Platelet adhesion, activation, & aggregation

1a

What are the three major steps involved in the platelet response to vascular injury?
1b

Platelet adhesion

2a

Interaction of platelets with non-platelet surfaces.

2b

Platelet activation

3a

In response to agonists, platelets undergo metabolic activation resulting in shape change and secretion.
3b

Platelet aggregation

4a

Cross linking of plateletplatelet surfaces.

4b

Endothelial cells

5a

What is plasma Von Willebrand factor (vWF) derived from?

5b

GP Ib/IX complex

6a

Serves as the binding site on platelets for vWF to mediate platelet adhesion.
6b

collagen & fibronectin

7a

Multiple proteins in the subendothelial matrix can bind vWF, including ____ & ____.
7b

vWF, GP Ib/IX (platelet receptor), & subendothelial binding site for vWF
8a

What are the three things required for platelet adhesion?

8b

calcium

9a

Platelet activation requires an increase in cytoplasmic ____. This comes from internal storage sites (dense tubular system) and the external environment through membrane channels.
9b

Phospholipase C; diacylglycerol (DG); inositol trisphosphate (IP3); protein kinase C; calcium; calmodulindependent protein kinases
10a

____ converts phosphatidyl-inositol-bisphosphate (PIP2) into ____ and ____. The former activates ____ in contact with the inner leaflet of the platelet membrane, which phosphorylates substrate proteins, including a 40-47 kd protein involved in platelet secretion. The latter releases ____ from its storage sites. The increased cytoplasmic concentration activates ____ and results in shape change and contraction.
10b

Phospholipase A2; thromboxane A2 (TxA2)

11a

____ releases arachidonic acid from membrane phospholipids, activating the prostaglandin pathway. In the platelet this results in synthesis of ____, a potent agonist which activates the phospholipase C pathway.
11b

adenylate cyclase; phosphodiesterase; Prostacyclin; nitric oxide (NO)

12a

cAMP and cGMP serve as regulators of the platelet response; increased levels of cAMP is regulated by synthesis (____) and degradation (____). ____ is a potent stimulator of the former. cGMP is synergistic with cAMP and its level is increased by ____.
12b

GP IIb-IIIa; ADP

13a

Platelet aggregation requires activation of ____; in the resting state, it does not bind fibrinogen or other adhesive proteins. Once it has been activated (e.g., by ____ binding to its receptor), it binds fibrinogen and other adhesive proteins, including vWF.
13b

Fibrinogen

14a

____ is a dimeric molecule and its two terminal ends are mirror images of each other. Consequently, it serves as an excellent cross-linking agent.
14b

Monomeric

15a

____ forms of fibrinogen can serve as fibrin degradation products because they contain a single binding domain that can compete for binding sites on GP IIb-IIIa and block platelet aggregation.
15b

high shear stress; vWF; fibrinogen

16a

Aside from ADP activation, ____ can activate GP IIb-IIIa; with this mechanism of activation, high molecular weight multimers of ____, rather than ____ can mediate platelet-platelet interaction.
16b

Mucocutaneous bleeding, including ecchymoses, petechiae, oral mucosal bleeding. Evidence of splenomegaly, hepatomegaly and lymphadenopathy should be sought.
17a

What are the clinical manifestations of platelet dysfunction?

17b

Bleeding time, platelet count, PT, APTT, vWF:antigen, vWF:Ristocetin cofactor activity, & vWF multimers
18a

List the laboratory procedures used to determine platelet function.

18b

Von Willebrand's disease (vWD) type 1

19a

Decrease in quantity of vWF which appears to function normally.

19b

vWD type 2

20a

Mutated form of vWF, often causing a decrease in high molecular weight multimers of vWF; total antigen may be normal. Mutation may affect binding site for factor VIII.

20b

vWD type 3

21a

Absent vWF (autosomal recessive).

21b

Recurrent mucocutaneous bleeding (epistaxis, bruising, menorrhagia) & positive family history of bleeding
22a

What are the clinical features of vWD?

22b

Childhood & early adulthood

23a

At what point in life are the symptoms of vWD most evident?

23b

Pregnancy and acute inflammatory reactions

24a

When can vWF normalize for individuals with vWD?

24b

Bernard-Soulier syndrome

25a

Rare, autosomal recessive disorder due to deficiency of GP Ib.

25b

Bernard-Soulier syndrome

26a

Thrombocytopenia with giant platelets, abnormal (absent) aggregation with ristocetin and normal vWF concentration and function.
26b

Glanzmann's thrombasthenia

27a

A rare autosomal recessive hereditary disorder characterized by a deficiency of GP IIb-IIIa.

27b

Glanzmann's thrombasthenia

28a

A normal platelet count and morphology, absent primary wave of aggregation to ADP (and collagen and epinephrine), normal aggregation response to ristocetin and absent clot retraction.
28b

Altered platelet membrane antigens (PIA1, Baka and Leka).

29a

What is the defect associated with in Glanzmann's thrombasthenia?

29b

Immune thrombocytopenic purpura (ITP)

30a

Patients may be asymptomatic, or complain of easy bruising or petechiae commonly found on one the lower extremities when the platelet count is less than 20,000.

30b

Acute (childhood type) ITP

31a

Type of ITP in which a viral prodrome is common, there is frequent spontaneous remission, and male:female ratio close to 1.
31b

Chronic (adult type) ITP

32a

Type of ITP in which there is no antecedent infection, there is infrequent spontaneous remission, and a male:female ratio of less than 1.
32b

ITP

33a

Caused by antibodies directed at the platelet membrane; GP Ib and IIb-IIIa are frequent targets of autoantibodies but may not be the only antigen targeted on the platelet. 33b

ITP

34a

Bone marrow megakaryocytes are often increased with active platelet shedding, but in some patients megakaryocytic hyperplasia may not be present. No microangiopathic changes (fragmented RBC's) on peripheral blood film.
34b

Isolated thrombocytopenia with an otherwise normal complete blood count.

35a

What is the typical presentation of an ITP?

35b

Thrombotic thrombocytopenia purpura (TTP)

36a

Patients typically present with an unexplained anemia and thrombocytopenia, and typically were previously very healthy.
36b

women; African Americans; Caucasians

37a

TTP is more common in ____, and may have an increased risk in ____ compared to ____.
37b

TTP

38a

Characterized by the spontaneous development of microthrombi in multiple arterioles throughout the body.
38b

TTP

39a

Severe thrombocytopenia, fever, neurologic signs, microangiopathic changes on peripheral blood film, and impaired renal function.
39b

Multi-organ microvascular thrombosis

40a

What is the hallmark pathologic lesion in TTP?

40b