116 Thrombocytopenia

Question 1

One-third of the platelets are stored in the _________, and the remaining two-thirds circulate in _____________ human

Answer 1

Spleen: one-third

Blood vessels: two-thirds

Question 2

Platelets have a mean lifespan in the circulation of ______ days

Answer 2

7–10 days

Approximately 1 × 10 11 platelets are produced per day

Question 3

Every day approximately ________% of circulating platelets are removed by the mononuclear phagocyte system, primarily by macrophages in the ____________.

Answer 3

10% to 12%

spleen and liver

Question 4

The normal platelet count

Answer 4

150–400 × 10 9 /L

Question 5

Classically thrombocytopenia is defined as platelet count less than __________

Answer 5

less than 150 × 10 9 /L

Question 6

Throbocytopenia

Severe:
Moderate:
Mild:

Answer 6

Severe (platelet count <20 × 10 9 /L)
Moderate (platelet count 20–70 × 10 9/L)
Mild (>70 × 10 9/L)

Question 7

The blood-to-anticoagulant ratio should be as recommended. The International Council for Standardization in Hematology recommends the use of ____________ as the anticoagulant.

Answer 7

Ethylenediaminetetraacetic acid (EDTA)

Question 8

Conditions associated with pseudo thrombocytopenia

Answer 8

Use of EDTA as an anticoagulant, platelet cold agglutinins, and myeloma

Question 9

ANTIBODY-INDUCED PLATELET AGGLUTINATION

The antibodies usually are of the Immunoglobulin ________ type.

Answer 9

Immunoglobulin (Ig) G type

IgM and IgA antibodies also have been described

Question 10

ANTIBODY-INDUCED PLATELET AGGLUTINATION

In most cases, the antibodies are directed against the __________

Answer 10

Integrin αIIbβIII (also termed glycoprotein [GP] IIb/IIIa)

Question 11

Antibodies directed against integrin αIIbβIII may react simultaneously with the leukocyte Fcγ receptor III (FcγRIII) and attach the platelets to neutrophils and monocytes, inducing a phenomenon known as ______________

Answer 11

Platelet-leukocyte satellitism

The platelets form a rosette around the periphery of leukocytes.

Neutrophils are most frequently involved, but the phenomenon also is occasionally observed with monocytes.

Question 12

Some antiplatelet antibodies from patients with pseudothrombocytopenia cross-react with negatively charged phospholipids and may exhibit _______________ activity.

Answer 12

Anticardiolipin activity

Question 13

Thrombocytopenia has been described in patients with acute coronary syndromes treated with the ___________ and other _________________

Answer 13

Abciximab

Integrin αIIbβIII antagonists

Abciximab is associated with both pseudothrombocytopenia and true thrombocytopenia.

The mechanism for platelet clumping with abciximab is unknown; the drug itself likely is not crosslinking the platelets because it is monovalent.

True abciximab-induced thrombocytopenia occurs in approximately 0.3% to 1% of patients treated with the drug.

Question 14

TRUE OR FALSE

Pseudothrombocytopenia may be accompanied by pseudoleukocytosis

Answer 14

TRUE

Pseudothrombocytopenia may be accompanied by pseudoleukocytosis

Because platelet clumps tend to exceed 20 fl, the clumps may be counted as leukocytes,and even if counted as platelets, several platelets are counted as one.

Question 15

How can platelet clumping be prevented

Answer 15

• Collecting the sample in EDTA and maintaining its temperature at 37 C.
• Use of sodium citrate, which chelates calcium more weakly than does EDTA but still causes platelet clumping in approximately 10% to 20% of cases with EDTA-induced clumping
• An accurate platelet count can be obtained only by sampling blood directly into ammonium oxalate and manually counting the platelets using a Bruker chamber.
• Flow cytometry may help for determining exact platelet number by immunostaining of the platelets

Even with these measures, however, clumping will still occur in approximately 20% of cases.

Question 16

Patients with IPD usually present witH

Answer 16

Mucocutaneous bleeding

Spontaneous life-threatening bleeding is rare

Most IPDs cause mild bleeding tendencies, and IPDs may be more prevalent than previously thought.

Question 17

TRUE OR FALSE

Majority of IPDs are inherited as autosomal dominant traits.

Answer 17

FALSE

Majority of IPDs are inherited as autosomal recessive traits.

Question 18

Laboratory PBS findings of a potential IPD

Answer 18

• MYH9-related diseases (giant platelets and Döhle-like inclusion bodies within leukocytes)
• Bernard-Soulier syndrome (macrothrombocytopenia)
• Gray platelet syndrome (pale platelets)
• Sitosterolemia (giant platelets surrounded by a circle of vacuoles, stomatocytosis).

Question 19

TRUE OR FALSE

The skin bleeding time is no longer recommended for use in patients with platelet disorders because it is invasive and poorly reproducible.

Answer 19

TRUE

The skin bleeding time is no longer recommended for use in patients with platelet disorders because it is invasive and poorly reproducible.

Platelet function analyzer (PFA-100) occlusion times are usually found to be prolonged.

Question 20

Gold standard in diagnosing IPDs

Answer 20

Light transmission aggregometry

Uses different concentrations of adenosine diphosphate (ADP), collagen, ristocetin, epinephrine, and arachidonic acid

Question 21

Test recommended in patients with platelet granule deficiencies

Answer 21

Platelet nucleotide content and release

Question 22

Test that can be used in patients with platelet surface glycoprotein deficiencies such as Bernard-Soulier syndrome

Answer 22

Flow cytometric analysis

Question 23

Test that is able to define characteristic ultrastructural abnormalities; western blotting, enzymelinked immunosorbent assay (ELISA), or radioimmunoassay can be used for qualitative and quantitative analysis of specific platelet proteins.

Answer 23

Electron microscopy

Question 24

TRUE OR FALSE

Isolated thrombocytopenia is common in patients with nutritional deficiencies.

Answer 24

FALSE

Isolated thrombocytopenia is rare in patients with nutritional deficiencies.

Question 25

Iron-deficiency anemia (IDA) generally develops after acute or chronic bleeding and is usually accompanied by (thrombocytosis OR thrombocytopenia)

Answer 25

Thrombocytosis

Thrombocytopenia associated with IDA is relatively rare, reported in only 2.3% and 2.4% of pediatric and adult IDA patients, respectively.

Question 26

TRUE OR FALSE

Thrombocytopenia may be seen in association with vitamin B12 deficiency when the latter results from autoantibodies against parietal cells or intrinsic factor and is associated with ITP.

Answer 26

TRUE

Thrombocytopenia may be seen in association with vitamin B12 deficiency when the latter results from autoantibodies against parietal cells or intrinsic factor and is associated with ITP.

Various other autoimmune disorders can coexist with pernicious anemia, including autoimmune vitiligo and autoimmune thyroiditis.

Question 27

Mineral deficiency seen in patients who have undergone gastric bypass surgery and may cause anemia, leukopenia, and thrombocytopenia associated with neurologic deficits resembling vitamin B12 deficiency.

Answer 27

Copperdeficiency

May be misdiagnosed as having MDS because increased ring sideroblasts and dysplastic precursor cells can be seen in on bone marrow smears

Question 28

In acute ethanol intoxication, platelet counts in these cases are usually mildly (increased or decreased) severe thrombocytopenia is quite rare.

Answer 28

Platelet counts in these cases are usually mildly decreased (generally >100   109/L)

Usually resolves within 5–21 days with cessation of ethanol ingestion, sometimes with a transient rebound thrombocytosis that may reach up to 1,000,000   109/L.

Question 29

Suggested mechanism of acute alcohol-related thrombocytopenia

Answer 29

It has been suggested that metabolites of ethanol, especially acetaldehyde, impair the late stages of platelet production and increase platelet destruction

Thus, thrombocytopenia associated with acute alcohol ingestion would be expected to be more frequent in those with poor nutrition (delayed oxidation of acetaldehyde) and those with partial acetaldehyde dehydrogenase defiance.

Question 30

Mechanisms of thrombocytopenia in chronic ethanol consumption

Answer 30

Alcoholic liver cirrhosis (both splenomegaly and thrombopoietin deficiency), folic acid deficiency, and alcohol-induced marrow suppression

Question 31

Alcoholism (chronic ethanol consumption, which is defined as consumption of >_____ g of ethanol per day

Answer 31

> 80 g of ethanol per day

Question 32

Thrombocytopenia attributable to pure aplasia or hypoplasia of megakaryocytes

Answer 32

ACQUIRED PURE AMEGAKARYOCYTIC THROMBOCYTOPENIA

Rare

Anticipates the development of full-blown MDS or aplastic anemia and is associated with subtle abnormalities of other lineages, such as macrocytosis and dyserythropoiesis.

Most commonly, the disorder is caused by autoimmune suppression of megakaryocyte development

May achieve durable remission with therapies designed to blunt the autoimmune response, such as cyclosporine or antithymocyte globulin.

Question 33

The most common cause of isolated thrombocytopenia in clinical practice

Answer 33

PRIMARY IMMUNE THROMBOCYTOPENIA

Question 34

Childhood OR Adult ITP

Typically is acute in onset, often developing after a viral infection or vaccination.

Although thrombocytopenia may be severe, it usually resolves spontaneously, within a few weeks up to 6 months.

Answer 34

Chidhood ITP

Question 35

Childhood OR Adult ITP

A chronic disease of insidious onset and rarely resolves spontaneously.

Answer 35

Adult ITP

Question 36

TRUE OR FALSE

Most patients with ITP had an decreased number of megakaryocytes, and very few of them were producing platelets, so “actual platelet-producing tissue”.

Answer 36

FALSE

Most patients with ITP had an increased number of megakaryocytes, but very few of them were producing platelets, so “actual platelet-producing tissue” might be decreased.

Question 37

Majority of antiplatelet antibodies in patients with ITP are directed against _________, and the remainder are against the GPIb-IX-V complex and other platelet glycoproteins such as GPIV and integrin αIIβI (GPIa-IIa).

Answer 37

Integrin αIIb–βIII (~80%)

In the late 1980s, two specific assays for the target antigens were described: the immunobead assay100 and the monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay.

Most antiplatelet autoantibodies are IgG; the remainder are IgM and IgA.

Question 38

TRUE OR FALSE

PAIgG could not be used as a specific laboratory test for ITP in the same way that the direct antiglobulin test is used for the diagnosis of autoimmune hemolytic anemia.

Answer 38

TRUE

PAIgG could NOT be used as a specific laboratory test for ITP in the same way that the direct antiglobulin test is used for the diagnosis of autoimmune hemolytic anemia.

Unfortunately, elevated levels of PAIgG later were found in patients with nonimmune thrombocytopenia

Question 39

TRUE OR FALSE

There is still no specific laboratory test for ITP, the diagnosis of ITP being based on exclusion of other causes.

Answer 39

TRUE

There is still no specific laboratory test for ITP, the diagnosis of ITP being based on exclusion of other causes.

Question 40

TRUE OR FALSE

In patients with ITP, both Th1 and Th17 cells have been found to be downregulated, whereas the number and the suppressor functions of the Tregs were found to be increased.

Answer 40

FALSE

In patients with ITP, both Th1 and Th17 cells have been found to be upregulated, whereas the number and the suppressor functions of the Tregs were found to be decreased.

Increased platelet-associated C3, C4, and C9 have been demonstrated on the platelets from patients with ITP.

Question 41

The main regulator of megakaryopoiesis

Enhances megakaryocyte colony formation and increases the size, number, and ploidy of megakaryocytes, as well as platelet production

Answer 41

Thrombopoietin

TPO binds to the cell-surface receptor c-MPL

TPO levels are markedly elevated in patients with thrombocytopenia associated with megakaryocytic hypoplasia, including disorders such as aplastic anemia or acute leukemia.

Question 42

TPO is synthesized in greatest quantity in the

Answer 42

LIver

Found in other organs kidney, muscle, and marrow stromal cells.

Hepatic production of TPO is both constitutive (in the steady state) and inducible (by IL-6 during inflammation), and the concentration of TPO to which megakaryocytes are exposed is also determined by the platelet concentration.

Question 43

This agent,which binds to a region of the TPO receptor that overlaps that bound by authentic TPO

Answer 43

Romiplostim

Question 44

A small organic thrombopoietin receptor agonist (TRA) that activates TPO receptor signaling by binding to the transmembrane domain of the receptor, a site quite distinct from native and romiplostim binding.

Answer 44

Eltrombopag

Eltrombopag has been approved for use in patients with **aplastic anemia **

Question 45

ITP is classified based: on the absence or presence of other diseases :

Answer 45

Primary ITP: absence of any other identified pathology

Secondary ITP

The IWG definition proposed use of the term “immune thrombocytopenia” instead of “idiopathic thrombocytopenic purpura” as the basis for the ITP acronym because the immune nature of ITP is clear, but most patients with ITP do not have purpura.

Question 46

TRUE OR FALSE

Heparin-induced thrombocytopenia (HIT) and alloimmune thrombocytopenias are not classified as ITP and maintain their standard classifications

Answer 46

TRUE

Heparin-induced thrombocytopenia (HIT) and alloimmune thrombocytopenias are not classified as ITP and maintain their standard classifications

Question 47

Three phases of ITP:

Answer 47

(a) Newly diagnosed ITP (within 3 months of diagnosis),
(b) Persistent ITP (patients who do not achieve a stable remission between 3–12 months after diagnosis), and
(c) Chronic ITP (continuing for more than 12 months).

ITP was formerly classified as mild, moderate, and severe depending on the platelet counts. However, the degree of thrombocytopenia does not always correlate with bleeding, likely because of the functional effects of the autoantibody on the platelet.

Question 48

Criteria for response to ITP treatment

Answer 48

• Complete response, CR: platelet count >100 x 109/L and no bleeding symptoms)
• Response, R: platelet count > 30 x 109/L or at least a twofold increase from the baseline count and no bleeding symptoms
• No response, NR: platelet count < 30 x 109/L, < a twofold increase from the baseline count, or presence of bleeding symptoms

Question 49

The IWG proposed that the term “severe ITP” only be used for

Answer 49

Patients with clinically significant bleeding requiring additional therapy regardless of platelet count.

Question 50

Duration of response

Answer 50

Time between first measured CR or R to relapse

Question 51

Corticosteroid dependence

Answer 51

The need for ongoing or repeated glucocorticoid use for at least two months to maintain CR or R.

Question 52

Refractory ITP

Answer 52

Relapsed after splenectomy (failure to maintain CR or R) and required therapy

Question 53

On-demand therapy

Answer 53

Therapies used to temporarily increase the platelet count in special situations such as trauma or surgery.

Question 54

Adjunctive therapies

Answer 54

Treatments that are not designed to increase platelet counts but that may decrease bleeding symptoms by other means, for example, treatment with oral contraceptives or antifibrinolytic drugs.

Question 55

TRUE OR FALSE

The overall incidence was higher in women than in men

Answer 55

TRUE

The overall incidence was higher in women than in men

ITP can affect males and females of any age

A male predominance was seen in patients younger than 18 years of age and older than 65 years.

Question 56

Approximately _________ of patients have platelet counts greater than 30 x 109/L at diagnosis and no significant bleeding, unlike patients with a similar platelet level caused by states of reduced production.

Answer 56

One-third

Question 57

Pattern of bleeding in ITP

Answer 57

Mucocutaneous

Intracerebral hemorrhage is rare and generally occurs in patients with platelet counts less than 10 x 109/L and usually is associated with trauma or vascular lesion

Question 58

Patients with ITP who present with severe thrombocytopenia (<30 x 109/L) and do not respond to any therapy within 2 years have a _____ fold increased risk of death compared with the general population.

Answer 58

Fourfold

Question 59

TRUE OR FALSE

The purpuric lesions seen in ITP are palpable, blanch with pressure, and often develop on distal regions of the extremities and on skin areas exposed to pressure (eg, around tight belts and stockings and at tourniquet sites).

Answer 59

FALSE

The purpuric lesions seen in ITP are not palpable, do not blanch with pressure, and often develop on distal regions of the extremities and on skin areas exposed to pressure (eg, around tight belts and stockings and at tourniquet sites).

Question 60

TRUE OR FALSE

The spleen in ITP usually is enlarged and palpable in some patients, a finding considered to occur with the same incidence as in normal adults.

Answer 60

FALSE

The spleen in ITP usually is not enlarged but may be palpable in some patients, a finding considered to occur with the same incidence as in normal adults.

However, splenomegaly should trigger a search for secondary ITP, such as lymphoma or chronic lymphocytic leukemia

Constitutional symptoms, such as fever, significant weight loss, marked splenomegaly, hepatomegaly, and lymphadenopathy provide evidence that the thrombocytopenia has another cause.

Question 61

TRUE OR FALSE

Patients with ITP are at an approximately twofold increased risk of venous and arterial thrombosis.

Answer 61

TRUE

Patients with ITP are at an approximately twofold increased risk of venous and arterial thrombosis.

Question 62

Laboratory Features OF ITP

Answer 62

• Isolated thrombocytopenia without erythrocyte or leukocyte abnormalities
• Platelet anisocytosis is a common finding as is large platelet forms
• Platelet distribution width is increased.

The ultrastructure of ITP platelets viewed by electron microscopy is similar to that of normal platelets.

Question 63

Condition wherein Autoimmune hemolytic anemiav with a positive direct antiglobulin (Coombs) test and reticulocytosis with ITP

Answer 63

Evans syndrome

Question 64

TRUE OR FALSE

Marrow examination, which is always required to make a diagnosis of ITP

Answer 64

FALSE

Marrow examination, which is not always required to make a diagnosis of ITP

Reveals a normal or increased number of megakaryocytes of normal morphology, although a decreased number of megakaryocytes does not rule out ITP.

Question 65

Indications for BMA in ITP

Answer 65

• Patients older than 60 years
• Those with systemic symptoms or other signs
• Those for whom splenectomy is contemplated

The ASH 2019 guidelines, however, conclude that a marrow examination is unnecessary even in older patients or before splenectomy if the ITP presentation is typical.

Question 66

Basis of therapy in ITP

Answer 66

Bleeding signs and symptoms and on the presence of factors that increase the bleeding risk

Question 67

The primary therapeutic goal in ITP

Answer 67

To reach a safe platelet count at which the risk of bleeding is minimal.

Not simply to increase the platelet count

Patients with no bleeding and consistent platelet counts in excess of 30 x 109/L do not require treatment

Question 68

ITP

Simple observation is not recommended for

Answer 68

• Patients with platelet counts lower than 10 x 109/L
• Those with platelet counts between 10 and 30 x109/L and significant mucosal bleeding
• Those with risk factors for bleeding

Question 69

Presence of _____ should be regarded as a harbinger of life-threatening bleeding and treated as such

Answer 69

Extensive purpura or hemorrhagic bullae in mucosal tissues (wet purpura)

Question 70

Indications of emergency treatment in ITP

Answer 70

• Patients with intracranial or GI bleeding, massive hematuria or internal hematoma
• Those in need of emergency surgical intervention or about to go into labor

Question 71

Recommended treatment for emergent cases of ITP

Answer 71

IVIG and parenteral glucocorticoids in combination

IVIG is given as 1 g/kg per day for 2 days, and high-dose parenteral glucocorticoid therapy includes high dose prednisone or methylprednisolone (1 g/day for 1–3 days).

In most patients, IVIG increases the platelet count within 2–3 days

Although platelet transfusions may not increase the platelet counts because the transfused platelets are destroyed rapidly, they nevertheless may contribute to the formation of platelet plugs at sites of bleeding and improve hemostasis

Platelet transfusion following IVIG infusion may increase the platelet count because IVIG may improve platelet survival.

Question 72

Inhibits fibrinolysis, can be used to reduce bleeding and is safe except in the presence of hematuria, in which case it can cause thrombi of the glomeruli, renal pelvises, and ureters.

Answer 72

Aminocaproic acid

Initial dose, 0.1 g/kg over 30 minutes; then given either by continuous infusion at 0.5–1 g/hour or as an equivalent intermittent dose every 2–4 hours

Question 73

Can be used in combination with glucocorticoids and IVIG in older patients.

Answer 73

Vincristine

Question 74

Accepted as the standard therapy for initial treatment in adult patients with ITP

Answer 74

Glucocorticoids

Inhibiting phagocytosis of antibody-coated platelets by macrophages, decreasing autoantibody production, and improving marrow platelet production

Reduce capillary leakage, thereby decreasing blood loss

Prednisolone, dexamethasone, and methylprednisolone are all used.

Question 75

Dose of steroids

Answer 75

Oral prednisone 1–2 mg/kg per day (or methyl prednisolone at equivalent doses)

Patients usually respond to prednisone therapy within 1 week.

Although no consensus exists regarding the duration of initial therapy, treatment should continue until platelet counts reach a safe range.

In patients who respond, the recommendation is to continue glucocorticoid therapy 1 mg/kg per day for a total of 3 weeks before initiating a slow tapering of doses.

If the patient does not respond to 3 weeks of prednisone therapy, other therapeutic options should be considered.

Question 76

ASH 2019 guidelines recommend shorter (< ____ weeks) courses of corticosteroids (either prednisone [0.5–2.0 mg/kg per day] or dexamethasone [40 mg per day for 4 days]) as a first-line treatment of ITP, but only if the initial platelet count is below 30 x 109/L.

Answer 76

<6 weeks

Question 77

Major site both for synthesis of antiplatelet antibodies and for destruction of antibody-coated platelets

Answer 77

Spleen

Splenectomy decreases antibody production and platelet destruction and is effective in patients in whom antibodymediated platelet destruction rather than platelet production is the major cause of thrombocytopenia.

Question 78

Produces the highest long-term response rates for patients with ITP compared with all other therapies

Answer 78

Splenectomy

The duration of the disease before splenectomy does not affect the outcome of the procedure because it can be effective even years after ITP is diagnosed.

Increases the risk of serious bacterial infection, bleeding, and thrombosis.

Question 79

Splenectomy can be performed during pregnancy preferably during

Answer 79

Second trimester

Question 80

Splenectomy should be postponed at least _______ months after diagnosis if possible and only after immunization against encapsulated bacterial pathogens

Answer 80

6–12 months

Over the past decade, minimally invasive laparoscopic splenectomy has gained preference over open splenectomy.

Question 81

TRUE OR FALSE

Splenectomy is not recommended in patients with CVID, with chronic infections such as chronic hepatitis and HIV, or with known thrombophilia.

Answer 81

TRUE

Splenectomy is not recommended in patients with CVID, with chronic infections such as chronic hepatitis and HIV, or with known thrombophilia.

Question 82

To minimize the risk of sepsis, patients should be immunized at least _____ weeks before splenectomy with _________________.

Answer 82

2–3 weeks

Polyvalent pneumococcal vaccine, Haemophilus influenzae type B vaccine, and quadrivalent meningococcal polysaccharide vaccine

Any fever should be carefully evaluated and the patient treated with broad-spectrum antibiotics.

Question 83

TRUE OR FALSE

Splenectomy also increases the risk of thrombosis in patients with ITP.

Answer 83

TRUE

Splenectomy also increases the risk of thrombosis in patients with ITP.

Question 84

Accepted as useful predictors of the long-term efficacy of splenectomy

Answer 84

Time required to reach a normal platelet count and the magnitude of platelet recovery

In most cases, platelet counts recover within 10 days

Patients who attain a normal platelet count within 3 days of splenectomy generally have a good long-term response

Question 85

In patients refractory to splenectomy or return to significantly lower level platelet levels than achieved early after splenectomy, _______ should be suspected

Answer 85

Presence of accessory splenic tissue

Particularly if the blood film shows no evidence of splenectomy (ie, pitting and Howell-Jolly bodies are absent in the erythrocytes

Question 86

Screening used to identify residual or accessory splenic tissue

Answer 86

Sensitive radionuclide or magnetic resonance scans

Question 87

The effect of IVIG is similar whether or not the patient has undergone splenectomy and is transient, generally lasting only

Answer 87

3–4 weeks

Postulated mechanisms for the action of IVIG include blockade of macrophage Fc receptors, which slows clearance of antibody-coated platelets, antiidiotype neutralization of antiplatelet autoantibodies, cytokine modulation, immunomodulation (increased suppressor T-cell function and decreased autoantibody production), complement neutralization, and dendritic cell priming.]

Question 88

The recommended total dose of IVIG

Answer 88

2 g/kg administered either as 0.4 g/kg per day on 5 consecutive days or as 1 g/kg per day on 2 consecutive days

If the need to increase the platelet count is urgent, the preferred dosing is 1 g/kg per day for 2 days combined with glucocorticoids.

In adult ITP, however, IVIG is usually reserved for patients with life-threatening bleeding, when a prompt increase in platelet count is needed, or as first-line therapy when glucocorticoids are contraindicated.

Adverse effects of IVIG therapy include headache, backache, nausea, fever, aseptic meningitis, alloimmune hemolysis, hepatitis, renal failure, pulmonary insufficiency, and thrombosis.

Question 89

Dose of IVIG for maintenance therapy

Answer 89

0.5–1.0 g/kg as a single dose may be used, administered every 3–4 weeks, or as needed

Question 90

Anaphylactic reactions in IVIG may occur in patients with

Answer 90

Congenital IgA deficiency

Question 91

A polyclonal γ-globulin containing high titers of antibodies against the Rho(D) antigen of erythrocytes.

Listed in current ASH ITP guidelines as a first-line agent when glucocorticoids are contraindicated.

Answer 91

Anti-(Rh)D

Binds Rh-positive erythrocytes and leads to their destruction in the spleen–> Because splenic Fc receptors are blocked, more antibody-coated platelets survive in the circulation

Not effective in patients who have undergone splenectomy or in Rh-negative patients and is not recommended in patients with a positive direct antiglobulin test result

Question 92

Occur in all Rh-positive patients after anti-(Rh)D infusion

Answer 92

A positive direct antiglobulin test result, a decrease in serum haptoglobin levels, and mild and transient hemolysis

Generally without requiring a blood transfusion

Question 93

Dose of Anti-(Rh)D

Answer 93

Single dose of 50–100 mcg/kg by IV infusion over 3–5 minutes

Adverse effects of anti-(Rh)D therapy resemble those observed with both γ-globulin infusion and autoimmune hemolytic anemia; symptoms include headache, asthenia, chills, fever, abdominal pain, diarrhea, vomiting, dizziness, and myalgia.

Question 94

A chimeric monoclonal antibody against CD20

Depletes B cells in patients with autoimmune diseases, with the effect usually lasting 6–12 months

Answer 94

Rituximab

Still considered “off label” for ITP

Question 95

Dose of Rituximab

Answer 95

100–375 mg/m2.

weekly infusion for 4 consecutive weeks

Splenectomy does not affect response rates to rituximab therapy.

In patients with ITP who have relapsed more than 1 year after rituximab therapy, retreatment with the drug induces similar responses in 75% of patients who responded initially.

All patients should be screened for HBV before rituximab therapy

Question 96

A peptibody that carries four copies of a 14-amino-acid TPO-receptor–binding peptide fused to an immunoglobulin scaffold and binds to the TPO-binding site of the TPO receptor with high affinity

Answer 96

Romiplostim

Has no homology with endogenous TPO; thus, the risk of the development of antibodies against TPO is very low.

Can be used in patients with hepatic or renal insufficiency but is not recommended in pregnant patients because it can cross the placenta

Question 97

Dose of Romiplostim

Answer 97

Weekly subcutaneous injection at doses of 1–3 mcg/kg

Produced a dose-dependent increase in the platelet count, starting from day 5, with peak platelet levels reached by days 12–15 and platelet counts returning to baseline by day 28 following discontinuation of the drug

If the platelet count does not increase to safe levels after 4 weeks of romiplostim treatment at the maximum dose, the drug should be discontinued.

Question 98

A small (442-Da) nonpeptide molecule that binds to the transmembrane domain of the TPO receptor and triggers megakaryocyte growth and differentiation, increasing platelet production

Answer 98

Eltrombopag

Does not compete with TPO binding, and although it induces the phosphorylation of STAT proteins, it does not affect the AKT pathway.

Has no effect on platelet activation in response to platelet agonists (eg, thrombin or epinephrine).

Question 99

Dose of Eltrombopag

Answer 99

25–75 mg

Should be given 2 hours before or after meals
Divalent cations such as calcium interfere with absorption of the drug, so it should not be taken with dairy products or antacids.
Can also interfere with the uptake and metabolism of statins, increasing their plasma concentrations.

Lower initial doses and slower titration are preferred in East Asian patients.

Causes liver function abnormalities in approximately 13%

Question 100

An oral, nonpeptide TPO-receptor agonist that binds to the transmembrane domain of TPO receptor, and increases platelet counts.

Lack of significant food interaction

Answer 100

Avatrombopag

Question 101

New TRA found to be effective in patients with ITP who have not responded to other treatments, including some who had failed other TRAs.

Answer 101

Fostamatinib

Question 102

Purine analogue is converted to 6-mercaptopurine after GI absorption and works by suppressing the immune response

Can be used in pregnancy if necessary

Answer 102

Azathioprine

At least 4 months of azathioprine therapy at doses ranging from 50 to 250 mg/day are necessary to evaluate therapeutic efficacy.

Major adverse effects are marrow suppression and possible increased risk of secondary malignancy.

Question 103

This alkylating drug can be used in patients with refractory ITP.

Answer 103

Cyclophosphamide

Orally (50–200 mg/day) or parenterally (1.0–1.5 g/m2 IV every 4 weeks)

The major complications of cyclophosphamide therapy are marrow suppression, hemorrhagic cystitis, infertility, alopecia, and secondary malignancy.

Question 104

Synthetic androgen, with reduced virilizing effects compared with other androgens, has been used to treat patients with refractory ITP.

Answer 104

Danazol

** 400–800 mg/day for at least 6 months**

Should not be given to pregnant women or patients with liver disease.

Question 105

Possesses antibacterial and antiinflammatory effects; it is primarily used for leprosy, malaria, and some types of dermatitis

Can be used in persistent, refractory, or chronic ITP

Answer 105

Dapsone

75–100 mg/day

The median time to response is long, up to 2 months.

Should not be given to patients with glucose-6-phosphate dehydrogenase deficiency

Question 106

Vinca Alkaloids used in ITP

Answer 106

Vincristine and vinblastine

The recommended dose of vincristine is 1–2 mg and of vinblastine is 0.1 mg/kg (maximum, 10 mg), both given by bolus injection at 1-week intervals for a minimum of three courses.

Question 107

Immune-mediated platelet destruction in the presence of other conditions, including infections, lymphoproliferative disorders, solid tumors, SLE, or the antiphospholipid syndrome (APS)

Answer 107

Secondary ITP

Question 108

TRUE OR FASLE

Thrombocytopenia is reported in approximately 20% to 40% of patients with APS, usually is mild (70–120 x 109/L), and does not require clinical intervention.

Answer 108

TRUE

Thrombocytopenia is reported in approximately 20% to 40% of patients with APS, usually is mild (70–120 x 109/L), and does not require clinical intervention.

Antithrombotic prophylaxis should be considered in these patients whenever it is possible.

Immunosuppressive treatment in these patients increases the platelet count and reduces the titers of anti-GP antibodies but not the titers of APLAs.

IVIG and immunosuppressive drugs such as azathioprine and cyclophosphamide can be used in patients with **severe bleeding and “catastrophic” APS. **

Question 109

TRUE OR FASLE

Among the many potential contributors to thrombocytopenia in patients with SLE, platelet destruction by autoantibodies is the major mechanism.

Answer 109

TRUE

Among the many potential contributors to thrombocytopenia in patients with SLE, platelet destruction by autoantibodies is the major mechanism.

Specific antiplatelet antibodies, especially those against platelet integrins, have an important role in the pathogenesis of thrombocytopenia in patients with SLE.

There are no well-established treatment strategies for severe thrombocytopenia in patients with SLE.

Question 110

Infection can decrease platelet levels in several ways:

Answer 110

• By decreasing production in the marrow
• By increased immune destruction, or
• By inducing microangiopathy as seen in patients with infection induced DIC or HUS

Question 111

Viral infection that is a leading cause of isolated thrombocytopenia in Western countries

Answer 111

HIV

Others: rubella, mumps, and infectious mononucleosis, HCV, HBV

Question 112

Thrombocytopnia in HCV

The ASH 2019 guideline recommends _________ as a first-line therapy because glucocorticoids may increase viral load in addition to treating the HCV.

TRAs may increase the risk of abdominal thrombosis in HCV patients with liver cirrhosis.

Answer 112

IVIG

HCV causes thrombocytopenia through several mechanisms, including hypersplenism, decreased TPO level associated with hepatic insufficiency, the effect of drugs (eg, pegylated interferon [IFN] and ribavirin), and immune-mediated platelet destruction.

Question 113

TRUE OR FALSE

The 2019 ASH ITP guideline suggests that patients with ITP be screened for H. pylori and for eradication therapy to be used if testing is positive.

Answer 113

TRUE

The 2019 ASH ITP guideline suggests that patients with ITP be screened for H. pylori and for eradication therapy to be used if testing is positive.

Question 114

The second most common hematologic problem in pregnancy, after anemia

Answer 114

Thrombocytopenia

Question 115

Platelet counts tend to decrease during normal pregnancy, and mild thrombocytopenia (platelet counts ranging from 120 to 150 x 109/L) occurs with moderate frequency, especially during the ________________

Answer 115

Third trimester

Bleeding symptoms are generally mild

Key steps in the evaluation of thrombocytopenia in a pregnant woman include blood pressure measurement, evaluation of coagulation parameters, liver and kidney function tests, and examination of the blood film.

If there are no suspicious clinical or laboratory findings, marrow aspiration is considered unnecessary.

Question 116

Gestational thrombocytopenia

Platelet counts are usually greater than _____ x109/L and return to normal after delivery.

Answer 116

Greater than 70 x109/L

Question 117

TRUE OR FALSE

Pregnancy itself may induce ITP or exacerbate preexisting ITP, but generally the platelet count returns to the prepregnancy level after delivery.

Answer 117

TRUE

Pregnancy itself may induce ITP or exacerbate preexisting ITP, but generally the platelet count returns to the prepregnancy level after delivery.

The diagnosis of ITP is favored if the patient had a previous episode of ITP unassociated with pregnancy or if the thrombocytopenia is severe and associated with bleeding that occurs in the first trimester.

Question 118

IMMUNE THROMBOCYTOPENIA IN PREGNANCY

• Platelet count is greater than 30 x 109/L and the patient has no bleeding symptoms
• Bleeding, have a platelet count less than 20x 109/L in any trimester, or have a platelet count of 20–30 x 109/L in the third trimester

Answer 118

• Platelet count is greater than 30 x 109/L and the patient has no bleeding symptoms: OBSERVE
• Bleeding, have a platelet count less than 20x 109/L in any trimester, or have a platelet count of 20–30 x 109/L in the third trimester: TREAT

Question 119

Preferred initial therapy for ITP in pregnancy

Answer 119

Glucocorticoids

The recommended starting dosage of prednisone is 10 mg/day, which can be modified as appropriate.

Fetal side effects are minimal with a low-dose glucocorticoid regimen because approximately 90% of the glucocorticoid dose is metabolized in the placenta.

Question 120

Indicated in pregnant patients who do not respond to or tolerate glucocorticoid treatment or when it is necessary to rapidly increase the platelet count.

Answer 120

IVIG

1 g/kg per day for 2 days or 400 mg/kg per day for 5 days alone or combined with low-dose prednisone.

Question 121

TRUE OR FALSE

The optimal mode of delivery in pregnant patients with ITP has not been determined.

Answer 121

TRUE

The optimal mode of delivery in pregnant patients with ITP has not been determined.

**The mother’s platelet count at delivery does not correlate with the infant’s platelet count. **

In patients with ITP who have given birth more than once, however, the first infant’s platelet count at birth may be a predictor of severe thrombocytopenia in subsequent pregnancies and may justify further obstetric management.

Question 122

During vaginal delivery, the target maternal platelet count should be

Answer 122

50 x 109/L or higher

Question 123

If cesarean section or epidural anesthesia is required, the platelet count should be maintained over

Answer 123

70–80  x 109/L

Question 124

Preferred in neonates with severe thrombocytopenia

Answer 124

IVIG

Severe neonatal thrombocytopenia (platelet counts <20 x 109/L) occurs in 3% to 5% of ITP pregnancies and moderate neonatal thrombocytopenia (platelet counts <50   109/L) in 9%.

Question 125

Although there is no defined threshold platelet level for these patients, platelet counts over _________ are considered safe for both anticoagulant and antiplatelet therapy.

Answer 125

50 x 109/L

Question 126

Thrombocytopenia is seen in approximately ____% of women with preeclampsia, with the severity of thrombocytopenia correlating with the severity of the preeclampsia.

Answer 126

50%

Question 127

This syndrome occurs in the peripartum period and is defined by the presence of microangiopathic hemolytic anemia, elevated liver enzymes, and low platelets.

Answer 127

HELLP Syndrome

In approximately 70% to 80% of patients, HELLP occurs in the setting of preeclampsia

Question 128

A very severe, but fortunately very rare (1 in 20,000–100,000 pregnancies), condition that occurs during the third trimester of pregnancy or early postpartum period

Characterized by microvesicular fatty infiltration of liver, resulting in hepatic failure and encephalopathy.

Answer 128

Acute fatty liver of pregnancy (AFLP)

The platelet count nadir and the peak of serum lactate dehydrogenase may occur postpartum, during the first postpartum day in most patients, but as late as 5–7 days in some.

Question 129

“Swansea criteria” used for the diagnosis of AFLP

Answer 129

Encephalopathy, vomiting, abdominal pain, polydipsia and polyuria, elevated transaminases, elevated ammonia, elevated uric acid, elevated bilirubin, leukocytosis, coagulopathy, renal impairment, hypoglycemia, ascites or bright liver on ultrasound evaluation, and microvesicular steatosis on liver biopsy

Six or more of these criteria should be present in a patient who has no obvious reason for hepatic failure.

Question 130

The most effective treatment for preeclampsia, HELLP syndrome, and AFLP

Answer 130

Delivery of the fetus

Question 131

Acute Fatty Liver of Pregnancy

Indicated if the fetus cannot be delivered or if improvement does not follow delivery

Answer 131

Plasma exchange

Question 132

Acute Fatty Liver of Pregnancy

Indicadted for patienta with liver insufficiency, encephalopathy, and coagulopathy may not improve despite immediate delivery and intensive supportive care

Answer 132

Liver transplantation.

Question 133

The platelet count in the fetus reaches normal adult levels (>150 x 109/L) after the ___________ trimester and is maintained throughout gestation.

Answer 133

First trimester

Question 134

Caused by the transplacental transfer of maternal alloantibodies against fetal platelet antigens inherited from the father.

Answer 134

Fetal–neonatal alloimmune thrombocytopenia (NAIT)

Question 135

Difference of NAIT and neonatal alloimmune hemolytic anemia (Rh hemolytic disease of the newborn)

Answer 135

Unlike neonatal alloimmune hemolytic anemia, which tends to spare the first-born child, the first child is affected in 40% to 60% of NAIT cases.

In both diseases, maternal alloantibodies against fetal blood cell antigens cross the placenta and destroy antigen-positive fetal cells, resulting in significant fetal or neonatal morbidity and mortality.

In contrast to maternal ITP, the maternal platelet count is normal in NAIT, a key differential diagnostic finding.

Question 136

Responsible for platelet destruction in NAIT

Answer 136

Maternal alloantibodies against human platelet alloantigens (HPAs)

In populations of European ancestry, the most frequently implicated antigens are HPA-1a or PlA1 (78% of cases) and HPA-5b or Bra (19% of cases).

HPA-4a (80% of cases) and HPA-3a (15% of cases) are responsible for platelet destruction in the majority of Asian NAIT cases.

NAIT tends to be clinically more severe in cases with alloantibodies against HPA-1a.

Question 137

HPA alloimmunization is strongly correlated with the presence of specific class II HLA antigens, with increased risk demonstrated in HPA-1a–negative mothers expressing

Answer 137

HLA-B8, HLADR3, and HLA-DR52a antigens

The presence of the HLA-DRB3*0101 allele in HPA-1a–negative women increases the NAIT risk as much as 140-fold.

Question 138

Features that may alert the physician to the possibility of NAIT

Answer 138

Unexplained fetal deaths in the maternal history or fetal hydrocephalus or bleeding in previous pregnancies

NAIT should be suspected in a thrombocytopenic neonate with extensive purpura or visceral hemorrhage but no evidence of sepsis, skeletal anomalies, or other systemic diseases that may cause thrombocytopenia, including maternal ITP.

Platelet counts recover to normal in 1–2 weeks.

Question 139

The diagnosis of NAIT usually can be confirmed by

Answer 139

Tests for circulating maternal alloantibodies against fetal antigens (usually by MAIPA) or modified antigen capture enzyme-linked immunosorbent assay (MACE) or by platelet typing of the parents and neonate by either genotyping or ELISA

Question 140

TRUE OR FALSE

An infant born with severe thrombocytopenia with no obvious cause such as sepsis should be regarded as having ITP.

Answer 140

FALSE

An infant born with severe thrombocytopenia with no obvious cause such as sepsis should be regarded as having NAIT.

Question 141

The alternatives in the management of affected neonates with NAIT

Answer 141

IVIG, glucocorticoids (alone or combined with IVIG), and platelet transfusions.

Transfused platelets should be ABO and (Rh)D compatible and HPA-1a–negative if possible.If such platelet suspensions are not available, transfusion of washed and irradiated maternal platelets to the affected fetus is another alternative.

All affected infants should be screened with ultrasound for intracranial hemorrhage

Question 142

Treatment options in high-risk NAIT at prenatal

Answer 142

Weekly IVIG administration to the mother, with or without glucocorticoids, serial in utero platelet transfusions, in utero IVIG administration, and early delivery (after 32 weeks of gestation).

Pregnant women who had a previous thrombocytopenic infant attributable to NAIT should be carefully monitored in a center with experience with NAIT because thrombocytopenia will be more severe in a second affected child

Question 143

Splenomegaly may lead to thrombocytopenia by inducing a reversible pooling of up to ___% of total body platelets.

Answer 143

90%

Question 144

The most common disorder causing thrombocytopenia because of splenic pooling is

Answer 144

Chronic liver disease with portal hypertension and congestive splenomegaly

In patients with cirrhosis and portal hypertension, moderate thrombocytopenia is the rule

However, in such cases, the thrombocytopenia often results from both splenic pooling and reduced hepatic production of TPO

Question 145

TRUE OR FALSE

Thrombocytopenia associated with splenomegaly is often with clinical importance and generally require therapy.

Answer 145

FALSE

Thrombocytopenia associated with splenomegaly is often of no clinical importance and generally does not require therapy.

Question 146

Condition wherein pooling is accompanied by increased destruction of platelets, leukocytes, and erythrocytes in association with increased marrow precursors of the deficient lines and correction of the cytopenia by splenectomy

Answer 146

Hypersplenism

Question 147

Transient thrombocytopenia occurs during hypothermia, in both animals and humans, when the body temperature falls below ____

Answer 147

25C

In this case, the drop in platelet count likely results from splenic and hepatic pooling and from cold activation and clearance of platelets.

Question 148

Defined as profound thrombocytopenia related to platelet trapping within a vascular tumor, either a Kaposi-like hemangioendothelioma or a tufted angioma

Answer 148

Kasabach-Merritt syndrome

The syndrome presents predominantly during infancy, but several adult cases have been reported.

The mainstay of treatment is eradication of the tumor

Question 149

A locally aggressive, low-grade malignant tumor characterized by infiltrating sheets or lobules of poorly formed vascular channels and aberrant lymphatic vessels

Answer 149

Kaposi-like hemangioendothelioma

These tumors are composed predominantly of plump, round, oval, and/or spindled endothelial cells with hemosiderin deposits.

Question 150

A lesion characterized by the presence of vascular tufts and aggregates of round dilated capillaries, lymphangiomatosis, microthrombi, and hemosiderin deposits.

Answer 150

Tufted angioma

Question 151

Thrombocytopenia in Kasabach-Merritt syndrome usually is severe and associated with ______.

Answer 151

DIC

Contributing factors include “platelet trapping” by abnormally proliferating endothelium within the hemangioma and platelet consumption associated with DIC.

Question 152

A very rare acquired disorder characterized by a periodic decrease in the platelet count, sometimes followed by rebound thrombocytosis without therapy (>500   109/L)

Answer 152

Cyclic thrombocytopenia (CTP)

Each thrombocytopenic cycle typically spans a period of 3–6 weeks, and women are more often affected than men.

Rebound thrombocytosis is an important and distinctive feature of CTP.

Question 153

Drugs may cause thrombocytopenia by different mechanisms:

Answer 153

Dose-dependent myelosuppression and immune destruction of the platelets

Question 154

An immune-mediated disorder caused by antibodies that recognize a neoepitope in platelet factor 4 that is exposed when platelet factor 4 binds heparin.

Answer 154

HIT

Question 155

Most commonly cited drug that cause thrombocytopenia

Answer 155

Quinidine

Question 156

Drugs that may induce true autoantibodies, with those induced by gold being unique in targeting platelet GPV.

Answer 156

Gold salts and procainamide

Question 157

TRUE OR FALSE

The diagnosis of drug-induced thrombocytopenia can be made only by recovery from thrombocytopenia upon discontinuation of the drug and can be confirmed if thrombocytopenia recurs with rechallenge by the drug.

Answer 157

TRUE

The diagnosis of drug-induced thrombocytopenia can be made only by recovery from thrombocytopenia upon discontinuation of the drug and can be confirmed if thrombocytopenia recurs with rechallenge by the drug.

Prompt recovery within 5–7 days is usual.

Gold-induced thrombocytopenia is an exception because gold salts are retained for long periods of time within the body, and thrombocytopenia can persist for months, becoming indistinguishable from ITP.

With rechallenge, acute thrombocytopenia may occur within minutes but almost always within 3 days.