CH4 - Hemostasis and Related Disorders Flashcards
What is hemostatsis?
Sealing break in blood vessel wall
Hemostasis involves the formation of?
a thrombus (clot) at the site of vessel injury
What are the 2 stages of Hemostasis?
primary and secondary
Primary hemostasis?
forms a weak platelet plug
Primary hemostasis is mediated by?
interaction between platelets and the vessel wall
Purpose of secondary hemostasis?
stabilizing platelet plug
Secondary hemostasis is mediated by?
the coagulation cascade.
What is 1st in primary hemostasis?
Transient vasoconstriction of damaged vessel
How is 1st step in primary hemostasis mediated?
by reflex neural stimulation and endothelin release from endothelial cells
What is 2nd step in primary hemostasis?
Platelet adhesion to the surface of disrupted vessel
In the 2nd step of primary hemostasis, how does platelet adhesion occur?
Von Willebrand factor (vWF) binds exposed subendothelial collagen,
How do platelets bind to vWF?
via the GPIb receptor on platelets
vWF originates from?
primarily Weibel-Palade bodies of endothelial cells but also alpha-granules of platelets.
What is the 3rd step in primary hemostasis?
Platelet degranulation
In 3rd step of primary hemostasis what does Adhesion induce?
shape change in platelets and degranulation with release of multiple mediators
What are the mediators released in step 3 of primary hemostasis?
ADP and TXA2
What is the role of ADP in step 3 of secondary hemostasis?
it is released from platelet dense core granules; promotes exposure of GPIIb/IIIa recept ors on platelet surface
What is the role of TXA2 in step 3 of secondary hemostasis?
it is synthesized by platelet cyclooxygenase (COX) and released; promotes platelet aggregation
What is the 4th step in primary hemostasis?
Platelet aggregation
Where and how do Platelets aggregate in step 4 of primary hemostasis?
at the site of injury via GPIIb/IIIa using fibrinogen (from plasma) as a linking molecule;
What does platelet aggregation result in?
formation of platelet plug
is Platelet plug strong?
It is weak; coagulation cascade (secondary hemostasis) stabilizes it.
What are disorders of primary hemostasis usually due to?
Usually due to abnormalities in platelets;
Disorders of primary hemostasis are divided into?
quantitative (not enough platelets) or qualitative (enough platelets but of poor quality) disorders
What are some Clinical features for disorders of primary hemostasis?
mucosal and skin bleeding.
What is the most common overall symptom in mucosal bleeding?
epistaxis
Feared Complication of Severe Thrombocytopenia
Intracranial bleeding
What are symptoms of mucosal bleeding?
epistaxis, hemoptysis, GI bleeding, hematuria, and menorrhagia. Intracranial bleeding occurs with severe thrombocytopenia.
How does skin bleeding present?
include petechiae (1-2 mm), purpura (> 3 mm), ecchymoses(> 1 cm), and easy bruising;
Do petechiae, ecchymoses, and purpura blanch when pressed?
NO
Petechiae are a sign of what?
thrombocytopenia and are not usually seen with qualitative disorders.
What are some useful laboratory studies for disorders of primary hemostasis?
platelet count, bleeding time, blood smear, bone marrow biopsy
Platelet count
normal 150,000-400,000/μL; < 50,000/μL leads to symptoms,
Bleeding time
normal 2-7 minutes; prolonged with quantitative and qualitative platelet disorders. Considered Outdated test.
Blood smear
used to assess number and size of platelets
Bone marrow biopsy
used to assess megakaryocytes, which produce platelets, to figure out if megakaryocyte dysfunction causing thrombocytopenia
What is immune thrombocytopenic purpura?
(ITP) is an autoimmune production of IgG against platelet antigens (GPIIb/IIIa)
What is the most common cause of thrombocytopenia in children and adults?
immune thrombocytopenic purpura
In ITP what leads to thrombocytopenia?
Antibody-bound platelets are consumed by macrophages in the spleen
ITP is divided into?
acute and chronic forms
Acute form of ITP?
arises in children weeks after a viral infection or immunization;
Antibodies formed against platelet antigen
How is acute ITP treated
Corticosteroids
It is a self-limited disorder, usually resolving within weeks of presentation. If platelet count goes down significantly in the mean time, support patient with platelet transfusion?
Who gets Chronic ITP?
arises in adults, usually women of chilbearing age. May be primary (unknown cause) or secondary (e.g SLE).
What are the causes of Chronic ITP?
Primary (Unknown) or Secondary (e.g. SLE since these patients usually have Ab against one of their blood cells, whether it’s RBC’s, WBC’s, or Platelets )
What is the risk involved for women with chronic ITP?
May cause short-lived thrombocytopenia in fetus during pregnancy and soon after birth since antiplatelet IgG can cross the placenta. This would resolve quickly as the mom’s IgG lingering would be consumed shortly after birth.
Platelet Count in ITP
<50,000/µL
PT/PTT in ITP
Normal because coagulation factors (the convert fibrinogen to fibrin) not affected
What will bone marrow biopsy show in ITP
Increased megakaryocytes (hyperplasia in response to thrombocytopenia)
What is the Initial treatment for ITP?
corticosteroids
How will children and adults respond to steroids for ITP?
Children respond well to steroids; adults may show early response, but often relapse.
In addition to corticosteroids what else is an emergency treatment for ITP if pt starts bleeding from multiple sites and you are afraid that intracranial bleeding is next?
IVIG is given to temporarily raise the platelet count in symptomatic bleeding
How does IVIG provide emergency relief for ITP
Splenic Macrophages are overwhelmed by IVIG, consuming them rather than native Ab’s bound to platelets -> short-lived increase in platelets
What is a permenant solution for patients with ITP?
Splenectomy
How does Splenectomy help in refractory cases of ITP?
1) Helps eliminates the plasma cells that were producing Anti-platelet Ab’s (b/c spleen together with lymph nodes are the secondary lymphoid organs)
2) Eliminates the spleen, which was the site of platelet destruction by Macrophages
What is microangiopathic hemolytic anemia?
A set of disorders with Pathologic formation of platelet microthrombi in small vessels (Micro-angio)
Why do platelet microthrombi cause bleeding?
Platelets are consumed in the formation of microthrombi->thrombocytopenia
How do platelet microthrombi cause hemolysis/anemia?
By sheering passing RBC’s
What evidence does blood smear provide for Microangiopathic Hemolytic Anemia?
Schistocytes (RBC’s that were sheared by microthrombi)
Which 2 diseases result in microangiopathic hemolytic anemia?
thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS)
What is the origin of the name TTP
Thrombotic -> platelet microthrombi form
Thrombocytopenia -> Low platelets because platelets are consumer in microthrombi formation
Purpura -> Resultant skin bleeding
What is decreased in TTP?
decreased ADAMTS13 (enzyme that normally cleaves vWF multimers into monomers for eventual degradation)
How does TTP lead to microangiopathic hemolytic anemia?
- Large, uncleaved multimers lead to abnormal platelet adhesion, resulting in microthrombi.
Why do microthrombi form in TTP?
vWF polymers accumulate, linking subendothelial collagen to platelets ->abnormal accumulation of platelets
Decreased ADAMTS13 is usually due to what?
an acquired autoantibody (Anti-ADAMTS13 Ab) secondary to autoimmune process.
Inherited mutation far less likely.
TTP is most commonly seen in?
adult females (auto-immune production of Anti-ADMTS13 Ab)
What is the origin of the name HUS?
Hemolytic (microthrombi form and shear RBC’s (hemolysis) -> schistocytes)
Uremia -> Implies damage to kidneys -> Uremia because body cannot effectively clear toxins
Why do patients get platelet microthrombi in HUS?
endothelial damage by verotoxin from Infection with E. coli O157:H7
or endothelial damage from toxic medication
How is E Coli related to microangiopathic hemolytic anemia?
E coli produces a verotoxin which damages endothelial cells and lowering ADAMTS13 ->resulting in platelet microthrombi in kidney and brain -> hemolysis
HUS is classically seen in?
children with E coli O157:H7 who ate undercooked beef
How do children with HUS present?
present with dysentery (mucosy diarrhea with blood + fever, abdominal pain, and a feeling of incomplete defecation)
The clinical findings for HUS and TTP include
- Skin and mucosal bleeding (due to thrombocytopenia)
- Microangiopathic hemolytic anemia
- Fever (secondary to inflammation)
- Renal insufficiency (predominantly in HUS -> think UREMIC) (because affects small vessels of kidney AND….
- CNS abnormalities (Predominantly in TTP) (brain)
Renal insufficiency is more common in HUS or TTP?
HUS ? thrombi involve vessels of the kidney->Uremia
CNS abnormalities are more common in HUS or TTP?
TTP ? Thrombi involve vessels of the CNS
Laboratory findings for microangiopathic hemolytic anemia include?
Thrombocytopenia
increased bleeding time
Normal PT/PTT (coagulation cascade is not activated, only platelets accumulating)
Anemia with schistocytes
Increased megakaryocytes on bone marrow biopsy (in response to thrombocytopenia)
Treatment for TTP?
Plasmapheresis (removes proteins, including Anti-ADAMTS13 Ab)
Corticosteroids lead to decreased production of Anti-ADAMTS13 Ab by plasma b cells.
Treatment for HUS
Supportive with IV fluids
Blood transfusion if significant anemia
Temporary dialysis if kidney failure.
What are the qualitative platelet disorders?
Bernard-soulier, Glanzmann thrombasthenia, asprin, uremia
Bernard-Soulier syndrome
is due to a genetic GPIb deficiency; platelet adhesion to vWF (linker molecule from platelet to subendothelial collagen) is impaired
In Bernard-Soulier what lab test are you interested in?
Blood smear which shows mild thrombocytopenia (GP1B deficient platelets have shorter life) with enlarged platelets (Big Suckers mnemonic->due to megakaryocytes pumping out slightly premature bigger platelets).
Glanzmann thrombasthenia is due to?
a genetic GPIIb/IIIa deficiency-> platelet aggregation is impaired.
Which step is compromized in Glazmann thrombasthenia?
AGGREGATION
How can Aspirin cause qualitative problems with platelets?
it irreversibly inactivates cyclooxygenase-> lack of TXA production-> impairs aggregation because TXA normally attracts platelets to the site of injury
How can Uremia lead to qualitative problems with platelets?
(BUILDUP OF NITROGENOUS WASTE PRODUCTS secondary to kidney damage-> disrupts platelet function by interfering with both adhesion and aggregation
What does secondary hemostasis do?
Stabilizes the weak platelet plug via the coagulation cascade
In secondary hemostasis the coagulation cascade generates?
thrombin (Factor 2), which converts fibrinogen in the platelet plug to fibrin
In secondary hemostasis what happens to fibrin?
It is cross-linked, yielding a stable platelet-fibrin thrombus.
What is the metaphor for the platelet-fibrin-thrombus?
A band-aid that covers the broken blood vessel
Where are the factors of the coagulation cascade produced?
liver (in inactive state)
What happens to the inactive coagulation factors produced by the liver?
hepatocytes release them into the blood where they float around until activated
What do the endothelial cells that form blood vessel sit on?
basement membrane
What does activation of coagulation factors require?
exposure to an activating substance
Phospholipid surface (surface Plasma Membrane of platelets)
calcium (released by dense core granules of platelets)
What are the activating substances involved in the activation of the factors of the coagulation cascade?
Tissue thromboplastin (TT) activates factor VII (extrinsic pathway) (Measured PT) (Tx with WRferin) *mnemonic 2 letters each
Sub-Endothelial collagen (SEC )activates factor XII (intrinsic pathway). (measured by PTT) (Treat ith HEP) *mnemonic 3x1x letters each
Where does the Calcium involved in the activation of the factors of the coagulation cascade come from?
derived from platelet dense core granules
Disorders of secondary hemostasis are usually due to?
factor abnormalities
What are the clinical features of disorders of secondary hemostasis?
they include deep tissue bleeding into muscles and joints (hemarthrosis)
rebleeding after surgical procedures (e.g circumcision and wisdom tooth extraction)
While disorders of Primary hemostasis caused skin bleeding
Laboratory studies for Disorders of secondary hemostasis include?
PT (prothrombin time) and PTT (partial thromboplastin time)
Prothrombin time (PT)
measures extrinsic (factor VII) and common (factors II, V, X, and fibrinogen) pathways of the coagulation cascade
Extrinsic pathway of the coagulation cascade
factor VII
Why do you follow Warfarin (Coumadin) with PT?
Because PT is more sensitive because Factor 7 has the shortest half-life,
el
Relying on PTT where one would have to wait for all factors 8 and 9 to run out to find out if it is working, would over-compromise Secondary hemostasis (because 7 would already be exhausted) and could lead to dangerous bleeds
Common pathway of the coagulation cascade
factors II, V, X, and fibrinogen
Partial thromboplastin time (PTT) measures
intrinsic (factors XII, XI, IX, VIII) and common (factors II, V, X, and fibrinogen) pathways of the coagulation cascade
What is involved in Hemophilia A?
Genetic factor VIII (FVIII) deficiency, X-linked recessive (predominantly affects males) *Call it Hemophelia 8
Does Hemophilia A require a family history of it?
It is possible for it arise from a new mutation (de novo) without any family history
Hemphilia A presents with?
deep tissue, joint, and postsurgical bleeding (like all secondary hemostasis disorders)
Clinical severity of hemophilia A depends on?
the degree of deficiency
Laboratory findings of hemophilia A include
- increased PTT; because Factor 8 is part of Intrinsic Pathway
normal PT 2. decreased FVIII 3.
Normal platelet count (platelets not affected) and bleeding time (because primary hemostasis determines bleeding time and it works)
Treatment for hemophilia A?
recombinant (produced by bacteria with human Factor 8 gene added) FVIII.
What is christmas disease?
Hemophilia B - Genetic factor IX deficiency, Resembles hemophilia A, except FIX levels are decreased instead of FVIII
What is coagulation factor inhibitor?
Acquired antibody against a coagulation factor resulting in impaired factor function; anti-FVIII is most common,
Clinical and lab findings for hemophilia B?
its similar to hemophilia A
HOWEVER
PTT does not correct upon mixing normal plasma with patient’s plasma (mixing study) due to Ab inhibitor binding up recombinant Coag factor; PTT does correct in hemophilia A.
How can you tell the difference between hemophilia A and B?
mixing study (mixing normal plasma (with functional factor 8) with patient’s plasma)
What will be mixing study result for Hemophilia B?
Prolonged PTT persists because Anti-Factor 8 Ab (Inhibitor) will inactivate functional Factor 8 from Normal Plasma
von Willebrand Disease
Genetic vWF deficiency
What is the most common inherited coagulation disorder?
von Willebrand disease
Is von Willebrand Disease due to qualitative (poorly functioning) or quantitative (low levels) deficiency of vWF?
Multiple subtypes exist, causing quantitative and qualitative defects;
What is the most common type of von Willebrand Disease?
is autosomal dominant with decreased vWF levels
Autosomal Dominant von Willebrand Disease presents with?
mild mucosal and skin bleeding; not enough vWF to link sufficient platelets to sub-endothelial collagen (impaired adhesion)
What tests should you run for von Willebrand Disease?
- bleeding time
- PTT: normal
- Ristocetin test
How does vWF Disease Affect Ristocetin Test?
Abnormal ristocetin test (Ristocetin won’t be able to cause massive aggregation of platelets because 1st step (Adhesion does not happen, therefore))
How does vWF Disease Affect Bleeding time
- increased bleeding time
How does vWF Disease Affect PTT?
- increased PTT: normal PT ? Decreased FVIII half-life (vWF normally stabilizes FVIII);
What is usually not seen with von Willebrand Disease that is unusual
deep tissue, joint, and postsurgical bleeding are usually not seen (Absence of problems with Secondary Hemostasis because even though low vWF causes laboratory Increase in PTT, this difference is not clinically significant)
Why is there an Abnormal ristocetin test in von Willebrand disease
Ristocetin induces platelet aggregation by causing vWF to bind platelet GPIb; lack ofvWF ?> impaired aggregation ?> abnormal test.
What will be mixing study result for Hemophilia A?
Prolonged PTT will normalize because functional Factor 8 from Normal Plasma will replace non-functional Factor 8 in coag cascade
What is the treatment for von willebrand disease?
desmopressin (ADH analog), which increases vWF release from Weibel-Palade bodies of endothelial cells
How does vitamin K deficiency relate to hemostasis?
Disrupts function of multiple coagulation factors
What is involved in Vitamin K activation?
1) Vitamin K enters from gut where it is made by bacteria
2) It is Activated by Epoxide Reductase in the Liver
What does Activated vitamin K do?
it gamma carboxvlates factors II, VII, IX, X, and proteins C and S; gamma carboxylation is necessary for factor function.
How does Warfarin (Coumadin) work?
It shuts down Epoxide Reductase in the Liver
Therefore Vitamin K can’t be activated
Therefore Vit K can’t Gamma Carboxylate Factors 7, 8, 9, 10 + Proteins C and S and therefore activate them
Without functioning Factors 7, 8, 9, 10 Secondary coagulation cascade is impaired
Vitamin K deficiency occurs in?
- Newborns (not yet colonized by bacteria -> No Vit K -> give Vit K to all newborns to prevent hemorrhagic disease of the newborn)
- Long-term antibiotic therapy (kills of gut flora)
- Malabsorption (Vit K is one of the fat soluble Vitamins so will not be taken up especially if fat malabsorption)
4) Liver Failure
Why is there vitamin K deficiency in newborns?
its due to lack of GI colonization by bacteria that normally synthesize vitamin K; vitamin K injection is given prophylactic ally to all newborns at birth to prevent hemorrhagic disease of the newborn
How does Long-term antibiotic therapy elad to Vitamin K deficiency?
disrupts vitamin K-producing bacteria in the GI tract
How does Malabsorption lead to Vitamin K deficiency?
leads to deficiency of fat-soluble vitamins, including vitamin K
What are some other causes of secondary hemostasis?
liver failure, large volume transfusion,
How does liver failure lead to secondary hemostasis?
decreased production of coagulation factors and decreased activation of vitamin K by epoxide reductase;
How is the effect of liver failure on coagulation followed?
followed using PT.
Why is the PT preferred over the PTT to monitor liver failure?
The PT assesses factor VII, which is the coagulation factor with the shortest half-life.
So PT becomes abnormal first. If liver continues to fail, as all other factors run out, PTT becomes prolonged too.
How does Large-volume transfusion lead to secondary hemostasis?
it dilutes coagulation factors, resulting in a relative deficiency
What is Heparin induced thrombocytopenia?
Platelet destruction that arises secondary to heparin therapy
How can Heparin cause HIT?
Heparin can form complex with Platelet Factor 4 (PF4), a molecule on platelet surface.
IgG auto-antibodies form against this complex
these anti-HEP-PF4 Ab’s carry platelets to spleen where they are destroyed by Macrophages
How can feard complication of Heparin induced thrombocytopenia arise?
Throbosis can arise because fragments of destroyed platelets may activate remaining platelets, leading to thrombosis of blood vessel -> occlusion of critical blood vessels
In patients with thrombosis secondary to HIT, what anticoagulant should not be used to treat thrombosis?
Warfarin (Coumadin) because of Increased incidence of Coumadin Skin Necrosis in these patients
What is disseminated intravascular coagulation?
Pathologic activation of the coagulation cascade
What does disseminated intravascular coagulation result in?
- Widespread microthrombi (blockage of small vessels) results in ischemia and infarction of tissues
- Massive consumption of platelets and factors in small vessels results in bleeding in other sites, especially from IV sites and mucosal surfaces (bleeding from body orifices from gut, lung, hematuria).
Is disseminated intravascular coagulation usually primary or secondary?
Almost always secondary to another disease process
What are some complications that may result in disseminated intravascular coagulation?
1) Obstetric complications
2) sepsis, adenocarcinoma
3) Acute promyelocytic leukemia
4) Rattlesnake bite
Obstetric complications and disseminated intravascular coagulation
If Tissue thromboplastin (strong activator of coagulation cascade) in the amniotic fluid enters mother’s circulation can activate DIC
Sepsis and disseminated intravascular coagulation
(especially with E. coli or Neisseria meningitidis) ?
1) Endotoxins from the bacterial wall
2) Macrophages produce cytokines (e.g TNF and IL-1) in response to infection, which induce endothelial cells to make tissue factor (same as thromboplastin).
Adenocarcinoma and disseminated intravascular coagulation
Mucin overproduced by rapidly proliferating adenocarcinoma activates coagulation.
Acute promyelocytic leukemia and disseminated intravascular coagulation
APL is a cancer of Immature granulocytes (promyelocytes). These immature granulocytes are loaded with primary granules (which can coalesce to form Auer rods) which can leak into the blood and activate coagulation cascade.
How can rattlesnake bite cause disseminated intravascular coagulation?
Venom goes into circulation and activates coagulation
What is the last step of coagulation?
Fibrinolysis - Removal of thrombus (band aid) because new tissue or scar have replaced damaged tissue -> Ultimate healing
Platelet count in DIC
Decreased platelet count - platelets consumed making tons of platelet-fibrin thrombi
PT/PTT in DIC
Increased PT/PTT - Coag factors consumed making tons of platelet-fibrin thrombi
Why are there Fibrin Split Products in DIC?
Fibrin degradation products (FDPs) aka fibrin split products, are produced when the clot and fibrin net dissolve,
Elevated fibrin split products, particularly D-dimer (this is the product of cleaved cross-linked fibrin that is necessary )
D dimer is derived from?
splitting of cross-linked fibrin; D-dimer is not produced from splitting of fibrinogen.
What will blood smare show in DIC?
Shistocytes - because all these thrombi cause Microangiopathic hemolytic anemia
Treatment of DIC involves?
addressing the underlying cause and transfusing blood products and cryoprecipitate (comains coagulation factors), as necessary.
What is the best screening test for DIC?
Elevated D-dimer because it means that coagulation has been activated to such a degree that there is now breakdown of clots already
What does normal fibrinolysis do?
Normal fibrinolysis removes thrombus after damaged vessel heals
Tissue plasminogen activator (tPA)
converts plasminogen to plasmin
What does Plasmin do?
1) cleaves fibrin (breaking up clot)
2) Cleaves serum fibrinogen and destroys coagulation factors (so future thrombus can’t be made ->shutting down the whole coag system )
3) Blocks platelet aggregation (so new clot can’t be initiated)
alpha-2-antiplasmin does what?
inactivates plasmin, so that people won’t bleed out if the actually need to form a clot
What are the disorders of fibrinolysis due to? What does this result in?
Abnormal plasmin overactivity without actual need for fibrinolysis ->resulting in excessive cleavage of serum fibrinogen.
Situations that lead to fibrinolysis?
1) radical prostatectomy
2) cirrhosis of the liver
How does radical prostatectomy lead to a disorder of fibrinolysis?
Release of urokinase activates plasmin
Elevated expression levels of urokinase and other components of the plasminogen activation system are correlated with tumor malignancy
the tissue degradation following plasminogen activation facilitates tissue invasion and, thus, contributes to metastasis
How does cirrhosis of the liver lead to a disorder of fibrinolysis?
reduced production of alpha -2-antiplasmin (liver product that inactivates plasmin) -> plasmin overactivity
How does disorders of fibrinolysis present?
Increased bleeding (VERY SIMILAR to DIC)
Laboratory findings for disorders of fibrinolysis include
1) Increased PT/PTT
2) Increased bleeding time with normal platelet count
3) Increased fibrinogen split products without D-dimers
Why is there increased PT/PTT with disorders of fibrinolysis?
because plasmin degrades coag factors and fibrinogen
Why is there increased fibrinogen split products without D-dimers in disorders of fibrinolysis?
Serum fibrinogen is lysed; however, D-dimers are not formed because fibrin thrombi are absent
Fibrinogen degraded by plasmin, but since this is abnormal plasmin activation and there are no fibrin clots to break down, there will be no D-dimers (because D-dimers are the result of cross-linked fibrin cleavage)
Why is there increased bleeding time with disorders of fibrinolysis?
Plasmin blocks platelet aggregation and overall coagulation severely disrupted but Platelets not affected by plasmin
Why are D-dimer levels critical for differentiating DIC from Disorders of Fibrinolysis
Both cause bleeding, but #1 screening test for DIC is D-Dimer because tons of microthrombi form and then break down releasing Fribrin Split Products.
In Disorders of Fibrinolysis there aren’t tons of thrombi, so no D-dimer. Instead, it is due to pathologic plasmin overactivity.
What is the treatment for disorders of fibrinolysis?
it is aminocaproic acid, which blocks activation of plasminogen.
What is thrombosis?
Pathologic formation of an intravascular blood clot (thrombus) obstructing the flow of blood through a vessel
Can occur in an artery or vein
What is the most common location for thrombosis?
it is the deep veins (DVT) of the leg below the knee
What is thrombosis characterized by?
lines of Zahn and attachment to vessel wall
What are the lines of Zahn?
alternating layers of platelets/fibrin and RBCs
How to distinguish thrombus from a postmortem clot?
Because as blood pools after death, all the blood in the vessels coagulates,
HOWEVER post-mortem clot WILL NOT HAVE
lines of Zahn and attachment to vessel wall
What are three major risk factors for thrombosis?
Virchow triad
1) Disruption in blood flow
2) Endothelial cell damage
3) Hypercoagulable state
What is normal blood flow?
Blood flow is normally continuous and laminar (layered = not turbulent); this keeps platelets and factors dispersed and inactivated because they are not actively mixing.
What happens to blood flow that causes an increase in the risk for thrombosis?
1) Stasis
2) Turbulence of blood flow
increase risk for thrombosis because platelets and factors start mixing and getting activated
What are some examples of disruption of normal blood flow?
1) Body Immobilization -> increased risk of DVT
2. Cardiac wall dysfunction (e.g arrhythmia or myocardial infarction) (Atria stop moving blood properly, OR post -MI damage to section of heart wall can cause slowed movement of blood in that area)
3. Aneurysm - balloon-like dilatation of a portion of a blood vessel leading to turbulent instead of laminal flow
How does endothelial cell damage increase the risk for thrombosis?
Endothelial damage disrupts the protective function of endothelial cells, increasing the risk for thrombosis
How do endothelial cells prevent thrombosis?
- Block exposure to subendothelial collagen and underlying tissue factor
- Produce prostoglandin I2, which blocks platelet aggregation (PGI2 = opposite of Thromboxane A2 produced by platelets) and NO which causes vasodilation that helps restore laminar flow and therefore
- Secrete heparin-like molecules (HLM), which activates AT3 (anti-thrombin 3) which gets rid of thrombin and other coag factors (Remember: thrombin (from Factor 2 is generated from coag cascade and cross-links fibrin))
- Secrete tissue plasminogen activator (tPA), which converts plasminogen->pasmin. (Plasmin has 3 functions: 1. cleaves fibrin in existing clot, / cleaves serum fibrinogen so that new clots can’t form 2. destroys coag factors 3. blocks platelet aggregation )
- Secrete thrombomodulin - takes thrombin and modulates its activity to do something else. (thrombin converts fibrinogen to fibrin, which allows cross-linking fibrin to form stable platelet-fibrin thrombus). Thrombomodulin REDIRECTS thrombin to INSTEAD Activate Protein C (inactivates Factors5,8 - important Amplifying factors in Coag Cascade)
How does endothelial cells use the secretion of tPA to prevent thrombosis?
converts plasminogen to plasmin, which (1) cleaves fibrin and serum fibrinogen, (2) destroys coagulation factors, and (3) blocks platelet aggregation
How does the secretion of thrombomodulin from endothelial cells prevent thrombosis?
redirects thrombin to activate protein C, which inactivates factors V and VIII
How do endothelial cells use the secretion of heparin-like molecules to prevent thrombosis?
augment antithrombin III (ATIII) which inactivates thrombin and coagulation factors
How does endothelial cells use the production of prostacyclin (PGI2) and NO to prevent thrombosis?
vasodilation and inhibition of platelet aggregation
What are the causes of endothelial cell damage?
1) atherosclerosis - endothelial damage -> major risk factor for thrombosis
2) vasculitis
3) high levels of serum homocysteine
Vitamin B12 and folate deficiency result in?
mildly elevated homocysteine levels, increasing the risk for thrombosis.
What does folic acid circulate as?
methyl-THF (tetrahydrofolate, THF) in the serum
How does THF participate in the synthesis of DNA precursors?
Methyl is added to THF (tetrahydro-folate) absorbed from the gut.
In order for THF to participate in DNA synthesis, Methyl group transferred to cobalamin (vitamin B12) = Methyl-B12
Cobalamin transfers methyl to homocysteine resulting in methionine
What does a lack of vitamin B12 or folate lead to thrombosis?
Methyl can’t be transferred to Homocysteine
Therefore, decreased conversion of homocysteine to methionine resulting in buildup of homocysteine
Homocysteine damages endothelial cells -> thrombosis
Cystathionine beta synthase (CBS) deficiency results in what?
high homocysteine levels with homocystinuria,
What does CBS do?
CBS converts homocysteine to cystathionine
CBS deficiency leads to?
homocysteine buildup
CBS deficiency is characterized by?
1) endothelial damage->vessel thrombosis (25% of these patients die at young age due to thrombosis)
2) mental retardation
3) lens dislocation
4) long slender fingers
what is a hypercoagulabe state due to?
Disrupted balance between procoagulant proteins and anticoagulant proteins
Excessive procoagulant proteins or Deficient anticoagulant proteins
may be inherited or acquired
What is the classic presentation of a hypercoagulable state?
recurrent DVTs, or DVT at a young age
usually occurs in the deep veins of the leg
Hepatic and Cerebral veins also occur
What are some causes of a hypercoagulable state?
1) Protein C and S deficiency
2) Factor V Liden deficiency
3) Prothrombin 20210A
4) ATIII deficiency
5) Oral Contraceptives
protein C or S deficiency
(autosomal dominant) decreases negative feedback on the coagulation cascade (hypercoagulable state)
Proteins C and S normally do what?
Anticoagulants: Inactivate factors V and VIII (Remember: Amplifying factors in coagulation cascade)
Protein C and S deficiency increases the risk for what?
warfarin skin necrosis
What does the initial stage of warfarin (Coumadin) therapy result in?
a temporary deficiency of proteins C and S (due to shorter half-life) relative to factors II, VII, IX, and X
warfarin (Coumadin) blocks epoxide reductase in the liver so VitK can’t be activated -> Inability to activate Factors 2, 7, 9, 10, and Protein C, S (anticoagulant factors). Since all of these factors degrade, they will start running out. Since the anticoagulant Protein C, S, run out first (shortest 1/2 life), but Factors 2, 7, 9, 10 are still around, there is an Increased risk of thrombus. We normally start Heparin simultaneously with Coumadin, to protect patient until Factors 2, 7, 9, 10 run out as well.
In preexisting C or S deficiency, what danger does the initial stage of warfarin therapy present?
a severe deficiency in Protein C+S is seen at the onset of warfarin therapy (because levels of Protein C+S were low to begin with) dramatically increasing the risk for thrombosis, especially in the skin -> necrosis of skin (called coumadin skin necrosis)
What is Factor V Leiden?
a mutated form of factor V that lacks the cleavage site for deactivation by proteins C and S. Therefore Factor V is overactive, and causes hypercoagulable state
What is the most common inherited cause of hypercoagulable state?
Factor V Leiden
What is Prothrombin 20210A?
it is an inherited point mutation in non-coding region of prothrombin gene results in overexpression of prothrombin
Increased prothrombin (prothrombin 20210A) results in what?
increased thrombin, promoting thrombus formation.
What does ATIII deficiency result in?
decreases the protective effect of heparin-like molecules produced by the endothelium, increasing the risk for thrombus
What do heparin-like molecules normally do?
bind and activate ATIII, which in turn inactivates thrombin and coagulation factors
PTT following Standard Heparin dosing in patients with ATIII deficiency results in?
PTT will not rise because not enough ATIII to activate for anticoagulant effects
Pharmacologic heparin works by doing what?
binding and activating ATIII
High doses of heparin in someone with ATIII deficiency results in what?
activate limited ATIII; Coumadin is then given to maintain an anticoagulated state. Once you are no longer worried about Coumadin induced skin necrosis (because Factors 7, 8, 9,10 are now exhausted), you can stop the heparin.
How are oral contraceptives associated with a hypercoagulable state?
Estrogen induces increased production of coagulation factors, thereby increasing the risk for thrombosis
What is an embolism?
Intravascular mass that travels from bigger vessels and occludes downstream (smaller) vessels
What determines the symptoms of embolism?
Symptoms depend on the vessel involved
What is a thromboembolus due to?
a thrombus that dislodges from the wall of a blood vessel and lodges itself further down stream
What is the most common type of embolus?
thromboembolus (>95%)
Atherosclerotic embolus is due what?
to an atherosclerotic plaque that dislodges and gets stuck further downstream
Atherosclerotic embolus is characterized by what?
the presence of cholesterol clefts in the embolus, because only atherosclerotic plaques have cholesterol crystals
cholesterol clefts - a space caused by the dissolving out of cholesterol crystals in sections of tissue embedded in paraffin
Fat embolus is associated with what?
bone fractures, particularly long bones, and soft tissue trauma
When does a fat embolus develop?
while fracture is still present or shortly after repair
What is fat embolus characterized by?
dyspnea (fat, often with bone marrow elements, is seen in pulmonary vessels (because usually get lodged in lung) and petechiae on the skin overlying the chest
Gas embolus is classically seen in what?
decompression sickness.
Decompression sickness
Initially as diver went down, high pressure caused N2 gas to dissolve in blood
Nitrogen gas then precipitates out of blood due to rapid ascent by a diver (gas embolus)
What does gas embolus presents with?
joint and muscle pain because N2 gas can get lodged in joints and muscles (bends)
and
respiratory symptoms when embolize in the lung (chokes)
Caisson disease
Chronic form of gas emboli from Nitrogen-> infarction of the bone (from multiple dives) -> multifocal ischemic necrosis of bone
Gas embolus and laproscopic surgery?
may also occur during laparoscopic surgery (air is pumped into the abdomen, could then get into bloodstream-> air embolus)
Amniotic fluid embolus
amniotic fluid enters maternal circulation during labor or delivery -> usually embolizes to lung circulation
How does amniotic fluid embolus present?
with shortness of breath, neurologic symptoms (emboli in brain), and DIC (because tissue thromboplast in amniotic fluid -> activates coag cascade)
How is amniotic fluid embolus characterized?
by squamous cells and keratin debris, from fetal skin, in the embolus that sloughed into amniotic fluid
pulmonary embolism is usually due to?
thromboembolus;
What is the most common source of thromboembolus?
deep venous thrombus (DVT) of the lower extremity usually involving the femoral, iliac, or popliteal veins
Pulmonary embolism is most often clinically silent because?
1) the lung has a dual blood supply via pulmonary and bronchial arteries
2) emboli are usually small, so once londged in lung it gets lysed (self-resolves)
When does pulmonary infarction occur?
if it is a big embolus that can obstruct a large- or medium-sized artery (the bigger the vessel the greater the damage) is obstructed
AND
pre-existing cardiopulmonary compromise (because dual blood supply will be consequently compromised)
only 10% of PEs cause infarction
How does pulmonary infarction present clinically?
- shortness of breath (because compromised blood flow not picking up enough O2)
- hemoptysis (infarction causes tissue to necrose and bleed out or backed up blood builds up pressure and bursts upstream vessel)
- pleuritic chest pain (from damage and stretching)
- and pleural effusion (blood forced out into intrapleural space)
In pulmonary infarction what does the V/Q lung scan show?
a mismatch; perfusion is abnormal
In pulmonary infarction what does the spiral CT show?
a vascular filling defect in the lung -> indicating an embolus blocking blood supply within lung
What is useful in determining DVT?
lower extremity Doppler ultrasound is useful to detect DVT
In pulmonary infarction what happens the the D-dimer
it is elevated because the patient is lysing both the PE and the DVT
In pulmonary infarction what does gross examination reveal?
a hemorrhagic, wedge-shaped infarct
wedge shaped because blood supply in lung is dichotomously branching (like tree branch), so an embolus at a branch point knocks out two downstream branches, and results in infarct of tissue in between them
That’s why we say that the wedge points to the area of occlusion
It is hemmorhagic because a second blood supply brings blood to dead tissue, which is loose. To have hemorrhagic infarction you need:
1) blood to re-enter dead tissue
2) dead tissue needs to have loose consistency so it can be filled with blood
In pulmonary infarction sudden death occurs with?
a large saddle embolus that blocks both left and right pulmonary arteries
or
significant occlusion of a large pulmonary artery
In pulmonary infarction sudden death with a large saddle embolus, death is due to?
electromechanical dissociation -> heart is pumping but the blood supply is totally blocked. So, heart just pumping air. Without reoxygenated blood, tissues die quickly.
Pulmonary hypertension may arise with what?
chronic emboli that are reorganized over time.
When the body cannot reabsorb a pulmonary embolism (PE), it can trigger Chronic Thromboembolic Pulmonary Hypertension
Systemic embolism is usually due to?
thromboembolus
Where does systemic embolism most commonly arise?
in the left heart and travels down systemic circulation to occlude flow to organs, most commonly lower extremities
Where is Extrinsic Coag Pathway initiated
Outside of blood vessel?
How is Extrinsic Pathway initiated
FV7 leaves circulation and reacts with tissue factor (TF) expressed on fibroblasts and leukocytes
Activated (TF-FVIIa) complex Activates FIX and FX
What is the point of Extrinsic (TF Pathway)?
Generate “thrombin burst” = process by which thrombin, the most important constituent of the coagulation cascade, is released very rapidly
