The document provides an overview of platelet disorders, describing how platelets function in hemostasis and how genetic and acquired factors can influence this process, leading to bleeding or clotting symptoms. It discusses various qualitative and quantitative platelet disorders, outlining approaches to diagnosing and differentiating disorders based on platelet production, distribution, or destruction. Evaluation of thrombocytopenia and diagnostic tools for platelet functional disorders are also reviewed.

1. Overview of Disorders of
Platelets
Vidur Singh

2. Haemostasis
• Hemostasis is a dynamic process in which the platelet and the blood vessel wall
play key roles.
• Platelets become activated upon adhesion to von Willebrand factor (vWF) and
collagen in the exposed subendothelium after injury.
• Platelet activation is also mediated through shear forces imposed by blood flow
itself, particularly in areas where the vessel wall is diseased, and is also affected by
the inflammatory state of the endothelium.
• The activated platelet surface provides the major physiologic site for coagulation
factor activation, which results in further platelet activation and fibrin formation.
Genetic and acquired influences on the platelet and vessel wall, as well as on the
coagulation and fibrinolytic systems, determine whether normal hemostasis, or
bleeding or clotting symptoms, will result.

4. Normal Haemostasis

5. Normal Haemostasis CONT’D

6. Prothrombotic effects of
endothelial cells
Antithrombotic effects
of endothelial cells

8. Platelets (*)
• (*) are released from the megakaryocytes, likely
under the influence of flow in the capillary sinuses.
• Main regulator of (*)production is the hormone
thrombopoietin (TPO), which is synthesized in the
liver.
• Normal BLOOD platelet count = 150,000–450,000/L.
• (*) synthesis increases with inflammation and
specifically by interleukin 6.

9. Platelets
• Are very active, aneucleate and they have limited
capacity to synthesize new proteins
• Circulate with an average life span of 7–10 days.
• Approximately 1/3 of the platelets reside in the
spleen, and this number increases in proportion to
splenic size, although the platelet count rarely
decreases to <40,000/L as the spleen enlarges.

10. THROMBOPOIETIN (TPO) AND PLATELET PRODUCTION
INTERACTION
• TPO binds to receptor on • HENCE, a reduction in
platelets and platelet and
megakaryocytes • removed from the megakaryocyte mass 
circulation. • increases the level of TPO,
which then stimulates
platelet production.

11. Thrombopoietin

13. Functional
Disorders
(Qualitative)
Disorders
of
platelets
Disorders in
the number
of platelets

14. Diagnostic Tools
• Peripheral blood smears
• Platelet-associated immunoglobulin G
• In vitro platelet function analyzer 100
• Platelet aggregation
• Imaging studies
• Bone marrow examination

15. Disorders that cause
Thrombocytopenia (lower
number of platelets, than the
normal range of platelet count,
in the blood)

16. Thrombocytopenias
• Thrombocytopenia  a platelet count of less than
150,000/mm3 (<150,000/mm3)
• N.B. With normal platelet function, thrombocytopenia is
rarely the cause of bleeding unless the count is less than
50,000/mm3.
• Thrombocytopenia should always be confirmed by
examination of a peripheral smear.
• It can be caused by:
– decreased platelet production
– increased destruction
– Sequestration (DISORDERS OF DISTRIBUTION of platelets)
– or a combination of these causes.

17. Thromboyctopenia

18. vitamin deficiency
(e.g., folate, vitamin
B12) Marrow
infiltration by
Storage diseases tumor
Infections Drugs (frequently
(including HIV) chemotherapeutic
agents or alcohol, but
Causes of other medications in
platelet rare cases)
underproduction
Marrow failure
radiotherapy syndromes (e.g.
aplastic anemia)

19. Types of thrombocytopenias
Infection-Induced Thrombocytopenia
Drug-Induced Thrombocytopenia
Heparin-Induced Thrombocytopenia
Immune Thrombocytopenic Purpura (ITP)
Inherited Thrombocytopenia
Thrombotic Thrombocytopenic Purpura
Hemolytic Uremic Syndrome

20. Differential diagnosis of thrombocytopenia. Evaluation of thrombocytopenia is best
organized according to the apparent defect in platelet production, distribution, or
destruction.

21. Algorithm for
thrombcytopenia
evaluation

22. Platelet Underproduction
• The hallmark of platelet underproduction is
decreased marrow megakaryocytes or, when
available, a decreased peripheral blood reticulated
platelet count

23. Platelet Sequestration
• Hypersplenism from a variety of causes, including liver
disease or malignancy, may result in platelet
sequestration.
• Mild to moderate thrombocytopenia is caused by
platelet sequestration when there is an associated mild
reduction in neutrophil count and hemoglobin and with
minimal impairment of hematopoiesis on bone marrow
examination.
• If physical examination fails to detect splenomegaly,
evaluation with ultrasonography or radionuclide
imaging is recommended to document splenomegaly.

24. Increased Platelet Destruction
• The hallmark of increased platelet destruction is increased
marrow megakaryocytes or, when available, high reticulated
platelet count. Platelet destruction results from various
immune conditions, including the following:
• Immune thrombocytopenic purpura (ITP)
• Thrombotic microangiopathies
• Post-transfusion purpura (PTP)
• Heparin-induced thrombocytopenia (HIT)
• Disseminated intravascular coagulation (DIC)

25. Hemolytic Uremic Syndrome
• HUS is a syndrome characterized by acute renal failure,
microangiopathic hemolytic anemia, and thrombocytopenia.
• It is seen predominantly in children and in most cases is
preceded by an episode of diarrhea, often hemorrhagic in
nature. Escherichia coli O157:H7 is the most frequent,
although not only, etiologic serotype. HUS not associated
with diarrhea (termed DHUS) is more heterogeneous in
presentation and course.
• Some children who develop DHUS have been found to have
mutations in genes encoding Factor H, a soluble complement
regulator, and membrane cofactor protein that is mainly
expressed in the kidney.

26. Treatment of hemolytic uremic syndrome:
Treatment
• Treatment of HUS is primarily supportive. In D+HUS,
many (~40%) children require at least some period of
support with dialysis; however, the overall mortality is
<5%. In D–HUS the mortality is higher, approximately
26%.
• Plasma infusion or plasma exchange has not been
shown to alter the overall course. ADAMTS13 levels are
generally reported to be normal in HUS, although
occasionally they have been reported to be decreased.
• As ADAMTS13 assays improve, they may help in
defining a subset that better fits a TTP diagnosis and
may respond to plasma exchange.

27. Pathogenesis of thrombotic
thrombocytopenic purpura (TTP)

28. Increased Platelet Destruction
• The hallmark of increased platelet destruction is increased
marrow megakaryocytes or, when available, high reticulated
platelet count. Platelet destruction results from various
Thrombocytosis
immune conditions, including the following:
• Immune thrombocytopenic purpura (ITP)
• Thrombotic microangiopathies
• Post-transfusion purpura (PTP)
• Heparin-induced thrombocytopenia (HIT)
• Disseminated intravascular coagulation (DIC)

29. Thrombocytosis
• Thrombocytosis is almost always due to:
 Iron deficiency;
 Inflammation, cancer, or infection (reactive thrombocytosis); or
 An underlying myeloproliferative process [essential thrombocythemia or polycythemia vera or, rarely, the 5q-
myelodysplastic process.
 Medications that can cause reactive thrombocytosis include:
– Epinephrine (Adrenalin Chloride, EpiPen)
– Tretinoin
– Vincristine
• Patients presenting with an elevated platelet count should be evaluated for underlying inflammation or
malignancy, and iron deficiency should be ruled out.
• Thrombocytosis in response to acute or chronic inflammation has not been associated with an increased
thrombotic risk. In fact, patients with markedly elevated platelet counts (>1.5 million), usually seen in the
setting of a myeloproliferative disorder, have an increased risk of bleeding. This appears to be due, at least in
part, to acquired von Willebrand disease (vWD) due to platelet-vWF adhesion and removal.

30. Blood smear of thrmobocytosis

31. Essential thrombocythemia
• Essential thrombocythaemia (ET) is a condition affecting the cells in the bone marrow
that make platelets [A myeloproliferative disorder], whereby there is overproduction of
platelets, leading to an increased propensity to thrombosis formation and hence,
blockage of blood vessels.
• It is a rare condition that can affect people at any age, including children, but it's most
common in people over 50.
• Some people have a change (mutation) in a gene, called the JAK2 gene, that may have
caused their condition. This gene produces an important protein involved in blood
production. The fault in the gene occurs during the person's lifetime. It isn't inherited
and can't be passed onto children. Finding this faulty gene can help to make the
diagnosis.

32. Thrombopoietin

33. Treatment
• Essential Thrombocytosis
– Low-dose aspirin -- may treat headache and burning
pain in the skin.
– Hydroxyurea (Droxia, Hydrea) or anagrelide (Agrylin) --
reduces number of blood cells.
– Aminocaproic acid -- reduces bleeding. This treatment
may be used before surgery to prevent bleeding as well.

34. Signs and Symptoms of essential
thrombocytosis
– Heart attack or stoke
– Headache
– Burning or throbbing pain, redness, and swelling of the hands and
feet
– Bruising
– Gastrointestinal bleeding or blood in the urine

35. Increased Platelet Destruction
• The hallmark of increased platelet destruction is increased
marrow megakaryocytes or, when available, high reticulated
platelet count. Platelet destruction results from various
Disorders of Platelet
immune conditions, including the following:
Function
• Immune thrombocytopenic purpura (ITP)
• Thrombotic microangiopathies
• Post-transfusion purpura (PTP)
• Heparin-induced thrombocytopenia (HIT)
• Disseminated intravascular coagulation (DIC)

36. Congenital disorders of platelet function
Von Willebrand Disease
Glanzmann’s Thrombasthenia
Bernard-soulier Syndrome

37. Gp IIb-IIIa complex on platelet surface

38. Gp Ib receptor on platelets

39. N.B. WITH
BERNARD-
SOULIER; the
abnormal RISTO
is not corrected
by the addition
of vWF
Aggregometer studies in patients with congenital disorders of platelet function. Upper panels:
The normal pattern of aggregation to ADP, epinephrine, collagen, arachidonic acid, and
ristocetin. von Willebrand disease can be identified because of an abnormal ristocetin
aggregation pattern. This condition is distinctly different from patterns seen with storage pool
disease, aspirin inhibition, and Glanzmann thrombasthenia.

40. Acquired Abnormalities of Platelet Function
MYELOPROLIFERATIVE DISEASE
DYSPROTEINEMIA
CARDIOPULMONARY BYPASS
UREMIA
LIVER DISEASE
DRUG INHIBITION

41. MYELOPROLIFERATIVE DISEASE
• Patients with myeloproliferative disorders (ie, polycythemia vera, myeloid
metaplasia, idiopathic myelofibrosis, essential thrombocythemia, and chronic
myelogenous leukemia) frequently exhibit abnormal platelet function.
• Some of these patients have very high platelet counts and demonstrate either
abnormal bleeding, or a tendency for arterial or venous thrombosis, or even both.
Although the height of the platelet count alone does not correlate with the
bleeding or thrombotic tendency, thrombocytosis in excess of 1 million/µL is
considered to be a risk factor.
• At the same time, increased platelet turnover, as measured by the reticulated
platelet count, may correlate with thrombotic risk. In patients with polycythemia
vera, expansion of the total blood volume and an increase in blood viscosity may
also contribute to the thrombotic risk.
• Other laboratory findings can be quite variable. The BT may be prolonged, but is a
poor predictor of abnormal bleeding. Perhaps the most consistent laboratory
abnormalities in bleeding patients are defects in epinephrine-induced aggregation
and dense and alpha granule function. Bleeding caused by an acquired form of
vWD also may be observed in these disorders, secondary to a loss of higher-
molecular-weight vWF multimers.

42. CLINICAL FEATURES
• There are no specific symptoms or signs that indicate a platelet functional defect.
• Inherited defects are rare and are generally characterized by a relatively mild bleeding
tendency. von Willebrand disease (vWD) is an exception to this rule, since certain vWD
subtypes are associated with severe and even fatal bleeding.
• Patients with platelet functional defects generally present with:
 Easy bruisability
 Mucocutaneous bleeding of a purpuric nature
 Bleeding from the gastrointestinal and genitourinary tracts (often with severe menorrhagia) rather than
the petechial bleeding that characterizes thrombocytopenia.
 It is not unusual for the bleeding tendency to escape detection until aggravated by another
abnormality. For example, the defect may first be suspected because of excessive bleeding
following minor surgery or a dental extraction or unusual mucocutaneous bleeding following
the administration of anticoagulants or a platelet inhibitor such as aspirin. Therefore, a
history of unusual bleeding, a family history suggestive of a congenital abnormality, and the
clinical picture can provide important clues.

43. CLINICAL FEATURES
Bleeding gums
Easy Bruising

44. Laboratory Studies
1. BLEEDING TIME AND TESTS FOR FACTOR DEFICIENCIES
• The bleeding time (BT) has traditionally been used as a screening
test for the presence of a platelet functional defect. If performed
carefully in a well-standardized manner, the BT correlates with
both platelet number and function.
• With platelet counts greater than 100,000/µL, the BT should be
less than 8 minutes. As the count falls below this level, the BT
lengthens, reaching times of 20 to 25 minutes when the count falls
to 10,000/µL.
• Patients with functional defects, such as severe vWD, can show BTs
in excess of 20 minutes with a normal platelet count. Patients with
an acquired functional defect secondary to aspirin therapy or
uremia show more modest prolongations of the BT (8 – 20
minutes).

45. Laboratory Studies
2. COMPLETE BLOOD COUNT AND BLOOD FILM
• A complete blood count (CBC) with examination of
the blood film can also be helpful.
• The CBC can provide evidence of hematopoietic
disease, especially a myeloproliferative disorder
where high numbers of circulating platelets are
associated with abnormal function.
• Platelet morphology can help in diagnosing
disorders such as Bernard-Soulier syndrome and α-
granule deficiency (gray platelet syndrome).

46. Laboratory Studies
3. MEASUREMENTS OF PLATELET ACTIVATION/AGGREGATION
• Direct measurements of platelet activation/aggregation are
possible using an aggregometer or flow cytometer.
• The aggregometer provides a graphic display of the wave of
platelet aggregation seen in response to agonists such as ADP,
epinephrine, or collagen, and the agglutination response to
ristocetin. Specific functional defects respond differently to
these agonists.
• For example, patients with vWD specifically show decreased
or absent agglutination with ristocetin [ristocetin-induced
platelet agglutination assay (RIPA)], whereas other disorders
such as storage pool disease demonstrate poor responses to
ADP, epinephrine, and collagen.

47. ASSAYS FOR VON WILLEBRAND FACTOR
• Full evaluation of the patient with vWD requires an
array of tests, including assays for factor VIII activity,
vWF antigen, vWF activity, and vWF multimer
pattern by agarose gel electrophoresis.
• Together with the patient's bleeding history, family
history, and BT, these assays will diagnose and
classify vWD into one of several clinically important
subtypes.

48. TREATMENT for abnormalities of platelet
function
• Abnormalities in platelet function are often first appreciated as a complication of an acute
illness or surgery and multiple aggravating factors may play a role in determining the severity
of the bleeding tendency.
• An accurate diagnosis is not usually easily made
• Hence, treatment should address as many potential contributing factors as possible.
• This list includes discontinuing drugs that inhibit platelet function, empirically replacing vWF
or treating with DDAVP (Desmopressin) and, according to the severity of the patient's
bleeding, transfusing normal platelets.
• Although this approach lacks precision, it is effective. Both acquired and congenital disorders
of platelet function can be acutely reversed in order to control severe clinical bleeding.

49. Treatment cont’d
• Long-term management of a platelet functional defect should be based on an
accurate diagnosis. Patients with congenital defects should be counseled to avoid
drugs that can aggravate the functional abnormality and cause bleeding.
• Obviously, aspirin and nonsteroidal analgesics are prime offenders. vWD and
thrombasthenia patients demonstrate significant prolongations of the bleeding
time with aspirin ingestion and are at greater risk for clinical bleeding.
• These patients should also be educated regarding the nature of their abnormality
and should carry identification or wear a medical alert bracelet. This information
can be invaluable as a guide to appropriate transfusion therapy in an emergency
situation.

50. Treatment Cont’d
• As a general principle, the nature of the functional abnormality will guide the
choice of therapy.
• For example, the vWD patient who lacks normal amounts of vWF will respond to
agents that increase plasma vWF levels. In this situation, the platelets will function
normally once the vWF abnormality is corrected. In contrast, patients with
congenital defects of platelet receptor expression, granule content, or platelet
metabolism will require platelet transfusion.
• As for the acquired abnormalities of platelet function, the best approach to therapy
lies somewhere in between. There is clinical evidence that patients with acquired
defects secondary to drug ingestion, uremia, and liver disease will respond to
DDAVP, vWF replacement, or both. These data suggest that an increase in plasma
vWF levels may partially compensate for a platelet-based defect.

51. Bibliography
• http://emedicine.medscape.com/article/201722-
overview#aw2aab6b9
• http://home.kku.ac.th/acamed/kanchana/bsi.htm
• Kumar, V., Abbas, A. K., Fausto, N., & Mitchell, R. N.
(2007). Robbin's Basic Pathology 8th Edition.
Philadelphia, PA: Saunders Elsevier.
• al, F. e. (2008). Harrison's Principles of Internal
Medicine, 17th Edition. USA: The McGraw-Hill
Companies, Inc.