Bleeding disorders and Thrombocytopenia Flashcards Preview

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Flashcards in Bleeding disorders and Thrombocytopenia Deck (30):
1

What is the definition of hemostasis and what are the general overarching steps?

Hemostasis: process that prevents blood loss from damaged blood vessels

Vasoconstriction

Adhesion, activation and cohesion of platelets (platelet plug)

Clot stabilization by fibrin

2

What are some important receptors on platelets?

GPIa/IIa

GPIIb/IIIa

GPIbalpha

GPVI

3

GPIa/IIa

GPIIb/IIIa

GPIbalpha

GPVI

GPIa/IIa               Collagen/Adhesion

GPIIb/IIIa             Fibrinogen/Aggregation

GPIbalpha           von Willebrand Factor/Adhesion

GPVI                     Collagen/Adhesion

4

What types of granules are in platelets?

Dense granules

Alpha granules

5

In platelets,

What do Dense Granules contain?

What do Alpha Granules contain?

Dense: ADP, ATP, Serotonin, Ca2+

(ADP and ATP receptors are also on platelets)

 

Alpha:

Coagulation proteins: F-v, Fibrinogen/vWF

Growth factors:TGF-beta/PDGF

Platelet factor 4

6

What are activating substrates for platelets?

What are their respective receptors?

What intracellular signaling goes on?

What actions are a result of activation?

ADP/5'-HT/TxA2/Thrombin

P2Y1/SR/TxR/PAR1/PAR4

Gq, PLCbeta increasing IP3 and DAG

Integrin activation/Granule secretion/Cytoskeletal rearrangements (shape change)

7

Steps of platelet adhesion?

Endothelial damage

Collagen exposed

vWF sticks

Platelets adhere

8

Compare

Arterial thrombosis

to

Venous thrombosis

Arterial thrombosis: injury of blood vessel wall

Venous thrombosis: altered blood flow/hypercoagulability

9

What are the steps to platelet adhesion?

Damage exposes collagen

von Willebrand factor in plasma sticks to collagen and becomes activated, expressing domains GPIb and GPIIb/IIIa

Platelets GPIb receptors bind vWF

Platets release granules, activating other platelets (free, not adhesed to epithelium)

Membrane procoagulant expression leading to thrombin and clot (more phosphatidylserine)

Platelet cohesion via fibrinogen bridges (activated platelets activate fibrinogen receptors which is constitutively in the plasma phase)

Result: primary platelet plug. But not stable (so requires coagulation)

10

What is cell based coagulation?

Series of transformations of proenzymes to activated enzymes resulting in formation of thrombin (IIa) driving fibrin clot formation.

11

What are the steps to cell based coagulation?

I. Initiation: Tissue factor/VIIa activate factor IXa and Xa

II. Amplification: Initial thrombin activation Va, VIIIa, XIa, and platelets

III. Propagation: XIa augments process by driving further IXa formation. IXa catalyzes further thrombin formation on platelets

IV. Thrombin drives transformation of fibrinogen to fibrin and crosslinking

12

What are the vitamin K dependent proteins?

Why do they require Ca2+ for action?

2, 7, 9, 10 (pro-coagulant)

Protein C and S (anticoagulant)

These contain alpha-glutamic acids that are carboxylated, negatively charged able to sit down on membranes through mechanism involving Ca2+ ions to neutralize the negative charge).

13

What type of protein is Thrombin

What is it's mechanism?

Is it stable at this point?

Thrombin is a protease

Binds to fibrinogen and cleaves fibrinopeptides, generating fibrin monomers consisting of one E domain and two D domains. Adjacent monomers self-assemble.

 

Not stable. Needs factor 13 (which is activated by thrombin) which makes peptide bonds to crosslink polymerizations covalently

14

Compare and contrast PT vs. PTT

PT/Tissuefactor/VII/Extrinsic

PTT/surface factors/XI, IX/Intrinsic (deficiency can be asymptomatic because not important for systemic coagulation

15

What is the fibrinolytic system comprised of?

Each of their actions?

t-PA, Plasminogen, alpha2-antiplasmin, D-dimer

t-PA-Activates plasminogen to plasmin

Plasminogen activates to plasmin, which degrades fibrin clots (main targeT) as well as factors VIII, V

Alpha2 antiplasmin-degrades plasmin

16

How does inflammation and injury favor thrombosis?

Inflammation: tissue factor

Injury: exposed collagen

17

How is thrombosis inhibited?

PGI2, NO are normally released from endothelial cells to prevent clots

Heparan/antithrombin

Thrombomodulin system (Protein C system to degrade coagulation factors and when thrombin bound acts as an anticoagulant)

Fibrinolysis (t-PA)

18

Immune thrombocytopenia Purpura

How does the blood film appear?

What types are there and what are important details of each?

Treatment?

Blood film: RBC and WBC normal. Large platelets

There are 2 types, childhood and Adult

Childhood: abrupt onset with severe thrombocytopenia with antecedent viral syndrome common. Mechanism of autoab to platelet surface glycoproteins. Most patients recover

Adult: Onset insidious with minor bleeding and no antecedent viral illness. Decreased paltelet survival with decreased production. Only 5% survive spontaneously

Treatment: steroids/immunoglob/antiCD20 Rituxumab/Platelet growth factors

19

What is Heparin induced thrombocytopenia?

How to dx?

What are characteristics?

Treatment?

Platelet factor 4 interacts with heparin, autoantibodies to this complex form. These antibodies also bind to surface of platelets and activates them. Thus moderate thrombocytopenia and thrombotic events.

Dx: Lab confirm PF4-Heparin ELISA or SRA (a paltelet function assay)

4Ts: Thrombocytopenia, timing, thrombosis, no oTher causes

Treatment: Stop heparin and begin alternative anticoagulant such as direct thrombin inhibitor (DTI) argatroban, bivalirudin

20

Thrombotic Thrombocytopenic Purpura

What is it

Clinical presentations?

What are required parts of diagnosis?

Other parts of diagnosis?

Mechanism of pathogenesis

Idiopathic autoab to ADAMTS13 protein

Hemolytic uremic syndrome (shiga toxin associated HUS)

DIC, sepsis

Dx: Required: Microangiopathic hemolytic anemia and thrombocytopenia

also but not required for dx: Renal failure, mental status change, fever

Need to rule out other dx.

ADAMTS13=enzyme regulator of vWF/platelet interactions. Dysfunction results in failed cleavage of vWF causing string of platelets, breaking off and embolizing.

21

What is PFA-100?

How does it work?

How do you use the results of this test in diagnosis?

Membrane coated with collagen with holes.

Screens for platelet and vWF function through measured aperture closure time. Not very specific thugh so if no suspicion and normal aperture closure time-->stop

However if prolonged or high suspicion, then go ahead with tests of von Willebrand factor. If normal still then check platelets.

22

What are functions of von Willebrand factor?

Support platelet adhesion to exposed collagen

Carrier for factor VIII (so maintains it in circulation. Thus abn vWF may lead to FvIII deficiency [long PTT]

23

How can you evaluate vWF?

vWF:Ag immunoassays

Ristocetin cofactor assay (activates vWF like collagen)

fVIII quantification

24

What are types of platelet dysfunction?

Acquired: drugs

Congenital absence of 

GPIb: Bernard Soulier syndrome

GPIIB/IIIa/Glanzman's Thrombasthenia

25

How is Prothrombin time measured?

 

Use?

Tissue factor, phospholipid ca2+ added to citrated plasma and clotting time measured

Reported in seconds and INR

INR=(patient PT time/Mean normal prothrombin time)^ISI

Monitors vit k antagonism from Warfarin

26

How is PTT measured?

What can make it prolonged?

Surface activators, phospholipid, ca2+ added to citreated plasma

Prolonged if missing IX or VIII (hemophilia)

 

27

What is a 1:1 mix

Mix patient plasma with nromal containing 100% of all factors.

If clotting time is normal, then factor deficiency likely

If clotting time remains prolonged, inhibitor is likely

28

Differential dx for Long PTT w normal PT

Factor def: VIII, IX, XI, XII

vWD if VIII low.

Inhib: heparin, lupus anticoag, specific factor inhibition

29

Differential dx for Long PT

Factor deffic: Factor VII, combination of factor deficiency from Vit K deficiency/oral anticoag/liver disease

Inhib: Factor inhibition, lupus inhibition (rare)

30

Diferential dx for Long pt AND long PTT

Factor def isolated: X, V, II, fibrinogen

Multiple factor def: liver disease if severe, vit k defic if severe, DIC

Inhib: Isolated factor inhib of X, V, II

drugs: heparin, direct thrombin inhibitors, lupus inhibitor, inhibition of fibrin polymerization