Platelet Role in Hemostasis

Role In Homeostasis

• HMWK (high molecular weight kininogen) from alpha granules activates the intrinsic coagulation pathway through contact.
• Fibrinogen is made in order to be converted to fibrin for clot formation.
• Platelet factor 4 and thrombospondin, both alpha granules, aid with platelet function.
• Serotonin, from dense bodies, promotes vasoconstriction at injury sites.
• Thromboxane A2 precursors, from membrane phospholipids, are potent platelet aggregators, inhibited by aspirin therapy.
• Platelet-derived growth factor and beta-thromboglobulin, both from alpha granules, promote smooth muscle growth, vessel repair and are chemotactic for fibroblasts
• Plasminogen, the precursor to plasmin, induces blood clot lysis.
• Factor V is a cofactor to factor X, assists prothrombin converting into thrombin, assisting fibrin clot formation.
• Von Willebrand Factor aids platelet adhesion to the subendothelium for coagulation.
• ADP and calcium, from dense bodies, promote platelet aggregation, and calcium is even involved in coagulation.
• Alpha2-antiplasmin inhibits plasmin to inhibit clot lysis.
• C1 esterase inhibitor complements the system inhibitor.

Physical Properties and Function of Platelets

• Platelets cling, roll, and adhere to damaged endothelium during injury.
• Adhesion requires GP Ib/IX complex with V, which serves as a receptor for Von Willebrand Factor.
• Platelets stick to non-platelet structures, adhering only in detached or injured endothelium.
• Von Willebrand Factor is vital for platelet adhesion in high shear areas.
• This factor is reversible and will be dislodged, but since the veins and capilllaries don't have as much as pressure, the platelets directly adhere to GP6.
• Platelets undergo shape change with alpha and dense granule releases, contributing to platelet aggregation, activating the coagulation system.
• ADP is released from dense granules for aggregation.
• Serotonin is secreted from dense granules for vasoconstriction.
• Thromboxane A2 releases from membrane phospholipids for vasoconstriction and aggregation, but are irreversible.
• Platelet aggregation requires Gp Ilb-Illa as a receptor for fibrinogen, along with plasma fibrinogen/Factor 1, serving as a glue for platelet adhesion resulting in viscous metamorphosis. The initial aggregation is reversible, while secondary aggregation is irreversible.
• Aggregating agents include ADP, thrombin, collagen, arachidonic acid, thromboxane A2, reptilase, epinephrine ristocetin, and thrombospondin.
• Platelets enhance vasoconstriction through serotonin and thromboxane A2 release, acting as primary hemostasis.
• Clot formation needs platelet factor 3 to form active plasma thromboplastin, acting as a secondary reaction.

Qualitative Platelets and Adhesion Defects

• Bernard-Soulier syndrome presents with Gp 1b/IX deficiency, resulting in an intrinsic defect, abnormally low and abnormal platelet morphology, giant platelets, thrombocytopenia, and prolonged bleeding time.
• Aggregation studies in Bernard-Soulier syndrome show abnormal response to ristocetin, but normal response to ADP, collagen, and epinephrine.
• Von Willebrand disease is a common coagulopathy with autosomal inheritance of impaired endothelial cell and platelet function due to a chromosome 12 defect, resulting in plasma VIIIc: VWF deficiency.
• Von Willebrand Disease Presents with prolonged bleeding time, the same aggregation test as Bernard-Soulier, and prolonged APTT due to decreased CF 8c.
• The multimeric molecule contains Ag epitope and binds GP Ib/IX/V complex and collagen, causing platelet adhesion.
• Factor 8c is cofactor in the intrinsic pathway.
• The activated partial thromboplastin time is a test for the intrinsic pathway that contains Ag epitope and has a receptor for Factor 8C (A8C) that is sex linked trait that is synthesized by the liver which is labile and prone to proteolysis
• Antihemophilic factors include Factor VIII (8:VWF & 8C), Factor IX, and Factor XI.

Von Willebrand Diagnosis and Labs

• Lab results from Von Willebrand include normal morphology and amount,
• Common sign: Mucocutaneous bleeding
• Bleeding time is severe & APTT is prolonged
• To determine its quantifiability (test will be quantitative or qualitative), perform a quantitive VWF test (VWF Ag assay)
• To determine the ability of its binding nature to platelets, perform WVF activity test / VWF RCo Assay (test will be qualitative)
• The severity of this factor disfunction could lead to secondary deficiency of Factor8, so the degree is determined using a Factors VIII Activity Assay

Von Willebrand Treatment and Classifications

• Cryoprecipitate treatment supplies the deficient Factor VIII & VWF
• Cryoprecipitate isn't longer recommended because it does not undergo the full viral inactivation process
• Instead, Desmopressin acetate is the standard treatment today
• This standard treatment is the release of VWF & Factor 8 endogenous sources to prevent bleeding
• Other treatment: A plasma-derived factor VIII/VWF concentrate
• The classifications for it in general can be labeled with one of three types.
• Type 1 is the partial quantitive deficiency of VWF (very commone and is 75-80% prevalent)
• Type 2 is the Qualitative disfunction of VWF (normal level, abnormal function)
• 2A has decreased platelet-dependent function which causes susceptible issues with ADMTS-13
• 2B has increased affinity for platelet glycoprotein Ib/IX/V
• increased ability to bind which causes susceptible issues with ADMTS-13
• 2M has decreased platelet receptor binding (glycoprotein Ib/IX/V)
• 2N, "Normandy Variant, has an impaired factor VIII binding site which is leading to APTT deficiencies which is also an autosomal hemophilia
• Lastly, Type 3 occurs when there is a nearly absent VWF and presents as a rare and is Autosomal Recessive

Acquired VWF Note and Aggregation issues

• Note: in this instance we are not congenital, but Acquired with autoimmunity like hypothyroidism that can occur when dealing with lymphoproliferative myoproliferative and benign monoclonal gammopathies disorders
• These are disorders like Wilms tumor, intestinal angiodyspasia, congenital heart disease + pesticides + hemolytic uremic syndrome
• B. Other issues in regard to Platelet-Platelet disfunction, is Aggregation Defects.
• Glanzmann issues is the decreased to no Gp IIb-Illa synthesis
• the cause is from an inherited autosomal recessive trait
• The lab bleeding times are prolonged, but the platelet count + morphology remain normal, the platelets are just isolated from bonding to each other
• Lastly, the tests will return normal when using resocetin, but fail on epinephrine, ADP, and collage
• Another congenital trait: Afibrinogemia and Hypofibrinogenimia:
  • The causes is Acquired/Inherited as either the total absence and or severe defiances in synthesis of fibrinogen
  • dysfibrinogemia is the inherited disfunction of lack of fibrinogenemia

Platelet Transduction

• Platelet secretion has Signal Transduction Disfunction in granules. In those cases there's:
  • Alpha Granules deficiency
  • deficiency of alpha granules
  • the platelets aggregate abnormally, grow to become largley giant and colored with blue-gray and it causes Thromocytopenia LAB wise the bleeding is prolonged the aggregation test will return disfunction
• Gray platelet syndrome = are abnormally large and gray-blue, and thrombocytopenia with Prolonged Bleeding. Time, decreased aggregation With all agents.

Quebec Platelet issues and coag

• There one common inherited disorder
• Quebec disorder
• characterized by autosomal disfunction wuth high concentration of destroyed proteins, and deficiencies in alpha granules.
  • Also will return abnormal urokinase results which in return affects Plasimongen production
  • the test will return platelet levels, and a delayed exposer time

Disorders of platelet procoagulant Actives

• ( resting position-Phoshatidal, Serene and other items- inner
• Phospatidyl choline - outter with these compounds in this form it's maintained (at time) by (enzyme) Aminophospholipid Translalcase.

with platelete transfussion there is a morphological change with it's cytoplasm which will lead to some extensions distribution with phospoties like serine, ethalamolie

• these items can be examined via enzymes like phoshpattial scambalase like PF3 factors... which effects Coagulation

1. scot -surafcae expression is decreased calcium disorder, platets activate with regular test - may be able to do regular secondary

2. Stormorne

• platetse are always active, and without any infection etc

• defetcts with transloase enzymes.

• phsopaides will always show abormal

  • Choline is always "major", but outter " serine - always internal"

Acquired defects in platelet functuion drug related

1. Drugs Arpsirn - Cycle-Oxygenase disfunction, so no platelet congregation Phospalies - Cycle oxygenase cant take arachandoe and prevent prosta cycles with lead to disfunction
   • Nsaids will also lead to this as cycle 2 inhibitors.

• others Ticlo, Calp, Dilute will thinning blood so no more platelet bonding.

2. Paraproteenimia dysprotineia -excecive plasma (in blood fluid) hyper issues (visocsuty) so blood slow distorder of marrow and issues etc

• increase is the Ben Joins protein

3- renal issues - leads to bad platets + not enough substnace (uremica/uroin levels)

• there will be an increase in substance - while decrease in platlette release
• platelets functions are normal.
• just now issues getting the right amount,
• Platelets are few or increased in #s,

Significant count

450,00/

455 count

thromb - higher lo wer "abnomally low" signal to decreased bleediung is not apparent possible- bleedign possible seconary, etc server is bad.

Thrombocytopenia

• Caused- decearse prodction bone-marrow issues bad

• mega - prolif, - aplastic aniemia, inflates bone to be like fa

• May Hegg - Large cells low numbers- body parts present

• Toxic condtions - toxic destorys them!

• intefective thropios - less thrombo - mainly form liver +kidnes

• neonate issues - inside infectrions w torhch - or certain diuretics

Blood Transfussion or Immune disfunctions

• Marrow relplce with new cells - or cancerous.
• blood transfusions well improve patient numbers
• ---blood transfusiojns- can cause recipients plasma found to contain allo on plateletes so anti gens and stuff
• diutinal loss - blood don't have many plattesl so it a mix (massive)
• ---- post transfusion proopia ( relared to antibodie - and serere thrmbo. increases DESTRUCTION OR CONSUPPTION NOn immune Premature - activating and bad- with activation - thrombus

diseminated problems intravucular-

 - makes a sub that activates both coagulation and  fibriono
       imbanace

Hem Uremic

• with diererial
• diarreria in git- with like organism produces it binds to capilaies and promoteo thrommbus. it does that in kids
• ----vertoxin (e/coli)

non diarrheal related with vaccines bad

• pplatele t looooss in valve cases - platete are destruoyed if contacted infections - dengue.

Immunie Defffetcs, and THrpombicytotosis

Immunuue - wutb angitbody Igg

itdopaathic ppurprura Tpp - unknown but it commin dureing younn and with presence anti-platelet anibodies

• or prevouuss- infecvtions

Drugg incuded: hetarin thromnbo- patienyt develps for heparin at spwc for factor 4 com

Spelci to hyper + splenosnmergaly where there lare spltus and keepin 50 tp 0 % leave 10 in circulation

uremia increease NPN for blood leadin to inablke and damage kidney - aklsie can duse.

Thrombiy or Throm

• Inrcrsar in plateter
• main defe t + abnormsl prodcute, in myeloprifative - disteorden with abnroal productuons a ) polychetiamia b) Essssennntal thrombi - mreooe then !0,00,000 w abotrrnal funvtiion c) chronjc granio c kukeim to abnormsl

Secondary and Reactie Throm

• secjondry duge to an underlying cond

• a) Splenic

  • durijnjfg hermm causes transtirens

• repionce tot e

• to seriss due to actute aloss platste b) repird regenerwatin - loss of bllod s the bone arrorry try to com and unceares platseters in cirulatouu to respond conmditon

lab eval primarly

direct

• csn per with machiubed

• • manuas will use

  Edys - choice - whtether prrvemns + agreagetgin

• When agretatrion fakse dracrease , how vsn eday platete shoulld be peeformrd - in preer