intrinsic platelet defect

 May involve loss of dense granules (storage sites for

ADP, ATP, Ca2+, and inorganic phosphate) and α granules

DENSE GRANULE DEFICIENCY

 Most prevalent

 May be an isolated defect or occur with partial albinism

in the Hermansky-Pudlak syndrome

 Bleeding is variable depending on how severe the

granule defect is

 Bleeding is primarily caused by the decreased release

of ADP from these platelets GRAY PLATELET SYNDROME

 Isolated defect of the α-granules  Bleeding is usually mild

 dense and α-granules: more severe bleeding disorder

o Treatment:

 DDAVP

 platelet transfusion: severe bleeding

Other intrinsic platelet defects:

 Deficiency of cyclooxygenase

 Abnormalities in platelet actin, myosin, cytoskeletal

proteins, and enzymes involved in various aspects of platelet metabolism

 Treatment:

 DDAVP- mild bleeding  Platelet transfusion

Quantitative Platelet Defects Inherited Thrombocytopenia

 Rare

 Treatment: platelet transfusion, if significant

Platelet Abnormalities a. Quantitative

 Due to failure of production

o as in bone marrow disorders (cuased by leukemia,

myelodysplastic syndrome, severe vitaminB12 or folate deficiency, chemotherapeutic drug use, radiation therapy, acute ethanol intoxication, or viral infection)

 Shortened survival  Sequestration

b. Qualitative

 With indicated treatment, due to symptoms or the

need for an invasive procedure

 platelet transfusion is used

Etiology of Platelet Disorders A. Quantitative disorders

1. Failure of production: related to impairment of bone marrow function

a. Leukemia

b. Myeloproliferative disorders c. Vitamin B12 or Folate deficiency d. Chemotherapy or radiation therapy e. Acute alcohol intoxication

f. Viral infections 2. Decreased survival

a. Immune-mediated disorders

o Idiopathic thrombocytopenia

o Heparin-induced thrombocytopenia

o Autoimmune disorders or B-cell

malignancies

o Secondary thrombocytopenia

b. Disseminated intravascular coagulation c. Disorders related to platelet thrombi

o Thrombocytopenic purpura o Hemolytic uremic syndrome

3. Sequestration a. Portal hypertension b. Sarcoid c. Lymphoma d. Gaucher's disease A. Qualitative disorders 1. Massive transfusion

2. Therapeutic administration of platelet inhibitors 3. Disease states

a. Myeloproliferative disorders b. Monoclonal gammopathies c. Liver disease

QUANTITATIVE DEFECTS

 marrow related diseases (leukemia or myelodysplasia,

vitamin B12  or folate deficiencies, chemotherapy or radiation therapy, acute alcohol intoxication, or viral illnesses ) affects bone marrow production

 Shortened platelet survival in immune

thrombocytopenia

o may be idiopathic

o associated with other autoimmune disorders or

low-grade B-cell malignancies disseminated intravascular coagulation

o secondary to viral infections (HIV infection) or use of

drugs and disorders (thrombotic thrombocytopenic purpura and hemolytic uremic syndrome)

 Secondary immune thrombocytopenia

o very low platelet count o with petechiae and purpura o with epistaxis

o initial treatment  _{corticosteroids}  _{IV gamma globulin}

 _{anti-D immunoglobulin in patients who are}

Rh-positive

Gamma globulin and anti-D immunoglobulin

 rapid onset

 Survival of transfused platelets

o Short

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 known as idiopathic thrombocytopenic

purpura(ITP)

o In children

o acute and short lived

o typically follows a viral illness

 In adults

o gradual in onset o chronic

o no identifiable cause

 Circulating platelets: young functional  Bleeding

o less for a given platelet count than when there is

failure of platelet production

 Pathophysiology

o involve both impaired platelet production and T cell–

mediated platelet destruction

Drug-Induced Immune Thrombocytopenia

 Treatment

o Withdrawal of the offending drug

 Hastens recovery

o Corticosteroids o Gamma globulin

o Anti-D immunoglobulin

Management of Idiopathic Thrombocytopenic Purpura (ITP) in Adults

First Line:

a.Corticosteroids: The majority of patients respond, but only a few long term.

b.IV immunoglobulin: Indicated with clinical bleeding, along with platelet transfusion, and when condition is steroid unresponsive. Response is rapid but t ransient. c. Anti-D immunoglobulin: Active only in Rh-positive

patients before splenectomy. Response is transient Second Line:

a. SPLENECTOMY: Open or laparoscopic. Criteria include severe thrombocytopenia, high risk of bleeding, and continued need for steroids. Treatment failure may be due to retained accessory splenic tissue.

Third Line:

a. Patients for whom firstand second-line therapies fail are considered to have chronic ITP. The objective in this subset of patients is to maintain the platelet count >20–30 x 109/L and to minimize side effects of medications.

b. Rituximab, an anti-CD20 monoclonal antibody: Acts by eliminating B cells.

c. Alternative medications producing mixed results and a limited response: Danazol, cyclosporine A, dapsone, azathioprine, and vinca alkaloids. Thrombopoietic agents: A new class of drugs for  patients with impaired production of platelets rather than accelerated destruction of platelets. Second-generation drugs still in clinical trials include AMG531 and eltrombopag.

Heparin-Induced Thrombocytopenia (HIT)

 form of drug-induced immune thrombocytopenia  immunologic disorder

o antibodies against PF4 affect platelet activation and

endothelial function with resultant thrombocytopenia and intravascular thrombosis

 platelet count

o fall 5 to 7 days after heparin has been started

 re-exposure

o decrease in count may occur within 1 to 2 days

 should be suspected if the platelet count falls to

<100,000/L or drops by 50% from baseline in a patient receiving heparinmore common with full-dose unfractionated heparin (1 to 3%)

 occur with prophylactic doses or with low molecular

weight heparins

 approximately17% of patients receiving unfractionated

heparin and 8% of those receiving low molecular weight heparin

o develop antibodies against PF4

 with high incidence of thrombosis  may be arterial or venous

 absence of thrombocytopenia in these patients

o does not preclude the diagnosis of HIT

Diagnosis of HIT

 uses either a serotonin release assay or enzyme-linked

immunosorbent assay (ELISA)

o serotonin release assay

o highly specific but not sensitive o ELISA has a low specificity o negative ELISA result

 _{essentially rules out HIT}

Initial treatment of HIT

o Goal

 to stop heparin

 start with alternative anticoagulant

 Alternative anticoagulants are primarily thrombin

inhibitors

o Lepirudin o Argatroban o Bivalirudin

o In Canada and Europe, danaparoid also is available

Danaparoid

 heparinoid that has approximately 20% cross reactivity

with HIT antibodies (vivo < vitro)

Thrombotic Thrombocytopenic Purpura (TTP)

 large vWF molecules interact with plateletsactivation  inhibition of metalloproteinase enzyme (ADAMTS13)  characterized by

 thrombocytopenia

 microangiopathic hemolytic anemia  fever

 renal and neurologic signs or symptoms

 finding of schistocytes on a peripheral blood smear

aids in the diagnosis

 most effective treatment for TTP

o plasmapheresis

RITUXIMAB

 Monoclonal antibody against the CD20 protein on B

lymphocytes

 Immunomodulatory therapy against acquired TTP

(majority:autoimmune mediated) Hemolytic Uremic Syndrome (HUS)

 often occurs secondary to infection

o Escherichia coli 0157:H7

o other Shiga toxin– producing bacteria

 metalloproteinase

o normal

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 less frequent neurologic symptoms

TTP and HUS developed by patients w/

 Autoimmune diseases (SLE)  HIV infection

 in association with certain drugs (such as ticlopidine,

mitomycin C, gemcitabin

 Associated with immunosuppressive agents (such as

cyclosporine and tacrolimus) Sequestration

 important cause of thrombocytopenia

 sequestration of platelets in an enlarged spleen

(related to portal hypertension, sarcoid, lymphoma, or Gaucher's disease)

In patients with hypersplenism:

 they have normal total body platelet mass

 larger fraction of the platelets are in the enlarged

spleen

 Platelet survival: mildly decreased

 Bleeding is less than anticipated from the count

 Platelet transfusion does not increase the platelet

count as much as it would in a normal person

o because transfused platelets are similarly

sequestered in the spleen Splenectomy

 do not correct the thrombocytopenia of hypersplenism

caused by portal hypertension QUALITATIVE PLATELET DEFECTS Thrombocytopenia

 most common abnormality of hemostasis bleeding in

the surgical patient

 reduced platelet count due to a variety of disease

processes

 marrow usually demonstrates a normal or increased

number of megakaryocytes also occurs in surgical patients as a result of massive blood loss and replacement with product deficient in platelets

 induced by

o heparin administration (in cardiac and vascular

disorders)

 In patients with leukemia or uremia and receiving

cytotoxic therapy

o reduced number of megakaryocytes in the

marrow

 In patient for whom an elective operation is being

considered

o management is contingent on the extent

and cause of platelet reduction

o count of >50,000/ L generally requires no

specific therapy

 In patients whose thrombocytopenia is refractory to

standard platelet transfusion

o use of human leukocyte antigen (HLA)–

compatible platelets coupled with special processors has proved effective

Platelets

 administered preoperatively

o to increase the platelet count in surgical

patients with underlying thrombocytopenia

 One unit of platelet concentrate

o with approx. 5.5 x 10platelets

o increase the circulating platelet count by

approximately 10,000/ L in the average 70-kg person

 Impaired function

o accompanies thrombocytopenia

Decreased effectiveness of platelet transfusion

 Fever  Infection

 Hepatosplenomegaly

 Presence of antiplatelet alloantibodies

o decrease the effectiveness of platelet

transfusions

Impaired ADP-stimulated aggregation

 occurs with massive transfusion (>10 units of packed

red blood cells) Uremia

 may be associated with increased bleeding time and

impaired aggregation

 can be corrected by hemodialysis or peritoneal dialysis

Defective aggregation and platelet secretion

 In patients with

o thrombocythemia o polycythemia vera o myelofibrosis

Drugs that interfere with platelet function by design

 Aspirin

o through irreversible acetylation of platelet

prostaglandin synthase

 Clopidogrel

o Both aspirin and clopidogrel irreversibly inhibit platelet

function, clopidogrel through selective irreversible inhibition of ADP-induced platelet aggregation

 Dipyridamole

 Glycoprotein IIB/IIIA Inhibitors

For each drugs (mentioned above)

o a period of approximately 7 days is required

from the time the drug is stopped until an elective procedure can be performed

Other disorders associated with abnormal platelet function

 Uremia

 Myeloproliferative Disorders

o intrinsic to the platelets

o usually improves if the platelet count can be reduced

to normal with chemotherapy

_{surgery should be delayed until the count has}

been decreased

_{These patients are at risk for both bleeding and}

thrombosis

 Monoclonal Gammopathies

o result of interaction of the monoclonal protein with

platelets

o treatment with chemotherapy, or occasionally

plasmapheresis

 _{to lower the amount of monoclonal protein}

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o corrects platelet dysfunction in surgical patients

Acquired Hypofibrinogenemia

Disseminated Intravascular Coagulation (DIC)

 Characterized by the intravascular activation of

coagulation with the loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, , can produce organ dysfunction

o Additional causes o Malignancy

o Organ injury (such as severe pancreatitis) o Liver failure

o Certain vascular abnormalities (such as large

aneurysms) o Snakebites o Illicit drugs o Transfusion reactions o Transplant rejection o Sepsis

o Accompanies sepsis and may be associated with

multiple organ failure

o Diagnosis

o inciting cause with associated thrombocytopenia o prolongation of the PT

o low fibrinogen level

o elevated levels of fibrin markers (fibrin degradation

products, D-dimer, soluble fibrin monomers)

 facets of treatment

o relieving the patient's causative primary medical or

surgical problem

o maintaining adequate perfusion

 heparin therapy has been proposed  Specific injuries (ofDIC)

o central nervous system injuries with embolization

of brain matter

o fractures with embolization of bone marrow o amniotic fluid embolization

Excessive Thrombin Generation

 leads to microthrombus formationconsumption and

depletion of coagulation factors and platelets _classic

picture of diffuse bleeding

Primary Fibrinolysis

 caused by acquired hypofibrinogenic state in the

surgical patient

 occur in patients after prostate resection when

urokinase is released during surgical manipulation of the prostate or in patients undergoing extracorporeal bypass

 Fibrinolytic bleeding

o dependent on the concentration of breakdown products

in the circulation

 Synthetic amino acid-aminocaproic acid

o interferes with fibrinolysis by inhibiting plasminogen

activation

Myeloproliferative Diseases

 Polycythemia -  particularly with marked

thrombocytosis

o presents a major surgical risk

 _{Operations are considered only for the most grave}

surgical emergencies

 _{Defer operation until medical management has}

restored normal blood volume, hematocrit level, and platelet count

 Spontaneous thrombosis

o complication of polycythemia vera

o explained in part by increased blood viscosity o increased platelet count

o increased tendency toward stasis

 Myeloid metaplasia

o frequently represents part of the natural history of

polycythemia vera

o Approximately 50% of patients with myeloid

metaplasia are postpolycythemic

 Thrombocytosis

o reduced by the administration of hydroxyurea or

anagrelide

o Elective surgical procedures should be delayed until

the institution of appropriate treatment

o hematocrit level is kept below 48% and platelet count

under 400,000/ L

o In emergency procedure

 _{phlebotomy and blood replacement with lactated}

Ringer's solution may be beneficial

Coagulopathy of Liver Disease Liver

 Plays a key role in hemostasis

o responsible for the synthesis of many of the

coagulation factors

 Most common coagulation abnormalities associated

with liver dysfunction:

o thrombocytopenia

o impaired humoral coagulation function

manifested as prolongation of the PT

o increase in the International Normalized

Ratio (INR)

Thrombocytopenia in Patients with Liver Disease

 typically related to hypersplenism  reduced production of thrombopoietin  immune-mediated destruction of platelets  Immune-mediated thrombocytopenia

o may also occur in cirrhotic patients (w/ hepatitis C and

primary biliary cirrhosis)

 Ameliorate thrombocytopenia

o before therapy, the actual need for correction should

be strongly considered

o In general, correction based solely on a low platelet

count should be discouraged Patients with Hypersplenism

 the total body platelet mass is basically normal  abnormally high proportion of the platelets

 Less bleeding is seen than would be anticipated from

the platelet count because some of the sequestered platelets can be released into the circulation

 Splenectomy

o less well accepted option is splenectomy or splenic

embolization

 _{reduce hypersplenism}  _{reduced splenic blood flow}

 reduce portal vein flow with subsequent portal vein

thrombosis

 _{Results are mixed after transjugular intrahepatic}

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o treatment of thrombocytopenia should not be the

primary indication for a TIPS procedure Thrombopoietin

 primary stimulus for thrombopoiesis

 responsible for some cases of thrombocytopenia in

cirrhotic patients

o should be withheld f or invasive procedures and surgery

Platelet transfusions

 mainstay of therapy

 effect typically lasts only several hours

Administration of Il-11

 potential alternative

 stimulates proliferation of hematopoietic stem cells and

megakaryocyte progenitors

 Most studies using interleukin-11 have been in patients

with cancer

 Significant side effects limit its usefulness

Decreased production or increased destruction of coagulation factors and vitamin K deficiency

 contribute to a prolonged PT

 increased INR in patients with li ver disease

Correction of Coagulopathy

 reserved for treatment of active bleeding and

prophylaxis for invasive procedures and surgery

 w/ liver disease, treated with FFP  Complete correction is not possible  Fibrinogen level is <100 mg/dL

 Administration of cryoprecipitate may be helpful  Cryoprecipitate

o source of factor VIII for the rare patient with a low

factor VIII level

Coagulopathy of Trauma

 Causes

o Acidosis o Hypothermia

o Dilution of coagulation factors

 Only patients in shock arrive coagulopathic and that it

is the shock that induces coagulopathy through systemic activation of anticoagulant and fibrinolytic pathways

 hypoperfusion

o causes activation of thrombomodulin on the surface of

endothelial cells Circulating thrombin

 complexes with thrombomodulin.

 induces an anticoagulant state through activation of

protein C

 enhances fibrinolysis by deinhibition of tPA through the

consumption of plasminogen activator inhibitor 1 Acquired Coagulation Inhibition Antiphospholipid Syndrome (APLS)

 most common acquired disorder of coagulation

inhibition

 lupus anticoagulant and anticardiolipin antibodies are

present

 these antibodies are associated with either arterial or

venous thrombosis

 APLS is very common in patients with systemic lupus

erythematosus (SLE), and associated with rheumatoid arthritis and Sjörgen’s Syndrome

 Hallmark is prolonged aPTT in vitro but an increased

risk of thrombosis in vivo

Other Diseases Paraprotein Disorders

 production of abnormal globulin or fibrinogen that

interferes with clotting or platelet function

IgM Waldenström's

macroglobulinemia

IgG or IgA multiple myeloma

Cryoglobulin or

cryofibrinogen

liver disease (especially hepatitis C) or autoimmune diseases

Treatment:

 Chemotherapy -effective in lowering the

paraproteins of macroglobulinemia and myeloma,

 Plasmapheresis - usually removes Cryoglobulins

and cryofibrinogens

Hypersplenism

 associated with platelet sequestration and

platelet survival is mildly decreased

 total body platelet mass essentially normal, but a

much larger fraction of the platelets than normal are in the enlarged spleen

 Bleeding is less anticipated  because

sequestered platelets can be mobilized and enter the circulation

 Platelet transfusion not helpful   will end up in

spleen

ACQUIRED HEMOSTATIC DEFECTS

 Spontaneous bleeding  - complication of

anticoagulant therapy with:

o low molecular weight heparins o factor Xa inhibitors

 To reduce bleeding with continuous infusion of

heparin:

o aPTT must be regulated between 1.5

and 2.5 times the upper limit of normal

 Therapeutic anticoagulation is more reliably

achieved with low molecular weight heparin

o laboratory testing is not routinely used to

monitor dosing of these agents

 An exaggerated response to oral anticoagulants

may occur if dietary vitamin K i s inadequate.

 Anticoagulant effect of the warfarin is reduced in

patients receiving barbiturates, contraceptives, other estrogen-containing compounds, corticosteroids, ACTH

o Reduced anticoagulant dosage should be

instituted after discontinuance  of any of these drugs.

 Medications known to increase the effect of oral

anticoagulants

o Phenylbutazone

o Clofibrate (cholesterol-lowering agent) o a variety of antibiotics (particularly the

Cephalosporins)

o Anabolic steroids (norethandrolone) o Amiodarone

o Glucagons o L-thyroxine o Quinidine

 Onset of hematuria or melena  in the patient

receiving anticoagulants should be investigated

 _{may unmask underlying tumors.}

o PE reveals other signs of bleeding, such

as ecchymoses, petechiae, or hematoma

10 of 17

great problem: anticoagulants should be discontinued, and, if necessary, reversed

 Rebound phenomenon –  risk of thrombotic

complications is increased   when anticoagulation therapy is discontinued suddenly

 When the aPTT is <1.3 times control in a

heparinized patient, or when the INR is<1.5 in a patient on warfarin, meticulous surgical technique is mandatory

 Certain surgical procedures should not be

performed in the face of anticoagulation; Procedures requiring blind needle introduction should be avoided

Management:

 Discontinuation of heparin   may be

sufficient if the operation can be delayed for several hours

 For more rapid reversal  1 mg of protamine

sulfate for every 100 units of heparin most recently administered

 The reversal of warfarin may take several hours;

more rapid reversal can be accomplished with fresh-frozen plasma or prothrombin complex concentrate (Konyne or Proplex)

 Parenteral administration of vitamin K 

indicated in elective surgical treatment of patients with biliary obstruction or malabsorption Excessive Bleeding Associated With

Cardiopulmonary Bypass

 Triggering factors:

o excessive fibrinolysis

o abnormal platelet functions

 Laboratory evaluation tests may include:

o INR, aPTT, CBC, platelet count,

peripheral blood smear examination and measurement of fibrin degradation products

 Treatment may include:

o Administration of platelets o Protamine o ε- aminocaproic acid o aprotinin o desmopressin acetate Local Hemostasis

 The goal is to prevent or interrupt the flow of

blood from a disrupted vessel that has been incised or transected.

 May be accomplished by:

o interrupting the flow of blood to the

involved area

o direct closure of the blood vessel wall

defect

 The techniques are classified as:

1. MECHANICAL 2. THERMAL

3. TOPICAL HEMOSTATIC AGENTS

MECHANICAL PROCEDURES Digital

Pressure

 pressure is applied to an artery

proximal to an area of bleeding to reduce profuse bleeding

 often effective and has the

advantage of being less traumatic than any hemostatic clamp

 cannot be used permanently

 Pringle maneuver process by

which a tourniquet is used to occlude the hepatic artery and portal vein in the hepatoduodenal ligament as a method of controlling bleeding from a transected cystic artery or the raw surface of the liver

Hemostatic Clamps

 represents a temporary

mechanical device to stem bleeding

 disadvantage: result in damage to

the intimal wall of a blood vessel Ligature or

Hemoclip

 replaces the hemostat as a

permanent method of effecting hemostasis of a single disrupted vessel.

 When a small vessel was

transected, a simple ligature is sufficient. For large arteries with pulsation and longitudinal motion, a transfixion suture to prevent slipping is indicated.

Sutures  Required when the bleeding is

from a lateral defect in a large vessel

 represent foreign material, and

selection is based on their intrinsic characteristics and the state of the wound

 Non-absorbable sutures, such

as silk, polyethylene, and wire

_{evoke less tissue reaction}

 Absorbable sutures such as

catgut, polyglycolic (Dexon), and polyglactin (Vicryl)  _preferable

for grossly infected wounds because the nonabsorbable material can lead to extrusion or sinus formation

 Monofilament wire and

coated sutures  have an advantage over multifilament material in the presence of infection because the latter tends to fragment and permit sinus formation

Harmonic Scalpel

 an instrument that cuts and

coagulates tissue via vibration at 55 kHz

 A device that converts electrical

energy into mechanical motion

 The motion of the blade causes

collagen molecules within the tissue to become denatured forming a coagulum

 advantageous in performing

thyroidectomy,

hemorrhoidectomy, transsection of the short gastric veins during splenectomy, and in transecting hepatic parenchyma

11 of 17

Heat  achieves hemostasis by

denaturation of protein that results in coagulation of large areas of tissue

 ACTUAL CAUTERYheat is

transmitted from the instrument by conduction directly to the tissue

 ELECTROCAUTERYheating

occurs by induction from an alternating current source

 DIRECT CURRENT  (20- to

100-mA range) have successfully controlled diffuse bleeding from a raw surface; because the protein moieties and cellular elements of blood have a negative surface charge, they are attracted to a positive pole where a thrombus is formed

Local Cooling (decreased temp)

 has been applied to control

bleeding from the eroded mucosa of the esophagus and stomach.

 Direct cooling with iced saline is

effective and acts by increasing the local intravascular hematocrit and by causing vasoconstriction of the arterioles

 EXTREME COOLING, i.e.,

cryogenic procedures, have been applicable in gynecology and as a method of destroying hepatic metastases

TOPICAL HEMOSTATIC AGENTS

 can be classified based on their mechanism of action

and include physical or mechanical, caustic, biologic, and physiologic agents

 Some agents induce protein coagulation and

precipitation _{occlusion of small cutaneous vessels}

 Others take advantage of later stages in the

coagulation cascade  _{activating biologic responses}

to bleeding

 The ideal topical hemostatic agent:

o With significant hemostatic action o Has minimal tissue reactivity o Is nonantigenic

o Biodegrades in vivo

o Provides ease of sterilization o Low in cost

o Can be tailored to specific needs

Thrombin-derivative products

 direct the conversion of fibrinogen

to fibrin, aiding in clot formation

 takes advantage of natural

physiologic processes   _avoiding

foreign body or inflammatory reactions  _{wound bed is not}

disturbed

 thrombin entry into larger-caliber

vessels can result in systemic exposure to thrombin with a risk of disseminated intravascular clotting or death

Fibrin sealants  prepared from cryoprecipitate

(homologous or synthetic)

 have the advantage of not

promoting inflammation or tissue necrosis

 particularly helpful in patients who

have received heparin or who have deficiencies in coagulation

(e.g., hemophilia or von

Willebrand's disease) Purified gelatin

solution

 can be prepared into several

vehicles, including powders, sponges or foams, and sheets or films

 Hygroscopic  - absorbing many

times its weight in water or liquid

 effectively metabolized and

degraded by proteinases in the wound bed over a period of 4 to 6 weeks

 provides effective hemostasis for

operative fields with diffuse small-vessel oozing

 Thrombin may be applied to boost

hemostasis

 Advantages: relatively

inexpensive, readily available, pliable, and easy to handle

 Disadvantages: implanted gelatin

can serve as a nidus for infection

BACKGROUND

Late 19th century social acceptance of  human blood replacement

therapy

1900 Introduction of ABO blood grouping (Dr. Karl Landsteiner)

1939 Rh grouping (Dr. Levine & Dr. Stetson)

Late 1970s Whole blood was

considered the standard in transfusion

Typing and Cross Matching

 serologic compatibility is established routinely for the

recipients' and donors' A, B, O, and Rh groups in selecting blood for transfusion

 cross-matching between the donors' red blood cells

and the recipients' sera (the major cross-match) is performed

 as a rule, Rh-negative recipients should be transfused

only with Rh-negative blood (If the recipient is an elderly male who has not been transfused previously, the administration of Rh-positive blood is acceptable if Rh-negative blood is not available

 anti-Rh antibodies form within several weeks of

transfusion

 anti-Rh antiserum (RhoGAM) should be given if

Rh-positive products have been given to an Rh-negative patient

REPLACEMENT THERAPY TRANSFUSION

12 of 17

Rh-negative females who are capable of child-bearing

 administration of hyperimmune anti-Rh globulin to

Rh-negative women shortly before or after childbirth largely eliminates Rh disease in subsequent offspring

 for patients receiving repeated transfusions, serum

drawn not more than 72 hours before cross-matching should be used for matching with cells of the donor (Emergency transfusion can be accomplished with type O blood)

 O-negative and type-specific red blood cells are equally

safe for emergency transfusion

 problems are associated with the administration of four

or more units of O-negative blood because there is a significant increase in the risk of hemolysis

 for patients with clinically significant cold agglutinins,

blood should be administered through a blood warmer (If these antibodies are present in high titer, hypothermia is contraindicated)

 for patients with multiple transfusion and who have

developed alloantibodies, or who have autoimmune hemolytic anemia with pan-red blood cell antibodies, typing and cross-matching is often difficult, and sufficient time should be allotted preoperatively to accumulate blood that might be required during the operation

 cross-matching should always be performed before the

administration of dextran because it interferes with the typing procedure

 for autologous transfusion, up to 5 units can be

collected for subsequent use during elective procedures

 patients can donate blood if their hemoglobin

concentration exceeds 11 g/dL or if the hematocrit is greater than 34%

 first procurement is performed 40 days before the

planned operation and the last one is performed 3 days before the operation

 donations can be scheduled at intervals of 3 to 4 days  recombinant human erythropoietin (rHuEPO)

accelerates generation of red blood cells and allows for more frequent harvesting of blood

Banked Whole Blood

 shelf life extended to 40 ± 5 days

 at least 70% of the transfused erythrocytes remain in

the circulation for 24 hours after transfusion and are viable

 rarely indicated and rarely available

 changes in the red blood cells that occur during

storage include reduction of intracellular ADP and 2,3-diphosphoglycerate (2,3-DPG), which alters the curve of oxygen dissociation from hemoglobin, decreasing the function of oxygen transport

 along with the clotting factors, only factor V and VIII

are stable in banked blood

 pH decreases from 7.00 to 6.68, and the lactic acid

level increases from 20 to 150 mg/dL within 21 days of storage

 potassium concentration rises steadily to 32 mEq/dL,

and the ammonia concentration rises from 50 to 680 mg/dL at the end of 21 days

Fresh Whole Blood

 blood administered within 24 hours of its donation  rarely indicated

 must be administered untested because of the time

required for testing for infectious disease

 1 unit of platelet concentrate has more viable platelets

than 1 unit of fresh blood

 poor source of platelets and factor VIII

Packed Red Blood Cells and Frozen Red Blood Cells

 product of choice for most clinical situations

 concentrated suspensions of red blood cells can be

prepared by removing most of the supernatant plasma after centrifugation

 preparation reduces but does not eliminate reaction

caused by plasma components (also reduces the amount of sodium, potassium, lactic acid, and citrate administered)

 provides oxygen-carrying capacity

 frozen red blood cells are not available for use in

emergencies (used for patients who are known to have been previously sensitized)

 improved red blood cell viability and the ATP and

2,3-DPG concentrations are maintained

Reduced and Leukocyte-Reduced/Washed Red Blood Cells

 prepared by filtration

 eliminate 99.9% of the WBCs and most of the

platelets (leukocyte-reduced red blood cells), and, if needed, by additional saline washing (leukocyte-reduced/washed red blood cells)

 leukocyte-reduction prevents almost all febrile,

nonhemolytic transfusion reactions (fever and/or rigors), alloimmunization to HLA class I antigens, and platelet transfusion refractoriness and cytomegalovirus transmission

 washed, leukocyte-reduced red blood cells are usually

given only to patients who have had reactions (rash, urticaria, anaphylaxis) to unwashed red blood cells

Platelet Concentrates

 indicated for thrombocytopenia caused by massive

blood loss and replacement with platelet-poor products; and by inadequate production

 also given to patients with qualitative platelet disorders  preparations should be used within 120 hours of

donation

 1 unit of platelet concentrate = 50 mL

 can transmit infectious diseases and account for

allergic reactions similar to those caused by blood transfusion

 elevate the platelet count to the range of 50,000 to

100,000/microL when treating bleeding caused by thrombocytopenia or preparing some thrombocytopenic patients for an operation

 leukocyte reduction through filtration prevents HLA

alloimmunization

 patients who become alloimmunized through previous

transfusion, or those patients who are refractory from sensitization through prior pregnancies, HLA-matched platelets can be used

 platelet transfusion thresholds can safely be lowered in

patients without signs of hemostatic deficiency and who have no history of poor tolerance to low platelet counts

 multiple platelet transfusions predispose to multiorgan

failure and mortality is dose-dependent

 shelf life of platelets: 120 hrs from time of donation

Frozen Plasma and Volume Expanders

 frozen plasma prepared from freshly donated blood is

the standard source of the vitamin K–dependent factors (and is the only source of factor V) factor V is less stable than the vitamin K–dependent factors)

 risk of infectious disease is the same whether FFP,

whole blood, or red blood cells is administered

 Lactated Ringer's solution or buffered saline solution

administered in amounts 2 to 3 times the estimated blood loss is effective and associated with fewer complications

13 of 17

and normal serum albumin are preferred for rapid volume expansion

 commercially available dextran should not be

administered more than 1 L/d because of prolonged bleeding time and consequent hemorrhage

 low molecular weight dextran (30–40,000 Da)

possesses a higher colloidal pressure than plasma and effects some reversal of erythrocyte agglutination Concentrates and Recombinant DNA Technology

 antihemophilic concentrates are prepared from plasma

and are available for treatment of factor VIII or factor IX deficiency

 various concentrates are 20 to 30 times as potent as

an equal volume of FFP

 concentrated albumin of 25 g can be administered to

provide the equivalent of 500 mL of plasma and has the advantage of being hepatitis-free

Human Polymerized Hemoglobin (Polyheme)

 universally compatible  immediately available  disease-free

 oxygen-carrying resuscitative fluid that has been

successfully used in massively bleeding patients when red blood cells were not transfused

 absence of blood-type antigens (no cross-match

needed) and viral infections

 long-term stability

 disadvantages though are shorter half-life in the

bloodstream and cardiovascular complications

General Indications

Improvement in Oxygen-Carrying Capacity

 oxygen-carrying capacity is chiefly a function of RBCs  transfusion should be withheld when anemia can be

treated by specific therapy, such as erythropoietin

 acute anemias are more disabling than chronic anemia

because patients with chronic anemia have undergone an adjustment to the deficiency

 moderate drop in the hematocrit level and transfusions

are not indicated to correct the physiologic anemia in pregnancy if an operation is required

 correction of chronic anemia before surgical

intervention is often not necessary

 hemoglobin value of less than 10 g/dL or a hematocrit

level less than 30% indicates a need for preoperative red blood cell transfusion

 cardiac output does not increase significantly in

healthy individuals until the hemoglobin value decreases to approximately 7 g/dL

 patients with chronic anemia and a hemoglobin value

of less than 7 g/dL in whom intraoperative bleeding is not anticipated do not require a transfusion preoperatively

 blood volume can be replaced with dextran solution or

lactated Ringer's solution with a reduction of the hemoglobin value to levels below 10 g/dL

 human polymerized hemoglobin can be used to

increase oxygen-carrying capacity

 whole blood substitute, Fluosol-DA, has been proposed

as a solution with increased oxygen-handling capability

Replacement of Clotting Factors

 transfusion of platelets and/or proteins contributing to

coagulation may be indicated in specific patients before or during an operative procedure

Table for replacement of clotting factors (refer to the last page)

Specific Indications Massive Transfusion

 entails a single transfusion greater than 2500 mL or

5000 mL transfused over a period of 24 hours

 circulatory overload or DIC might occur

 dilutional thrombocytopenia, impaired platelet

function, and deficiencies of factors V, VIII, and XI can also be encountered

 routine alkalization is not advisable because this could

have an adverse effect on the hemoglobin dissociation curve and also is accompanied by an increased sodium load

Percentage of Original Blood Volume Remaining in a Patient with a 5-L Blood Volume Transfused with 500-mL Units

Magnitude of Hemorrhage and Transfusion Situation 1 Blood Volume (10 Units) 2 Blood Volume (20 Units) 3 Blood Volume (30 Units) Best 37 14 5 Usual 25–30 10 2–4 Worst 18 3 0.4

"best" situation requires simultaneous and equal replacement during hemorrhage;

"worst" situation means initial loss of one-half blood volume not replaced until the hemorrhage has stopped

 citrate toxicity from the use of stored blood may result

in young children, in patients with severe hypotension, or in patients with liver disease (toxicity is related to an excessive binding of ionized calcium)

 use of stored blood also provides a potassium load, but

there are no effects in the face of normal renal function

 when large volume transfusions are administered, a

heat exchanger should be used because hypothermia can cause a decrease in cardiac rate and output and blood pH

 use of blood from multiple donors increases the risk of

hemolytic reaction as a consequence of incompatibility

 when massive transfusions are administered, the pH,

blood gases, and potassium should be measured regularly and abnormalities corrected immediately

 if diffuse bleeding is noted, coagulation tests and

platelet counts should be measured and deficiencies corrected

INDICATIONS FOR REPLACEMENT OF BLOOD AND ITS ELEMENTS

14 of 17

 rate of transfusion depends upon the patient's status  Usually 5 mL/min is administered for the first minute,

after which 10 to 20 mL/min is given

 when there is marked oligemia, 500 mL can be given

within 10 minutes and a second 500 mL also can be given within 10 minutes

 approximately 1500 mL/min can be administered

through two 7.5-F catheters Other Methods

 blood can be instilled intraperitoneally or into the

medullary cavity of long bones and the sternum

 approximately 90% of red blood cells injected

intraperitoneally enter the circulation, but uptake is n ot complete for at least a week

 intraoperative autotransfusion is a potentially

life-saving adjunct

 roughly 250 mL of blood can be retrieved, washed or

filtered, and returned to the patient over a 5-minute period

 another approach to anticipated intraoperative large

blood losses is hemodilution (at the onset of the procedure, RBCs are removed while the intravascular volume is maintained with crystalloid or colloid)

 reduced blood viscosity improves the microcirculatory

perfusion

 removed blood can then be retransfused during the

operation to replace lost blood

Nonhemolytic Reactions/Febrile Reactions

 _{increase in temperature [>1°C (1.8°F)]}

associated with a transfusion

 _{CAUSE: Preformed cytokines in donated blood}

and recipient antibodies reacting with donated antibodies

 _{PREVENTION:use of leukocyte-reduced and/or}

out of date blood products

 _{Acetaminophen/Paracetamol- reduces the}

severity of the reaction.

 _{Bacterial contamination of infused blood is rare.}  _{CLINICAL MANIFESTATIONS}

o Systemic Signs

- fever and chills - tachycardia - hypotension o GI Symptoms - abdominal cramps - vomiting - diarrhea o Hemorrhagic Manifestations - hemoglobinemia - hemoglobinuria

- disseminated intravascular coagulation

 _{UPON SUSPECTED DIAGNOSIS:} o STOP the transfusion

o Have the donated blood cultured  _{Emergency treatment}

o administration of oxygen o adrenergic blocking agents o antibiotics

Allergic Reactions

 _{relatively frequent (~1% of all transfusions)}  _{can occur after the administration of any blood}

product  _{CLINICAL MANIFESTATIONS} o usually mild o rash o urticaria o fever

(alloccurring within 60 to 90 minutes of transfusion)

o anaphylactic shock - rare

 _CAUSE

o transfusion of antibodies from hypersensitive

donors

o transfusion of antigens to which the recipient is

hypersensitive

 _{TREATMENT AND PROPHYLAXIS} o antihistamines

o epinephrine or steroids in more serious cases

Respiratory Complications

 _{associated with transfusion-associated}

circulatory overload_{avoidable complication}  _{occurs with rapid infusion of blood, plasma}

expanders, and crystalloids esp. in older patients with underlying heart disease

 _{Central venous pressure monitoring should be}

considered whenever large amounts of fluid are administered

 _{CLINICAL MANIFESTATION} o rise in venous pressure

o dyspnea o cough

o rales at the lung bases

 _TREATMENT

o initiating diuresis

o slowing the rate of blood administration

o minimizing delivery of fluids while blood products

are being transfused

Syndrome of Transfusion-related Acute Lung Injury (TRALI)

 _{noncardiogenic pulmonary edema related to}

transfusion

 _{can occur with the administration of any}

plasma-containing blood product

 _{CLINICAL MANIFESTATIONS}

o similar to those of circulatory overload o dyspnea

o hypoxemia o fever o rigors

o bilateral pulmonary infiltrates on CXR

o occurs within 1 to 2 hours of transfusion, but

virtually always before 6 hours

 _CAUSE

o not well established

o thought to be related to anti-HLA or anti–human

neutrophil antigen antibodies in transfused blood that primes neutrophils in the pulmonary circulation

 _{RISK FACTORS}

o Multiparity of the donor - major risk factor o Female donors

 _TREATMENT

o discontinuation of any transfusion

METHODS OF ADMINISTERING BLOOD