ANEMIASANEMIASMohammad Abu-Fara. MDMohammad Abu-Fara. MD

ANEMIAANEMIA

AnemiaAnemia: Is defined as a reduction in one or : Is defined as a reduction in one or more of major RBC measurements.more of major RBC measurements.HGB.HGB.HTC.HTC.RBC count .RBC count .AnemiaAnemia is not a disease by itself but is one is not a disease by itself but is one of the major signs of disease.of the major signs of disease.May be the first manifestation of a May be the first manifestation of a systemic disease, along with other systemic disease, along with other nonspecific complaints such as fever, nonspecific complaints such as fever, weight loss, anorexia.weight loss, anorexia.

HGB Concentration: HGB Concentration: measures the major measures the major oxygen-carrying pigment in whole oxygen-carrying pigment in whole blood.blood.

Values are expressed as grams of HGB Values are expressed as grams of HGB per dL of whole blood (g/dL).per dL of whole blood (g/dL).

The normal ranges for HB. Varies in men The normal ranges for HB. Varies in men and women and in different age group. and women and in different age group.

Normal range: M 13-16,5 g/dLNormal range: M 13-16,5 g/dL

F 12-15,5 g/dL F 12-15,5 g/dL

HematocritHematocrit (HTC): Is the percent of a (HTC): Is the percent of a volume of whole blood occupied by volume of whole blood occupied by intact RBCs.intact RBCs.

Values are expressed as a percentage.Values are expressed as a percentage.

Normal range: M 41-51%.Normal range: M 41-51%.

F 37-47%.F 37-47%.

RBC Count:RBC Count: Is the number of RBCs Is the number of RBCs contained in a unit of whole blood.contained in a unit of whole blood.

Values are expressed as millions of Values are expressed as millions of cells per uL of whole blood.cells per uL of whole blood.

Normal range: M 4,5-6,5Normal range: M 4,5-6,5

F 3,8-5,8 F 3,8-5,8

VOLUME STATUSVOLUME STATUSThe three measurements are all The three measurements are all

concentrations.concentrations.

As such they are dependent upon both the As such they are dependent upon both the RBC mass and the plasma volume.RBC mass and the plasma volume.

1.1.In acute bleeding anemia develops only In acute bleeding anemia develops only after 36-48 hours.after 36-48 hours.

2.2.Pregnancy:RBC mass is increased by Pregnancy:RBC mass is increased by 25% and plasma is increased by 25% and plasma is increased by 50%.Normal values in pregnancy are 50%.Normal values in pregnancy are different.different.

3.3.Dehydration.Dehydration.

SPECIAL POPULATIONSSPECIAL POPULATIONS

1.1.Living at high altitude.Living at high altitude.

2.2.Smoking and air pollution.Smoking and air pollution.

3.3.African-AmericansAfrican-Americans——lower values.lower values.

4.4.Populations with a high incidence of Populations with a high incidence of ch. diseases.ch. diseases.

5.5.Athletes.Athletes.

6.6.The elderly: should not have a lower The elderly: should not have a lower normal range for fear of missing a normal range for fear of missing a serious underlying disorder. serious underlying disorder.

ERYTHROPOESISERYTHROPOESIS

The rate of RBC production equals the The rate of RBC production equals the rate of RBC destruction.rate of RBC destruction.

Approximately 1% of RBCs is removed Approximately 1% of RBCs is removed from the circulation daily.from the circulation daily.

The rate of RBC production can The rate of RBC production can increase markedly under the increase markedly under the influence of high levels of EPO.5-7 influence of high levels of EPO.5-7 folds.folds.

CLINICAL CONSEQUENCES CLINICAL CONSEQUENCES OF ANEMIAOF ANEMIA

The signs and symptoms induced by The signs and symptoms induced by anemia are dependent upon the anemia are dependent upon the degree of anemia as well as the rate degree of anemia as well as the rate at which the anemia has evolved.at which the anemia has evolved.

Symptoms of anemia can result from Symptoms of anemia can result from two factors:two factors:

1.Decreased O2 delivery to tissues.1.Decreased O2 delivery to tissues.

2.Hypovolemia/acute blood. loss/.2.Hypovolemia/acute blood. loss/.

COMPENSATORY COMPENSATORY MECHANISMSMECHANISMS

Signs and symptoms depend also on the Signs and symptoms depend also on the compensatory mechanisms.compensatory mechanisms.

1.1.Extraction of O2 by the tissues can Extraction of O2 by the tissues can increase from 25% to 60%.increase from 25% to 60%.

2.2.Cardiac compensation :stroke volume and Cardiac compensation :stroke volume and heart rate/cardiac output/.heart rate/cardiac output/.

Thus normal O2 delivery can be maintained Thus normal O2 delivery can be maintained by 1 and 2 at rest at HBG as low as by 1 and 2 at rest at HBG as low as 5g/dL,assuming that the intravascular. 5g/dL,assuming that the intravascular. volume is maintained.volume is maintained.

Thus symptoms will develop when HBG falls Thus symptoms will develop when HBG falls below this level at rest or at higher HBG below this level at rest or at higher HBG during exertion or when cardiac during exertion or when cardiac compensation is impaired.compensation is impaired.

SYMPTOM AND SIGNSSYMPTOM AND SIGNS

Symptom Symptom :is a sensation or change in :is a sensation or change in health function experienced by the health function experienced by the patient. It is a subjective report.patient. It is a subjective report.

..Dyspnea /S.O.B. :on exertion/at rest.Dyspnea /S.O.B. :on exertion/at rest.Fatigue/tiredness.Fatigue/tiredness.Signs and symptoms of hyperkinetic Signs and symptoms of hyperkinetic

state:state: 11.bounding .bounding

pulses.pulses. 2.2.palpitations.palpitations. 3.3.roaring in roaring in

ears.ears.

In more severe anemia: Lethargy, confusion, In more severe anemia: Lethargy, confusion, CHF, angina, MI., Pallor.CHF, angina, MI., Pallor.

Headache.Headache.Visual impairment, syncope Visual impairment, syncope Complications of extra cellular volume Complications of extra cellular volume

depletion/in acute bleeding/depletion/in acute bleeding/Symptoms and sign due to the underlying Symptoms and sign due to the underlying

cause of anemia .cause of anemia .

Iron deficiencyIron deficiencyMost cases are caused by menstrual loss and Most cases are caused by menstrual loss and

increased iron requirements of pregnancyincreased iron requirements of pregnancy..GI bleeding is the presumed etiology in most patientGI bleeding is the presumed etiology in most patient

Decreased iron absorption (celiac disease, Decreased iron absorption (celiac disease, postgastrectomy, or increase iron requirement as in postgastrectomy, or increase iron requirement as in lactationlactation..

History of History of picapica (consmption of substances such as (consmption of substances such as ice, starsh or clay ) can be obtainedice, starsh or clay ) can be obtained . .

Signs : splenomegaly, kiolonychia (spoon nail ) and Signs : splenomegaly, kiolonychia (spoon nail ) and plummer- vinson syndrome (glossitis, dysphagia, plummer- vinson syndrome (glossitis, dysphagia,

and esophageal webs) are rare findingand esophageal webs) are rare finding . .

Vitamin B12 and Folate Vitamin B12 and Folate deficiencydeficiency

Glossitis, angular stomatitis, juandice, Glossitis, angular stomatitis, juandice, splenomegaly and neurological splenomegaly and neurological syndrome of pernicious anemia syndrome of pernicious anemia

( subacute combined degeneration-( subacute combined degeneration-demylination of dorsal and lateral demylination of dorsal and lateral

columns of spinal cord. unsteady gait columns of spinal cord. unsteady gait and progress to irreversible damage and progress to irreversible damage

and bladder disturbance (only in VB12 and bladder disturbance (only in VB12 def.)def.)

Sign: is an objective evidence of the Sign: is an objective evidence of the presence of a disease or presence of a disease or disorder .Signs are discovered and disorder .Signs are discovered and reported reported by the physician, not by the by the physician, not by the patient.patient.

Elevated BP.Elevated BP.

Skin rash.Skin rash.

Tachypnea.Tachypnea.

CAUSES OF ANEMIACAUSES OF ANEMIA

There are 2 interrelated approaches There are 2 interrelated approaches one can use to help identify the one can use to help identify the cause of anemia.cause of anemia.

1.Kinetic approach.1.Kinetic approach.

2.Morphologic approach.2.Morphologic approach.

KINETIC APPROACHKINETIC APPROACH

Anemia can be caused by one or more Anemia can be caused by one or more of 3 independent mechanisms.of 3 independent mechanisms.

1.Decreased RBC production.1.Decreased RBC production.

2.Increased RBC destruction.2.Increased RBC destruction.

3.RBC loss.3.RBC loss.

MORPHOLOGIC MORPHOLOGIC APPROACHAPPROACH

According to RBC size.According to RBC size.

Mean Corpuscular Volume /MCV/.Mean Corpuscular Volume /MCV/.

RBC size/MCV/ is 80-96 femtoliters(fL).RBC size/MCV/ is 80-96 femtoliters(fL).

Microcyte.Microcyte.

Macrocyte.Macrocyte.

Normocyte.Normocyte.

ANEMIAS ACCORDING TO ANEMIAS ACCORDING TO THE RBC SIZETHE RBC SIZE

1.1.Microcytic anemia.Microcytic anemia.

2.2.Macrocytic anemia.Macrocytic anemia.

3.3.Normocytic anemia.Normocytic anemia.

MICROCYTIC ANEMIASMICROCYTIC ANEMIAS

Are associated with an MCV below 80 Are associated with an MCV below 80 fL.fL.

IDAIDA

ACDACD

Thalassemias.Thalassemias.

MACROCYTIC ANEMIASMACROCYTIC ANEMIAS

Are characterized by an MCV above Are characterized by an MCV above 100 fL.100 fL.

Reticulocytosis.Reticulocytosis.

Vit.B12 def.Vit.B12 def.

Folate def.Folate def.

MDS.MDS.

Liver disease Liver disease

HypothyroidismHypothyroidism

NORMOCYTIC ANEMIASNORMOCYTIC ANEMIAS

By definition the MCV is normal.By definition the MCV is normal.

ACD.ACD.

MDS.MDS.

EVALUATION OF THE EVALUATION OF THE PATIENT WITH ANEMIA-1PATIENT WITH ANEMIA-1

Anemia is one of the major signs of Anemia is one of the major signs of disease.disease.

It is never normal and it's cause should be It is never normal and it's cause should be always be sought.always be sought.

History.History. Physical examination.Physical examination. Simple lab. tests.Simple lab. tests.

Are all useful in evaluating the anemic Are all useful in evaluating the anemic patient.patient.

EVALUATION OF THE EVALUATION OF THE ANEMIC PATIENT-2ANEMIC PATIENT-2

The workup should be directed The workup should be directed towards answering the following towards answering the following questions:questions:

1.Is the patient bleeding (now or in the 1.Is the patient bleeding (now or in the past) ?.past) ?.

2.Is there evidence of increased RBC 2.Is there evidence of increased RBC destruction?destruction?

3.Is the BM suppressed?.3.Is the BM suppressed?.4.Is the patient iron deficient?if so,why?.4.Is the patient iron deficient?if so,why?.

Anemia associated with red Anemia associated with red blood blood

cell loss or destructioncell loss or destruction Sickle cell diseaseSickle cell disease

G6PD deficiencyG6PD deficiency Hemolytic anemiaHemolytic anemia

BLEEDING BLEEDING DISORDERSDISORDERS

HEMOSTASIS-1HEMOSTASIS-1 In health hemostasis ensures that the blood In health hemostasis ensures that the blood

remains fluid and contained in the vascular remains fluid and contained in the vascular system.system.

If a vessel wall is damaged,a number of If a vessel wall is damaged,a number of mechanisms are activated promptly to limit mechanisms are activated promptly to limit bleeding, involvingbleeding, involving

1-Endothelial cells.1-Endothelial cells.

2-Plasma coagulation factors.2-Plasma coagulation factors.

3-Platelets.3-Platelets.

4-Fibrinolytic system.4-Fibrinolytic system.

HEMOASTASIS-2HEMOASTASIS-2 These activities are finely balanced These activities are finely balanced

between keeping the blood fluid and between keeping the blood fluid and preventing intravascular thrombosis.preventing intravascular thrombosis.

1-Pimary hemostasis: immediate but 1-Pimary hemostasis: immediate but temporary response to vessel injury . temporary response to vessel injury . Platelets and von willebrand interact to Platelets and von willebrand interact to form a primary plug , after which platelet form a primary plug , after which platelet activation occurs and blood vessels activation occurs and blood vessels constrict, limiting flow.constrict, limiting flow.

2-Secondary hemostasis: (coagulation) :is 2-Secondary hemostasis: (coagulation) :is slower process that results in the formation slower process that results in the formation of a fibrin clot .of a fibrin clot .

Coagulation is initiated when vascular Coagulation is initiated when vascular damage exposes extravascular tissue damage exposes extravascular tissue factor initiating activation of factor factor initiating activation of factor V11, factor X and prothrombin with V11, factor X and prothrombin with subsequent activation of factor subsequent activation of factor V,V111,1X,X1,and X111,leading to V,V111,1X,X1,and X111,leading to accelerated and sustained generation accelerated and sustained generation of fibrinogen to fibrin and formation of fibrinogen to fibrin and formation of durable clot.of durable clot.

3-Fibrinolysis: activation of fibrin-bound 3-Fibrinolysis: activation of fibrin-bound plasminogen resulting in clot lysis. plasminogen resulting in clot lysis.

ROLE OF ENDOTHELIAL ROLE OF ENDOTHELIAL CELLS IN HEMOSTASISCELLS IN HEMOSTASIS

Blood vessels are lined with Blood vessels are lined with endothelial cells,which synthesize and endothelial cells,which synthesize and secrete various agents,that regulate secrete various agents,that regulate hemostasis.hemostasis.

1-Procoagulant(prothrombotic) agents: 1-Procoagulant(prothrombotic) agents: tissue factor, von Willebrand factor, F tissue factor, von Willebrand factor, F V ,F VIII.V ,F VIII.

2-Anticoagulant(antithrombotic) agents: 2-Anticoagulant(antithrombotic) agents: prostacyclin,Nitric oxide,endothelin-1.prostacyclin,Nitric oxide,endothelin-1.

ROLE OF PLATELETS IN ROLE OF PLATELETS IN HEMOSTASISHEMOSTASIS

1.1. Each megacaryocyte produces 1000-Each megacaryocyte produces 1000-2000 platelets,which 2000 platelets,which

2.2. remain in the circulation for about 10 remain in the circulation for about 10 days. days.

3.3. Releasing of hemostatic proteins.Releasing of hemostatic proteins.

4.4. Platelet adhesion.Platelet adhesion.

5.5. Platelet aggregation.Platelet aggregation.

COAGULATION SYSTEMCOAGULATION SYSTEM Coagulation factors: are plasma proteins Coagulation factors: are plasma proteins

synthesized in the liver which ,when synthesized in the liver which ,when activated lead to the deposition of fibrin.activated lead to the deposition of fibrin.

1-Initiation phase: leads to the formation of 1-Initiation phase: leads to the formation of the complex TF-VIIa.the complex TF-VIIa.

2-Amplification phase: leads to the 2-Amplification phase: leads to the formation of a small amount of thrombin formation of a small amount of thrombin from prothrombin.from prothrombin.

3-Propagation phase: leads to the formation 3-Propagation phase: leads to the formation of much larger amounts of fibrin.of much larger amounts of fibrin.

INHIBITORS OF INHIBITORS OF COAGULATIONCOAGULATION

Are proteins that inhibit activated Are proteins that inhibit activated procaogulation enzymes and prevent procaogulation enzymes and prevent excessive intravascular coagulationexcessive intravascular coagulation

Raised levels are not associated with bleeding.Raised levels are not associated with bleeding.

Reduced levels may predispose to thrombosis.Reduced levels may predispose to thrombosis.

Antithrombin.Antithrombin.

Protein C, Protein S.Protein C, Protein S.

Tissue Factor Pathway Inhibitor (TFPI).Tissue Factor Pathway Inhibitor (TFPI).

FIBRINOLYSISFIBRINOLYSIS

Small amouns of fibrin are constantly Small amouns of fibrin are constantly deposited within the vascular system deposited within the vascular system and are removed by the fibrinolytic and are removed by the fibrinolytic systemsystem

Plasminogen PlasminPlasminogen Plasmin

Fibrin FDPsFibrin FDPs

ASSESSMENT OF BLEEDING ASSESSMENT OF BLEEDING SYMPTOMSSYMPTOMS

1-Careful and full clinical history and 1-Careful and full clinical history and examination.examination.

(determining whether a bleeding is (determining whether a bleeding is present or likely congenital or present or likely congenital or acquired, mild or severe and involving acquired, mild or severe and involving primary or secondary hemostasis ) primary or secondary hemostasis )

2-Appropriate lab. investigations.2-Appropriate lab. investigations.3-Other investigations.3-Other investigations.

HISTORYHISTORY

1.1. 1-Site of bleeding( dental extractions, 1-Site of bleeding( dental extractions, circumcision, menstration, labor or circumcision, menstration, labor or delivery and trauma or surgery. Or easy delivery and trauma or surgery. Or easy bruising bruising

2.2. 2-Duration of bleeding and severity.2-Duration of bleeding and severity.3.3. 3-Precipitating cause.3-Precipitating cause.4.4. 4-Surgery.4-Surgery.5.5. 5-Family history.5-Family history.6.6. 6-Systemic illnesses (acquired bleeding 6-Systemic illnesses (acquired bleeding

disorders).disorders).7.7. 7-Drugs. 7-Drugs.

Clinical Features of Bleeding Clinical Features of Bleeding DisordersDisorders

Platelet Coagulation disorders factor disorders

Site of bleeding Skin Deep in soft tissues Mucous membranes (joints, muscles) (epistaxis, gum, vaginal, GI tract)

Petechiae Yes No

Ecchymoses (“bruises”) Small, superficial Large, deep

Hemarthrosis / muscle bleeding Extremely rare Common

Bleeding after cuts & scratches Yes No

Bleeding after surgery or trauma Immediate, Delayed (1-2 days), usually mild often severe

LABORATORY STUDIESLABORATORY STUDIES

Initial studies should include a platelet Initial studies should include a platelet count, prothrombin time (Pt ), activated count, prothrombin time (Pt ), activated partial thromboplastic time (aPtt) and partial thromboplastic time (aPtt) and peripheral blood smear reviewperipheral blood smear review..

1.1. platelet count low : manual slide review platelet count low : manual slide review to rule out a platelet clumping artifact.to rule out a platelet clumping artifact.

2.2. Bleeding time (BT) : may detect Bleeding time (BT) : may detect quantitative or qualitative disorder of quantitative or qualitative disorder of platelets or vWF or abnormalities of platelets or vWF or abnormalities of capillary integrity. capillary integrity.

prolonged after medication as aspirinprolonged after medication as aspirin . .

In vitro platelet aggregationIn vitro platelet aggregation

Von Willebrand factor antigenVon Willebrand factor antigen

von Willebrand factor activity , von Willebrand factor activity , ristocetin cofactor (vWF :RCo )ristocetin cofactor (vWF :RCo )

Von Willbrand factor multimer Von Willbrand factor multimer analysisanalysis . .

Secondary hemostasisSecondary hemostasis

Prothrombin time (Pt) : extrinsic pathway (factor V11,and Prothrombin time (Pt) : extrinsic pathway (factor V11,and common pathway factor X,V ,prothrombin ) coagulation common pathway factor X,V ,prothrombin ) coagulation factors and fibrinogenfactors and fibrinogen..

INR : (patient PT/ mean normal PT)ISIINR : (patient PT/ mean normal PT)ISI Activated partial thromboplastin times (aPTT): intrinsic Activated partial thromboplastin times (aPTT): intrinsic

pathway (kininogen, prekallikrein, factor X11, factor pathway (kininogen, prekallikrein, factor X11, factor 1X,factor X1 and factor V111) and common pathway (factor 1X,factor X1 and factor V111) and common pathway (factor V,facter X ,prothrombin and fibrinogenV,facter X ,prothrombin and fibrinogen..

Thrombin time (TT)Thrombin time (TT) FibrinoginFibrinogin

Clot urea stabilityClot urea stability Mixing studies coagulation plasma activityMixing studies coagulation plasma activity . .

Coagulation factor disordersCoagulation factor disorders

1.1. Inherited bleeding Inherited bleeding disordersdisorders

1.1. Hemophilia A and BHemophilia A and B

2.2. Von Willebrand Von Willebrand diseasedisease

3.3. Other factor Other factor deficienciesdeficiencies

Acquired bleeding Acquired bleeding disordersdisorders

1.1. Liver diseaseLiver disease

2.2. Vitamin K Vitamin K deficiency/warfarin deficiency/warfarin overdoseoverdose

3.3. DICDIC

Hemophilia A and BHemophilia A and BHemophilia A Hemophilia B

Coagulation factor deficiency Factor VIII Factor IX

Inheritance X-linked X-linkedrecessive recessive

Incidence 1/10,000 males 1/50,000 males

Severity Related to factor level<1% - Severe - spontaneous bleeding1-5% - Moderate - bleeding with mild

injury5-25% - Mild - bleeding with surgery or

trauma

Complications Soft tissue bleeding

HemophiliaHemophilia

Clinical manifestations Clinical manifestations (hemophilia A & B are (hemophilia A & B are indistinguishable)indistinguishable)

Hemarthrosis (most common)Hemarthrosis (most common)Fixed jointsFixed joints

Soft tissue hematomas (e.g., muscle)Soft tissue hematomas (e.g., muscle)Muscle atrophyMuscle atrophyShortened tendonsShortened tendons

Other sites of bleedingOther sites of bleedingUrinary tractUrinary tractCNS, neck (may be life-threatening)CNS, neck (may be life-threatening)

Prolonged bleeding after surgery or dental Prolonged bleeding after surgery or dental extractionsextractions

Hemarthrosis (acute)Hemarthrosis (acute)

Treatment of hemophilia ATreatment of hemophilia A

Intermediate purity plasma productsIntermediate purity plasma products Virucidally treatedVirucidally treated May contain von Willebrand factorMay contain von Willebrand factor

High purity (monoclonal) plasma productsHigh purity (monoclonal) plasma products Virucidally treatedVirucidally treated No functional von Willebrand factorNo functional von Willebrand factor

Recombinant factor VIIIRecombinant factor VIII Virus free/No apparent riskVirus free/No apparent risk

No functional von Willebrand factorNo functional von Willebrand factor

Dosing guidelines for hemophilia Dosing guidelines for hemophilia AA

Mild bleedingMild bleeding Target: 30% dosing q8-12h; 1-2 days (15U/kg)Target: 30% dosing q8-12h; 1-2 days (15U/kg) Hemarthrosis, oropharyngeal or dental, epistaxis, hematuriaHemarthrosis, oropharyngeal or dental, epistaxis, hematuria

Major bleedingMajor bleeding Target: 80-100% q8-12h; 7-14 days (50U/kg)Target: 80-100% q8-12h; 7-14 days (50U/kg) CNS trauma, hemorrhage, lumbar punctureCNS trauma, hemorrhage, lumbar puncture SurgerySurgery Retroperitoneal hemorrhageRetroperitoneal hemorrhage GI bleedingGI bleeding

Adjunctive therapyAdjunctive therapy Tranexemic acid or DDAVP (for mild disease only)Tranexemic acid or DDAVP (for mild disease only)

Complications of therapyComplications of therapy Formation of inhibitors (antibodies)Formation of inhibitors (antibodies)

10-15% of severe hemophilia A patients10-15% of severe hemophilia A patients 1-2% of severe hemophilia B patients1-2% of severe hemophilia B patients

Viral infectionsViral infections Hepatitis BHepatitis B Human parvovirusHuman parvovirus Hepatitis CHepatitis C Hepatitis AHepatitis A HIVHIV OtherOther

RITUXIMAB AND ACQUIRED RITUXIMAB AND ACQUIRED HEMOPHILIA(F VIII INHIBITORS)HEMOPHILIA(F VIII INHIBITORS)

STUDYSTUDY# OF PATS# OF PATSOUTCOMEOUTCOME

Stasi R,Bld Stasi R,Bld 103:4424,20103:4424,200404

10 10 acquired,titer acquired,titer 4-96BU4-96BU

80% CR80% CR

FW 28.5mFW 28.5m

Mazj S,Bld Mazj S,Bld 102,03,abs2102,03,abs2955955

4 acquired4 acquired100% CR100% CR

Wiestner Wiestner A,Bld A,Bld 100,02,3426100,02,3426

4(3 4(3 acquired,1 acquired,1 hemophilia)hemophilia)

100% CR100% CR

FW 7-12mFW 7-12m

Treatment of hemophilia BTreatment of hemophilia B

Agent Agent High purity factor IXHigh purity factor IX Recombinant human factor IXRecombinant human factor IX

DoseDose Initial dose: 100U/kgInitial dose: 100U/kg Subsequent: 50U/kg every 24 hoursSubsequent: 50U/kg every 24 hours

von Willebrand Disease: Clinical von Willebrand Disease: Clinical FeaturesFeatures

von Willebrand factorvon Willebrand factor Synthesis in endothelium and megakaryocytesSynthesis in endothelium and megakaryocytes Forms large multimer Forms large multimer Carrier of factor VIIICarrier of factor VIII Anchors platelets to sub endotheliumAnchors platelets to sub endothelium Bridge between plateletsBridge between platelets

Inheritance - autosomal dominantInheritance - autosomal dominant Incidence - 1/10,000Incidence - 1/10,000 Clinical features - mucocutaneous bleedingClinical features - mucocutaneous bleeding

Laboratory evaluation of Laboratory evaluation of von Willebrand diseasevon Willebrand disease

ClassificationClassification Type 1 Type 1 Partial quantitative deficiencyPartial quantitative deficiency Type 2 Type 2 Qualitative deficiencyQualitative deficiency Type 3Type 3 Total quantitative deficiencyTotal quantitative deficiency

Diagnostic tests:Diagnostic tests:

vonWillebrand typeAssay 1 2 3

vWF antigen Normal vWF activity Multimer analysis Normal NormalAbsent

VWF MultimersVWF Multimers

NP 1 2B 32A

Proteolysis

2Aplt

Treatment of von Willebrand DiseaseTreatment of von Willebrand Disease

CryoprecipitateCryoprecipitate Source of fibrinogen, factor VIII and VWFSource of fibrinogen, factor VIII and VWF Only plasma fraction that consistently contains VWF multimersOnly plasma fraction that consistently contains VWF multimers

DDAVP (deamino-8-arginine vasopressin)DDAVP (deamino-8-arginine vasopressin) plasma VWF levels by stimulating secretion from endotheliumplasma VWF levels by stimulating secretion from endothelium Duration of response is variableDuration of response is variable Not generally used in type 2 diseaseNot generally used in type 2 disease Dosage 0.3 Dosage 0.3 µµg/kg q 12 hr IVg/kg q 12 hr IV

Factor VIII concentrate (Intermediate purity)Factor VIII concentrate (Intermediate purity) Virally inactivated productVirally inactivated product

Pathogenesis of DICPathogenesis of DIC

Coagulation Fibrinolysis

Fibrinogen

FibrinMonomers

FibrinClot

(intravascular)

Fibrin(ogen)Degradation

Products

Plasmin

Thrombin Plasmin

Release of thromboplastic

material intocirculation

Consumption ofcoagulation factors;

presence of FDPs aPTT PT TT

Fibrinogen

Presence of plasmin FDP

Intravascular clot Platelets

Schistocytes

Disseminated Intravascular Coagulation Disseminated Intravascular Coagulation (DIC)(DIC)

MechanismMechanismSystemic activation

of coagulation

Intravasculardeposition of fibrin

Depletion of plateletsand coagulation factors

BleedingThrombosis of smalland midsize vessels

with organ failure

Common clinical conditions associated Common clinical conditions associated withwith

Disseminated Intravascular CoagulationDisseminated Intravascular Coagulation

SepsisSepsis

TraumaTrauma Head injuryHead injury Fat embolismFat embolism

MalignancyMalignancy

Obstetrical Obstetrical complicationscomplications Amniotic fluid embolismAmniotic fluid embolism Abruptio placentaeAbruptio placentae

Vascular disordersVascular disorders

Reaction to toxin (e.g. Reaction to toxin (e.g. snake venom, drugs)snake venom, drugs)

Immunologic disordersImmunologic disorders Severe allergic reactionSevere allergic reaction Transplant rejectionTransplant rejection

Activation of both coagulation and fibrinolysisTriggered by

Disseminated Intravascular Disseminated Intravascular CoagulationCoagulation

Treatment approachesTreatment approaches Treatment of underlying disorderTreatment of underlying disorder

Anticoagulation with heparinAnticoagulation with heparin

Platelet transfusionPlatelet transfusion

Fresh frozen plasmaFresh frozen plasma

Coagulation inhibitor concentrate (ATIII)Coagulation inhibitor concentrate (ATIII)

Classification of platelet Classification of platelet disordersdisorders

Quantitative Quantitative disordersdisorders

Abnormal distributionAbnormal distribution Dilution effectDilution effect Decreased Decreased

productionproduction Increased Increased

destructiondestruction

Qualitative disordersQualitative disorders

Inherited disorders Inherited disorders (rare)(rare)

Acquired disordersAcquired disorders MedicationsMedications Chronic renal failureChronic renal failure Cardiopulmonary Cardiopulmonary

bypassbypass

Platelet interactionPlatelet interaction

ThrombocytopeniaThrombocytopenia

Immune-mediatedIdioapthicDrug-inducedCollagen vascular diseaseLymphoproliferative diseaseSarcoidosis

Non-immune mediatedDICMicroangiopathic hemolytic anemia

Incidence of adult ITP increases with Incidence of adult ITP increases with ageage

Incidence (per 105 / year)

Age (yrs) Female Male Total

15-39 2.3 1.3 3.640-59 3.2 1.1 4.360+ 4.6 4.4 9.0

Total 3.2 2.0 2.6

Frederiksen and Schmidt, Blood 1999:94;909

Initial Treatment of ITPInitial Treatment of ITPPlatelet count Symptoms Treatment (per µl)

>50,000 None

20-50,000 Not bleeding NoneBleeding Steroids

IVIG

<20,000 Not bleeding Steroids

Bleeding IVIG

Hospitalization

Liver Disease and HemostasisLiver Disease and Hemostasis

1.1. Decreased synthesis of Decreased synthesis of II, VII, IX, X, XI, and II, VII, IX, X, XI, and fibrinogenfibrinogen

2.2. Dietary Vitamin K deficiency (Inadequate Dietary Vitamin K deficiency (Inadequate intake or malabsortion)intake or malabsortion)

3.3. DysfibrinogenemiaDysfibrinogenemia

4.4. Enhanced fibrinolysis (Decreased alpha-2-Enhanced fibrinolysis (Decreased alpha-2-antiplasmin)antiplasmin)

5.5. DICDIC

6.6. Thrombocytoepnia due to hypersplenismThrombocytoepnia due to hypersplenism

Management of Hemostatic Defects Management of Hemostatic Defects in Liver Diseasein Liver Disease

Treatment for prolonged PT/PTTTreatment for prolonged PT/PTT Vitamin K 10 mg SQ x 3 days - usually ineffectiveVitamin K 10 mg SQ x 3 days - usually ineffective

Fresh-frozen plasma infusionFresh-frozen plasma infusion 25-30% of plasma volume (1200-1500 ml) 25-30% of plasma volume (1200-1500 ml) immediate but temporary effectimmediate but temporary effect

Treatment for low fibrinogenTreatment for low fibrinogen Cryoprecipitate (1 unit/10kg body weight)Cryoprecipitate (1 unit/10kg body weight)

Treatment for DIC (Elevated D-dimer, low factor VIII, thrombocytopeniaTreatment for DIC (Elevated D-dimer, low factor VIII, thrombocytopenia Replacement therapyReplacement therapy

Laboratory Evaluation of BleedingLaboratory Evaluation of BleedingOverviewOverview

CBC and smearCBC and smear Platelet countPlatelet count ThrombocytopeniaThrombocytopeniaRBC and platelet morphologyRBC and platelet morphology TTP, DIC, etc.TTP, DIC, etc.

CoagulationCoagulation Prothrombin timeProthrombin time Extrinsic/common pathwaysExtrinsic/common pathwaysPartial thromboplastin timePartial thromboplastin time Intrinsic/common pathwaysIntrinsic/common pathwaysCoagulation factor assaysCoagulation factor assays Specific factor deficienciesSpecific factor deficiencies50:50 mix50:50 mix Inhibitors (e.g., antibodies)Inhibitors (e.g., antibodies)Fibrinogen assayFibrinogen assay Decreased fibrinogenDecreased fibrinogenThrombin timeThrombin time Qualitative/quantitativeQualitative/quantitative

fibrinogen defectsfibrinogen defectsFDPs or D-dimerFDPs or D-dimer Fibrinolysis (DIC)Fibrinolysis (DIC)

Platelet functionPlatelet function von Willebrand factorvon Willebrand factor vWDvWDBleeding timeBleeding time In vivoIn vivo test (non-specific) test (non-specific)Platelet function analyzer (PFA)Platelet function analyzer (PFA) Qualitative platelet disorders Qualitative platelet disorders

and vWD and vWDPlatelet function testsPlatelet function tests Qualitative platelet disordersQualitative platelet disorders

XIIaXIIa

Coagulation cascadeCoagulation cascade

IIa

Intrinsic system Intrinsic system (surface contact)(surface contact)

XIIXII

XIXI XIa

Tissue factorTissue factor

IXIX IXa VIIa VIIVII

VIIIVIII VIIIaVIIIa

Extrinsic system Extrinsic system (tissue damage)(tissue damage)

XX

VV VaVa

IIII

FibrinogenFibrinogen FibrinFibrin

(Thrombin)(Thrombin)IIa

Vitamin K dependant factorsVitamin K dependant factors

Xa

Laboratory Evaluation of the Laboratory Evaluation of the Coagulation PathwaysCoagulation Pathways

Partial thromboplastin time(PTT)

Prothrombin time(PT)

Intrinsic pathway Extrinsic pathway

Common pathwayThrombin timeThrombin

Surface activating agent (Ellagic acid, kaolin)PhospholipidCalcium

Thromboplastin Tissue factor PhospholipidCalcium

Fibrin clot

Initial Evaluation of a Bleeding Initial Evaluation of a Bleeding Patient - 1Patient - 1

Normal PTNormal PTT

Consider evaluating for: Mild factor deficiency Monoclonal gammopathy Abnormal fibrinolysis Platelet disorder (2 anti-plasmin def) Vascular disorder Elevated FDPs

Ureasolubility

Normal

Abnormal

Factor XIII deficiency

Initial Evaluation of a Bleeding Initial Evaluation of a Bleeding Patient - 2Patient - 2

Normal PTAbnormal PTT

Test for factor deficiency: Isolated deficiency in intrinsic pathway (factors VIII, IX, XI) Multiple factor deficiencies (rare)

Repeatwith

50:50mix

50:50 mix is normal

50:50 mix is abnormal

Test for inhibitor activity: Specific factors: VIII,IX, XI Non-specific (anti-phospholipid Ab)

Initial Evaluation of a Bleeding Patient - Initial Evaluation of a Bleeding Patient - 33

Abnormal PTNormal PTT

Test for factor deficiency: Isolated deficiency of factor VII (rare) Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC)

Repeatwith

50:50mix

50:50 mix is normal

50:50 mix is abnormal

Test for inhibitor activity: Specific: Factor VII (rare) Non-specific: Anti-phospholipid (rare)

Initial Evaluation of a Bleeding Patient - Initial Evaluation of a Bleeding Patient - 44

Abnormal PTAbnormal PTT

Test for factor deficiency: Isolated deficiency in common pathway: Factors V, X, Prothrombin, Fibrinogen Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC)

Repeatwith

50:50mix

50:50 mix is normal

50:50 mix is abnormal

Test for inhibitor activity: Specific : Factors V, X, Prothrombin, fibrinogen (rare) Non-specific: anti-phospholipid (common)

Coagulation factor deficienciesCoagulation factor deficienciesSummarySummary

Sex-linked recessiveSex-linked recessive Factors VIII and IX deficiencies cause bleedingFactors VIII and IX deficiencies cause bleeding

Prolonged Prolonged PTT; PTT; PT normalPT normal

Autosomal recessive Autosomal recessive (rare)(rare) Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleedingFactors II, V, VII, X, XI, fibrinogen deficiencies cause bleeding

Prolonged Prolonged PTPT and/or and/or PTTPTT

Factor XIII deficiency is associated with bleeding andFactor XIII deficiency is associated with bleeding andimpaired wound healingimpaired wound healing

PT/ PTT normal; PT/ PTT normal; clot solubilityclot solubility abnormal abnormal

Factor XII, prekallikrein, HMWK deficienciesFactor XII, prekallikrein, HMWK deficienciesdo not cause bleedingdo not cause bleeding

Thrombin TimeThrombin Time

Bypasses factors II-XIIBypasses factors II-XII

Measures rate of fibrinogen conversion to fibrinMeasures rate of fibrinogen conversion to fibrin

Procedure:Procedure: Add thrombin with patient plasmaAdd thrombin with patient plasma Measure time to clotMeasure time to clot

Variables:Variables: Source and quantity of thrombinSource and quantity of thrombin

Causes of prolonged Thrombin TimeCauses of prolonged Thrombin Time

HeparinHeparin HypofibrinogenemiaHypofibrinogenemia DysfibrinogenemiaDysfibrinogenemia Elevated FDPs or paraproteinElevated FDPs or paraprotein Thrombin inhibitors (Hirudin)Thrombin inhibitors (Hirudin) Thrombin antibodiesThrombin antibodies

Bleeding time and bleedingBleeding time and bleeding

5-10% of patients have a prolonged bleeding 5-10% of patients have a prolonged bleeding timetime

Most of the prolonged bleeding times are due to Most of the prolonged bleeding times are due to aspirin or drug ingestionaspirin or drug ingestion

Prolonged bleeding time does not predict excess Prolonged bleeding time does not predict excess surgical blood losssurgical blood loss

Not recommended for routine testing in Not recommended for routine testing in preoperative patientspreoperative patients

Treatment Approaches toTreatment Approaches tothe Bleeding Patientthe Bleeding Patient

Red blood cellsRed blood cells Platelet transfusionsPlatelet transfusions Fresh frozen plasmaFresh frozen plasma CryoprecipitateCryoprecipitate CyclokapronCyclokapron DDAVPDDAVP Recombinant Human factor VIIaRecombinant Human factor VIIa

Red blood cell transfusionsRed blood cell transfusionsAdverse reactionsAdverse reactions

Immunologic reactions

Hemolysis RBC incompatibilityAnaphylaxis Usually unknown; rarely against IgAFebrile reaction Antibody to neutrophilsUrticaria Antibody to donor plasma proteinsNon-cardiogenic Donor antibody to leukocytes pulmonary edema

Platelet transfusionsPlatelet transfusions

SourceSource Platelet concentrate (Random donor)Platelet concentrate (Random donor) Pheresis platelets (Single donor)Pheresis platelets (Single donor)

Target levelTarget level Bone marrow suppressed patient (>10-20,000/Bone marrow suppressed patient (>10-20,000/µµl)l) Bleeding/surgical patient (>50,000/Bleeding/surgical patient (>50,000/µµl)l)

Platelet transfusions - complicationsPlatelet transfusions - complications Transfusion reactionsTransfusion reactions

Higher incidence than in RBC transfusionsHigher incidence than in RBC transfusions Related to length of storage/leukocytes/RBC Related to length of storage/leukocytes/RBC

mismatchmismatch Bacterial contaminationBacterial contamination

Platelet transfusion refractorinessPlatelet transfusion refractoriness Alloimmune destruction of platelets (HLA Alloimmune destruction of platelets (HLA

antigens)antigens) Non-immune refractoriness Non-immune refractoriness

Microangiopathic hemolytic anemiaMicroangiopathic hemolytic anemia CoagulopathyCoagulopathy Splenic sequestrationSplenic sequestration Fever and infectionFever and infection Medications (Amphotericin, vancomycin, ATG, Medications (Amphotericin, vancomycin, ATG,

Interferons)Interferons)

Fresh frozen plasmaFresh frozen plasma Content - plasma (decreased factor V and VIII)Content - plasma (decreased factor V and VIII) IndicationsIndications

Multiple coagulation deficiencies (liver disease, trauma)Multiple coagulation deficiencies (liver disease, trauma) DICDIC Warfarin reversalWarfarin reversal Coagulation deficiency (factor XI or VII)Coagulation deficiency (factor XI or VII)

Dose (225 ml/unit)Dose (225 ml/unit) 10-15 ml/kg10-15 ml/kg

NoteNote Viral screened productViral screened product ABO compatibleABO compatible

CryoprecipitateCryoprecipitate

Prepared from FFPPrepared from FFP ContentContent

Factor VIII, von Willebrand factor, fibrinogenFactor VIII, von Willebrand factor, fibrinogen IndicationsIndications

Fibrinogen deficiencyFibrinogen deficiency UremiaUremia von Willebrand diseasevon Willebrand disease

Dose (1 unit = 1 bag)Dose (1 unit = 1 bag) 1-2 units/10 kg body weight1-2 units/10 kg body weight

Hemostatic drugsHemostatic drugsTranexemic acid (Cyclokapron)Tranexemic acid (Cyclokapron)

MechanismMechanism Prevent activation plaminogen -> plasminPrevent activation plaminogen -> plasmin

DoseDose1g iv q6-8hrs1g iv q6-8hrs

UsesUses Primary menorrhagiaPrimary menorrhagia Oral bleedingOral bleeding Bleeding in patients with thrombocytopeniaBleeding in patients with thrombocytopenia Blood loss during cardiac surgeryBlood loss during cardiac surgery

Side effectsSide effects Optic atrophyOptic atrophy

Hemostatic drugsHemostatic drugsDesmopressin (DDAVP)Desmopressin (DDAVP)

MechanismMechanism Increased release of VWF from endotheliumIncreased release of VWF from endothelium

DoseDose 0.30.3µµg/kg IV q12 hrsg/kg IV q12 hrs 150mg intranasal q12hrs150mg intranasal q12hrs

UsesUses Most patients with von Willebrand diseaseMost patients with von Willebrand disease Mild hemophilia AMild hemophilia A

Side effectsSide effects Facial flushing and headacheFacial flushing and headache Water retention and hyponatremiaWater retention and hyponatremia

Recombinant human factor VIIa (rhVIIa; Recombinant human factor VIIa (rhVIIa; NovosevenNovoseven))

MechanismMechanism Direct activation of common pathwayDirect activation of common pathway

UseUse Factor VIII inhibitorsFactor VIII inhibitors Bleeding with other clotting disordersBleeding with other clotting disorders Warfarin overdose with bleeding Warfarin overdose with bleeding CNS bleeding with or without warfarinCNS bleeding with or without warfarin

DoseDose 100 100 µµg/kg IV q 2 hrX2 g/kg IV q 2 hrX2 ““Adjust as clinically indicatedAdjust as clinically indicated””

Cost (70 kg person) - JD0.66per Cost (70 kg person) - JD0.66per µµgg 4,800/dose4,800/dose

Approach to bleeding disordersApproach to bleeding disordersSummarySummary

Identify and correct any specific defect of Identify and correct any specific defect of hemostasishemostasis Laboratory testing is almost always needed to establish the cause Laboratory testing is almost always needed to establish the cause

of bleedingof bleeding

Screening tests (PT,PTT, platelet count) will often allow Screening tests (PT,PTT, platelet count) will often allow placement into one of the broad categoriesplacement into one of the broad categories

Specialized testing is usually necessary to establish a specific Specialized testing is usually necessary to establish a specific diagnosisdiagnosis

Use non-transfusional drugs whenever possibleUse non-transfusional drugs whenever possible

RBC transfusions for surgical procedures or large RBC transfusions for surgical procedures or large blood lossblood loss

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