Plasma
Albumin as a key binding protein and the major contributor to oncotic pressure.
Curriculum
Plasma contains variety of proteins and majority are synthesized in the Liver (Except γ-globulins). Proteins can act as buffers – can donate or accept H+ ions (because of the presence of both NH2 and COOH groups which can become NH3+ or COO– ).
They are classified into albumin, globulin and fibrinogen fractions (albumin being the predominant protein).
Globulins can be α-, β- and γ-globulins.
Proteins in plasma have various functions. Albumin binds to hormones or metals to help regulate the available free form or help transport them (e.g. cortisol, thyroxine, iron). Albumin also contributes to the Oncotic pressure of plasma which tries to pull water into capillaries acting against the hydrostatic blood pressure which pushes water out of capillaries. The 2 forces acting against will decide whether filtration or reabsorption takes place at tissue / capillary interface.
Liver failure can lead to Ascites as proteins are not synthesized. Such patients will receive protein supplements. Less proteins in plasma = Less oncotic pressure, fluids leaks out.
Clinical pearl
Platelets
Role following vessel wall damage
Importance of release of 5-HT and thromboxane A2 in haemostasis
Fibrin and thrombin’s role in coagulation
Detailed knowledge of the coagulation cascade is NOT required
Curriculum
Haemostasis – formation of the blood clot. Clot is a tough mesh of fibrin with entrapped platelets and blood cells.
Platelets are not true cells (lack nucleus). They are formed from megakaryocytes in the bone marrow.
They are short lived ( a lifespan of ∼4 days ).
Primary haemostasis
When there is a damage to a blood vessel, there is protective vasoconstriction to reduce blood flow.
The damage exposes collagen and tissue factor on the vessel wall.
Plasma protein von Willebrand factor (vWF) binds to the collagen.
Platelets have glycoprotein (GP) receptors which bind to vWF.
Platelet integrins bind directly to collagen and this adhesion leads to platelet activation.
Platelets make thromboxane A2 (TXA2) which stimulates release of serotonin (5-HT; 5-Hydroxytryptamine) and ADP.
TXA2 and 5HT also enhance the vasoconstriction.
ADP activates fibrinogen receptors (GPIIb/IIIa) on platelet surface, which bind to fibrinogen in the plasma resulting in a soft platelet plug.
The soft plug is stabilized when fibrinogen is converted to fibrin by thrombin.
Formation of the blood clot (coagulation cascade is not part of the curriculum)
Liver produces most of the clotting factors. Factors 2, 7, 9, 10 are Vitamin K dependent. Their production is disturbed if the vitamin is deficient.
In uncontrolled bleeding due warfarin overdose, fresh frozen plasma (FFP) can help replace all factors if Prothrombin complex concentrate (PCC) is not available (This has 2,7,9,10 Protein C/S). Inj Vitamin K helps produce those factors in liver but it takes time.
Clinical pearl
Prothrombinase converts prothrombin to thrombin.
Thrombin activates more platelets.
Propagation phase.
Thrombin activates a short cascade leading to formation of prothrombinase and massive thrombin production
Thrombin cleaves the fibrinogen in the soft clot into fibrin monomers, which polymerize to a fibrous mesh cross-linked by factor XIIIa (also activated by thrombin) to create a tough stable clot.
Prevention of inappropriate clotting.
Endothelium produces prostacyclin and nitric oxide which inhibit platelet adhesion and activation.
Plasma has antithrombin to inhibit thrombin, factor Xa and Tenase.
Antithrombin is potentiated by heparin and heparans on endothelial cells (rationale for giving Heparin sulphate to anticoagulate).
In Heparin overdose, antidote is “Protamine sulphate” if stopping heparin infusion is not enough.
Clinical pearl
Protein C (APC; activated protein C) and protein S inactivate factors Va and VIIIa, and hence tenase and prothrombinase. (No more thrombin = no clotting).
Fibrinolysis
The clot is broken down by plasmin – the fibrinolysis.
On binding to fibrin the plasminogen is converted to plasmin by tissue plasminogen activator (tPA).
Plasmin is itself inactivated by α2-antiplasmin.
In cases of ischemic stroke or myocardial infarction (MI) we use recombinant tPA (rtPA) to lyse the fibrin.
Clinical pearl
Ex: Alteplase, Reteplase, Tenecteplase