Haemostasis part2 ROLE OF ENDOTHILIUM Hemostasis: BV Injury Platelet Activation Plt-Fusion Blood Vessel Constriction Coagulation Activation Stable.

Blood Coagulatio

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Haemostasispart2

ROLE OF ENDOTHILIUM

Hemostasis:BV Injury

PlateletActivation

Plt-Fusion

Blood Vessel Constriction

CoagulationActivation

Stable Hemostatic Plug

Thromibn,

Fibrin

Reduced

Blood flow

Tissue Factor

Primary hemostatic plug

Neural

Coagulation:

Intrinsic 12,11,9,8 (aPTT-)

Extrinsic-7(PT)

Prothrombin Thrombin

Fibrinogen Fibrin

Common Path (TT)FX FXa

Clot formation & retraction

Fibrinogen

Fibrin Mononer

Fibrin Polymer

Cross LinkedFibrin

Thrombin

F-XIIIa

ProcoagulantPlateletsFactorsFibrinogenvon Willebrand Factor

AnticoagulantAntithrombin IIIProtein CProtein S

ProfibrinolyticPlasminogentPAFibrin Fragment D-dimer

AntifibrinolyticPAI-1Alpha-2 Antiplasmin

clotclot RESOLUTIONFORMATION

Role of thrombin

Fibrinolysis

Coagulation Made Easy- The Mixing Study

• Useful to differentiate etiologies of prolonged clotting in a coagulation assay.

• Patient’s plasma is mixed 50:50 with normal plasma. Coagulation assay is repeated.

• If “substantial” correction is noted after mix, suspect clotting factor deficiency.

• If no or minimal correction seen, suspect inhibitor.

Disorders of the haemostatic mechanism are devided into three main groups:

• Disorders of the vessels• Disorders of the platelets

• Disorders of the coagulation mechanism („coagulopathies”)

„ purpuric diseases”

The investigation of a patient with a suspected disorder of haemostasis

– case history (personal details, family history)

– inspection (type of bleeding)– physical examination– other known diseases– drugs and medications– laboratory tests

Certain signs and symptoms are virtually diagnostic of disordered haemostasis.

The main symptom of all diseases is the bleeding:

● in the „purpuric disorders” cutaneous and mucosal bleeding usually is prominent

● in different types of „coagulopathies” hemarthroses, haematomas are the characteristic bleeding manifestations.

The onset of bleeding following trauma frequently is delayed (recur in a matter of hours) (the temporary hemostatic adequacy of the platelet plug may explain this phenomenon).

Petechiae, purpuras: small capillary haemorrhages ranging from the size of a pinhead to much larger

Petechiae, purpuras

Haematomas: may be spontaneous (in a serious hemorrhagic disease) or may occur after trauma (in a mild hemorrhagic disease).

Haematomas

Intramuscular injection may be very dangerous to the patient with a bleeding disorder

Venipuncture (if skilfully performed) is without danger becouse the elasticity of the venous walls.

Bleeding Disorders

Coagulopathies

• Aquired: generally several coagulation abnormalities are present. Clinical picture is complicated by signs and symptoms of the underlying disease.

Deficiencies of the vitamin K dependent coagulation factors (FII, VII, IX, X) Hepatic disorders Accelerated destruction of blood coagulation (DIC) Inhibitors of coagulation Others (massive transfusion, extracorporal circulation)

• Hereditary: deficiency or abnormality of a single coagulation factor.

– Hemofilia A (FVIII)– Hemofilia B (FIX)– Von Willebrand’s disease– Rare coagulopathies

(FI. II. V. VII. X. XI. XIII)

Hereditary Factor DeficienciesHemophilia

• x-linked recessive conditions (males only)

• type A : F VIII:C deficiency (Classical Hemophilia)

B : F IX deficiency (Christmas disease)

C : F XI deficiency

• unexplained bruising or bleeding in young males,

usually ~ 1 yr of age

• joint & muscle bleeding → arthropathy

HaemophiliaA bleeding disorder in which clotting factor VIII (eight) /Haemophilia A/ or IX (nine) /Haemophilia B/ in a person's blood plasma is missing or is at a low level.

Prevalence:haemophilia A: 105/million menhaemophilia B: 28/million men

• In haemophilia, VIII or IX clotting factor is missing, or the level of that factor is low.

• This makes it difficult for the blood to form a clot, so bleeding continues longer than usual.

The hemophilia gene is carried on the X chromosome in males who lack a normal allele, the defect is manifested by clinical haemophilia. Women may be carriers.

Haemophilia is a lifelong disease

• A person born with haemophilia will have it for life.

• The level of factor VIII or IX in his blood usually stays the same throughout his life.

hemophilia A

Hereditary Factor DeficienciesHemophilia

■ screening: prolonged PTT■ hemophilia A

mild

moderate

severe : life-threatening (CNS bleed)

• treatment

factor replacement

rFVIIa

Factor VIII Concentrate Necessary for Hemostasis

Factor VIII Concentrate

(% of normal)

Spontaneous hemorrhage 1-3 %

Moderate trauma 4-8 %

Hemarthrosis/deep skeletal

muscle hemorrhage

10-15 %

Major surgery > 30%

Hemophilia B(Christmas disease, Factor IX def.)

•less common than hemophilia A•similar clinical Sx and inheritance pattern as hemophilia A (sex-linked)

II

XII

XI

IX

VIII VII

X

V

I

XIII

Stable clot

von Willebrand’s disease• easy bruisability (no bleeding

into joints)• unable to release VIII-vWF• intact VIII-vWF synthesis• VIII-C level is also decreased

(unknown reason)• autosomal dominant

• 1 in 30,000 population• usually diagnosed in childhood

or young adults• increased bleeding time• normal plt, PT• normal or increased aPTT

Hereditary Platelet Disordervon Willebrand Disease (vWD)

• most common congenital bleeding disorder

• quantitative or qualitative abn. of vWF

• Type 1: most common form

• partial quantitative deficiency of vWF

• autosomal dominant

• mucocutaneous bleeding

• hematology consult prior to surgery

• prolonged bleeding time, normal platelet

Hereditary Platelet Disordersvon Willebrand Disease (vWD)

Type 2: qualitative alterations in the vWF structure

& function

Type 3: least common and most severe

• Complete absence of vWF in plasma or storage organelle

• Autosomal recessive

• acquired vWD• Lymphoproliferative disease ▪ cardiac/valvular disease

• Tumors ▪ medications (valproic acid)

• Autoimmune disease ▪ hypothyroidism

Hereditary Platelet Disordersvon Willebrand Disease

• Treatment: Desmopressin (DDAVP)

• synthetic analog of vasopressin

• ↑ both F VIII and vWF 3 - 5x in 30 mins

• preop prophylactic dose: 0.3 mcg/kg IV in 50 -100

ml NS infused 30-60 mins q 12-24 hrs PRN

• duration 8-10 hrs

• intranasal dose: 300 mcg – for home treatment,

not for preop prophylaxis

Hereditary Bleeding Disordersvon Willebrand Disease

• DDAVP

• vasomotor effect: flushing, ↑HR, headache

• SE: hyponatremia, seizures

• not for children < 3 yrs old

• unresponsive to DDAVP (15%)

• cryoprecipitate

• FFP

• factor VIII / vWF concentrate

Vitamin K Deficiency

vitamin K dependent factors : II, VII, IX, X

•acquired disorder•may occur in malnutrition, malabsorption, biliary obstruction, drug

•increased PT•normal bleeding time, plt•normal or increased aPTT

II

XII

XI

IX

VIII VII

X

V

I

XIII

Stable clot

Severe Liver Disease

factors synthesized in liver : II, V, VII, IX, X, fibrinogen

• increased PT, aPTT• normal bleeding time, plt

II

XII

XI

IX

VIII VII

X

V

I

XIII

Stable clot

Platelet Dysfunction, Factor Deficiencies & Presence of Inhibitors

• Liver disease

• synthesis of coagulation factors (except VIII),

anticoagulants, ATIII, protein C & S, plasminogen

• clearance of activated clotting factors, tPA, FDPs

• DIC

Blood Component TherapyTransfusion of FFP

1) replacement of isolated factor deficiency

2) reversal of coumadin

3) antitrombin III deficiency

4) treatment of immunodeficiencies

5) treatment of TTP

6) massive blood transfusion

Blood Component TherapyCryoprecipitate

• contains significant levels of factor VIIIC,

factor VIII: vwF, XIII, fibrinogen

• indications:

1) hemophilia

2) von Willebrand disease

3) fibrinogen deficiencies

4) uremic platelet dysfunction

Coagulopathies

Disseminated Intravascular Coagulation (DIC)

- an acute, subacute, or chronic thrombohemorrhagic disorder occurring as a secondary complication in a variety of diseases

- activation of clotting system resulting in wide spread formation of microthrombi throughout the microcirculation

- as a consequence, causing consumption of platelets, fibrin and coagulation factors, and activation of thrombolytic mechanism

Two major triggering mechanisms1. release of tissue factor or thromboplastic substance2. widespread endothelial injury

DICTriggering Mechanisms

1. release of tissue factor or thromboplastic substance- placental tissue- granules from leukemic cells- bacterial endotoxin- mucus from adeno CA

2. widespread endothelial injury- Ag-Ab immune complex deposit- extreme temperature- microorganisms

DICPathology: - wide spread thrombi

(brain, heart, lungs, kidneys, adrenals, spleen , liver)- microinfarcts

Clinical: - ~50% associated with obstetric complications- ~30% with carcinomatosis

- microangiopathic anemia- dyspnea, cyanosis- convulsions, coma- oliguria, acute renal failure- shock, circulatory failure

DICClinical: acute DIC with a predominance of thrombin generation

and consumption of coagulation factors

bleeding tendency(oozing from venopuncutres or operating site)

subacute and chronic DIC

thrombotic tendency