Hematology: hemostasis

- clot
- enhance activation of coagulation: negatively charged phospholipid surface and receptors for coagulation factors.
- would healing: PDGF

Primary:
- vasoconstriction
- platelet aggregation (plug)

Secondary:
- coagulation (clotting)
- regulation and confinement (anticoagulation and fibrinolysis)

release vasoactive substances such as serotonin and TXA2

- sympathetic neural input
- vasoactive substances: serotonin and TXA2

COX1

COX2

- swelling
- disintegration of membrane
- release intracellular content

carboxyglutamic acid (GLA)

external factors that activate the cascade:
- tissue factor
- factor VII

Coagulation cascade:
- II
- VII
- IX
- X

Anti-coagulation
- protein C

XII (Hageman factor)

XI

IX

X

X

intrinsic

extrinsic

III( tissue factor/thromboplastin)

VII

Tissue factor(III)

VII-tissue factor complex activates X in extrinsic pathway.

But it can also activate IX in the intrinsic pathway.

- factor X
- factor V
- thrombin (II)
- fibrinogen (I)
- factor XIII

X

thrombin

fibrinogen

XIII

1. plasma inhibitors (anticoagulation):
- protein C (vit.K dependent): anti-V and anti-VIII (in the presence of protein S (vitK dependent)
- antithrombin III: antiserine protease, activity enhanced by heparin or haparin-like substances
- alpha2-macroglobulin: antiprotease

2. finrinolytic system
- plasminogen: convert to plasmin by tPA
- alpha2-antiplasmin: prevent plasmin acition outside the clot site or from happening too soon.

3. role of endothelium:
- thrombomodulin (TM)
- haparin
- tPA
- PGI2: inhibit platelet aggregation
- smooth nonwetable surface: no platelet adhesion

- by thrombin in the presence of TM.

- low levels of TM (intact vasculature) increases acitvated protein C.

antithrombin III
alpha-2 macroglobulin

protein C

antithrombin III

TM

PGI2

tPA

heparan

plasmin

alpha2- antiplasmin

1. hereditary
- hemophilia A
- hemophilia B
- vWD

2. Acquired
- decreased production of coagulation factors: liver disease, vitK deficiency, ingestion of coumarin compounds.
- inactivation of coagulation factors: inhibitors, DIC, enzymatic destruction of coagulation factors

3. Thrombocytopenia
- underproduction: marrow disease/suppression
- high destruction: ITP, splenic squestration, sepsis.

hemophilia A

hemophilia B (christmas disease)

vWD

hemophilia

vWF

- Warfarin lowers vitK.

- Warfarin initially decreases PC levels faster than coagulation factors.

desmopressin

acquired

1. vasoconstriction
- endothelin

2. antithrombosis
- PGI
- NO
- heparan
- TM
- tPA

3. prothrombosis
- vWF
- TF

endothelin

- vWF
- TF

- PGI
- NO
- TM
- heparan
- tPA

test extrinsic pathway: V, X, VII
* espacially factor VII

- test intrinsic pathway
- especially factor VIII, IX

- test platelet function

PFA

PTT

PT

platelet disorder

coagulation disorder

fibrinolytic disorders (factor XIII)

factor XII, HMWK, prekallikrein problem

factor XI problem

factor VIII, IX problem

- factor VII deficiency
- Vit K deficiency (early)
- warfarin ingestion

afibrinogenemia

dysfibrinogenemia

- factor II, V, X deficiency
- vitamine K deficiency (late)
- warfarin ingestion

- afibrinogenemia, dysfibrinogenemia
- heparin inhibitors
- fibrin/fibrinogen degradation products
- uremia
- lupus anticoagulants

specific or non-specific inhibitor syndromes

- factor XIII deficiency
- inhibitors or defective crosslinking

alpha2 plasmin inhibitor deficiency

Bernard-Soulier syndrome

Glanzmann's Thrombasthenia

- vascular wall abnormality
- reduced platelet number
- defective platelet function
- clotting factor deficiency

1) infections
- meningococcal
- endocarditis
- rickettsiosis

2) drugs: induce antobodies
3) Scurvy, ED, Cushing syndrome, Henoch-schonlein pupura, herediatry hemorrhagic telangiectasia
4) amyloid infiltration of blood vessels

- meningococcal
- endocarditis
- rickettsiosis

induce antibodies
deposition of immune complexes

excessive corticosteroid production -> protein wasting -> loss of perivascular support -> bleed

systemic hypersensitivity
- purpuric rash
- coliky abdominal pain
- polyathralgia
- acute glomerulonephritis

tortuous blood vessels within walls that bleed easily (epistaxis, tongue, mouth, GI)

perivascular deposition -> weakening of blood vessels

most commonly seen in plasma cell dyscrasia

Cushing syndrome

5. all the above

1) immunological
- ITP
- drugs: HIT, quinine, quinidine, sulfonamide.
- HIV

2) mechanical injury
- TTP
- HUS
3) sequestration
4) dilutional

1. aplastic anemia
2. leukemia
3. B12 deficiency
4. folate deficiency

IgG antibodies against GPIIb/IIIa and GPIb/IX

- nomral/increased megakaryocytes
- megathrombocytes in blood smear
- long TT
- normal PT, PTT

seen more in women under age 40.

- post-transfusion purpura
- neonatal purpura

TypeI:
- occur rapidly after onset of heparin therapy
- modest in severity
- clinically insignificant

TypeII:
- occur 5-14 days after onset of therapy
- antibody against platelet factor 4.
- thromosis and thrombocytopenia

other drugs: quinine, quinidine, sulfonamide

- megakaryocytes also infected -> apoptosis -> decreased platelet production
- dysregulation of B cell -> immune complexes with GPIIb/III -> decreased paletlet survival

- widespread formation of hyaline thrombi(platelet aggregates) in microcirculation
- deficiency in enzyme ADAMTS13 "vWF metalloprotease"
- often see neurologic problems

- absence of neurologic symptoms
- acute renal failure
- frequently in chidren (E. Coli O157:H7)

- defects in adhesion: Bernard-Soulier syndrome
- defects in platelet aggregation: Glanzmann's thrombasthenia
- disorders of platelet secretions: TXA2, ADP

- drugs: aspirin, NSAIDs
- uremia

Bernard-Soulier syndrome

Glanzmann thrombasthenia

Disorders of platelet secretion

TTP/HUS: normal PT and PTT
DIC: long PT and PTT (coagulation cascade involved too)

HUS:
- no neurologucal deficits
- prominent acute renal failure
- more often in children
- ADAMTS13 normal

XII

defects in platelet:
- spontaneous petechiae, purpura often

defects in coagulation factors:
- large post-traumatic ecchymoses/hematoma
- prolonged bleeding after a laceration or any surgical procedure

T.

Ex.
acquired: vit. K defiency
hereditary: vWD, hemophilia

- platelet: alpha granules
- endothelial cells: Weibel-Palade bodies

VIII is carried by very large?(small) vWF multimer.

- carry factor VIII
- mediate adhesion of platelets to endothelial cells

- kidney(major source): glomerular, tubular eqithelial cells
- liver: sinusoidal cells, Kuffer cells

normal: 12 hrs
vWD: 2.4 hrs

ristocetin agglutination test.

GPIb/IX

Type I

Type III

Type II: missence mutation leading to missing large and intermediate multimers

type III

pseudo vWD: increased binding -> less free large vWF multimers

vWD (type I and III)

- autoimmune
- malignancies
- infections
- cardiac defects
- hypothyroidism

vWD type III

- spontaneous bruise
- bruise in odd places
- large bruises
- multiple bruises

* menorrhagia, post-partum bleeding

- stress: raises vWF
- age: newborn has high levels of vWF
- hyperthyroid: induce vWD
- estrogen: raises vWF

- ristostein
- vWF antigen
- VIII activity
- multimer analysis

1) DDAVP (desmopressin): releases vWF from endothelial cell stores
- need to do a trial before therapy
- only use for type I
- limit hydration for 24 hrs after

2) factor VIII concentrates
- have only low vWF

3) cryoprecipitate:
- only when have to
- viral contamination

4) vWF concentrates
- coming soon

- Aspirin
- NSAID
- anti-Platelet drugs

hemophilia

All daughters are carriers
All sons are not affected

50% risk for daughter to be carriers
50% risk for sons to be affected

- DDAVP for moderate type
- factor VIII replacement (plasma or recombinant VIII/FIX): expensive
- anti-fibrinolytics: tranexamic acid, epsilon-aminocaproic acid.

- epsilon-aminocaproic acid
- tranexamic acid

*caution with GU bleed

- infections(HIV, HBV, HCV, B19, CJD, vCJD)
*HBV still has long window period for blood testing.
- immunogenicity

1) obstetric complications
- abruptio placentae
- toxemia
- amnionic fluid embolism

2) infections
- gram negative sepsis(meningococcemia)
- RMSF
- histoplasmosis, aspergillus
- malaria

3) neoplasms
- APL
- pancreatic cancer, lung cancer, prostate cancer

4) trauma, burns

DIC

inversion of X chromosome

hemophilia

F.

- release of tissue factor
- endothelial injury

- activate both intrinsic and extrinsic clotting pathway
- inhinit PC by suppressing thrombomodulin expression on endothelial cells.

1) ischemia, hemolytic anemia(chronic DIC): widespread deposit of fibrin within microcirculation

2) hemorrhagic diathesis (acute DIC): consumption of platelets and clotting factors, acitvation of plasmin.

Obstetric patients having complications with pregnancy.

carcinomatosis

- factor V laiden
- protein C deficits
- Protein S deficits
- antithrombin III deficits
- defects in fibrinolytic pathway.
- heparin cofactor II deficiency

- lupus antocoagulant: long PTT
- HIT