Platelet Disorders

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Platelets

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disc shaped, 2-4 mircons, anuclear
- blue gray on wrights stain with reddish purple granules
-norma cts 150-450K
-circulate for 7-9 days
-2/3 in blood, 1/3 in spleen

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Megakaryocytes

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where platelets come from . They break of from their ctoplasm in the bone marrow

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Thrombopoietin (TPO)

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a glycoprotein that binds to its receptor on platelets and megakaryocytes
-produced at a constant rate by the liver
-inverse realtionship bw serum TPO and platelet levels
-TPO concentration regulated by the total mass of PLTs/megakaryocytes available to bind and degrade the protein

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Role of TPO in differentiation and maturation of platelets

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TPO is involved in all levels/stages.

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Platelet granule contents:
alpha granules

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fibrinogen, von willebrand factor, platelet factor 4

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Platelet Granule contents: Dense Bodies:

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ADP (activates neighboring platelets)
Serotonin

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Platelets role in hemostasis

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platelet adhesion

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Overview of plasma coagulation

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injury:
-vascular endothelial stimulation
-coaglation cascade
-plastelet adhesion agg
all leading to hemostasis

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Platelet Function

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-mainly- formation of mechanical plugs during the normal haemostatic response to vascular injury ( if absent, leakage of blood through small vessels may occur.

-local release of vasoconstrictors to decr blood flow to the injured area

-catalysis of rxns of the soluble coagulation cascade leading to fibrin clot formation

- initiation of the tissue repair process

-regulation of local inflammation

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Platelet process

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adhere, spread and aggregate, thrombus

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Adhesion

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plts roll and cling to non platelet surfaces

reversible, seals endothelial gaps, req's VWF in arterioles

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Aggregation

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plts cling to each other

irreversible, platelet plugs form, secretion of platelet contents, req's fibrinogen

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Secretion

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platelets discharge the contents of their granules.

irreversible, occurs during aggregation, essential to coagulation

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Staes of Platelet fnuction

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Platelets are pushed to the periphery of the column of blood by circulating red cells, facilitating their ability to adhere to breaks in the vascular endothelium

When platelets encounter a break in the endothelium, they adhere to components of the exposed subendothelial connective tissue

Activated platelets aggregate upon the layer of adherent platelets to form a stable hemostatic plug

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Defects in GPIb

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results in Bernard Soulier Disease

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platelet activation is achieved by

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glycoprotin IIb/IIIa binding fibrinogen to produce platelet aggregation

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activated platelet morphology

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pseudopods

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Defects in GP IIn IIIa result in

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Glanzmann Thrombasthenia

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mechanism of platelet aggregations

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agonist binding to the receptors on the platelet surface initiate a signal transduction cascade that converts the integrin from its inactive to active conformation. Fibrinogen binds the active integrin (GIIbIIIa) on adjacent platelts cross linking platelets into aggregates

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Irreversible inhibitors of aggregations

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ADP (ticlopidine), ADP (clopidogrel), COX (aspirin)

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reversibleinhibitors of aggregation

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Adenosine, NO, PGI2, Dipyridamole

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Secondary hemostasis

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comprises the reactions needed to generate the cross-linked fibrin required to stabilize the platelet plug and form a durable thrombus.

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Thrombocytopenia

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plts < 150K

- <50K bleeding following surgery or trauma

-<10K spontaneous hemorrhage

transfusion threshold

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Sites of bleeding

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cutaneous- petichiae, purpora, echymosis, venipuncture sites

mucosal- epistaxis, menorrhagia, hemorrhagic bullae in mouth 9blood blisters), GI bleeds

CNS
ooze rather than gush

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Causes of thrombocytopenia

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no plt production
incr consumption of plt
abnormal dist of plt
dilutional loss

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Failure of Platelet production caused by:

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Selective megakaryocyte depression: rare congenital defects, drugs/chemicals/viral infxns

Part of general bone marrow failure: cytotoxic drugs, marrow infiltration, radiation, HIV

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May Hegglin anomaly

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neutrophil inclusion

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Thrombocytopenia and absent radii syndrome

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congenital hypoplastic thrombocytopenia with absent radia (TAR)

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Gray plt Syndrome

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no normal granule content

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Immune thrombocytopenia purpura

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acute: abrupt onset of bruisinf, petechiae, mucosal bleeding--previously healthy person
-may follow infection, usu URI of GI virus
-majority recover w/o treatment

Chronic- adults more likely
-less responsive to therapy

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Giant platelet

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platelet larger than normal rbc
found in incr plt turnover, myeloproliferative disorders and myelodysplastic disorders

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ITP pathophysiology

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Incr platelet destruction in the spleen: plts are covered by autoantibodies and are recognized by macrophages in the spleen and destroyed

eTPO is being bound by platelets that end up getting destroyed.

Autoantibodies bind some meakaryocytes and cause them to undergo apoptosis leaving fewer to prod more plts

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Treatment of ITP

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target immune system with steroids, splenectomy, Ig

Increase plt prod- TPO receptor agonists

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drugs producing thrombocytopenia

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ethanol, heparin, phenytoin, quinine, quinidine, sulfas

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Heparin induced thrombocytopenia

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IgG antibodies directed against heparin plt factor 4 complex. Suspect if plts are <100000 5-15 days post therapy

-venous, arterial, and microvascular thrombosis threaten life and limb

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TTP- thrombotic thrombocytopenic purpura

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devastating disorder, fatal
Clinically: fever, anemia, thrombocytopenia, renal dysfxn, neurologic defects

Blood film: schistocytes and few plts

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Pathophysiology of TTP

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The absence or impairment of ADAMTS13 (VWF cleaving enzyme) allows for the persistence of the ultralarge “sticky” forms of VWF, which trap platelets and cause thrombi in vessels, thus leading to end-organ damage, and the appearance of the pentad of clinical features.

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Thrombocytopenia due to dilution

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Massive transfusion
Thrombocytopenia occurs in patients receiving massive transfusions (10-20 units) of PRBCs over a brief time frame due to the absence of viable platelets in stored PRBCs

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Normally your spleen holds what percentage of your plts?

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30%
bigger spleen, less plts in circulation

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Pseudothrombocytopenia

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fibrin strands allow platelets to clump giving falsely low plt ct read

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Thrombocytosis

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too many plts!
PLT> 500K

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Mechanisms of thrombocytosis

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reactive: cytokine driven (80%)
autonomous/clonal/neoplastic (essential thrombocytsosis)

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Complications of Thrombocytosis

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thrombosis in 15-20%, bleeding in 3-5%

neither typical in pts with reactive thrombocytosis

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Cases of reactive thrombocytosis

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acute blood loss, infxn, inflamm, exercise, iron def, hemolytic anemia, asplenia, cancer, chronic inflamm or infxs diseases, drug rxns