Hemostasis, Coagulation, and Fibrinolysis

• The provided text includes details on coagulation, fibrinolysis, hemostasis, related disorders, and lab evaluations

Overview of Hemostasis

• Hemostasis serves as a rapid, localized, and regulated physiological response to vascular injury
• The process minimizes blood loss
• The hemostatic system involves interplay of cellular components (endothelium, platelets, immune cells)
• The system involves plasma proteins for coagulation, fibrinolysis, and anticoagulation
• The current cell-based model of hemostasis recognizes tissue factor (TF) and FVIIa as initiators
• Natural anticoagulants regulate thrombin generation
• The fibrinolytic system dissolves clots after they have served their purpose

Physiological Hemostasis

• The physiological hemostatic system achieves a balance between clot formation and dissolution
• It comprises a cellular component (platelets, endothelial cells neutrophils and monocytes)
• It comprises plasma proteins involved in coagulation, fibrinolysis, and anticoagulation

Endothelium and Platelets

• Normal hemostasis entails interplay between cellular components and clot formation proteins
• Intact endothelium, in a physiological state, maintains hemostatic balance
• Breaching vascular integrity initiates coagulation
• Intact endothelial cells secrete ectonucleotidase CD39 thus degrade ADP
• Endothelial cells secrete prostacyclin and nitric oxide (NO) preventing platelet activation/aggregation
• Intact endothelium additionally binds plasminogen, tissue plasminogen activator, and single-chain urokinase
• The glycosaminoglycans on endothelium bind antithrombin (AT), neutralizing thrombin and FXa
• Thrombomodulin on endothelium binds thrombin converting protein C to activated protein C (APC)
• Vessel wall injuries expose subendothelial collagen, platelets adhere
• This adhesion activates platelets, stimulating granule release, aggregation, and coagulation factor activity
• Factor XII autoactivates when exposed to collagen or activated platelets in flowing blood
• Activated platelets facilitate thrombin generation via phospholipids and procoagulant membranes

Coagulation Protein System

• The coagulation system includes zymogens and cofactors categorized as phospholipid-bound or surface-bound
• Phospholipid-bound zymogens needing vitamin K for gamma-carboxylation are crucial for hemostasis
• These proteins include FX, FIX, FVII, FII (prothrombin), and protein C
• Protein S serves as a cofactor for APC, exerting anticoagulant effects
• Surface-bound proenzymes, like FXII, prekallikrein, and FXI, activate with negatively charged surfaces
• Deficiencies in surface-bound proteins may affect blood pressure or thrombosis, but have no role in hemostasis
• Tissue factor a cofactor for activated FVIIa, initiating hemostasis
• Factor VIII a cofactor for FIXa in FX activation
• FV serves as a cofactor for FXa in prothrombin activation
• Fibrinogen, acted on by thrombin, forms fibrin for monomers which form the polymerized blood clot
• Factor XIII stabilizes fibrin through crosslinking with strands of fibrin

Physiological protein assemblies

• Vital protein complexes central to hemostatic events accelerate their respective proteolytic processes
• Observed patient conditions, along with murine knockout research, determined said factors needed for effective bleeding control
• VII, X, V, or II deficiencies are severe in mice, may have some function in human models, can be offset with human factors or compensatory mechanism
• Tenase and prothrombinase complexes are essential to normal hemostasis
• Extrinsic tenase has PL surface, FVIIa for FX to FXa conversion
• The Intrinsic tenase has IXa for FIX, VIIIA components
• Prothrombinase comprises ordered FXa, FVa, and FII; accelerates FII to FIia
• Coagulation reactions act as target sites for anticoagulants aimed at treating venous thrombosis

Fibrin clot and the fibrinolytic system

• Fibrinogen has two terminal D domains and an E central domain
• Thrombin separates fibrinopeptide A from the Aa chain and fibrinopeptide B from the Bẞ chain of fibrinogen making a soluble fibrin monomer
• A noncovalent fibrin polymer is made through the assembly of fibrin monomers with end to end and side associations
• Insoluble cross-strands are linked by FXIIIA, an enzyme
• Degradation and clot dissolution are regulated by the natural pathway in which plasminogen gets to its active enzyme form, plasmin through the action of activators
• tPA, ScuPA, and TcuPA are natural plasminogen activators, triggering plasmin creation for fibrin degradation
• tPA gets created constantly and ScuPA flares up during bouts of inflammation
• PAI-1 will be the major regulator of tPA and TcuPA
• Active plasmin degrades proteins, soluble fibrinogen gets degraded into fibrinogen degradation products (FDP)
• Action on a factor creates neo epitopes only to get chewed up creating fragment X, plasmin chews X fragments for fragments Y, plus soluble D and E fragments

Anticoagulation Protein Systems

• Three regulation systems exist to regulate enzyme production which will help inhibit clot formation
• The protein C/protein S system has serine proteases, Kuntiz factor, protease inhibitor systems, and AT

Protein C/Protein S System

• Endothelium reduces clots and inflammation
• Complex separates after endothelial Protein C receptor ligation, allows protein S to allow APC/S assembly to activate FVa/VIIIA
• Protein then binds to PAR1, ApoER2 also reducing thrombosis risk

Antithrombin

• Serpin, blocks factors exerting effect via binding with endogenous or heparin
• Prevents FVII, IX, XI, XII kallikrein from being active

Tissue Factor pathway Inhibitor

• Inhibits TFPI, needs quaternary complex with VIIa.TF then inhibit otherwise

Current Hypothesis For Initiation of The Hemostatic System

• Most in vitro coagulation parts are key in in vivo reactions. Regulation of TF is a major key control for hemostatsis
• Encrypted TF becomes able to do it's job when cell properties get modified

Clinical Hemostasis

• Primary hemostasis at cell injury
• Subendothelial collagen and more is exposed, laminer outflow now shifts, breach now open as binds to WF, become spherical
• This adhesion causes secretion and granulation factor expressions
• TXA2 factor with more expression lead to similar things

Secondary Hemostasis

• Different phases - extrinsic and intrinsic path
• Starts injury, endoth, expresses TF and forms TF + VII a (extrinsic tenase) activate factor X and turn into FXa, converts Pro + throm to Th
• TFPI shuts pathway by stopping complex activation of X
• Pathway happens again but turning on IF too creates more FIX into FIXa using Surface + calcium to convert factor X to Xa
• Amplification to FT mainly thrombin

Laboratory Evaluation of Hemostasis

• Evaluate bleeds with family hist, do congential with ecchymosis, soft joint bleeds
• If so then perform an aPTT, PT, time and D-dimers with platelet count for eval

Prothrombin Time

• Mix patients plasma, reagents with phosphids and Ca with tissue thromboplastin
• Tissue matters - non hum sens vs human
• Norm ratio developed to horm PT with VKA TH therapy monitor
• So perform above as first measure
• A single long then find it out next via FVII
• 10% can survive surgeries

Activated Partial Thromboplastin Time

• Use when PT poor sensitivity and espec for bleeding
• assess coags inner
• Activator added to PT and activate con factors in presence of Ls
• Time record
• But not standard for all
• Different to find sen levels
• More to see at a more sensitive with a FSL or APTT, LA

Thrombin Time

• Just for testing normal fibrin production time - if high most like def in hypofibrogenia
• Use bovine thrombin on plasma to record

Fibrinogen Essay

• See routine cases
• Measure as Cluss way, calf throm at 50 units

Mixing Study

• Not used in a while- mixing parts of parts if suspected a factor
• Mixing only on immediate and if do not then will have a mix of problems
• Hemophila has tissue hematomas and easy wounds due to autoant F8 + other cond

Hep Monitoring

• avoid over or under
• Un fractionated hep, un predic K or and PD due to cell attachments

Coagulation Factor Assays

• One based assays = most cmon, measure with prepa curve with factor def plasma etc

The formation of Fibrin Clot and the Fibrinolytic System

• Fibronectin a fibrin with E and two end D domains
• TPA/SCUPA/TC up converts as its main function, reg fibronectin degredatio
• tPA, SCUPA, TCuPA converts zymogen to plasmin enzymes (FIg 40.3

Anticoagulation Protein System

• Coags re TIGHLY regulated by naturals avoi TH extensions, P C S,
• TFPI is Kunitz

Protein C/Protein S sys

• enz inhibitor. Complex then converts protein c to APC increased when bound to EPCR

• Reduces thrombin, reduces inflammation

Tissue Factor Pathway Inhibitor.

• Pot inhibitor of TFPI TF under psyc cond, inhibits quat complex
• Imp murine is embryonical lethal

Current Hyporthesis Fo Initiatin of Hemostatic Sys

• New TF and FVII initiated system replaced FXII is ubiq

Clinical Hemostasis. Primi Hem.

• Endothel cell injury/WilleB facto are ex
• Alter lamin flows the end altered

Secondary Hemostasis

• 2 step initiate+amplify - TP Path and itern
  • TF path beg with exp of TP, binds VIIa
  • Complex acti FX to FXa, the actis prot - conv PT > T

Selected References

• Adcock and et al
• important book for knowing the best blood

Clinical Hemostasis- Primary Hemostasis

• The site of endothelial cell/Subendo col
• Platelets go spheroidal form and binds WFactor via GPIbIXV receptor
• Release occurs alpha and dense form, produce procol

Primary Hemostasis

Sub Coll W factor exposure and all this - disrupt, plate change from disk and spere, and then to proe pseudopodia - this allows damage

• First step PLATE adhesion
• second followed secreation and granule and thromboxan A@ and causes to become vaso contra and then plate act via plate recepx
• Then Act the signal of transuction which leads exposure similarily,

Selection Secondary H

• There are factors extrinsic and then int,
  • TF pathway initiator for generation thrombin the TP, to the VII - so binds together, known to Extrin Ten, causes activate fx which caa will to act factor Xa
• NOTE The factors to get for FX is to create the PT pathway by activation, TFP, will shut the path, so initiate Inntrin Path, activate and now

Hemostatic Disorders

• Clincial bleeding in disorders of hemostasis broken down to two
  • Platelet/vascular problem versus Coagulation factor problem
  • The onsets, sites, forms, location and clinical signs differ depending on which it is.

Other Points

• Also, differential diagnosis of coags with screen, and classification of hemorphilia
• Plus, a short definition of key points about both those topics