MANAGEMENT OF PLATELET DISORDERS

Platelet Count
Thrombocytopenia: The Most Common Cause of Bleeding
Thrombocytosis
Platelet Diameter and Morphology
Qualitative Platelet Abnormalities
Drugs with Anti-platelet Activity
Platelet Aggregometry
Platelet Concentrate Therapy
Treating Uremic Platelet Dysfunction with Red Blood Cells
Thrombotic Thrombocytopenic Purpura (TTP) and the vWF-Cleaving Protease (ADAMTS-13) Assay
Platelet Count Ranges and Thrombocytopenia

150-400,000/uL	Platelet count reference interval; < 150,000 is thrombocytopenia
50-150,000/uL	Bleeding is unexpected, implies qualitative platelet disorder
10-50,000/uL	Bleeding may follow trauma, surgery, or dental extraction
<10,000/uL	Spontaneous bleeding may require therapy

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Thrombocytopenia: the most common cause of bleeding

Marrow hypoplasia: chemotherapy, drug sequelae, ethanol
Immune-mediated platelet consumption: acute and chronic autoimmune thrombocytopenic purpura, drug-induced immune thrombocytopenia, neonatal alloimmune thrombocytopenia, post-transfusion purpura
Non-immune mediated platelet consumption: thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), disseminated intravascular coagulation (DIC), heparin-induced thrombocytopenia (HIT), type 2B VWD, and others.

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Thrombocytosis: Count > 400,000/uL

Reactive thrombocytosis: hemorrhage, surgery, iron deficiency anemia, inflammation - normal platelets - no bleeding risk
Myeloproliferative disorders: essential thrombocythemia, chronic myelocytic leukemia, polycythemia vera - abnormal platelets may cause thrombosis or bleeding

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Platelet Diameter and Morphology

2.5 mm diameter	Average normal diameter
4 mm diameter	Large physiologic platelets may indicate increased turnover with shortened marrow release time
>7 mm diameter	Giant platelets imply myeloproliferative disorder, myelodysplastic syndrome, May-Hegglin anomaly
Gray platelets	Slightly enlarged gray platelets seen in Bernard-Soulier syndrome or alpha-granule deficiency (Gray platelet syndrome)
Platelet clumps	Clotting due to improper specimen management or agglutination due to EDTA-dependent antibody
Platelet satellitism	Artifact of EDTA-dependent antibody

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Qualitative Platelet Abnormalities

These disorders may be suspected after abnormal platelet aggregation results:

Congenital storage pool deficiency: dense granules

Normal platelet dense (d) granules store ADP, ATP, calcium, pyrophosphate, and serotonin, and release these during activation.
Hermansky-Pudlak and Chediak-Higashi syndromes are rare autosomal recessive disorders with oculocutaneous albinism.
Wiskott-Aldrich syndrome, an X-linked recessive disorder, is characterized by severe eczema.
All three have reduced dense granule distribution (diagnosed by electron microscopy) and moderate thrombocytopenia.
Dense granule deficiency in non-albinos may be caused by an autosomal dominant inability to package the normal contents despite producing normal granules. Platelet counts are normal.

Congenital storage pool deficiency: a granules

The a granules store coagulation factors, platelet-derived growth factor (PDGF) and platelet factor 4. They provide the granular appearance of platelets by light microscopy.
Gray platelet syndrome is the absence of a granules; the platelets are large and gray. Patients experience thrombocytopenia and moderate life-long bleeding.

Acquired storage pool deficiency: MPD or MDS

Platelets in myeloproliferative disorders and myelodysplastic syndromes have reduced a and d granules, abnormal membranes, and vary in size and count.
Patients may have mild to moderate bleeding, although thrombosis is also a risk.
Platelet aggregometry may be used to predict clinical bleeding.

Platelet receptor defects

Following is a table of platelet membrane receptor defects that may associate with mucocutaneous bleeding. These may be detected using platelet aggregometry.

Receptor	Function	Agonist	Defect
GP Ib/V/IX	VWF binding	Ristocetin	Bernard-Soulier syndrome
GP IIb/IIIa	Fibrinogen and VWF binding	ADP, collagen, epinephrine	Glanzmann thrombasthenia
GP Ia/IIa	Collagen binding	Collagen	Unnamed mucocutaneous bleeding
P2Y1 and P2Y12	ADP binding	ADP
Thromboxane A₂receptor	Thromboxane A₂binding	Arachidonic acid
a-adrenergic receptor	Epinephrine binding	Epinephrine	May/may not cause bleeding

Metabolic pathway defects

Defects in cyclooxygenase and thromboxane synthetase result in decreased thromboxane A2 production and poor platelet secretion despite normal granule distribution. These are called platelet release or secretion defects. They resemble the effect of aspirin on cyclooxygenase, giving the name, "aspirin-like disorders." These are detected by a reduced aggregation response to arachidonic acid agonist.

Other acquired platelet response deficiencies

Multiple myeloma, cardiopulmonary bypass surgery, liver disease, and uremia may all be associated with reduced platelet function.

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Drugs with Anti-Platelet Activity

Platelets are inhibited by many common drugs such as aspirin, NSAIDs, various antibiotics, herbs, garlic, and vitamin E (among many others). Specific platelet inhibitors include clopi-dogrel and ticlopidine which block the ADP receptors, and abciximab, eptifibatide and tirofiban which bind to the IIb/IIIa receptors. Complications of some of these drugs include drug-induced immune thrombocytopenia which can be severe.

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Platelet Aggregometry

Platelet aggregometry is a functional test performed on whole blood or platelet-rich plasma. An agonist (platelet activator) is added to the suspension and a dynamic measure of platelet clumping is recorded. ATP release is simultaneously assayed using a luminescence marker.

Expected aggregation and secretion results for aspirin, release defect, membrane defect, or storage pool disorder using a variety of agonists

Agonist	Aspirin or Release Defect	Membrane Defect	Storage Pool Deficiency
Thrombin	Normal secretion and aggregation	Normal secretion and aggregation	Decreased secretion and aggregation
Arachidonic acid	Decreased secretion and aggregation	Normal secretion and aggregation	Decreased secretion and aggregation
ADP, epinephrine, and collagen	Decreased secretion and aggregation	Decreased secretion and aggregation	Decreased secretion and aggregation

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Platelet Concentrate Therapy

Two types of platelet components are used for platelet replacement:

"Platelets", also called random donor platelets, are pooled concentrates prepared from whole blood donations by centrifugation. Usually a pool consists of 6-8 units, for an adult dose of one unit/10 kg of body weight. Each random unit contains at least 5 x 1010 platelets.
"Platelets, pheresis", or single donor platelets, are prepared by apheresis of one donor and contain a minimum of 300,000,000 platelets.

Therapeutic platelet transfusions are given to treat bleeding due to defects in platelet production or platelet function. Transfusion of platelets is contraindicated for diseases involving thrombotic consumption of platelets, including thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and heparin-induced thrombocytopenia (HIT).

Platelet transfusions are not usually effective in immune-mediated thrombocytopenias, such as idiopathic thrombocytopenia purpura (ITP), although there may be some benefit in life-threatening situations.

Recommended triggers for the use of platelet concentrate:

10,000/uL	Stable oncohematological recipient, lumbar puncture in stable pediatric leukemia, thrombocytopenia 2° to GPIIb/IIIa receptor inhibitors
20,000/uL	Bone marrow aspiration and biopsy
20-40,000/uL	Gastrointestinal endoscopy in cancer
20-50,000/uL	DIC, fiber-optic bronchoscopy in a bone marrow transplant recipient
30,000/uL	Neonatal alloimmune thrombocytopenia
50,000/uL	Major surgery in leukemia, thrombocytopenia secondary to massive transfusion, invasive procedure in cirrhosis
50-60,000/uL	Cardiopulmonary bypass
50-100,000/uL	Liver biopsy, non-bleeding premature infant, neurosurgery

Ideally, the effectiveness of platelet transfusions will be confirmed by bleeding cessation. If there are no complicating factors affecting response, such as hemorrhage, fever, or splenomegaly, a single unit of random platelets should increase the recipient's platelet count by 5000-10,000/uL, and a unit of apheresis platelets should increase the count by 30,000-50,000/uL. Many multi-transfused patients do not show the expected increment after platelet transfusion. The most common method to determine if the recipient is refractory to platelets is to measure the platelet count within one hour post transfusion and calculate the corrected count increment (CCI):

CCI = (Posttransfusion PLT count – Pretransfusion PLT count) x body area (m²)

Number of platelets transfused (multiples of 10¹¹)

A CCI above 7500/uL indicates an adequate response to platelet transfusion. A CCI below 7500/uL suggests immune-mediated clearance and are the basis for the procurement of crossmatched platelets for subsequent transfusions.

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Treating Uremic Platelet Dysfunction with Red Blood Cells

Uremic hemorrhage results from platelet abnormalities secondary to kidney failure. While platelet transfusions may be used, they are not very effective. Cryoprecipitate may be helpful but red blood cells are the treatment of choice, particularly if the patient is anemic. A target hematocrit of 30% has been shown to improve platelet function in uremic patients.

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Thrombotic Thrombocytopenic Purpura (TTP) and the VWF-Cleaving Protease (ADAMTS-13) Assay

Thrombotic thrombocytopenic purpura (TTP) is caused by ultra-high molecular weight von Willebrand factor multimers, present when endothelial cell-secreted von Willebrand factor is not properly proteolysed by its cleaving protease (ADAMTS-13). Lack of enzyme activity is most commonly the consequence of an autoantibody in the acquired form of TTP. In rare patients, TTP is familial and due to absence of ADAMTS-13. Hemolytic-uremic syndrome (HUS) resembles TTP, however bacterial toxins trigger HUS and the von Willebrand factor cleaving protease level remains normal. Although measurement of the von Willebrand factor cleaving protease activity is helpful in the diagnosis of TTP, the assay is complex and the turnaround time is too long to wait prior to making the diagnosis and starting plasmapheresis. However, it is important to collect a blood sample in sodium citrate for testing of ADAMTS-13 activity and its inhibitor prior to starting the first plasma exchange. One of the current available assays is based on the ability of vWF to bind collagen and is available from the Blood Center of Wisconsin.

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Test Interpetation & Therapy Menu:

Reference Intervals for Premature Infants | Reference Intervals for Full-term Infants | Reference Intervals for Children | UAB Reference Intervals For Adults | Biochemical Properties of the Coagulation Proteins | The Coagulation Cascade Mechanism | Dos and Don'ts in Coagulation Testing | Blood Specimen Management | UAB Hemostasis and Coagulation Test Menu | Thrombophilia |Anticoagulant Therapy Monitoring | Management of Bleeding | Management of Platelet Disorders | Glossary of Hemostasis Terms with Abbreviations