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Transition to Clinical Medicine > Hemostasis > Flashcards

Hemostasis Flashcards

1
Q

Normal Hemostasis Sequence

A

Endothelial injury/dysfunction with reflex vasoconstriction

Clot initiation/formation: primary hemostasis

Clot propagation/stabilization: secondary hemostasis

Clot inhibition/cessation: antithrombotic activity

Clot dissolution: fibrinolysis

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2
Q

Virchow’s Triad

A

Endothelial injury or dysfunction
Hypercoagulability
Stasis (esp. on venous side, leads to thrombosis)

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3
Q

Activity post endothelial injury: 1- vasoconstriction

A

Reflex neurogenic vasoconstriction

Endothelin released from injured endothelial cells

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4
Q

Activity post endothelial injury: 2- primary hemostasis

A

forms primary hemostatic plug

Adhesion- activation- recruit- aggregate

vWF on exposed collagen causes platelet adhesion
Adhesion, thrombin (via PAR G-protein receptor) and
ADP cause platelet activation
Shape change
Platelets release granule contents (alpha granules- vWF, coag factor V, fibrinogen, p selectin, PDGF, TGF-beta; and delta, dense, granules- ADP, ATP, inoized calcium, serotonin, epinephrine)

Additional platelets recruited
Partially via released thromboxane (TxA2), platelets aggregate
GpIIb/IIIa attaches to circulating fibrinogen or vWF
Thrombin leads to irreversible platelet contraction via cytoskeletal changes

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5
Q

Activity post endothelial injury/ dysfunction: 3- Secondary hemostasis

A

(forms clot=thrombus)
Tissue factor release from injured subendothelial cells binding FVII
Coagulation cascade also initiated by phospholipid complex and Ca++ on platelet surface
Thrombin activation
Fibrin polymerization

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6
Q

PTT vs PT

A

PTT measures intrinsic cascade

PTT measures extrinsic cascade

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7
Q

What factors require vitamin K?

A

7, 9, 10 and 2

be aware that warfarin will cause trouble

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8
Q

Which factors are deactivated by antithrombin III?

A

12a, 11, 9a, 10a, 2a

note that unfractionated heparin will cause trouble here.

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9
Q

clotting in vivo

A

T.F. + Ca + VIIa –> IXa–> Xa–> IIa–> Ia

The rest is amplification/ activation via Thrombin (IIa)

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10
Q

activity post endothelial injury: 4- clot inhibition/ cessation

A

Clot stabilization and resorption:
Fibrin and platelet aggregate contracts to form “permanent” plug
Nearby healthy endothelial cells secrete tissue plasminogen activator and thrombomodulin

Inhibition of Platelet Functions:
Endothelial prostacyclin (PGI2) inhibits aggregation
Endothelial nitrous oxide inhibits adhesion and aggregation
Endothelial adenosine diphosphatase destroy ADP inhibiting aggregation

Proteins C & S
Thrombomodulin on endothelial cells surface binds thrombin
This complex, in combination with the endothelial protein C receptor, activates circulating protein C (which was originally produced by endothelial cells)
Activated protein C in the presence of proteins S inhibits
Va
VIIIa
Activated protein C is inhibited by protein C inhibitor

Antithrombin
Antithrombin = antithrombin III
Other “antithrombins” (I, II, IV) are not antithrombin
Activated by heparan sulfate proteoglycans on the endothelial cell surface
Neutralizes activated serine proteases:
IIa=thrombin
IXa
Xa
(XIa and XIIa)
(+/- VIIa and VIIIa)
Antithrombin’s binding reaction is amplified 1000-fold by heparin
Noprolongation of PT after injecting a standard dose of heparin (but will see it with overdosage)

Tissue Factor Pathway Inhibitor
Tissue factor pathway inhibitor on the endothelial cell surface, in the presence of protein S, inhibits
VIIa/TF complex
Xa

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11
Q

Activity post endothelial injury: clot dissolution

A

= fibrinolysis

Plasmin
Endothelial cells secrete tissue plasminogen activator
Transforms plasminogen to active plasmin
Can be inhibited by plasminogen activator inhibitor in plasma
Plasmin is also made by an alternate factor XII-dependent pathway
Factor XII deficiencies produce a hypercoagulable state
Plasmin breaks down fibrin (& fibrinogen)
Breakdown leads to formation of fibrin degradation products
D-dimers
Fibrin split products
Plasmin is inhibited by α2 plasmin inhibitor

Tissue Plasminogen Activator (t-PA)
from uninjured endothelial cells binds to fibrin and forms plasmin from plasminogen

XIIa pathway via coagulation cascade converts plasminogen to plasmin

Urokinase (first isolated from urine)
from endothelial cells, etc. converts plasminogen in circulation into plasmin

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12
Q

Antithrombotic/ Fibrinolytic stuff

A

Prostacyclin (PGI2)
Nitrous oxide (NO)
Adenosine diphosphatase
Thrombomodulin
- Activates Protein C
Activated Protein C
-Inactivates Va and VIIa
Heparin-like molecules activate antihrombin
Antithrombin
- Inactivates thrombin (IIa), Xa and IXa
Tissue factor pathway inhibitor
- Inactivates VIIa/TF complex and Xa
Tissue plasminogen activator activates plasmin
Factor XII pathway activates plasmin
Plasmin breaks down fibrin

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13
Q

Any disruption in the balance between clot formation and clot dissolution results in

A

Hemorrhaging due to Anti-Coagulation OR Thrombosis due to Hypercoagulation

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14
Q

Thrombosis

A

Thrombus
Clot that has grown larger than required for its physiologic role as a hemostatic plug
Arterial
Diminished (→ischemia) or occluded
(→ infarction) blood flow distal to the thrombus location

Venous
Vascular congestion and edema proximal to the obstruction of blood flow
Can have lines of Zahn

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15
Q

Fates of thrombi

A

Propagation – Continue to grow
Embolization - Dislodge and travel to other sites
Dissolution - Fibrinolysis
Organization and recanalization in older thrombi

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16
Q

organization is

A

scarring (collagen in the thrombus, etc.)

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17
Q

hypercoagulable disorders, genetic and acquired (only the important ones)

A

Hyperhomocysteinemia, heterozygous (genetic)
medium important genetic ones: Factor V Leiden, Prothrombin G20210A mutation

Acquired:
Antiphospholipid antibody syndrome
(lupus antioagulant)
Hyperhomocysteinemia (acquired)

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18
Q

Protein C deficiency

A

Occurs with hereditary deficiency, surgery, trauma, pregnancy, liver or renal failure, DIC and warfarin (Coumadin) use
Warfarin skin necrosis - Potential for heterozygote carriers of protein C deficiency to develop hemorrhagic skin necrosis when placed on warfarin
Causes cutaneous vessel thrombosis and concomitant skin necrosis

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19
Q

Factor V Leiden mutations in Factor V

A

“Activated Protein C Resistance”
Mutant V converts to Va and is fully functional in its coagulant role
Mutant has decreased affinity to Activated Protein C and is not deactivated

20
Q

Prothrombin G20210 A mutation

A

Causes increased prothrombin levels which are converted to working thrombin

21
Q

Heparin-Induced Thrombocytopenia Syndrome (HIT), type II

A

Unfractionated (and occasionally low molecular weight) heparin induces autoantibodies to a molecular complex with Platelet Factor 4
1-5% of patients with repeated use of heparin
Patients have thrombocytopenia and disseminated clots
Autoantibody-heparin-platelet complexes activate platelets and cause endothelial injury, causing a prothrombotic state

22
Q

Antiphospholipid autoantibodies

A

Patients may have SLE or other autoimmune disorders
Affinity for bound phospholipids on the platelet surface that are combined with coagulation factors Antiphospholipid antibodies detected clinically
Lupus anticoagulant detected during aPTT testing
False positive VDRL (syphillis) test (anticardiolipin autoantibody)
Recurrent venous or arterial thrombosis and/or fetal loss
One or more late-term
Morphologically healthy neonate at or before 34 weeks’ gestation because of severe preeclampsia or eclampsia or severe placental insufficiency
Three or more unexplained, consecutive, spontaneous abortions before 10 weeks’ gestation

23
Q

Homocysteine

A

Contributes to arterial and venous thrombosis and atherosclerosis with severe elevations
Seen with homozygous deficiency of cystathione β-synthetase (CBS) = homocystinuria
Heterozygous CBS and other abnormalities cause mild to moderate homocysteine elevations
Some data supports increased risk of ASCVD with moderate elevations
Reducing homocysteine levels in moderate homocysteinemia does not decrease ASCVD risk
Folic acid, pyridoxine, and/or vitamin B12 supplements can reduce plasma homocysteine concentrations

24
Q

Factor XII deficiency

A

Causes decreased plasmin activation and is prothrombotic

25
Q

Prothrombotic factors

A 
Factor V Leiden (protein C resistance)
Prothrombin G20210A
Elevated VIII, IX, XI or fibrinogen
Dysfibrinogenemia
Antithrombin III deficiency
Protein C deficiency
Protein S deficiency
Factor XII deficiency
Increased antifibrinolytic substances 
Polycythemia 
Hypergammaglobulinemia
Lupus inhibitor (antiphospholipid antibody)
Malignancies
Nephrotic syndrome
ESTROGEN (oral contraceptives)
Thrombotic thrombocytopenic purpura
Disseminated intravascular coagulation
Heparin induced thromocytopenia
26
Q

Stasis stuff

A 
Prolonged immobilization   
  Economy class syndrome
Myocardial infarction
Cardiomyoipathy 
Atrial fibrillation 
Atrial dilatation
Aortic aneurysms with no re-entry
Sickle cell anemia
27
Q

Endothelial injury stuff

A 
Turbulence 
Inflammation
 Atherosclerotic plaques
   Homozygous homocystinuria 
  Prosthetic valves
  Smoking
Aortic aneurysms with re-entry
Tissue injury
    -  Tissue factor release sets off coagulation cascade
     - Exposure of subendothelial connective tissue allows platelets to adhere to vWF
28
Q

Emboli

A

Embolus Detached intravascular solid, liquid, or gaseous mass that is carried by blood to a site distant from its point of origin
Thromboembolus is generally used when such a thrombotic fragment moves through the venous or arterial system to a different site
Systemic emboli = Arterial emboli that lodge in systemic capillary beds causing ischemia and necrosis of tissues (80% originate from mural thrombi)
Pulmonary Embolism (PE) = venous emboli lodge in pulmonary capillary bed causing shortness of breath and possibly right sided heart failure
#1 cause: deep vein thrombosis (DVT)
60 - 80% of pulmonary emboli are clinically silent
Paradoxical embolism – venous embolism that ends up in systemic circulation causing tissue ischemia and necrosis – How?

29
Q

Other forms of emboli

A 
Bone marrow
Fat
Tumor
Air
Nitrogen
Talc and metal oxides
Bullets
Amniotic fluid
30
Q

periorbital edema is a hint of what?

A

could be from nephrotic syndrome

  • frothy urine from high protein
31
Q

severe edema =

A

anasarca or hydrops

32
Q

different types of edema, esp: Abdominal (ascites), Pleural and Pericardial Cavities

A

Serous: CHF, hypoalbuminemia
Serosanguinous: Malignancy, trauma, ruptured MI, aortic dissection
Sanguinous: Hemopericardium (aortic/cardiac rupture)
Purulent: Infection
Chylous: Lymphatic obstruction
Malignant (neoplastic): Associated with malignant cells

33
Q

Hyperemia vs Congestion

A

Hyperemia
Arterial dilation lets more blood into the area
Blushing, etc.
Get erythema

Congestion
Heart failure
Blockage of venous outflow
Veins dilate and blood can exit into tissues

34
Q

Shock

A

A critical condition that is brought on by a sudden drop in blood flow through the body. The circulatory system fails to maintain adequate blood flow, sharply curtailing the delivery of oxygen and nutrients to vital organs.

Distributive shock (vasodilation)
Septic Shock (Gm+ bacteria #1) The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)
Neurogenic Shock
Anaphylactic Shock

Cardiogenic shock (cardicac pump failure)

Hypovolemic shock (intravascular volume loss) 
Hemorrhagic Shock

Obstructive shock (physical obstruction of blood circulation and inadequate blood oxygenation

3 types of shock according to Robbins
Cardiogenic - same
Hypovolemic - same
Shock associated with inflammation – closest to distributive shock above

35
Q

Mucocutaneous bleeding

A

(primary hemostasis defects) with petechiae, purpura, bruising, epistaxis, GI bleeding,
+/- menorrhagia
- Disorders of platelets, vWD, Bernard-Soulier syndrome, Glanzmann thrombasthenia, or vasculature

36
Q

Von Willebrand Disease (vWD)

A

Majority vWD: Mild deficiency - no significant bleeding symptoms
Severe disease with life-threatening bleeding in less than 0.1%
Types 1 and 3 have reduced quantity of circulating vWF
Type 3 also has low circulating factor VIII and severe bleeding resembles hemophilias
Type 2 vWD have qualitative defects

37
Q

Genetic Bleeding Disorders (Uncommon to Rare)

A 
Hemophilia A  (x-linked recessive or sporadic Factor VIII deficiency)
	Hemophilia B (x-linked recessive or sporadic Factor IX deficiency “Christmas Disease”) 
	Hemophilia C (autosomal recessive/haploinsufficiency Factor XI deficiency with no bleeding in joints but have prolonged bleeding post trauma and nose bleeds from high fibrinolytic activity ) 
	All other genetic cascade factor deficiencies
		Extremely rare
38
Q

acquired bleeding disorders (coagulation factor deficiencies)

A

Vitamin K deficiency -essential factor to a hepatic gamma-glutamyl carboxylase that adds a carboxyl group to glutamic acid residues on factors II, VII, IX and X, as well as Proteins S, C and Z
Anticoagulation
Unfractionated heparin: antithrombin III activation against IIa (thrombin), IXa, Xa, XIa & XIIa
LMW heparin: antithrombin III activation only against factor Xa (does not act on thrombin)
Warfarin (Coumadin): creates vitamin K dependent factor deficiency
“Washout”: Depletion factors by massive blood loss
Hepatic Failure: Lack of synthesis of factors (except VIII and vWF)
Disseminated Intravascular Coagulation (DIC): consumes all coagulation factors

39
Q

Platelet adhesion defects in step I

A

Step I
Adhesion - vWF:GpIb adhesion

Defects in adhesion
von Willebrand disease
Bernard-Soulier syndrome
Giant platelets with dark granules seen with Bernard-Soulier syndrome

Laboratory test
Ristocetin induced vWF:GpIb agglutination

Step 1, 1B, Bernard. Ristocetin tests for step 1, either vWD or Bernard

40
Q

Platelet adhesion defects in step II

A

Aggregation - fibrinogen or vWF binds to GpIIb/IIIa
Defects in aggregation
Glanzmann thrombasthenia

Laboratory test
ADP/collagen/epinephrine/arachidonic acid/thrombin agonist induced aggregation

Step 2, 2b, aggregation has 2 gs, lab test is anything that’s not ristocetin

41
Q

acquired platelet defects

A

Aspirin (ASA) and NSAIDs -potent, irreversible inhibitor of the enzyme cyclooxygenase (Tx A2 and PGs), antiplatelet effects of aspirin used in the prophylaxis and treatment of coronary thrombosis
Uremia- pathogenesis involves defects in adhesion, granule secretion, and aggregation.
Acquired platelet storage pool defects
SLE-platelet-specific autoantibodies and immune complexes bind platelet surface leading to platelet activation and secretion of granule contents
Cardiopulmonary bypass-platelet activation caused by contact with the membrane oxygenator
Thrombocytopenia – numerous etiologies

42
Q

Bleeding disorders: quantitative platelet deficiency

A

Acute Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
Childhood disease with acute onset (2 weeks post virus)
Self-limited (resolves spontaneously within 6 months)
Autoantibodies against platelet antigens (GpIIb-IIIa or Gp1b-IX)

Chronic ITP of Childhood
20% of Acute Childhood ITP will become chronic (>6 months)
Spontaneous remissions are rare

Chronic Immune (Refractory) Thrombocytopenic Purpura (ITP) of Adults (>6 months)
20 to 40 years; 3F:1M with no history of antecedent infection
Spontaneous remissions are rare (

43
Q

Thrombotic Microangiopathies (TMAs)

A

Group of disorders characterized by thrombocytopenia and microangiopathic hemolytic anemia, neurological symptoms (less likely in HUS), fever, and renal dysfunction (specially in HUS in children)
Hemolytic anemia with anisocytosis,, reticulocytosis and elevated LDH, and thrombocytopenia
PT and aPTT tests are usually normal (unlike DIC)

Thrombotic Thrombocytopenic Purpura
Congenital and idiopathic thrombotic thrombocytopenic purpura (TTP)
Usually deficiency of ADAMTS13 which degrades large vWF multimers
Sometimes secondary to acquired autoantibodies
Treated via plasma exchange removing antibodies and providing normal ADAMTS13
Secondary TTP (includes TMAs in patients with metastatic cancer)

Hemolytic Uremic Syndrome
STEC-HUS - Shiga toxin-producing E Coli (epidemic; typical) hemolytic uremic syndrome
E. coli strain O157:H7 producing bloody diarrhea (1993 Jack in the Box E. coli outbreak )
aHUS - atypical hemolytic uremic syndrome (activated alternate complement pathway)
HELLP syndrome - Hemolysis; Elevated Liver enzymes; Low Platelet count occurring in pregnant women with hypertension +/- proteinuria

Can also be induced by
Drugs (cyclosporine, chemotherapeutic agents)
Radiation
Bone marrow transplantation
Infections (HIV, pneumococcal sepsis)
Immune reactions (SLE, HIV, lymphoid neoplasms)

44
Q

DIC

A

Disseminated Intravascular Coagulation (DIC)

All the clotting steps are occurring simultaneously continuously EVERYWHERE!

Usually initiated by release of tissue factor or endothelial injury
Microthrombi 5-25 micron formed but NOT attached to vessel walls
Diffusely narrow or obstruct pre-capillary arterioles and capillaries
Leads to
Microantiopathic hemolysis (schiztocytes)
Consumptive coagulopathy
Prolonged PT and PTT
Platelet consumption
Bleeding
Ischemic tissue injury
Release of products d-dimer and fibrin split products

All the clotting steps are occurring simultaneously continuously EVERYWHERE!

Usually initiated by release of tissue factor or endothelial injury
Microthrombi 5-25 micron formed but NOT attached to vessel walls
Diffusely narrow or obstruct pre-capillary arterioles and capillaries
Leads to
Microantiopathic hemolysis (schiztocytes)
Consumptive coagulopathy
Prolonged PT and PTT
Platelet consumption
Bleeding
Ischemic tissue injury
Release of products d-dimer and fibrin split products

45
Q

difference between serum and plasma

A

whether it clotted or not.

Plasma– with anticoagulant
Serum– clot; cells + consumed clotting factors

Red tube: no anticoagulants in it. tests for electrolytes, proteins, lipid, drugs, etc.

Purple tube– CBC, sed rate, etc. (with EDTA)

Blue tube– for coagulation studies. Added citrate.

Transition to Clinical Medicine (6 decks)

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