1 Bleeding disorders K. Bernášková. 2 The Hemostatic System

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Bleeding disorders

K. Bernášková

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The Hemostatic System

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Hemostasis (clot formation)

• Primary hemostasis = function of blood vessels and platelets:

• Vasoconstriction

• Platelet plug formation

• Secondary hemostasis

= function of coagulation factors

• Definitive (insoluble) plug formation

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Primary hemostasis

(a) Platelet adhesion

(b) P. aggregation

(c) P. activation

1. Vasoconstriction

2. Primary clot formation

sympaticus

serotonin

TXA2

axo-axonal reflex

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Secondary hemostasisCoagulation factors

No Clotting factor Liver Vit K.

I. Fibrinogen

II. Prothrombin

III. Tissue factor (thromboplastin)

IV. Calcium

V. Proaccelerin

VII. Proconvertin

VIII. AHF A, vW

IX. Christmas factor (AHF B)

X. Stuart – Prower factor

XI. Plasma thromboplastin antecedent (AHF C)

XII. Hageman factor

XIII. Fibrin stabilizing factor

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Secondary hemostasisCoagulation factors

No Clotting factor Liver Vit K.

I. Fibrinogen +

II. Prothrombin + +

III. Tissue factor (thromboplastin) -

IV. Calcium -

V. Proaccelerin +

VII. Proconvertin + +

VIII. AHF A, vW +(-)

IX. Christmas factor (AHF B) + +

X. Stuart – Prower factor + +

XI. Plasma thromboplastin antecedent (AHF C)

+

XII. Hageman factor +

XIII. Fibrin stabilizing factor (+)

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Secondary hemostasis

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Laboratory Diagnosis of Bleeding and Coagulation Disorders

Patient IDDate

Special Studies

PTCont.

INRAPTTBTPlat.TTFibr.FDPD-Dimer

HEMOSTASIS

Prothrombin time (Quick) N = 16 s

International normalized ratio N = 1 ± 0,2Activated ProThrombine Time N = 35 sBleeding Time N = 1-6 minPlatelet count N = 150 -300 000/ lThrombine time N < 22sFibrinogen N = 1.5-2.77 g/l

Fibrin Degradation ProductsD-dimers < 0,25 mg/L

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Laboratory Diagnosis of Bleeding and Coagulation Disorders

1. Tests of Primary Hemostasis – Bleeding Time

– Platelet Count

– (Capillary fragility test)

http://www.nlm.nih.gov/medlineplus/bleedingdisorders.html

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Signs of primary hemostasis failure

Petechiae Ecchymoses

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Signs of primary hemostasis failure

PurpuraEpistaxis

Haevy menstrual bleeding

Easy bruising

Superficial bleeding into the skin and mucous membranes

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Laboratory Diagnosis of Bleeding and

Coagulation Disorders

2. Tests of Secondary Hemostasis

Partial Thromboplastin Time (PTT), activated partial thromboplastin time (aPTT). (INR)

– Normal range = 25-35 seconds

– The PTT is commonly used to monitor heparin therapy.

Prothrombin Time (PT)

– Normal range = 11-13 seconds (INR = 1 ± 0,2)

– The PT is commonly used to monitor coumarin therapy.

Thrombin Time (TT)

– Normal range = < 22 seconds

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Signs and symptoms of secondary hemostasis failure

Suffusions Bleeding into deep tissues (muscles, joints)

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Signs and symptoms of secondary hemostasis failure

• Epistaxis

• Haevy menstrual bleeding

• Easy bruising (deep tissues)

• Bleeding into the deep tissues, muscles, joints

• Delayed bleeding, healing disorders

Laboratory Diagnosis of Bleeding and Coagulation Disorders

3. Tests of fibrin degradation

FDP (fibrin degradation products) D-dimers

Plazmin  Fibrinogen, Fibrin monomer Fibrin polymer  

FDP D-dimers

Coagulation disorders

- Bleeding

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Stay calm, there is no danger, we have stopped bleeding

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Case 1

Patient IDDate

Special Studies

PTCont.

INRAPTTIBTPlat.TTFibr.FDPD-Dimer

HEMOSTASIS

12.1 Sec.12.4 Sec.

1.130.0 Sec.

5.5 Min.32 x109/L

Patient IDDate

Special Studies

PTCont.

INRAPTTIBTPlat.TTFibr.FDPD-Dimer

HEMOSTASIS

12.1 Sec.12.4 Sec.

1.130.0 Sec.

5.5 Min.32 x109/L

What phase of hemostasis is

affected?

What test(s) is (are) most likely to be performed

next?

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Case 1

Patient IDDate

Special Studies

PTCont.

INRAPTTIBTPlat.TTFibr.FDPD-Dimer

HEMOSTASIS

12.1 Sec.12.4 Sec.

1.130.0 Sec.

5.5 Min.32 x109/L

Patient IDDate

Special Studies

PTCont.

INRAPTTIBTPlat.TTFibr.FDPD-Dimer

HEMOSTASIS

12.1 Sec.12.4 Sec.

1.130.0 Sec.

5.5 Min.32 x109/L

The patient is thrombocytopenic

indicating a defect of primary

hemostasis.

The most likely test to follow: bone marrow examination

32 x109/l3

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Primary hemostasis defectThrombocytopenia

Decreased production Myelophthisic process

Ineffective thrombopoiesis

Bone marrow suppression

Dilutional loss

Non-immune destruction

Immune destruction

Hypersplenism Hepatosplenomegally

Sequestration

Increased destruction or loss

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Case 2

Patient IDDate

Special Studies

PTCont.

INRAPTTBTPlat.TTFibr.FDPD-Dimer

HEMOSTASIS

12.1 Sec.12.4 Sec.

1.130.0 Sec.

>15 Min.302 x109/L

What conclusion can be drawn from this data?

What disorders can lead to these findings?

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Case 2

Patient IDDate

Special Studies

PTCont.

INRAPTTBTPlat.TTFibr.FDPD-Dimer

HEMOSTASIS

12.1 Sec.12.4 Sec.

1.130.0 Sec.

>15 Min.302 x109/L

The increased bleeding time and normal platelet count

primary hemostasis function problem.

platelet function or vascular disorders

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Primary hemostasis defects Thrombocytopathias

(failure in the adherence, aggregation or secretion of thrombocytes)

➢ Inherited (v Wilebrand disease, Glanzmann thrombasthenia,

Heřmanský – Pudlák sy, Chediak-Higashi sy)

➢ Acquired (drugs (aspirin), uremia)

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Primary hemostasis defects Vascular Defects

(structurally weak vessels or vessels damaged by inflammation)

➢ Inherited vessel wall defects (M. Rendu Osler),

(Connective tissue defects: Marfan‘s syndrome, M. Ehlers – Danloss)

➢ Acquired vessel wall defects (Vitamin C

deficiency)

➢ Vessel wall inflammation (Immunocomplex

vasculitis)

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• Morbus Rendu Osler

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Marfan‘s syndrome

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Morbus Ehlers - Danloss

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Scorbut

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Case 3Patient IDDate

Special Studies

PTCont.

INRAPTTBTPlat.TTFibr.FDPD-Dimer

HEMOSTASIS

12.1 Sec.12.4 Sec.

1.160.5 Sec.

6.0 Min.332 x109/L

What conclusions can be drawn from this data?

What tests are likely to be ordered next?

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Case 3Patient IDDate

Special Studies

PTCont.

INRAPTTIBTPlat.TTFibr.FDPD-Dimer

HEMOSTASIS

12.1 Sec.12.4 Sec.

1.160.5 Sec.

7.0 Min.332 x109/L

The abnormal APTT defect of the secondary hemostasis, the intrinsic pathway

TTFactor concentrations

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Secondary hemostasis defects

Inherited coagulation defectsHemophilia A,B,CParahemophiliasHypofibrinogenemia

Acquired diseasesAvitaminosis K

Liver diseases Drugs (antibiotics, coumarine derivatives)

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Secondary hemostasis diseases

No Clotting factor Liver

Vit K.

Diseases

I. Fibrinogen + Afibrinogenaemia

II. Prothrombin + +

III. Tissue factor (thromboplastin)

IV. Calcium

V. Proaccelerin + Parahemophilia

VII. Proconvertin + +

VIII. AHF A, vW + Hemophilia A

IX. Christmas factor (AHF B) + + Hemophilia B

X. Stuart – Prower factor + +

XI. Plasma thromboplastin antecedent (AHF C)

+ Hemophilia C

XII. Hageman factor +

XIII. Fibrin stabilizing factor (+)

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Primary hemostasis defects - survey

Positive tests

Signs

Vascular disorders

Vessel wall failure Morbus Rendu – Osler Morbus Ehlers – Danloss Vitamin C deficiencyVessel wall inflammation Immunocomplex vasculitis Rumpel–

LeedeDuke(Platelet count)

• Petechias

• Purpura

• Easy bruising

• Haevy menstrual bleeding

• Epistaxis

Platelet defects(number,

adherence or aggregation failure)

Thrombocytopenias Decreased plt. production Decreased plt. survival Increased pooling of plt.Thrombocytopathias Inherited (v Wilebrand‘s disease, Glanzmann‘s thrombasthenia) Acquired (drugs, uremia)

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Secondary hemostasis defects - survey

Coagulopaties Positive tests

Signs

Coagulation defects

(Deficiencies of one or more clotting

factors)

Inherited Haemophilias (A,B,C) Parahaemophilias

Acquired Vitamin K disorders Liver diseases

Abnormal consumption

(DIC)

APTTQuick

FDP Concentration

of Factors

• Bleeding into deep tissues• Larger ecchymoses• Suffusions

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Clinical evaluation of bleeding Disorders Primary

hemostasisSecondary hemostasis

Sex distribution females > males females < males

Family history of bleeding

rarely positive (except vWD)

usually positive

Trauma relationship immediate delayed (often 2 – 3 days)

Prolonged after cut yes (30 min) no

Direct pressure controls bleeding

effective not effective

Petechiae very common not common

Ecchymoses small, multiple none – or large and solitary

Hemarthrosis/ deep hematomas

no yes

Screening test prolonged bleeding time

prolonged PT or PTT

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Patterns of haemostatic tests

Platelet count (Plat.)

Bleeding time (BT)

aPTT PT

ITP(Idiopathic thrombocytopenic purpura)

N N

Haemophilia AHaemophilia B

N N N

von Willebrand disease N

N (or slightly )

N

DIC

Hypercoagulability states

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Endothelial injury

Alteration of blood flow

Increased coagulability

Virchows trias 1.

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Endothelial injury

•Trauma or surgery•Venipuncture•Heart valve disease or replacement•Atherosklerosis •Acute myocardial infarction•Indwelling catheters 

Virchows trias 2.

Alteration of blood flow

•Atrial fibrillation, left heart failure•Immobility•Long flights•Venous insuficiency or varicous veins•Venous obstruction (pelvic tumours)

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Virchows trias 3.

Increased coagulability

• Increased viskozity (malignancy, pregnancy)

• Protein C + S deficiency• Nephrotic sy• Hyperfibrinogenemia (metabolic sy)

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Change (Disturbance): Reason: Example:

Disturbances of the flow Platelets not kept away from the wall

Turbulent flow stenosis

Stasis Atrial fibrillation, immobilisation, failing valves in veins

Vessel wall damage

Endothelial activation, decreased smoothness

Mechanical Hypertension, atherosclerosis; injury

Chemical Endothelial dysfunction sy in diabetes, sepsis; homocystein; inflammation

Platelet activity Increased stickiness due to Ab Antiphospholipid sy in LE

activity adrenalin, chronic stress, smoking

Coagulation factors

Increased concentration

Severe dehydration Chronic inflammation, metabolic sy, neoplasias

Dysballance Nephrotic sy

Anticoagulation factors

Decreased

Concentration

Decreased formation of protein C + S in liver failure Increased loss - of AT3, plasminogen (nephrotic sy)

Sensitivity to Protein C + S in Leyden V. factor Activity of Protein C + S, AT3 (Contraceptive drugs)

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A 25 year old female medical student is found to be anemic by her gynecologist. Her Hgb is 7.0 g/dl, Hct is 21%, and her MCV is 60. She reports heavy menstrual bleeding throughout her life. She also complains of epistaxis and a "funny rash" on her lower extremities whenever she takes aspirin. Her mother needed several transfusions with delivery of each of her children.

1. Does this patient have any type of anaemia? Which?

2. What might be the cause of this state?

3. Which type of coagulation abnormality are you suspicious for?

4. Which other signs and symptoms could she have?

5. How would you treat this patient?

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A 3 year old boy presents with a painful left elbow after mild trauma. Evaluation reveals a hemarthrosis. The child is adopted so no family history is available. The patients mother reports no other problems with the child. A PT is normal, an aPTT is prolonged.

1.1. Is there primary or secondary hemostasis failure? Why? Is there primary or secondary hemostasis failure? Why?

2.2. What does mean, that PT is normal and aPTT is prolonged?What does mean, that PT is normal and aPTT is prolonged?

3.3. Which mechanism might cause the prothrombine time to be longer?Which mechanism might cause the prothrombine time to be longer?

4.4. Discuss the genetics of the disease.Discuss the genetics of the disease.

5.5. Discuss therapy of this disorder.Discuss therapy of this disorder.

Thank you for your attention

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