Chapter 4: Hemostasis And Related Disorders Flashcards
Formation of weak platelet plug mediated between interaction btw platelets and endothelium
Primary Hemostasis
Strengthening of weak platelet plug via coagulation cascade
Secondary Hemostatsis
What are the 4 steps of Primary Hemostatsis
Transient vasoconstriction
Platelet Adhesion
Platelet degranulation
Platelet aggregation
What 2 processes mediate transient vasoconstriction
Neural Reflex
Release of ENDOTHELIN from damage cells
Before platelets can bind, what molecule must interact with exposed collagen on the damaged endothelium
vWF !
where if vWF produced in the body
Alpha granules of platelets
Weibel Palade Bodies of the endothelium
Once vWF is bound to exposed to collagen what receptor on platelets interacts with vWF ?
Gp1B
What other important adhesion molecule is made in the Weibel Palade bodies besides vWF ?
P-selectin (used in rolling of WBC)
Upon interation of vWF to Gp1b what occurs ?
Platelet Degranulation
What two products are released by platelet degranulation
ADP
TxA2
ADP causes the up regulation of which protein on platelets ?
GpIIB/IIIA receptor
TxA2 has what effect ?
Increases platelet aggregation
What enzyme makes TxA2 ?
COX (platelet)
What is the function of GpIIB/IIIA receptor ?
Platelet aggregation
What does GpIIB/IIIA receptor bind to ?
Fibrinogen (linker protein between two platelets)
Quantitative primary hemostasis disorder are due to …
NOT ENOUGH PLATELETS (Thrombocytopenia)
Qualitative primary hemostasis disorder are due to …
Defective Platelets
What are common symptoms of primary hemostasis disorders ?
SKIN BLEEDING Mucosal bleeding: Epistaxis GI bleeding Intracranial bleeding (Thrombocytopenia) Hemoptysis
Petechiae
1-2 mm lesions of skin bleeding
Purpura
3mm or greater lesions of skin bleeding
Ecchymoses
Greater than 1cm lesion of skin bleeding
Normal level of platelets
150-400 K/uL
Level at which symptoms of thrombocytopeina are notices
<50K/ uL
Normal bleeding time
2-7 minutes
Is bleeding time affected by disorders of primary hemostasis ?
YES (elevated)
Immune Thrombocytopenic Purpura (ITP) is due to what type of Ig directed at platelets ?
IgG (often to GpIIB/IIIA)
What is the most common cause of thrombocytopenia in children AND adults ?
ITP !
Where are the Ab’s to platelets produced in the body ?
Plasma Cells in the SPLEEN !
What occurs that leads to thrombocytopenia in ITP ?
Platelets are brought to the spleen and destroyed by macrophages
The acute form of ITP occurs in CHILDREN and is preceded by what event ?
Viral infections or Immunizations (weeks prior)
What is the prognosis for Acute ITP ?
WIll resolve in weeks after presentation.
In which patients is Chronic ITP most likely ?
Pregnant Women and those with Auto Immune Disease such as Lupus.
What may occur in fetus/neonates who are born to mothers with Chronic ITP ?
Short lived ITP due to crossing of IgG through the Placenta
What would you expect to see of the lab values for Bleeding Time , PT, PTT and Megakaryocyte counts in ITP ?
Bleeding time increased
PT and PTT normal (No effect on coagulation cascade)
Increased megakaryocytic (to make up for platelets being destroyed)
What is the initially treatment for ITP
Corticosteroids (dial down the immune response)
How does IV IgG help in ITP ?
Give another substrate for the macrophages in the spleen to latch onto (dilution principle)
What is the treatment for refractory cases of ITP ?
Splenectomy (remove the spleen, remove the sours of destruction/Ab production)
In Microangiopathic Thrombocytopenic Purpura (MTP), what occurs that leads to low platelets ?
Consumption of platelets due to the formation of micro thrombi in small blood vessels
Why are schistocytes/anemia formed in MTP ?
The micro thrombi stack up in the small vessels and as the RBC’s try to get by they are damaged –> Schistocytes. Schistocytes are removed in the spleen by splenic macrophages.
What are the two main diseases associated with MTP ?
Thrombotic Thrombocytopenic Purpura (TTP)
Hemolytic Uremic Syndrome (HUS)
What occurs in TTP that leads to micro thrombi formation and thrombocytopenia ?
A decrease in ADAMTS13 levels –> Microthrombi production
What is the function of ADAMTS13 ?
Cleaves vWF to inactivate it so that there can be resolution of clotting
In low ADAMTS13, vWF is not cleaved leading to increased thrombi formation and platelet exhaustion –> thrombocytopenia
What is the cause for low ADAMTS13 ?
Antibody to it !
What leads to the formation of microthrombis in HUS ?
Damage to the endothelium by drugs or infection
Mainly associated with children who are infected with E.coli O157:H7
How does E.coli O157:H7 damage endothelium ?
Production fo E.coli verotoxin
Both HUS and TTP present with skin/mucosal bleeding, hemolytic anemia, and fever. Which of the two is more associated with CNS abnormalities ?
TTP
Both HUS and TTP present with skin/mucosal bleeding, hemolytic anemia, and fever. Which of the two is more associated with Renal insufficiency?
HUS
Will bleeding time be increased in MTP ?
Yes
What would you expect of the PT/PTT in MTP ?
Normal (no effect on clotting cascade)
Will the number of megakaryocytes be increased or decreased in MTP ?
Increased
What are the two main treatments for MTP ?
Plamaphoresis and Corticosteroids.
Bernadr-Soulier is due to a gentic defect in which receptor ?
Gp1B (binds to vWF)
What would you see on blood smears for Bernard-Soulier ?
Thrombocytopenia and enlarged platelets (BS = Big Suckers)
Glanzmann Thrombocyopenia is due to a defect in which receptor ?
GpIIB/IIIA (Limited platelet aggregation)
How does Aspirin affect platelet aggregation /
Decreases the amount of TxA2 produced by inhibiting COX irreversibly.
What does Uremia disrupt that causes platelet disorders ?
Inhibits platelet adhesion and aggregation
What is the main end product of the coagulation cascade ?
Thrombin
What is the role of Thrombin ?
Cleaves fibrinogen to fibrin allowing for cross linking and stabilization of clot
Where are the factors of the clotting cascade produced ?
Liver (liver disease may lead to increased bleeding)
What clotting factors are associated with the Inctrinsic Pathway ?
12, 11,9,8 –> activation of factor 10
What clotting factors are associated with the extrinsic pathway ?
7 –> activation of factor 10
What clotting factors are associated with the common pathway ?
10, 5,2,1 (Firbrinogen)
2 is prothrombin
1 is fibrinognen
What leads to the activation of Factor XII (starting point of the intrinsic pathway) ?
Subendothelial Collagen
What leads to the Activation of Factor VII (starting point of the extrinsic pathway) ?
Tissue THromboplastin
What is a major sign of Secondary Hemostasis Disorders ?
Deep tissue bleeding into muscles and joint (hemarthrosis) and rebreeding after surgical procedures
What test is used for the intrinsic pathway ?
PTT (Factor XII,XI, IX, VIII and common factors)
What test is used for extrinsic Pathway ?
PT (Factor VII and common pathway)
Hemophilia A is a X-linked Recessive trait (can come on from spontaneous mutation) in what gene ?
Clotting Factor VIII (A for 8)
What would you expect to see on PTT for Hemophilia A ? PT
Increased PTT
No Change for PT
Reason: Factor VIII is in the Intrinsic pathway.
What would the Bleeding Time be in Hemophilia A ?
NORMAL (normal platelet count too)
Treatment for Hemophilia A
Recombinant Factor VIII
Hemophilia B is due to a mutation in which clotting factor ?
Factor IX
PTT and PT in Hemophilia B ?
Increased and Normal respectively (extrinsic is not affected)
Presentation for Hemophilia B ?
Same as for A (Hemarthrosis and post surgical bleeding)
What is the most common Coagulation Factor that is inhibited by Ab produced against it ?
Factor VIII !
Presents like Hemophilia A
How can you differentiate between Hemophilia A and Factor VIII inhibitor disease ?
Mix the blood with Normal Serum”
In Hemophilia A the PTT will correct due to increased factor VIII
In Factor VIII inhibitor disease, it will not since the inhibitor will still neutralize the Factor VIII
What is THE MOST COMMON inherited coagulation disorder ?
von Willebrands Disease
Describe the etiology of Von willebrands disease
AUtosomal Dominant disorder leading to decreased vWF
Why would you see and altered Bleeding Time and PTT in Von Willebrands Disease ?
Bleeding Time increases due to lack of vWF
PTT increases because vWF STABILIZES factor VIII in the blood. Without sufficient vWF factor VIII will be decreased leading to increased PTT.
What is Risocetin and how can it be used to test for von Willebrands Disease ?
Risocetin iduces platelet aggregation which occurs after vWF binding Gp1B. If risocetin is admin and there is still no change then that is suspicious for vWD
Quick Quiz: What drugs efficacy is being measured by PT ?
Warfarin
Quick Quiz: What drugs efficacy is being measured by PTT?
Heparin
What is the treatment for vWD ?
Desmopressin
ADH analog –> increased vWF release.
Where in the body is epoxide reductase located (enzyme that activates Vitamin K) ?
Liver
What clotting factors are need vitamin K to work ?
2,7,9,10, proteins C and S.
What drug is used to inhibit Vitamin K epoxide reductase ?
Warfarin
Where do we get most of our vitamin K from ?
Gut colonies of bacteria
LONG TERMA AB THERAPY DISRUPTS VIT K LEVELS !
Describe the Etiology of Heparin Induced Thrombocytopenia (HIT)
Heparin binds to factor IV and then attaches to platelet acting as a hapten. The spleen plasma cells make Ab’s agains them leading to destruction of the platelets.
Platelet fragments activate other platelets –> Thrombosis and consumption of remaining platelets
What should you never give to a patient with HIT ?
Warfarin –> Skin Necrosis
Disseminated Intravascular Coagulation (DIC)
Pathologic Activation of the coagulation cascade –> widespread micro thrombi , iscehmia and infarction
Consumption of the platelet factors –> bleeding (IV sites, mucosal surfaces)
What is the cause of DIC ?
Secondary to other disease processes ( Sepsis, Cancer, AML, Rattlesnake bite
Labs for DIC
Platetlet Count
PTT/PT
Fibrinogen
Decreased
Increased
Decreased (activation of clotting cascade eats up all of the fibrinogen by converting it to fibrin)
What products of fibrin degradation are elevated in DIC and can be used to screen the disorder ?
D-dimer !!!
What is the treatment for DIC ?
Treat underlying problem
Transfusion
Cryoprecipitates
tissue plasminogen activator (tPA)
converts plasminogen to Plasmin
Plasmin
Cleaves fibrin (and serum fibrinogen), destroys clotting factors and block platelet aggregation–> clot resolution
alpha2 Antiplasmin
Inactivates Plasmin
What is the main reason for Disorders of Fibrinolysis ?
Plasmin Overactivity !
What molecule released after radical prostatectomy leads to activation of plasmin ?
Urokinase (sort of an endogenous tPA)
What is the consequence of Liver disease in terms of diseases of fibrinolysis ?
alpha2 Antiplasmin is produced in the liver
Liver disease leads to low alpha2 Antiplasmin and thus inability to turn off Plasmin –> increased fibrolysis and inability to clot.
Diseases of Fibrinolysis :
PT/PTT
Bleeding time
D-dimers
Increased (Plasmin destroys clotting factors)
Increased (fibrin and fibrinogen are destroyed)
Not Present (Lysis products will be increased but D dimers not present since clots don’t form)
What is the treatment for Fibrinolytic Disorders ?
Aminocaproic Acid (MATT CAPADARCO)
tPA inactivator…(antidote for tPA tox)
Although thrombi can form in artery or veins where is the most likely place to see them ?
Deep Veins of the leg (DVT)
How do you know a thrombus formed before death and not due to post mortem coagulation ?
Lines of Zahn
(alternating lines of platelets/fibrin and RBC’s)
Attachment to the vessel wall
Virchows Triad (major risk factor for forming thrombus)
Disruption of blood flow (Stasis and turbulence)
Endothelial cell damage
Hypercoaguable state
What are some examples of situations where normal blood flow is disrupted /
Immobilization
Cardiac wall dysfunction (leads to stasis from unordered contraction)
Aneurysm
What is the purpose of Prostacyclin (PGI2) and NO ?
Vasodialation and inhibition of platelet aggregation.
What molecules are secreted by endothelium that inactivate thrombin ?
Anti-Thrombin III
What molecules are secreted by endothelium that breakdown Fibrin, Fibrinogen and Clotting factors ?
tPA
Also inhibits platelet aggregation
What is thrombomodulin ?
Redirects thrombin to activate Protein C
What is the MOA for Protein C ?
Inactivates Factors V and VIII (Common and Intrinsic Pathway)
What molecule is increased due to b12 deficiency that leads to vascular damage ?
Homocysteine
What is the role of B12 in Homocysteine management ?
Transfers a methyl group to Homocysteine –> methionine
How do you know you have a pure B12 deficiency and not a Folate/B12 deficiency ?
Measure the level of Methylmalonic Acid
Increased in B12 def not Folate
How does Cystathione Beta Synthase deficiency effect homocysteine ?
Defect –> high Homocysteine levels and homocysteinuria.
CBS def leads to what complications ?
vessel thrombosis
Mental retarded
Lens dislocation
Long Fingers
Hypercoaguable states are due to excess procoagulant proteins and classically present as :
Recurrent DVT
DVT at young age
Legs Head or hepatic (budd chiari ?)
How does Protein C or S deficiency lead to hypercoaguable state ?
Protein C/S inactivate Factor V and VIII
If they are deficient you will see increased coagulability in the common and intrinsic pathway
What otehre complication is associated Protein C/S def ?
Warfarin Skin Necrosis
Explain how Warfarin Skin necrosis develops in patients with Protein C/S deficiency
Warfarin inhibits Vit K Epoxide Reductase
Vit K Eposide Reductase activates Factors 2,7,9,10 , Protein C and S
Initially this will cause a steep decrease in C/S especially if there is a low amount to begin with
This leads to a transient HYPERCOAGUABLE state (C/S are anti-coagulatnt in nature) –> Necrosis of skin
What is Factor V Leiden ?
Mutated Factor V that cannot be inactivated (by protein C/S)
MOST COMMON CAUSE OF INHERITED HYPERCOAGUABILITY
Dont confuse with Von Willebrands which is the most common inherited Coagulation Disorder.
Point mutation in prothrombin gene that increases expression of prothrombin
Prothrombin20210A
Prothrmobin –> Thrombin cleaves Fibriongen to fibrin
Deficiency in Anti-Thrombin III would reduce the efficacy of which molecules ?
Heparin Like Molecules
Heparin
Both activate AT3
How can you diagnose an Anti-Thrombin III deficiency ?
Give a dose of Heparin
Measure PTT
If PTT does not rise despite heparin induction, you likely have AT3 def.
What is the treatment for Anti-Thrombin III def ?
HIGH DOSES OF HEPARIN (activates whats left) followed by Warfarin (coumidin)
before starting Warfarin, what must you give to be sure that there will not be a transient hypercoaguable state due to unknown Protein C/S deficiency ?
Heparin (maintains anticoagulation until Warfarins effect on Protein C/S subside)
What drugs taken by women increase the risk of hypercoaguable state ?
Oral Contraceptives (containing estrogen)
Estrogen –> increased production of clotting factors
Most common kind of embolus
Thromboembolus (95%)
Dislodged thrombus
Atherosclerotic embolus is due to a plaque that dislodges. How can you tell it is an atherosclerotic embolus ?
Cholesterol Clefts are seen in the embolus
What conditions are associated with Fat Embolus ?
Bone Fracture (long bones) Soft Tissue Trauma
What are two clinical signs of Fat embolus ?
Dyspnea and petechiae on chest after fracture
What is the most common causes of gas embolus ?
Scuba diving and coming up too quickly
Caisson Disease
Chronic Gas Embolus characterized by multifocal ischemic necrosis of the bones
During medical procedure may gas embolus form ?
Laproscopic surgery (gas is pumped in to expand abdomen)
What are three symptoms of Amniotic Fluid Embolus?
SOB
Neurlogic Symtpoms
DIC (Amniotic fluid is highly thrombogenic)
What is characteristic of amniotic embolus on histology ?
Swirling pattern of squamous cells from fetal skin.
Most common causes of Pulmonary Embolus
Thromboembolus (From DVT)
Why are most PE’s clinically silent ?
The lung has dual blood supply and emboli that reach the lung are usually small
Often self resolving
What two conditions must be met in order for Pulmonary Infarction to occur due to PE ?
Large or medium artery must be occluded
Pre-existing Cardiopulmonary Compromise
Presentation of Pulmonary Infarction
SOB
Hemoptysis
Pleuritic Chest Pain
Pleural Effusion
What will you see on Ventilation/Perfusion scan in a patient with pulmonary Infarction ?
Increased V:Q (Ventilation high, perfusion low)
What two imaging studies can be used to detect PE ?
Ultrasound
Spiral CT –> Hemorrhagic Wedge Shaped iNfarct
Sudden Death due to PE is often attributed to what kind of Lesion ?
Saddle Embolus (sits at the bifurcation of right and left pulmonary arteries)
Are D-dimers elevated in Pulmonary infarction ?
Yes
Where do most SYSTEMIC Emboli arise from ?
The left heart
Where does occlusion of blood flow often occur with systemic embolism ?
Lower extremities
