Hemostasis Disorders

Hemostasis

The process of blood clotting and The process of blood clotting and then the subsequent dissolution then the subsequent dissolution of the clot, following repair of the of the clot, following repair of the

injured tissue, is termed injured tissue, is termed hemostasishemostasis. .

Haemostasis overview:

BV Injury

PlateletPlateletAggregation

PlateletActivation

Blood VesselBlood Vessel Constriction

CoagulationCoagulation Cascade

Stable Hemostatic Plug

Fibrin formation

Reduced

Blood flow

Contact/ Tissue Factor

Primary hemostatic plug

Neural

Hemostasis - major events 1. Vascular constriction.

2. Platelets become activated by thrombin and aggregate at the site of injury, forming a temporary, loose platelet plug.

3. To insure stability of the initially loose platelet plug, a fibrin mesh (also called the clot) forms and entraps the plug.

4. The clot must be dissolved in order for normal blood flow to resume following tissue repair.

HK = high molecular

wt. kininogen.

PK = prekallikrein.

PL = phospholipid.

Endogeneous anticoagulants

• AT lll – (binds to thrombin and prevents fibrinogen-fibrin)

• Heparin co-factor II – (homologous with AT lll)

• Prot C – (inhibits activity of factors V and Vll)

• Prot S – (enhances the effect of protein C).

• TFPI – (tissue factor pathway inhibitor - inhibits the

tissue factor-Vlla complex)

Vitamin K Dependent Factors

• Factors II, VII, lX, X.

• Protein C and Protein S

Role of the liver

Loss of liver parenchyma decreases:– all coagulation factors - except F Vlll and von

Willebrand co-factor .– physiologic inhibtors of the coagulation (AT lll,

Prot C and Prot S)– components of the fibrinolytic system ( mainly

plasminogen, and a2 anti plasmines).

• Liver dysfunction induces:– platelet dysfunction– dysfibrinogenemia– accelerated fibrinolysis (impaired clearance of

tissue plasminogen activators t-PA)

Disorders of HemostasisDisorders of Hemostasis

Hematologic disorders causing bleedingHematologic disorders causing bleeding

• Vascular disorders– Scurvy, easy bruising,

• Platelet disorders– Low Number or abnormal

function

• Coagulation disorders– Factor deficiency.

• Mixed/Consumption – DIC

Approach to Bleeding Approach to Bleeding DisordersDisorders

HISTORY• Is the patient bleeding?• Surrogate markers of bleeding

– declining hemoglobin

• Age of onset• Surgical procedures• Medications

– Aspirin, anticoagulants, etc.

• Birth & Family

Approach to Bleeding DisordersApproach to Bleeding Disorders

•Petechiae,

• Echymoses,

• Menorrhagia

• GI bleeding

• Echymoses

• Late wounds bleeding

• Extensive hemorrhage

( joint spaces,

after immu.)

•

• Bleeding from

multiple sites in an

ill patient

Platelet Disorder

Coagulation Disorders

D.I.C.

Approach to Bleeding DisordersApproach to Bleeding Disorders

If a patient has

tolerated tonsillectomy

and / or adenoidectomy

or extraction of multiple wisdom teeth

without major hemorrhage,

a significant

bleeding disorder

is unlikely.

Clinical aspects of bleedingClinical aspects of bleeding

• Do not blanch with pressure (cf. angiomas)

• Not palpable (cf. vasculitis)

Petechiae - (typical of platelet disorders)Petechiae - (typical of platelet disorders)

Platelet Coagulation

Petechiae, Purpura Hematoma, Joint bl.

Clinical aspects of bleedingPlatelet factor disorders Coagulation disorders

Site of bleeding Skin, Mucous membranes (epistaxis, gum, vaginal, GIT)

Deep in soft tissues

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, usually mild Delayed (1-2 days), often severe

Mucus membrane bleeds

Spontaneous With trauma

InvestigationsInvestigations

Platelet countPlatelet count 150,000 to 450,000 platelets per ml of blood. 150,000 to 450,000 platelets per ml of blood. < 20,000 per mL - spontaneous bleeding< 20,000 per mL - spontaneous bleeding

Bleeding timeBleeding time Test for platelet function Test for platelet function in

Normal : 2 - 5 minutes

Prothrombin Prothrombin TimeTime

measures the clotting activity of factors I, II, V, measures the clotting activity of factors I, II, V,

VII, and X VII, and X Normal : 12-15 seconds

Activated Partial Activated Partial

Thromboplastin Thromboplastin

TimeTime

Measures clotting activity of factors I, II, V, VIII, Measures clotting activity of factors I, II, V, VIII,

IX, X, XI, and XII IX, X, XI, and XII Normal : 25 - 39 sec

Factor assays Factor assays Measure the amount of specific clotting factorsMeasure the amount of specific clotting factors

FDPsFDPs Fibrin degradation productsFibrin degradation products

Activated partial thromboplastin time (aPTT

or APTT)

• is a performance indicator measuring the efficacy of both the "intrinsic" (now referred to as the contact activation pathway) and the common coagulation pathways.

• It is also used to monitor the treatment effects with heparin, a major anticoagulant.

aPTT - Interpretation

• Normal = 25 to 39 sec • Prolonged APTT may indicate:

• heparin, • direct thrombin inhibitors, • a deficiency or inhibitor for factors in the intrinsic and

common pathway • factors II, V, VIII, IX, X, XI, XII,

• lupus anticoagulant, • vitamin K deficiency, or • severe liver disease

Whole blood clotting time• 5 ml of blood is placed in a glass container,

kept at body temperature and observed • A clot should occur in 5 to 15 minutes

• Prolonged = Severe deficiency of any of the coagulation proteins

• The clot should retract in 30 to 60 minutes • Weak friable clot = hypofibrinogenaemia • Early dissolution = enhanced fibrinolysis

(Inaccurate)(Inaccurate)

Prothrombin time

• The time taken for plasma to clot after addition of

tissue factor (obtained from animals) and calcium

to citrated blood.

• This measures the quality of the extrinsic pathway

(as well as the common pathway) of coagulation.

Prothrombin time • The reference range for prothrombin time is

usually around 12-15 seconds; • Prolonged

• Deficiencies of factors II, V, VII, X or fibrinogen;

• Liver disease; • Vitamin K deficiency and • Oral anticoagulants (warfarin)

International normalized ratio

• Each manufacturer gives an ISI (International Sensitivity Index) for any tissue factor they make. The ISI value indicates how the particular batch of tissue factor compares to an internationally standardized sample. The ISI is usually between 1.0 and 1.4

• The INR is the ratio of a patient's prothrombin time to a normal (control) sample, raised to the power of the ISI value for the control sample used.

Thrombin time• Time to clot formation after the addition of

thrombin to citrated blood • Prolonged by

• Heparin, • Direct thrombin inhibitors, • Fibrin degradation products (FDPs), • Paraproteins, and • Fibrinogen deficiency (both qualitative and

quantitative)

Bleeding time - Ivy method

• A blood pressure cuff is placed on the upper arm and inflated to 40 mm Hg. A lancet is used to make a stab wound on the underside of the forearm.

• The time from when the stab wound is made until all bleeding has stopped is measured and is called the bleeding time.

• Every 30 seconds, filter paper or a paper towel is used to draw off the blood.

• Normal values fall between 2 - 5 minutes depending on the method used

FDPs

• Fragments resulting from the action of plasmin on fibrin or fibrinogen

• Reflect high fibrinolysis states (such as DIC) when they are elevated

Platelet Count

• In an adult, a normal count is about 150,000 to 450,000 platelets / L of blood.

• Platelet levels fall below 20,000/L, spontaneous bleeding may occur and is considered a life-threatening risk.

• Increased platelet counts (thrombocytosis) • Myeloproliferative disorder

Others Tests

• Von Willebrand factor antigen (vWF:Ag): immunoassay for circulating vWF.

• Von Willebrand factor activity (vWF:RCo): measures the functional ability of a patient's vWF to agglutinate platelets in the presence of Ristocetin.

• Factor VIII C activity: is functional assay for factor VIII. It is measured by mixing normal plasma with factor VIII-deficient plasma

• Platelet function studies• Bone marrow examination – plt

Laboratory Evaluation of the Coagulation Pathways

Partial thromboplastin time(PTT)

Prothrombin time(PT)

Intrinsic pathway Extrinsic pathway

Common pathwayThrombin time

Fibrin clot

Thromboplastin Tissue factor Phospholipid

Calcium

Thromboplastin Tissue factor Phospholipid

Calcium

Surface activating agent (Ellagic acid, kaolin)

PhospholipidCalcium

Surface activating agent (Ellagic acid, kaolin)

PhospholipidCalcium

ThrombinThrombin

XII

XI

IX

VIII

XII

XI

IX

VIII

VII

*

*

*

VII

*

*

*

X

V

II

X

V

II

Intrinsic PathwayIntrinsic Pathway Extrinsic PathwayExtrinsic Pathway

- - - - - - - - - - I - - - - - XIII - - - - - - - - - - I - - - - - XIII

Prolonged PTT

ProlongedPT

Both PTT & PT Abnormal or DICor DIC

Urea Stability

Test

Urea Stability

Test

Abnormal PTT, PT &

TT

Abnormal PTT, PT &

TT

Correction Tests

Only PTT abnormal : XI, IX & VIII

(XII never presents clinically)

Abnormal PTT corrected by

Plasma Adsorbed Serum

VIII Yes No

IX No Yes

Some Rules of Thumb

Both aPTT and PT Elevated

Only PT prolonged

Only aPTT prolonged

von Willebrand Disease

An inherited bleeding disorder described by Finnish Physician

Erik Adolf von Willebrand

Low levels of a protein called von Willebrand factor that helps the blood to clot

Von Willebrand factor that doesn’t work properly

Platelet Activation and von Willebrand Factor (vWF)

In order for hemostasis to occur, platelets must adhere to exposed collagen, release the contents of their granules, and aggregate.

The adhesion of platelets to the collagen exposed on endothelial cell surfaces is mediated by von Willebrand factor (vWF).

The function of vWF is to act as a bridge between a specific glycoprotein on the surface of platelets (GPIb/IX) and collagen fibrils.

vWF binds to and stabilizes coagulation factor VIII.

Binding of factor VIII by vWF is required for normal survival of factor VIII in the circulation.

Platelet Activation and von Willebrand Factor (vWF)

Type 1Low level of von Willebrand factor. The level of

factor VIII may also be lower than normalMildest and most common form of the disease. About 3 out of 4 people diagnosed with vWD have

type 1 disease.

Type 2Defect in von Willebrand factor causes it to not

work properly. Type 2 is divided into 2A, 2B, 2M, and 2N. Each is treated differently, so knowing the exact type is important.

Type 3No von Willebrand factor and very low factor VIII. Type 3 is severe and very rare.



Incidenceroughly about 1 in 100 individuals.

Because most forms are rather mild, they are detected more often in women, whose bleeding tendency shows during menstruation.

It may be more severe or apparent in people with blood type O.

Genetics vWF gene is located on chromosome twelve (12p13.2).

o Types 1 and 2 are inherited as autosomal dominant traits and

o type 3 is inherited as autosomal recessive.

o Occasionally type 2 also inherits recessively.



Weibel-Palade bodies Organelles in the endothelial

cells There are two major

constituents

1. von Willebrand factor (vWF), a multimeric protein involved in blood coagulation

2. The second is P-selectin - binds to passing immune cells (leukocytes).

Manifestations:Bruising that's unusual in location or frequency

Abnormal menstrual bleeding Bleeding in the mucous membranesExcessive or prolonged bleeding after a tooth extraction or tonsillectomy


Bleeding time

Factor VIII level test (factor VIII coagulant)

von Willebrand factor antigen test (factor VIII antigen) - which measures the amount of von Willebrand factor. ( mild if a person has 20% to 40% of the normal, severe if the amount is less than 10% of normal. )

Ristocetin co-factor activity test measures how well the von Willebrand factor is working

von Willebrand factor multimers test - to classify the type of vWD

Platelet function tests which determine how well the platelets work and help identify the type of vWD or

the presence of another disorder

Tests may need to be done more than once because these levels may rise and fall over time in an individual.

Investigations

Treatment: No regular treatment Prophylactic treatment is sometimes

given for patients are scheduled for surgery.

They can be treated with human derived medium purity factor VIII concentrates complexed to vWF

Mild cases - treated with desmopressin (1-desamino-8-D-arginine vasopressin, DDAVP)

Rises patient's own plasma levels of vWF by inducing release of vWF stored in the Weibel-Palade bodies in the endothelial cells


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Health & Medicine

Hemostasis Disorders