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Pathoma > 4: Hemostasis and Related Disorders > Flashcards

4: Hemostasis and Related Disorders Flashcards

1
Q

Hemostasis occurs in two stages. What is the difference between primary and secondary hemostasis?

A

Primary - weak platelet plug, mediated by interaction between platelets and vessel wall

Secondary - stabilizes the platelet plug, mediated by the coagulation cascade

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2
Q

Steps in primary hemostasis are as follows:

  1. Transient vasoconstriction of damaged vessel (reflex, endothelin release)
  2. Platelet ADHESION
  3. Platelet DEGRANULATION
  4. Platelet AGGREGATION

What is the mechanism of platelet adhesion?
BONUS: Where is vWf derived from?

A

Basically, platelet binds to vwf via the GP1b receptor.

vWf is derived from the Weibel-Palade bodies of endothelial cells and a-granules of platelets.

(Recall: “W-P” bodies - vWf and P-selectins or speed bumps in inflammation)

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3
Q

Steps in primary hemostasis are as follows:

  1. Transient vasoconstriction of damaged vessel (reflex, endothelin release)
  2. Platelet ADHESION
  3. Platelet DEGRANULATION
  4. Platelet AGGREGATION

Adhesion induces shape change in platelets and degranulation with release of multiple mediators.

What are these mediators (2) and their function?

A

ADP - promotes exposure of GPIIb/IIIa receptor on platelets (for aggregation)

TXA2 - synthesized by platelet cycloxygenase, promotes aggregation

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4
Q

Steps in primary hemostasis are as follows:

  1. Transient vasoconstriction of damaged vessel (reflex, endothelin release)
  2. Platelet ADHESION
  3. Platelet DEGRANULATION
  4. Platelet AGGREGATION

What mediates platelet aggregation?

A

Platelets aggregate via the GPIIb/IIIa receptor (recall ADP mediator from platelet degranulation) using fibrinogen (from plasma) as a linking molecule, thus forming a platelet plug.

This is weak, so we need the secondary hemostasis via the coagulation cascade to stabilize it.

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5
Q

Disorders of primary hemostasis are due to abrnomalities in platelets and is divided into quanti or qualitative disorders.

What are the usual clinical features involved?

A

Mucosal and skin bleeding

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6
Q

What are the symptoms of skin bleeding, differentiate. (3)

A

Petechiae - 1-2mm
Purpura - >3mm
Ecchymosis - >1cm
Easy bruising

Remember, these are a sign of thrombocytopenia nad are not usually seen with qualitative disorders.

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7
Q

Useful labs for disorders of primary hemostasis are as follows:

  1. Platelet count (what count leads to symptoms?)
  2. Bleeding time
  3. Blood smear
  4. Bone marrow biopsy

What do we expect in each

A

PC - Normal value is 150-400 K/uL; <50 leads to symptoms

Bleeding time - Normal is 2-7 minutes; prolonged with quanti and quali platelet disorders

Blood smear - Number and size of platelets

Biopsy - Assessment of megakaryocytes which produces platelets

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8
Q

Immune thrombocytopenia purpura (ITP) is the most common cause of thrombocytopenia in children and adults.

What is the basic pathology behind this disease?

What are the populations involved in its acute and chronic forms? Why can babies also have thrombocytopenia from this condition?

A

Autoimmune production of IgG against platelet antigens, e.g. GPIIb/IIIa, which functions for platelet aggregation.

These autoantibodies are produced by plasma cells in the spleen, and antibody-bound platelets are also consumed by splenic macrophages. Basically, the spleen is making and also consuming antibodies.

Acute - children after viral infection or immunization; self-limited
Chronic - adults, usually women of childbearing age; may be primary or secondary; may cause short-lived thrombocytopenia in offspring since IgG can cross the placenta.

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9
Q

Immune thrombocytopenia purpura (ITP) is the most common cause of thrombocytopenia in children and adults.

Labs include platelet count, PT/PTT, and biopsy. What do we expect in these?

A

PC - decreased, often <50 k/uL (symptomatic)

PT/PTT - NORMAL, since coagulation factors are not affected

Biopsy - increased megakaryocytes - BM tries to produce more platelets due to splenic destruction

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10
Q

Immune thrombocytopenia purpura (ITP) is the most common cause of thrombocytopenia in children and adults.

What is the treatment? (2)

A

IVIG - splenic macrophages eat IVIG instead. But effect is short-lived (once IVIG is consumed)

Splenectomy - elimination of source of antibody and site of platelet destruction (performed in refractory cases)

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11
Q

Microangiopathic hemolytic anemia = small vessel pathology leading to hemolytic anemia

What is the basic pathology behind this disease?

A

Pathologic formation of PLATELET MICROTHROMBI in small vessels.
Platelets are consumed in the formation of microthrombi, leading to thrombocytopenia.
RBC’s are sheared as they cross microthrombi, resulting in hemolytic anemia with schistocytes or helmet cells.

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12
Q

Microangiopathic hemolytic anemia = small vessel pathology leading to hemolytic anemia

This disease is found in thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS).

What is the pathology in TTP?

A

TTP - decreased ADAMTS13 which normally cleaves vWF multimers into smaller monomers for degradation

Uncleaved monomers lead to abnormal platelet adhesion (recall: in primary hemostasis, platelets bind to vwf via the gp1b receptor), resulting in microthrombi

Decreased ADAMTS13 is usually due to an acquired autoantibody, most commonly seen in adult females

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13
Q

Microangiopathic hemolytic anemia = small vessel pathology leading to hemolytic anemia

This disease is found in thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS).

What is the pathology in HUS? Where is this classically seen?

A

Due to endothelial damage by drugs or infection

Classically seen in children with E coli O157:H7 dysentery from undercooked beef. E coli verotoxin damages endothelial cells, resulting in microthrombi.

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14
Q

Microangiopathic hemolytic anemia = small vessel pathology leading to hemolytic anemia

This disease is found in thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS).

What are clinical findings here?

A

Skin and mucosal bleeding - recall, thrombocytopenia due to platelet destruction

Microangiopathic hemolytic anemia :)

Fever

Renal insufficiency (HUS) - thrombi involves vessels of the kidney

CNS abnormalities (TTP) - thrombi involves vessels of CNS

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15
Q

Microangiopathic hemolytic anemia = small vessel pathology leading to hemolytic anemia

This disease is found in thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS).

What are expected labs (CBC, PT/PTT, BM biopsy)

A

thrombocytopenia with increased bleeding time
normal pt/ptt (coagulation cascade not affected)
anemia with schistocytes
inc megakaryocytes on biopsy

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16
Q

Microangiopathic hemolytic anemia = small vessel pathology leading to hemolytic anemia

This disease is found in thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS).

Treatment? (2, particularly in TTP, which is autoimmune)

A

Plasmapharesis - remove proteins from blood, so you remove autoantibody against ADAMTS13

Corticosteroids - decrease production of autoantibody

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17
Q

Qualitative disorders of primary hemostasis include:

Bernard-Soulier syndrome - finding in blood smear?
Glanzmann thrombasthenia
Aspirin
Uremia

Pathologies?

A

BS syndrome - genetic GP1b deficiency - impaired platelet adhesion (Plt-VWF). Blood smear shows mild thrombocytopenia with enlarged platelets (“Big Suckers”). Decreased GP1b results in early platelet death (thrombocytopenia), production of immature platelets results in enlarged ones.

Glanzmann - genetic GPIIb/IIIa deficiency - impaired platelet aggregation

Aspirin - irreversible inactivator of cycloxygenase - lack of TXA2, impaired platelet aggregation

Uremia - disrupts platelet function - impaired both adhesion and aggregation

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18
Q

Secondary hemostasis stabilizes the weak platelet plug via the coagulation cascade.

What is the final end product of the coagulation cascade?

A

Generation of thrombin, which converts fibrinogen in the platelet plug into fibrin. Fibrin is then cross-linked, resulting in a stable thrombus.

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19
Q

What is the difference in clinical features between disorders of primary and secondary hemostasis?

A

Secondary - deep tissue bleeding into muscles and joints (hemarthrosis), rebleeding after surgical procedures (circumcision, wisdom tooth extraction)
Vs primary - skin and mucosal bleeding

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20
Q

Draw the coagulation cascade!
Include activating substance, lab parameter affected, which is used to monitor heparin/coumadin (warfarin) therapy. Heheee

A
  1. Start with 10 (“X”) - common pathway
  2. On the left side, write 12, 11, (skip 10 because you already wrote it) 9, 8. On the right side, write 7 (the next number)
  3. Below “X”, write 5, 2, 1 (5 x 2 x 1 = 10)
  4. Pet ni Brad Pitt!
    Left side has more numbers so it is measured by PTT (more letters) - intrinsic pathway - 12, 11, 9, 8 + common pathway
    Right side is therefore measured by PT - extrinsic pathway 7 + common pathway
  5. Activators!
    Left side has more numbers so it is activated by SEC (more letters) - subendothelial collagen
    Right side therefore activated by TT - tissue thromboplastin
  6. Monitoring therapy - Hep vs Cou
    Left side has more numbers so Hep (H is farther down the alphabet)
    Right side Cou (but this is also Warfarin so, haha)
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21
Q

Differentiate the pathology between Hemophilia A and Hemophilia B.

Both of these are genetic. What is the pattern of heredity?

A

Hemophilia A - “Hemophilia 8” - Genetic factor 8 deficiency
Hemophilia B - plus one - Genetic factor 9 deficiency. Resembles hemophilia A except f9 is decreased instead of f8.

X-linked recessive (predominantly affects males) but can also arise de novo

22
Q

What are the expected lab findings (PT/PTT, factor, PC and bleeding time) and treatment in Hemophilia A?

Treatment?

A

Inc PTT - recall PITT - intrinsic pathway, “PTT” - more numbers 12, 11, 9, 8…
Normal PT
Decreased factor 8
Normal platelet count and bleeding time

Tx: Recombinant factor 8

23
Q

Coagulation factor inhibitor is another disorder of secondary hemostasis wherein there is an qcquired antibody against a coagulation factor. What is the most common factor affected? How to differentiate this from a similar disorder?

A

Anti f8 is most common, hence similar clinical and lab findings to hemophilia A.

PTT does NOT correct upon mixing studies (mixing normal studies with patient’s plasma) due to the INHIBITOR. Meanwhile, PTT does correct in hemophilia A.

24
Q

Von Willebrand Disease is the most common inherited coagulation disorder, most common type is autosomal dominant.

This presents with mild mucosal and skin bleeding. Low vWF impairs platelet adhesion.

What are the expected lab findings (bleeding time, PT/PTT, Ristocetin)?

Treatment?

A

Inc bleeding time

Inc PTT! vWF is involved in primary hemostasis, so bakit affected?
vWF normally STABILIZES factor 8!
However, note that deep tissue/postsurgical bleeding are usually not seen.

Abnormal ristocetin test
Ristocetin induces platelet agglutination by causing vWF to bind platelet GPIb

Treatment is DESMOPRESSIN (ADH analog) which increases vWF release from Weibel-Palade bodies of endothelial cells

25
Q

Vitamin K deficiency disrupts the function of multiple coagulation factors.

What activates Vitamin K, and what can possibly block this enzyme?
What factors does this affect?

A

Activated by epoxide reductase in the liver
Coumadin blocks epoxide reductase!

Factors 9, 10, 7, 2 and proteins C and S

26
Q

Vitamin K deficiency disrupts the function of multiple coagulation factors.

Give 3 instances where this deficiency is found.

A

Newborn - lack of GI colonization since vitamin K is generated by gut bacteria. This is why we give prophylactic vitamin K injection to prevent hemorrhagic disease of the newborn!

Long term antibiotic therapy - disrupts Vitamin K producing bacteria in the gut

Malabsorption - deficiency of fat-soluble vitamins, including vitamin K

27
Q

Mechanism behind heparin-induced thrombocytopenia?

A

Heparin forms complex with platelets via PF4, to which IgG antibodies form against

Fragments of destroyed platelets may activate remaining platelets, leading to thrombosis

If observed, stop heparin and give another anticoagulant but not coumadin (inc risk for coumadin skin necrosis)

28
Q

Disseminated intravascular coagulation cascade (DIC) involves pathologic activation of the coagulation cascade.

Widespread microthrombi result in ischemia and infarction, while consumption of platelets and factors result in bleeding, especially from IV sites and mucosal surfaces.

Explain how this happens secondary to other disease processes (OB, sepsis, adenoCA, acute promyelocytic leukemia, rattlesnake bite)

A

OB - Tissue thromboplastin in amniotic fluid

Sepsis - esp with E Coli or N meningitidis - endotoxins from bacterial cell wall and cytokines (TNF, IL1) induce endothelial cells to make tissue factor (factor 3, complex with f7?)

AdenoCA - Mucin activates coagulation

Acute promyelocytic leukemia - Primary granules (recall: abnormal fusion -> Auer rods) activate coagulation

Rattlesnake - venom

29
Q

Disseminated intravascular coagulation cascade (DIC) involves pathologic activation of the coagulation cascade.

Widespread microthrombi result in ischemia and infarction, while consumption of platelets and factors result in bleeding, especially from IV sites and mucosal surfaces.

Lab parameters include decreased platelet count, inc PT/PTT, dec fibrinogen, microangiopathic hemolytic anemia, and most importantly…?

A

Elevated fibrin split products, especially D-Dimer - best screening test!

This is derived from splitting of cross-linked FIBRIN (not produced from splitting of fibrinogen) - this means that the whole coagulation cascade has happened

30
Q

Disseminated intravascular coagulation cascade (DIC) involves pathologic activation of the coagulation cascade.

Widespread microthrombi result in ischemia and infarction, while consumption of platelets and factors result in bleeding, especially from IV sites and mucosal surfaces.

Treatment?

A

Treat underlying cause

Transfusion of blood products and cryoprecipitate (contains coagulation factors) PRN

31
Q

Normal fibrinolysis removes thrombus after damaged vessel heals.

What actually cleaves fibrin and fibrinogen, and how is this activated? How is this inactivated?

A

tPA (tissue plasminogen) converts plasminogen into plasmin

which then cleaves fibrin and serum fibrinogen, destroys coagulation factors, and blocks platelet aggregation

a2-antiplasmin then inactivates plasmin.

32
Q

Disorders of fibrinolysis are due to plasmin overactivity resulting in excessive cleavage of serum fibrinogen.

Examples include radical prostatectomy and liver cirrhosis. How?

A

Radical prostatectomy - release of urokinase activates plasmin

Liver cirrhosis - reduced production of a2-antiplasmin

33
Q

Disorders of fibrinolysis are due to plasmin overactivity resulting in excessive cleavage of serum fibrinogen.

This presents with increased bleeding and resembles DIC.
What do we expect in PT/PTT, bleeding time, PC, split products? How to differentiate this with DIC?

A

Inc PT/PTT - plasmin destroys coagulation factors

Inc bleeding time with normal platelet count (vs DIC which consumes platelets) - plasmin blocks platelet aggregation

Inc fibrinogen split products WITHOUT D Dimer - fibrinogen is lysed, but D Dimers are not formed because walang fibrin thrombi!

34
Q

Disorders of fibrinolysis are due to plasmin overactivity resulting in excessive cleavage of serum fibrinogen.

Treatment?

A

Aminocaproic acid - blocks activation of plasminogen

35
Q

Thrombosis is the pathologic formation of an intravascular blood clot.

This is characterized by (2)

A

Lines of Zahn (alternating layers of platelets/fibrin and RBCs)

Attachment to vessel wall

These distinguish a thrombus from a post mortem clot.

36
Q

Major risk factors for thrombosis (3)

A

Virchow triad

Disruption of blood flow
Endothelial cell damage
Hypercoagulable state

37
Q

Examples of disruption of normal blood flow (3)

A

Immobilization
Cardiac wall dysfunction (arrhythmia, MI); ex. Afib prone to thrombus formation in atrium
Aneurysm

38
Q

Endothelial damage disrupts the protective function of endothelial cells, increasing the risk for thrombosis.

Endothelial cells prevent thrombosis by several mechanisms.

  1. It blocks exposure to ____ and underlying tissue factor
  2. It produces ____ (hint: opposite of TXA2)
A

Blocks exposure to subendothelial collagen and underlying tissue factor

Produces prostacyclin (PGI2) and NO - for vasodilation and inhibition of platelet aggregation

PGI2 vs TXA2
PGI2 - endothelium, vasodilation, inhibit aggregation
TXA2 - platelet, vasoconstriction, promote aggregation

39
Q

Endothelial damage disrupts the protective function of endothelial cells, increasing the risk for thrombosis.

Endothelial cells prevent thrombosis by several mechanisms.

  1. It secretes heparin-like molecules, tPA, and thrombomodulin.

What are the functions of these substances?

A

Heparin-like molecule
Augment antithrombin III (ATIII), which inactivates thrombin and coagulation factors

tPA
Convets plasminogen to plasmin, which:
Cleaves fibrin and serum fibrinogen
Destroys coagulation factors
And blocks platelet aggregation

Thrombomodulin
Modulates/redirects thrombin to activate protein C, which inactivates Factors 5 and 8!

40
Q

Causes of endothelial cell damage include atherosclerosis, vasculitis, and high levels of homocysteine.

High levels of homocysteine can be the result of 1) Vitamin B12 and folate deficiency, and 2) Cystathionine beta synthase (CBS) deficiency.

What is the pathology of the first?

A

Essentially cannot convert homocysteine into methionine, resulting in mildly elevated homocysteine.

Folic acid (THF) circulates as methyl-THF.
Methyl is transferred to Vitamin B12/Cobalamin to allow THF to be used in the synthesis of DNA precursors.
Methyl is then transferred from VB12 to homocysteine resulting in methionine.
Lack of VB12 or folate therefore leads to buildup of homocysteine which cannot be converted to methionine.

41
Q

Causes of endothelial cell damage include atherosclerosis, vasculitis, and high levels of homocysteine.

High levels of homocysteine can be the result of 1) Vitamin B12 and folate deficiency, and 2) Cystathionine beta synthase (CBS) deficiency.

What is the pathology of the second?

A

CBS deficiency results in high homocysteine levels with homocystinuria.

CBS converts homocysteine to cystathionine. Deficiency therefore causes high homocysteine levels.

Characterized by vessel thrombosis, mental retardation, lens dislocation, long slender fingers (genetics).

42
Q

Hypercoagulable state occurs due to excessive procoagulant proteins or defective anticoagulant proteins and may be inherited or acquired.

What is the classic presentation of hypercoaguable state?

A

Recurrent DVTs or DVT at a young age (usually in deep veins of the leg, other sites include hepatic and cerebral veins)

43
Q

Hypercoagulable state occurs due to excessive procoagulant proteins or defective anticoagulant proteins and may be inherited or acquired.

Protein C or S deficiency (autosomal dominant) is an example of a condition which can result in a hypercoagulable state. What is the mechanism and what is the patient especially at risk for?

Bonus: How would you manage this patient?

A

Ptn C and S normally inactivate factors V and VIII (recall function of thrombomodulin)

There is increased risk for warfarin skin necrosis
Recall that warfarin blocks epoxide reductase
This leads to decreased activation of vitamin K, which then leads to less carboxylation of Factors 9, 10, 7, 2, and Proteins C and S.
Ptn C and S, having a shorter half life, would then degrade first. There is then a relative deficiency, mas maraming procoagulant than anticoagulants.

In a patient with Protein C or S deficiency, there is an even more severe deficiency at the onset of warfarin therapy, leading to inc risk for thrombosis, especially in the skin!

In management, when giving warfarin, also give simultaneous heparin in this window period when the factors are not yet destroyed, para mas balanced.

44
Q

Hypercoagulable state occurs due to excessive procoagulant proteins or defective anticoagulant proteins and may be inherited or acquired.

What is the most common inherited cause of hypercoagulable state? (Hint: mutation of a factor)

What mutation leads to increased thrombin?

A

Factor V Leiden is a mutated form of factor V that lacks the cleavage site for deactivation of proteins C and S. Recall that these proteins inactivate Factors 5 and 8.

Prothrombin 20210A is a point mutation that leads to increased gene formation of prothrombin.

45
Q

Hypercoagulable state occurs due to excessive procoagulant proteins or defective anticoagulant proteins and may be inherited or acquired.

What is the condition that decreases the protective effect of heparin-like molecules produced by endothelium?

How does this condition affect the efficacy of heparin and how do you manage this?

A

ATIII deficiency
Recall that this inactivates thrombin and coagulation factors

In patients with ATIII deficiency, PTT does not rise with standard heparin dosing, kasi parang wala nang effect yung heparin. Wala naman kasing ATIII.
So, give high levels of heparin which activates the lmited ATIII that you have, then coumadin to maintain this anticoagulated state.

46
Q

Hypercoagulable state occurs due to excessive procoagulant proteins or defective anticoagulant proteins and may be inherited or acquired.

How is OCP associated with hypercoagulable state?

A

Estrogen induces increased production of coagulation factors

47
Q

An embolus is an intravascular mass that travels and occludes downstream vessels.

Types:
Thromboembolus - most common type (>95%)
Atherosclerotic embolus - characterized by?
Fat embolus - associated with? Clinical picture?
Gas embolus - seen in?
Amniotic fluid embolus - during?

A

Atherosclerotic- characterized by cholesterol clefts in embolus

Fat embolus - bone fractures, ST trauma; dyspnea (fat goes to pulmonary vessels), petechiae on skin overlying the chest

Gas embolus - decompression sickness, laparoscopic surgery

Amniotic fluid - during labor or delivery

48
Q

Gas embolus mechanism? Presentation? (2)

Chronic form?

A

Nitrogen gas precipitates out of blood during rapid ascent of diver

Joint and muscle pain (bends) and respiratory symptoms (chokes)

Caisson disease - multifocal ischemic necrosis of bone

49
Q

Amniotic fluid embolus presentation? (3)

Characterized by?

A

Dyspnea, neurologic symptoms, DIC (thrombogenic nature of amniotic fluid - recall, contains tissue thromboplastin? or factor 3/tissue factor…?)

Characterized by squamous cells and keratin debris o_o

50
Q

Why are pulmonary emboli usually clinically silent? (2)

A

1) Lung has dual blood supply (pulmonary, bronchial arteries)
2) Embolus is usually small and self-resolving

51
Q

Pulmonary infarction occurs if (2)

A

1) large or medium sized artery is obstructed
2) in patients with pre-existing cardiopulmonary compromise

Only 10% of PEs cause infarction

This is also associated with SOB, hemoptysis, pleuritic chest pain, and pleural effusion.

VQ mismatch, abnormal perfusion
Vascular filling defect in spiral defect
LE doppler for detection of DVT
Elevated D Dimer
Hemorrhagic wedge-shaped infarct (wedge due to branching of vessels; hemorrhagic bc of dual blood supply - blood reenters loose tissue)
52
Q

Systemic embolism most commonly arise from and usually travels where

A

Arise in the left heart

Travel down systemic circulation, most commonly LE

Pathoma (2 decks)

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