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ANEMIAS Mohammad Abu-Fara. MD. ANEMIA. Anemia : Is defined as a reduction in one or more of major RBC measurements. HGB. HTC. RBC count . Anemia is not a disease by itself but is one of the major signs of disease.

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ANEMIAS

Mohammad Abu-Fara. MD


Anemia

ANEMIA

Anemia: Is defined as a reduction in one or more of major RBC measurements.

HGB.

HTC.

RBC count .

Anemia is not a disease by itself but is one of the major signs of disease.

May be the first manifestation of a systemic disease, along with other nonspecific complaints such as fever, weight loss, anorexia.


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

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

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

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

F 12-15,5 g/dL


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

Values are expressed as a percentage.

Normal range: M 41-51%.

F 37-47%.


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

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

Normal range: M 4,5-6,5

F 3,8-5,8


Volume status
VOLUME STATUS

The three measurements are all concentrations.

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

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

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

3.Dehydration.


Special populations
SPECIAL POPULATIONS

1.Living at high altitude.

2.Smoking and air pollution.

3.African-Americans—lower values.

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

5.Athletes.

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


Erythropoesis
ERYTHROPOESIS

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

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

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


Clinical consequences of anemia
CLINICAL CONSEQUENCES OF ANEMIA

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

Symptoms of anemia can result from two factors:

1.Decreased O2 delivery to tissues.

2.Hypovolemia/acute blood. loss/.


Compensatory mechanisms
COMPENSATORY MECHANISMS

Signs and symptoms depend also on the compensatory mechanisms.

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

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

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

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


Symptom and signs
SYMPTOM AND SIGNS

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

.

Dyspnea /S.O.B. :on exertion/at rest.

Fatigue/tiredness.

Signs and symptoms of hyperkinetic state:

1.bounding pulses.

2.palpitations.

3.roaring in ears.


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

Headache.

Visual impairment, syncope

Complications of extra cellular volume depletion/in acute bleeding/

Symptoms and sign due to the underlying cause of anemia .


Iron deficiency
Iron deficiency MI., Pallor.

  • Most cases are caused by menstrual loss and increased iron requirements of pregnancy.

  • GI bleeding is the presumed etiology in most patient

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

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

  • Signs : splenomegaly, kiolonychia (spoon nail ) and plummer- vinson syndrome (glossitis, dysphagia, and esophageal webs) are rare finding.


Vitamin b12 and folate deficiency
Vitamin B12 and Folate deficiency MI., Pallor.

Glossitis, angular stomatitis, juandice, splenomegaly and neurological syndrome of pernicious anemia ( subacute combined degeneration-demylination of dorsal and lateral columns of spinal cord. unsteady gait and progress to irreversible damage and bladder disturbance (only in VB12 def.)


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

Elevated BP.

Skin rash.

Tachypnea.


Causes of anemia
CAUSES OF ANEMIA or disorder .Signs are discovered and reported by the physician, not by the patient.

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

1.Kinetic approach.

2.Morphologic approach.


Kinetic approach
KINETIC APPROACH or disorder .Signs are discovered and reported by the physician, not by the patient.

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

1.Decreased RBC production.

2.Increased RBC destruction.

3.RBC loss.


Morphologic approach
MORPHOLOGIC APPROACH or disorder .Signs are discovered and reported by the physician, not by the patient.

According to RBC size.

Mean Corpuscular Volume /MCV/.

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

Microcyte.

Macrocyte.

Normocyte.


Anemias according to the rbc size
ANEMIAS ACCORDING TO THE RBC SIZE or disorder .Signs are discovered and reported by the physician, not by the patient.

1.Microcytic anemia.

2.Macrocytic anemia.

3.Normocytic anemia.


Microcytic anemias
MICROCYTIC ANEMIAS or disorder .Signs are discovered and reported by the physician, not by the patient.

Are associated with an MCV below 80 fL.

IDA

ACD

Thalassemias.


Macrocytic anemias
MACROCYTIC ANEMIAS or disorder .Signs are discovered and reported by the physician, not by the patient.

Are characterized by an MCV above 100 fL.

Reticulocytosis.

Vit.B12 def.

Folate def.

MDS.

Liver disease

Hypothyroidism


Normocytic anemias
NORMOCYTIC ANEMIAS or disorder .Signs are discovered and reported by the physician, not by the patient.

By definition the MCV is normal.

ACD.

MDS.


Evaluation of the patient with anemia 1
EVALUATION OF THE PATIENT WITH ANEMIA-1 or disorder .Signs are discovered and reported by the physician, not by the patient.

  • Anemia is one of the major signs of disease.

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

  • History.

  • Physical examination.

  • Simple lab. tests.

    Are all useful in evaluating the anemic patient.


Evaluation of the anemic patient 2
EVALUATION OF THE ANEMIC PATIENT-2 or disorder .Signs are discovered and reported by the physician, not by the patient.

The workup should be directed towards answering the following questions:

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

2.Is there evidence of increased RBC destruction?

3.Is the BM suppressed?.

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


Anemia associated with red blood cell loss or destruction
Anemia associated with red blood or disorder .Signs are discovered and reported by the physician, not by the patient.cell loss or destruction

  • Sickle cell disease

  • G6PD deficiency

  • Hemolytic anemia


BLEEDING DISORDERS or disorder .Signs are discovered and reported by the physician, not by the patient.


Hemostasis 1
HEMOSTASIS-1 or disorder .Signs are discovered and reported by the physician, not by the patient.

  • In health hemostasis ensures that the blood remains fluid and contained in the vascular system.

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

    1-Endothelial cells.

    2-Plasma coagulation factors.

    3-Platelets.

    4-Fibrinolytic system.


Hemoastasis 2
HEMOASTASIS-2 or disorder .Signs are discovered and reported by the physician, not by the patient.

  • These activities are finely balanced between keeping the blood fluid and preventing intravascular thrombosis.

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

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


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

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


Role of endothelial cells in hemostasis
ROLE OF ENDOTHELIAL CELLS IN HEMOSTASIS extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

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

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

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


Role of platelets in hemostasis
ROLE OF PLATELETS IN HEMOSTASIS extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • Each megacaryocyte produces 1000-2000 platelets,which

  • remain in the circulation for about 10 days.

  • Releasing of hemostatic proteins.

  • Platelet adhesion.

  • Platelet aggregation.


Coagulation system
COAGULATION SYSTEM extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • Coagulation factors: are plasma proteins synthesized in the liver which ,when activated lead to the deposition of fibrin.

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

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

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


Inhibitors of coagulation
INHIBITORS OF COAGULATION extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

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

Raised levels are not associated with bleeding.

Reduced levels may predispose to thrombosis.

Antithrombin.

Protein C, Protein S.

Tissue Factor Pathway Inhibitor (TFPI).


Fibrinolysis
FIBRINOLYSIS extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

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

    Plasminogen Plasmin

    Fibrin FDPs


Assessment of bleeding symptoms
ASSESSMENT OF BLEEDING SYMPTOMS extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

1-Careful and full clinical history and examination.

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

2-Appropriate lab. investigations.

3-Other investigations.


History
HISTORY extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

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

  • 2-Duration of bleeding and severity.

  • 3-Precipitating cause.

  • 4-Surgery.

  • 5-Family history.

  • 6-Systemic illnesses (acquired bleeding disorders).

  • 7-Drugs.


Clinical features of bleeding disorders
Clinical Features of Bleeding Disorders extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

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 studies
LABORATORY STUDIES extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

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

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

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

  • prolonged after medication as aspirin.


  • In vitro platelet aggregation extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • Von Willebrand factor antigen

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

  • Von Willbrand factor multimer analysis.


Secondary hemostasis
Secondary hemostasis extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

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

  • INR : (patient PT/ mean normal PT)ISI

  • Activated partial thromboplastin times (aPTT): intrinsic pathway (kininogen, prekallikrein, factor X11, factor 1X,factor X1 and factor V111) and common pathway (factor V,facter X ,prothrombin and fibrinogen.

  • Thrombin time (TT)

  • Fibrinogin

  • Clot urea stability

  • Mixing studies coagulation plasma activity .


Coagulation factor disorders

Inherited bleeding disorders extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

Hemophilia A and B

Von Willebrand disease

Other factor deficiencies

Acquired bleeding disorders

Liver disease

Vitamin K deficiency/warfarin overdose

DIC

Coagulation factor disorders


Hemophilia a and b
Hemophilia A and B extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

Hemophilia A Hemophilia B

Coagulation factor deficiency Factor VIII Factor IX

Inheritance X-linked X-linked

recessive recessive

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

Severity Related to factor level

<1% - Severe - spontaneous bleeding

1-5% - Moderate - bleeding with mild injury

5-25% - Mild - bleeding with surgery or trauma

Complications Soft tissue bleeding


Hemophilia
Hemophilia extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

Clinical manifestations (hemophilia A & B are indistinguishable)

Hemarthrosis (most common)

Fixed joints

Soft tissue hematomas (e.g., muscle)

Muscle atrophy

Shortened tendons

Other sites of bleeding

Urinary tract

CNS, neck (may be life-threatening)

Prolonged bleeding after surgery or dental extractions


Hemarthrosis acute

Hemarthrosis (acute) extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.


Treatment of hemophilia a
Treatment of hemophilia A extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • Intermediate purity plasma products

    • Virucidally treated

    • May contain von Willebrand factor

  • High purity (monoclonal) plasma products

    • Virucidally treated

    • No functional von Willebrand factor

  • Recombinant factor VIII

    • Virus free/No apparent risk

  • No functional von Willebrand factor


Dosing guidelines for hemophilia a
Dosing guidelines for hemophilia A extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • Mild bleeding

    • Target: 30% dosing q8-12h; 1-2 days (15U/kg)

    • Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria

  • Major bleeding

    • Target: 80-100% q8-12h; 7-14 days (50U/kg)

    • CNS trauma, hemorrhage, lumbar puncture

    • Surgery

    • Retroperitoneal hemorrhage

    • GI bleeding

  • Adjunctive therapy

  • Tranexemic acid or DDAVP (for mild disease only)


Complications of therapy
Complications of therapy extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • Formation of inhibitors (antibodies)

    • 10-15% of severe hemophilia A patients

    • 1-2% of severe hemophilia B patients

  • Viral infections

    • Hepatitis B Human parvovirus

    • Hepatitis C Hepatitis A

    • HIV Other


Rituximab and acquired hemophilia f viii inhibitors
RITUXIMAB AND ACQUIRED HEMOPHILIA(F VIII INHIBITORS) extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.


Treatment of hemophilia b
Treatment of hemophilia B extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • Agent

    • High purity factor IX

    • Recombinant human factor IX

  • Dose

    • Initial dose: 100U/kg

    • Subsequent: 50U/kg every 24 hours


Von willebrand disease clinical features
von Willebrand Disease: Clinical Features extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • von Willebrand factor

    • Synthesis in endothelium and megakaryocytes

    • Forms large multimer

    • Carrier of factor VIII

    • Anchors platelets to sub endothelium

    • Bridge between platelets

  • Inheritance - autosomal dominant

  • Incidence - 1/10,000

  • Clinical features - mucocutaneous bleeding


Laboratory evaluation of von willebrand disease
Laboratory evaluation of extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.von Willebrand disease

  • Classification

    • Type 1 Partial quantitative deficiency

    • Type 2 Qualitative deficiency

    • Type 3 Total quantitative deficiency

  • Diagnostic tests:

vonWillebrand type

Assay 1 2 3

vWF antigen ß Normal ßß

vWF activity ßßßß

Multimer analysis Normal Normal Absent


Vwf multimers
VWF Multimers extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

plt

NP

1

2A

2A

2B

3

Proteolysis


Treatment of von willebrand disease
Treatment of von Willebrand Disease extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • Cryoprecipitate

    • Source of fibrinogen, factor VIII and VWF

    • Only plasma fraction that consistently contains VWF multimers

  • DDAVP (deamino-8-arginine vasopressin)

    •  plasma VWF levels by stimulating secretion from endothelium

    • Duration of response is variable

    • Not generally used in type 2 disease

    • Dosage 0.3 µg/kg q 12 hr IV

  • Factor VIII concentrate (Intermediate purity)

    • Virally inactivated product


Pathogenesis of dic
Pathogenesis of DIC extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

Release of thromboplastic material into

circulation

Consumption of

coagulation factors;

presence of FDPs

 aPTT

 PT

 TT

 Fibrinogen

Presence of plasmin

 FDP

Intravascular clot

 Platelets

Schistocytes

Coagulation

Fibrinolysis

Fibrinogen

Plasmin

Thrombin

Fibrin

Monomers

Fibrin(ogen)

Degradation

Products

Fibrin

Clot

(intravascular)

Plasmin


Disseminated intravascular coagulation dic mechanism
Disseminated Intravascular Coagulation (DIC) extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.Mechanism

Systemic activation

of coagulation

Depletion of platelets

and coagulation factors

Intravascular

deposition of fibrin

Thrombosis of small

and midsize vessels

with organ failure

Bleeding


Common clinical conditions associated with disseminated intravascular coagulation

Sepsis extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

Trauma

Head injury

Fat embolism

Malignancy

Obstetrical complications

Amniotic fluid embolism

Abruptio placentae

Vascular disorders

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

Immunologic disorders

Severe allergic reaction

Transplant rejection

Common clinical conditions associated withDisseminated Intravascular Coagulation

Activation of both coagulation and fibrinolysis

  • Triggered by


Disseminated intravascular coagulation treatment approaches
Disseminated Intravascular Coagulation extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.Treatment approaches

  • Treatment of underlying disorder

  • Anticoagulation with heparin

  • Platelet transfusion

  • Fresh frozen plasma

  • Coagulation inhibitor concentrate (ATIII)


Classification of platelet disorders

Quantitative disorders extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

Abnormal distribution

Dilution effect

Decreased production

Increased destruction

Qualitative disorders

Inherited disorders (rare)

Acquired disorders

Medications

Chronic renal failure

Cardiopulmonary bypass

Classification of platelet disorders


Platelet interaction

Platelet interaction extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.


Thrombocytopenia
Thrombocytopenia extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

Immune-mediated

Idioapthic

Drug-induced

Collagen vascular disease

Lymphoproliferative disease

Sarcoidosis

Non-immune mediated

DIC

Microangiopathic hemolytic anemia


Incidence of adult itp increases with age

Incidence of adult ITP increases with age extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

Incidence(per 105 / year)

Age (yrs)Female Male Total

15-39 2.3 1.3 3.6

40-59 3.2 1.1 4.3

60+ 4.6 4.4 9.0

Total 3.2 2.0 2.6

Frederiksen and Schmidt, Blood 1999:94;909


Initial treatment of itp
Initial Treatment of ITP extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

Platelet count Symptoms Treatment

(per µl)

>50,000 None

20-50,000 Not bleeding None

Bleeding Steroids

IVIG

<20,000 Not bleeding Steroids

Bleeding IVIG

Hospitalization


Liver disease and hemostasis
Liver Disease and Hemostasis extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • Decreased synthesis of II, VII, IX, X, XI, and fibrinogen

  • Dietary Vitamin K deficiency (Inadequate intake or malabsortion)

  • Dysfibrinogenemia

  • Enhanced fibrinolysis (Decreased alpha-2-antiplasmin)

  • DIC

  • Thrombocytoepnia due to hypersplenism


Management of hemostatic defects in liver disease
Management of Hemostatic Defects in Liver Disease extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • Treatment for prolonged PT/PTT

    • Vitamin K 10 mg SQ x 3 days - usually ineffective

    • Fresh-frozen plasma infusion

    • 25-30% of plasma volume (1200-1500 ml)

    • immediate but temporary effect

  • Treatment for low fibrinogen

    • Cryoprecipitate (1 unit/10kg body weight)

  • Treatment for DIC (Elevated D-dimer, low factor VIII, thrombocytopenia

    • Replacement therapy


Laboratory evaluation of bleeding overview
Laboratory Evaluation of Bleeding extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.Overview

CBC and smear Platelet count Thrombocytopenia

RBC and platelet morphology TTP, DIC, etc.

Coagulation Prothrombin time Extrinsic/common pathways

Partial thromboplastin time Intrinsic/common pathways

Coagulation factor assays Specific factor deficiencies

50:50 mix Inhibitors (e.g., antibodies)

Fibrinogen assay Decreased fibrinogen

Thrombin time Qualitative/quantitative

fibrinogen defects

FDPs or D-dimer Fibrinolysis (DIC)

Platelet function von Willebrand factor vWD

Bleeding time In vivo test (non-specific)

Platelet function analyzer (PFA) Qualitative platelet disorders and vWD

Platelet function tests Qualitative platelet disorders


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

Intrinsic system (surface contact)

Extrinsic system (tissue damage)

XII

XIIa

Tissue factor

XIa

XI

IX

IXa

VIIa

VII

VIII

VIIIa

X

Vitamin K dependant factors

Xa

V

Va

(Thrombin)

IIa

IIa

II

Fibrinogen

Fibrin


Laboratory evaluation of the coagulation pathways
Laboratory Evaluation of the Coagulation Pathways extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

Partial thromboplastin time

(PTT)

Prothrombin time

(PT)

Surface activating agent

(Ellagic acid, kaolin)

Phospholipid

Calcium

Thromboplastin

Tissue factor

Phospholipid

Calcium

Intrinsic pathway

Extrinsic pathway

Common pathway

Thrombin time

Thrombin

Fibrin clot


Initial evaluation of a bleeding patient 1
Initial Evaluation of a Bleeding Patient - 1 extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

Normal PT

Normal PTT

Abnormal

Urea

solubility

Factor XIII deficiency

Normal

Consider evaluating for:

Mild factor deficiency Monoclonal gammopathy

Abnormal fibrinolysis Platelet disorder

(a2 anti-plasmin def) Vascular disorder

Elevated FDPs


Initial evaluation of a bleeding patient 2
Initial Evaluation of a Bleeding Patient - 2 extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

Normal PT

Abnormal PTT

50:50 mix is abnormal

Repeat

with

50:50

mix

Test for inhibitor activity:

Specific factors: VIII,IX, XI

Non-specific (anti-phospholipid Ab)

50:50 mix is normal

Test for factor deficiency:

Isolated deficiency in intrinsic pathway (factors VIII, IX, XI)

Multiple factor deficiencies (rare)


Initial evaluation of a bleeding patient 3
Initial Evaluation of a Bleeding Patient - 3 extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

Abnormal PT

Normal PTT

50:50 mix is abnormal

Repeat

with

50:50

mix

Test for inhibitor activity:

Specific: Factor VII (rare)

Non-specific: Anti-phospholipid (rare)

50:50 mix is normal

Test for factor deficiency:

Isolated deficiency of factor VII (rare)

Multiple factor deficiencies (common)

(Liver disease, vitamin K deficiency, warfarin, DIC)


Initial evaluation of a bleeding patient 4
Initial Evaluation of a Bleeding Patient - 4 extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

Abnormal PT

Abnormal PTT

50:50 mix is abnormal

Repeat

with

50:50

mix

Test for inhibitor activity:

Specific : Factors V, X, Prothrombin, fibrinogen (rare)

Non-specific: anti-phospholipid (common)

50:50 mix is normal

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)


Coagulation factor deficiencies summary
Coagulation factor deficiencies extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.Summary

Sex-linked recessive

 Factors VIII and IX deficiencies cause bleeding

Prolonged PTT; PT normal

Autosomal recessive (rare)

 Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleeding

Prolonged PT and/or PTT

 Factor XIII deficiency is associated with bleeding and

impaired wound healing

PT/ PTT normal; clot solubility abnormal

 Factor XII, prekallikrein, HMWK deficiencies

do not cause bleeding


Thrombin time
Thrombin Time extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • Bypasses factors II-XII

  • Measures rate of fibrinogen conversion to fibrin

  • Procedure:

    • Add thrombin with patient plasma

    • Measure time to clot

  • Variables:

    • Source and quantity of thrombin


Causes of prolonged thrombin time
Causes of prolonged Thrombin Time extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • Heparin

  • Hypofibrinogenemia

  • Dysfibrinogenemia

  • Elevated FDPs or paraprotein

  • Thrombin inhibitors (Hirudin)

  • Thrombin antibodies


Bleeding time and bleeding
Bleeding time and bleeding extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • 5-10% of patients have a prolonged bleeding time

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

  • Prolonged bleeding time does not predict excess surgical blood loss

  • Not recommended for routine testing in preoperative patients


Treatment approaches to the bleeding patient
Treatment Approaches to extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.the Bleeding Patient

  • Red blood cells

  • Platelet transfusions

  • Fresh frozen plasma

  • Cryoprecipitate

  • Cyclokapron

  • DDAVP

  • Recombinant Human factor VIIa


Red blood cell transfusions adverse reactions
Red blood cell transfusions extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.Adverse reactions

Immunologic reactions

Hemolysis RBC incompatibility

Anaphylaxis Usually unknown; rarely against IgA

Febrile reaction Antibody to neutrophils

Urticaria Antibody to donor plasma proteins

Non-cardiogenic Donor antibody to leukocytes

pulmonary edema


Platelet transfusions
Platelet transfusions extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • Source

    • Platelet concentrate (Random donor)

    • Pheresis platelets (Single donor)

  • Target level

    • Bone marrow suppressed patient (>10-20,000/µl)

    • Bleeding/surgical patient (>50,000/µl)


Platelet transfusions complications
Platelet transfusions - complications extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • Transfusion reactions

    • Higher incidence than in RBC transfusions

    • Related to length of storage/leukocytes/RBC mismatch

    • Bacterial contamination

  • Platelet transfusion refractoriness

    • Alloimmune destruction of platelets (HLA antigens)

    • Non-immune refractoriness

      • Microangiopathic hemolytic anemia

      • Coagulopathy

      • Splenic sequestration

      • Fever and infection

      • Medications (Amphotericin, vancomycin, ATG, Interferons)


Fresh frozen plasma
Fresh frozen plasma extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • Content - plasma (decreased factor V and VIII)

  • Indications

    • Multiple coagulation deficiencies (liver disease, trauma)

    • DIC

    • Warfarin reversal

    • Coagulation deficiency (factor XI or VII)

  • Dose (225 ml/unit)

    • 10-15 ml/kg

  • Note

    • Viral screened product

    • ABO compatible


Cryoprecipitate
Cryoprecipitate extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.

  • Prepared from FFP

  • Content

    • Factor VIII, von Willebrand factor, fibrinogen

  • Indications

    • Fibrinogen deficiency

    • Uremia

    • von Willebrand disease

  • Dose (1 unit = 1 bag)

    • 1-2 units/10 kg body weight


Hemostatic drugs tranexemic acid cyclokapron
Hemostatic drugs extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.Tranexemic acid (Cyclokapron)

  • Mechanism

    • Prevent activation plaminogen -> plasmin

  • Dose

    1g iv q6-8hrs

  • Uses

    • Primary menorrhagia

    • Oral bleeding

    • Bleeding in patients with thrombocytopenia

    • Blood loss during cardiac surgery

  • Side effects

    • Optic atrophy


Hemostatic drugs desmopressin ddavp
Hemostatic drugs extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.Desmopressin (DDAVP)

  • Mechanism

    • Increased release of VWF from endothelium

  • Dose

    • 0.3µg/kg IV q12 hrs

    • 150mg intranasal q12hrs

  • Uses

    • Most patients with von Willebrand disease

    • Mild hemophilia A

  • Side effects

    • Facial flushing and headache

    • Water retention and hyponatremia


Recombinant human factor viia rhviia novoseven
Recombinant human factor VIIa (rhVIIa; extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.Novoseven)

  • Mechanism

    • Direct activation of common pathway

  • Use

    • Factor VIII inhibitors

    • Bleeding with other clotting disorders

    • Warfarin overdose with bleeding

    • CNS bleeding with or without warfarin

    • Dose

    • 100 µg/kg IV q 2 hrX2

    • “Adjust as clinically indicated”

  • Cost (70 kg person) - JD0.66per µg

    • 4,800/dose


Approach to bleeding disorders summary
Approach to bleeding disorders extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.Summary

  • Identify and correct any specific defect of hemostasis

    • Laboratory testing is almost always needed to establish the cause of bleeding

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

    • Specialized testing is usually necessary to establish a specific diagnosis

  • Use non-transfusional drugs whenever possible

  • RBC transfusions for surgical procedures or large blood loss


THANK YOU extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot.


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