Hemodynamic & Thrombotic disorders

• tightly regulated process that forms a clot to stop bleeding at injury site (localized clot)

• involves platelets, clotting factors, and endothelium

1. Primary hemostasis

   • trigger: Endothelial injury exposing the subendothelial ECM

     1. Vasoconstriction (due to neurogenic mechanisms & endothelin)

     2. Platelet adhesion von Willebrand Factor (vWF)

     3. Platelet activation (shape change & granules secretion)

     4. Platelet aggregation (hemostathic plug formed)

1. Secondary hemostasis

   • trigger: tissue factor (Factor III / thromboplastin) & activation of platelet phospholipids

     1. Thrombin converts fibrinogen to fibrin

        -> platelet plug stabilized with a meshwork.

• Counter-regulatory mechanisms (f.e. fibrinolysis)

• Vasodilation

• intact endothelium

• Localization of neg. phospholipids

• Heparin-like molecules activate antithrombin III

• Thrombomodulin binds thrombin and activates protein C (which inactivates Factors Va and VIIIa)

• PGI₂ (prostacyclin) and NO inhibit platelet aggregation

• ADPase inhibits platelet recruitment (bc no ADP)

• Tissue plasminogen activator (tPA) activates plasmin, which digests fibrin clots

• in injury or when activated

• von Willebrand Factor (binds platelets to collagen -> primary hemostasis)

• Tissue Factor (induced by pro-infl. cytokines; activates extrinsic coagulation pathway -> secondary hemostasis)

• Plasminogen activator inhibitors (PAIs) converts plasminogen into active plasmin -> suppress fibrinolysis

• Form the primary hemostatic plug

• Provide a phospholipid surface for the coagulation cascade

• α-granules

• Dense (y) granules

• Intrinsic & Extrinsic pathway

  -> both converge on Factor X -> activates Thrombin (central enzyme)

• Thrombosis: pathologic formation of a blood clot (thrombus) within intact vessels

• Virchow’s triad: hypercoagulability, abnormal blood flow, endothelial injury (most critical)

• frequently occlusive, gray-white, friable

• Rich in platelets and fibrin

• platelets, fibrin, red cells & leukocytes

• often on atherosclerotic plaques

• site of endothelial injury/turbulence

• Grow retrograde to blood flow

• red (rich in red cells), fewer platelets

• occlusive, takes shape of the vein

• Often in deep leg veins

• site of stasis

• Grow in the direction of blood flow -> embolism

Laminations seen in thrombi when formed in the heart or aorta

Thrombus in heart chamber or aorta

Thrombi on heart valves

• infective: inf. endocarditis (bact.)

• sterile: nonbact. thr. endoc. (hypercoagulable state) & Libman-Sacks endocarditis

1. Propagation: enlargement by adding fibrin and platelets

2. Embolization: breaks off and travels to another site

3. Dissolution: fibrinolysis removes the clot

4. Organization and recanalization: ingrowth of endothelial and connective tissue, possible new channels

• Arterial thrombi: more significant clinically

• Venous thr.: more likely to embolize (e.g., pulmonary embolism)

Deep vein thrombosis (DVT)

usually in Popliteal, femoral or iliac veins

• bed rest/immobilization

• heart failure

• trauma/surgery

• pregnancy

• tumors

• advanced age

• Thrombophlebitis: DVT associated with vein inflammation

  • Trousseau syndrome: Migratory thrombophlebitis linked with disseminated cancers (e.g., pancreatic carcinoma)

• Disseminated intravascular coagulation

• widespread thrombosis and bleeding due to systemic

  activation of thrombin

• Obstetric complications: abruptio placentae, amniotic fluid embolism

• Infections: sepsis, meningococcemia

• Cancer/Neoplasms: pancreatic, prostate, lung carcinomas; leukemias

• Tissue injuries: burns

1. Thrombotic phase: Fibrin thrombi formation and consumption of clotting components

2. Bleeding phase: depletion of platelets and coagulation proteins; activation of fibrinolysis

• similar to venous thrombi but not as firm

• resembles melted & clotted chicken fat

• not attached to underlying wall

Coagulant

• Platelets

• Coagulation factors: Factor V, Prothrombin

Anticoagulant

• Protein C

• Protein S

• Antithrombin

• Factor V Leiden (gain of function, missense mut.)

  -> most common genetic cause of VTE

• Prothrombin G20210A (gain of function)

  Antithrombin deficiency (loss of fct)

  Protein C deficiency (loss of fct, frameshift mut)

  Protein S deficiency (loss of fct)

  -> cause of most remaining VTE cases

Missense point mutation -> lower protein cleavage rate

-> increased coagulation

mostly autosomal dominant -> 1 mutated allele enough to show phenotype

• genes

• age

• cancer, obesity, smoking

• previous VTE

• surgery, trauma, immobilisation

• Pregnancy, estrogens, oral contraceptives

Protein S cofactor for activated Protein C (APC) -> inactivate Factor Va -> anticoagulative

Protein S deficiency -> increased risk of thrombosis