Blood Coagulation

Haemostasis part2

ROLE OF ENDOTHILIUM

Stable Hemostatic Plug Hemostasis: BV Injury Tissue Factor Neural Coagulation Activation Blood Vessel Constriction Platelet Activation Primary hemostatic plug Reduced Blood flow Plt-Fusion Thromibn, Fibrin Stable Hemostatic Plug

Prothrombin Thrombin Coagulation: Intrinsic 12,11,9,8 (aPTT-) Extrinsic-7 (PT) Common Path (TT) FX  FXa Prothrombin Thrombin Fibrinogen  Fibrin

Clot formation & retraction Fibrinogen Thrombin F-XIIIa Fibrin Mononer Fibrin Polymer Cross Linked Fibrin

clot Procoagulant Profibrinolytic Anticoagulant Antifibrinolytic Platelets Factors Fibrinogen von Willebrand Factor Profibrinolytic Plasminogen tPA Fibrin Fragment D-dimer FORMATION RESOLUTION clot Anticoagulant Antithrombin III Protein C Protein S Antifibrinolytic PAI-1 Alpha-2 Antiplasmin

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

The main symptom of all diseases is the bleeding: 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 Deficiencies Hemophilia 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

Haemophilia A 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 men haemophilia 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 Deficiencies Hemophilia ■ screening: prolonged PTT ■ hemophilia A mild moderate severe : life-threatening (CNS bleed) treatment factor replacement rFVIIa

Factor VIII Concentrate Necessary for Hemostasis (% 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) XII XI IX VIII VII X V II 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 Disorder von 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 Disorders von 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 Disorders von 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 Disorders von 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 XII XI IX VIII VII X V PT II I XIII Stable clot

Severe Liver Disease factors synthesized in liver : II, V, VII, IX, X, fibrinogen XII increased PT, aPTT normal bleeding time, plt XI IX VIII VII X V aPTT PT II 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 Therapy Transfusion 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 Therapy Cryoprecipitate 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 mechanisms 1. release of tissue factor or thromboplastic substance 2. widespread endothelial injury

DIC Triggering 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

DIC Pathology: - 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

DIC Clinical: 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