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NAMES NG TRANS PEOPLE

Surgery

Hemostasis, Surgical Bleeding, and

Transfusion

DR. Bibera

July 5, 2012 1-4

a complex process whose function is to limit blood loss

from an injured vessel 4 major physiologic events

o vascular constriction o platelet plug formation o fibrin formation o fibrinolysis

Vascular Constriction

is the initial response to vessel injury, more pronounced in vessels with medial smooth muscles

dependent on local contraction of smooth muscle subsequently linked to platelet plug formation potent vasoconstrictors:

o Thromboxane A2 (TXA2) is produced locally at the site of injury via the release of arachidonic acid

from platelet membranes

o Endothelinsynthesized by injured endothelium and serotonin (5-hydroxytryptamine) released during platelet aggregation

o Bradykinin and Fibrinopeptides the extent of vasoconstriction varies with the degree of

vessel injury

Platelet Function

platelets are anucleate fragments of megakaryocytes, normal circulating number of platelets ranges between 150,000 and 400,000/ L

up to 30% may be sequestered in the spleen if not consumed in a clotting reaction, platelets are

normally removed by the spleen and have an average life span of 7 to 10 days

platelets play an integral role in hemostasis by forming a hemostatic plug and by contributing to thrombin formation

injury to the intimal layer in the vascular wall exposes subendothelial collagen to which platelets adhere, which requires von Willebrand's factor (vWF) binds to glycoprotein I/IX/V on the platelet

membrane

after adhesion, platelets initiate a release reaction that recruits other platelets from the circulating blood to seal the disrupted vessel. Up to this point, this process is known as primary hemostasis

platelet aggregation is reversible and is not associated with secretion

o heparin does not interfere with this reaction o adenosine diphosphate (ADP) and serotonin are

the principal mediators in platelet aggregation

arachidonic acid released converted by COX to

prostaglandin G2 (PGG2) prostaglandin H2 (PGH2) converted to TXA2

effects:Arachidonic acid shuttled to adjacent endothelial cells converted to prostacyclin (PGI2 )

vasodilation and acts to inhibit platelet aggregation

platelet COX is

o irreversibly inhibited by aspirin o reversibly blocked by NSAIDs

o but is not affected by COX-2 inhibitor

in the second wave of platelet aggregation, a release

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

fibrinogen is a required cofactor, acting as a bridge for the glycoprotein IIb/IIIa receptor on the activated platelets its release causes compaction of the plateletsinto a

plug, a process that is irreversible thrombospondin, secreted by the granule, stabilizes

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

platelet factor 4 (PF4), potent heparin antagonist, and thromboglobulin also are secreted during the release reaction

the second wave of platelet aggregation is inhibited by aspirin and NSAIDs, by (cAMP), and by nitric oxide

alterations occur in the phospholipids of the platelet membrane that allow Ca2+ and clotting factors bind

to the platelet surface enzymatically active

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 Xa50x 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

susceptible to lysis by plasmin

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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 circulationmarker 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

CONGENITAL FACTOR DEFICIENCIES

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Aminocaproic acid (Amicar): inhibitor of fibrinolysis, 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, platelets of thrombasthenic patients do not 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

ACQUIRED HEMOSTATIC DEFECTS

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Primary Immune Thrombocytopenia

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 transient.

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 plateletsactivation

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

usually is associated with some degree of renal failure

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many patients requiring renal replacement therapy

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 10 platelets

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

Liver Disease

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Administration of desmopressin acetate/ dialysis

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 formationconsumption 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 portosystemic shunt (TIPS)

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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 for 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 liver 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 is 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

ANTICOAGULATION AND BLEEDING

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CNS and eye surgeries minor bleeding poses a

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

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THERMAL AGENTS

Heat achieves hemostasis by

denaturation of protein that

results in coagulation of large areas of tissue

ACTUAL CAUTERYheat is

transmitted from the instrument by conduction directly to the

tissue ELECTROCAUTERYheating

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

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Rh-positive blood should not be transfused to 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

Leukocyte- 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

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Dextran or a combination of lactated Ringer's solution 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

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Routine Administration

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 not 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 overloadavoidable 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

COMPLICATIONS OF TRANSFUSION

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o notification of the transfusion service

o provision of pulmonary support

- supplemental oxygen

- mechanical ventilation

Hemolytic Reactions

high index of suspicion is needed to make the diagnosis

LABORATORY CRITERIA o hemoglobinuria o serologic findings that show incompatibility of

the donor and recipient blood o (+) Coombs' test presence of transfused cells

coated with patient antibody (diagnostic) GENERAL TREATMENT o STOP the transfusion immediately o sample of the recipient's blood drawn and sent

along with the suspect unit to the blood bank

o Monitor Urine output

o Maintain adequate hydration to prevent precipitation of hemoglobin within the tubules

Acute Hemolytic Reactions

occur with the administration of ABO-incompatible blood

fatal in up to 6% of cases CONTRIBUTING FACTORS o technical or clerical errors in the laboratory

o administration of blood of the wrong blood type CLINICAL MANIFESTATIONS o intravascular destruction of red blood cells

o hemoglobinemia o hemoglobinuria o pain at the site of transfusion o facial flushing

o back (flank) o chest pain o fever o respiratory distress o hypotension o tachycardia o for anesthetized patients:

- diffuse bleeding - hypotension

o DIC - can be initiated by activation of factor XII

and complement by antibody-antigen complexescoagulation cascade

o Acute Renal Insufficiency - results from the toxicity associated with free

hemoglobin in the plasma - tubular necrosis - precipitation of hemoglobin within the

tubules

Delayed Hemolytic Reactions

occur 2 to 10 days after transfusion occur when an individual has a low antibody titer

at the time of transfusion but the titer increases after transfusion as a result of an anamnestic response

Reactions to non-ABO antigens involve

immunoglobulin G–mediated clearance by the reticuloendothelial system.

do not usually require specific intervention

CLINICAL MANIFESTATIONS o extravascular hemolysis o mild anemia o indirect (unconjugated) hyperbilirubinemia o fever

o recurrent anemia o Jaundice o decreased haptoglobin levels

o low-grade hemoglobinemia and hemoglobinuria o (+) Coombs' test

Transmission of Disease

Diseases that can be transmitted by transfusion:

Malaria

Chagas' disease

Brucellosis

Syphilis (very rarely)

Malaria (most common: Plasmodium malariae)

incubation period: 8 to 100 days

initial manifestations

shaking chills

spiking fever

hepatitis C

HIV-1

Hepatitis B

Prion disorders (e.g., Creutzfeldt-Jakob disease)

Carefully review the patient's clinical history and drug use, and basic laboratory testing.

Common screening laboratory testing platelet count

PT or INR

Aptt

normal platelet count : 150,000 to 400,000/ µL.

bleeding or thrombotic complications Platelet counts >1,000,000/µL

Increased bleeding complications may be seen with major surgical procedures when

the platelet count is<100,000/ L minor surgical procedures when

counts are <50,000/ L Spontaneous hemorrhage:

o when count falls below 20,000/ L. PT and aPTT - variations of plasma recalcification

times initiated by the addition of a thromboplastic agent

PT reagent o contains thromboplastin and Ca

o when added to plasma, leads to the formation of a

fibrin clot PT test o measures the function of factors I, II, V, VII, and X o Factor VII -shortest half-life of the coagulation

factors, and its synthesis is vitamin K dependent. o best suited to detection of abnormal coagulation

caused by vitamin K deficiencies and warfarin

therapy Due to variations in thromboplastin activity, it can be

difficult to accurately assess the degree of anticoagulation on the basis of PT alone o determination of the INR is now the method of

choice for reporting PT values.

o International Sensitivity Index (ISI) is unique to each batch of thromboplastin and is furnished by the manufacturer tothe hematology laboratory

o Human brain thromboplastin has an ISI of 1, and the optimal reagent has an ISI between 1.3 and 1.5.

aPTT reagent

o phospholipid substitute, activator, and calcium

TEST OF HEMOSTASIS AND BLOOD

COAGULATION

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o in the presence of plasma leads to fibrin clot formation

o measures function of factors I, II, and V of the

common pathway and factors VIII, IX, X, and XII Heparin therapy-monitored by following aPTT values,

with a therapeutic target range of 1.5 to 2.5 times the control value (approx 50 to 80 seconds)

Low molecular weight heparins are selective factor Xa inhibitors and may mildly elevate the aPTT, but therapeutic monitoring is not routinely recommended.

bleeding time -used to evaluate platelet and vascular dysfunction

o Ivy bleeding time is most commonly

used determined by placing a

sphygmomanometer on the upper arm and inflating it to 40 mmHg and then making a 5-mm stab incision on the flexor surface

of the forearm

Time is measured to cessation of bleeding

upper limit of normal bleeding time – 7 min

o abnormal bleeding time suggests either platelet dysfunction (intrinsic or drug induced), vWD, or certain vascular

defects replacing the template bleeding time with an in vitro

test o which blood is sucked through a capillary and the

platelets adhere to the walls of the capillary and aggregate

o closure time in this system appears to be more

reproducible than the bleeding time o correlates with bleeding in patients with vWD,

primary platelet function disorders, or other platelet dysfunction disorders and patients who are taking aspirin

Additional medications may significantly impair

hemostatic function such as o antiplatelet agents (clopidogrel and glycoprotein

IIb/IIIa inhibitors) o anticoagulant agents (hirudin, chondroitin sulfate,

dermatan sulfate) o thrombolytic agents (streptokinase, tPA)

If abnormal results on any of the coagulation studies

cannot be explained by known medications->congenital abnormalities of coagulation or comorbid disease should be considered

Thromboelastography (TEG) o monitors hemostasis as a dynamic process rather

than revealing isolated information as in conventional coagulation screens.

o measures the viscoelastic properties of blood as it is induced to clot in a lowshear environment (resembling sluggish venous flow)

o patterns of change in shear elasticity allow the kinetics of clot formation and growth as well as the

strength and stability of the formed clot to be determined

o strength and stability data- provide information about the ability of the clot to perform the work of hemostasis

o kinetic data- determine the adequacy of quantitative

factors available for clot formation

o sample of celite-activated whole blood is placed into a prewarmed cuvette ->suspended piston is then lowered into the cuvette -> rotated through a 4.5-degree arc backwards and forwards

o Normal clot goes through an acceleration and strengthening phase

o fiber strands that interact with activated platelets attach to the surface of the cuvette and the suspended piston

o clot forming in the cuvette transmits its movement onto the suspended piston

o Weak clot stretches and therefore delays the arc movement of the piston, which is graphically

expressed as a narrow thromboelastogram o Strong clot will move the piston simultaneously and

proportionally to the cuvette's movements, creating a thick thromboelastogram

o strength of a clot is graphically represented over time as a characteristic cigar-shaped figure

o k- measure of the time from the beginning of clot

formation until the amplitude of the TEG tracing reaches 20 mm and represents the dynamics of clot formation

o alpha angle - angle between the line in the middle of the TEG(r) tracing and the line tangential to the developing body of the TEG(r) tracing. The alpha angle

represents the acceleration (kinetics) of fibrin buildup and cross-linking

o MA -maximum amplitude and reflects the strength of the clot, which is dependent on the number and function of platelets and the clot's interaction with

fibrin o MA60 - rate of amplitude reduction 60 minutes after

MA and represents the stability of the clot

Preoperative Evaluation of Hemostasis

Several hematologic disorders may have an impact on

the outcome of surgery.

pre-existing anemia and oral anticoagulation therapy-common clinical situations faced by the

surgeon Assessment of bleeding risk should also be considered

in patients with liver or renal dysfunction When feasible, diagnostic evaluation of the patient

with previously unrecognized anemia should be carried out before surgery, because certain types of anemia (particularly sickle cell disease and immune hemolytic anemias) may have implications for perioperative management

Hemoglobin levels below 7 or 8 g/dL appear to be associated with significantly more perioperative complications than higher levels

Determination of the need for preoperative transfusion in an individual patient must consider factors other than the absolute hemoglobin level, including

o presence of cardiopulmonary disease

o type of surgery o likelihood of surgical blood loss

Many patients have anemia postoperatively secondary to blood loss and hemodilution and do not necessarily require transfusion

directed bleeding history- most important component

of the bleeding risk assessment o provide meaningful clues to the presence

of a bleeding tendency

EVALUATION OF HEMOSTATIC RISK IN THE

SURGICAL PATIENT

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Patients who are reliable historians and who reveal no suggestion of abnormal bleeding on directed bleeding history and physical examination are at very low risk

for having an occult bleeding disorder o Laboratory tests of hemostatic

parameters is not required When the directed bleeding history is unreliable or

incomplete or when abnormal bleeding is suggested o formal evaluation of hemostasis should

be performed before surgery PT, the aPTT, and the platelet

count

Excessive bleeding during or after a surgical procedure may be the result of o ineffective hemostasis o blood transfusion o undetected hemostatic defect o consumptive coagulopathy

o fibrinolysis Excessive bleeding from the operative field

unassociated with bleeding from other sites usually

suggests inadequate mechanical hemostasis

Massive blood transfusion-well-known cause of

thrombocytopenia Bleeding after massive transfusion can occur due to o Hypothermia o dilutional coagulopathy

o platelet dysfunction, o fibrinolysis

o hypofibrinogenemia Another cause of hemostatic failure related to the

administration of blood is hemolytic transfusion reaction

diffuse bleeding -first sign of a transfusion reaction o release of ADP from hemolyzed red blood cells->

diffuse platelet aggregation->after which the platelet

clumps are removed out of the circulation->bleeding Transfusion purpura occurs when the donor platelets

are of the uncommon Pl(A1) group o an uncommon cause of thrombocytopenia and

associated bleeding after transfusion The platelets sensitize the recipient, who makes

antibody -> antibody then destroys the recipient's own

platelets-> thrombocytopenia and bleeding may continue for several weeks.

This uncommon cause of thrombocytopenia should be considered if bleeding follows transfusion by 5 or 6 days.

Platelet transfusions are of little help in the

management of this syndrome, because the new donor platelets usually are subject to the binding of antigen and damage from the antibody

Corticosteroids may be of some help in reducing the bleeding tendency.

Posttransfusion purpura is self-limited, and the passage of several weeks inevitably leads to

subsidence of the problem. DIC is characterized by systemic activation of the

blood coagulation system-> results in the generation

and deposition of fibrin ->leading to microvascular thrombi in various organs -> contributing to the development of multiorgan failure

Consumption and subsequent exhaustion of

coagulation proteins and platelets due to the ongoing activation of the

coagulation system may induce severe bleeding

complications

Severe hemorrhagic disorders due to thrombocytopenia have occurred as a result of gram-negative sepsis

o pathogenesis of endotoxin-induced thrombocytopemia- related to lability of factor V

Defibrination and hemostatic failure also may occur with meningococcemia, Clostridium perfringens sepsis,

and staphylococcal sepsis o Hemolysis appears to be one mechanism in sepsis leading to defibrination

From omgfacts.com:

Anatidaephobia is the fear that somewhere in the

world, there is a duck watching you.

If you touch your tongue while yawning, it can stop the yawn.

You're more likely to die on your way to buy a lottery ticket than you are to actually win the lottery.

Women speak about 7000 words a day. The average man averages just over 2000.

'Hippopotomonstrosesquippedaliophobia' is the fear of long words.

When a person is tickled, the response is actually a form of panic, as the brain interprets the tickling sensation as produced by spiders or

other creepy crawlies on your skin - the uncontrollable laughter is a response to panic.

Those stars and colours you see when you rub your eyes are called phosphenes.

Yawning is contagious - even thinking about yawning is enough. After reading this fact, there is a 50% chance you will yawn.

The total weight of all the ants on Earth is about the same as the weight of all the humans on earth.

When you kiss someone for a minute, you both burn about 2.6 calories.

An elephant can die from a broken heart.

'Dreamt' is the ONLY WORD in the entire English language that ends in the letters 'mt'.

'Dysania' is the state of finding it hard to get out of bed in the morning.

One tablespoon of semen has approximately 20 calories. Semen also contains zinc and calcium which helps prevent tooth decay.

Breathing the air in Mumbai, India for just ONE DAY, is equivalent to smoking 2.5 packs of cigarettes.

According to suicide statistics, Monday is the favored day for self-destruction.

If you walk and talk with someone, eventually you will synchronize your steps with each other.

Albert Einstein left his first wife for his COUSIN. A strawberry is not an actual berry, but a banana

is. Your earlobes line up with your nipples. (Go

try!) As a punishment for misbehavior, Thai cops have

to wear pink Hello Kitty armbands. Colgate faced big obstacle marketing toothpaste

in Spanish-speaking countries because Colgate

translates into the command 'go hang yourself.' In Topeka, Kansas it is illegal to sing the

alphabet on the streets at night. It is also illegal to install a bathtub, and you may not scream in a

haunted house. Justin Bieber can solve a Rubik's Cube in less

than 2 minutes. Humans don't just shrink with age. They shrink

EVERY DAY. (“Uh-oh.” – Deane)

EVALUATION OF EXCESSIVE

INTRAOPERATIVE OR POSTOPERATIVE

BLEEDING