116 Thrombocytopenia Flashcards
(160 cards)
1
Q
One-third of the platelets are stored in the _________, and the remaining two-thirds circulate in _____________ human
A
Spleen: one-third
Blood vessels: two-thirds
2
Q
Platelets have a mean lifespan in the circulation of ______ days
A
7–10 days
Approximately 1 × 10 11 platelets are produced per day
3
Q
Every day approximately ________% of circulating platelets are removed by the mononuclear phagocyte system, primarily by macrophages in the ____________.
A
10% to 12%
spleen and liver
4
Q
The normal platelet count
A
150–400 × 10 9 /L
5
Q
Classically thrombocytopenia is defined as platelet count less than __________
A
less than 150 × 10 9 /L
6
Q
Throbocytopenia
Severe:
Moderate:
Mild:
A
Severe (platelet count <20 × 10 9 /L)
Moderate (platelet count 20–70 × 10 9/L)
Mild (>70 × 10 9/L)
7
Q
The blood-to-anticoagulant ratio should be as recommended. The International Council for Standardization in Hematology recommends the use of ____________ as the anticoagulant.
A
Ethylenediaminetetraacetic acid (EDTA)
8
Q
Conditions associated with pseudo thrombocytopenia
A
- Use of EDTA as an anticoagulant
- Platelet cold agglutinins
- Myeloma
9
Q
ANTIBODY-INDUCED PLATELET AGGLUTINATION
The antibodies usually are of the Immunoglobulin ________ type.
A
Immunoglobulin (Ig) G type
IgM and IgA antibodies also have been described
10
Q
ANTIBODY-INDUCED PLATELET AGGLUTINATION
In most cases, the antibodies are directed against the __________
A
Integrin αIIbβIII (also termed glycoprotein [GP] IIb/IIIa)
11
Q
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 ______________
A
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.
12
Q
Some antiplatelet antibodies from patients with pseudothrombocytopenia cross-react with negatively charged phospholipids and may exhibit _______________ activity.
A
Anticardiolipin activity
13
Q
Thrombocytopenia has been described in patients with acute coronary syndromes treated with the ___________ and other _________________
A
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.
14
Q
TRUE OR FALSE
Pseudothrombocytopenia may be accompanied by pseudoleukocytosis
A
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.
15
Q
How can platelet clumping be prevented
A
- 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.
16
Q
Patients with IPD usually present witH
A
Mucocutaneous bleeding
Spontaneous life-threatening bleeding is rare.
17
Q
TRUE OR FALSE
Majority of IPDs are inherited as autosomal dominant traits.
A
FALSE
Majority of IPDs are inherited as autosomal recessive traits.
18
Q
Laboratory PBS findings of a potential IPD
A
- 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).
19
Q
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.
A
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.
20
Q
Gold standard in diagnosing IPDs
A
Light transmission aggregometry
Uses different concentrations of adenosine diphosphate (ADP), collagen, ristocetin, epinephrine, and arachidonic acid
May be normal in variant forms of IPDs and in some patients with storage pool diseases
21
Q
Test recommended in patients with platelet granule deficiencies
A
Platelet nucleotide content and release
22
Q
Test that can be used in patients with platelet surface glycoprotein deficiencies such as Bernard-Soulier syndrome
A
Flow cytometric analysis
23
Q
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.
A
Electron microscopy
24
Q
TRUE OR FALSE
Isolated thrombocytopenia is common in patients with nutritional deficiencies.
A
FALSE
Isolated thrombocytopenia is rare in patients with nutritional deficiencies.
25
Iron-deficiency anemia (IDA) generally develops after acute or chronic bleeding and is usually accompanied by (thrombocytosis OR thrombocytopenia)
Thrombocytosis
## Footnote
**Thrombocytopenia** associated with IDA is relatively rare, reported in only 2.3% and 2.4% of pediatric and adult IDA patients, respectively.
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.
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.
| autoimmune
## Footnote
Various other autoimmune disorders can coexist with pernicious anemia, including autoimmune vitiligo and autoimmune thyroiditis.
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.**
Copper deficiency
## Footnote
May be misdiagnosed as having MDS because **increased ring sideroblasts and dysplastic precursor cells** can be seen in on bone marrow smears
28
In **acute ethanol intoxication**, platelet counts in these cases are usually **mildly** (increased or decreased) **severe thrombocytopenia is quite rare**.
Platelet counts in these cases are usually mildly decreased (generally >100 109/L)
## Footnote
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.
29
Suggested mechanism of **acute alcohol-related thrombocytopenia**
It has been suggested that metabolites of ethanol, especially **acetaldehyde**, *impair the late stages of platelet production and increase platelet destruction*
## Footnote
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**.
30
Mechanisms of thrombocytopenia in **chronic ethanol consumption**
* Alcoholic liver cirrhosis (both splenomegaly and thrombopoietin deficiency)
* Folic acid deficiency
* Alcohol-induced marrow suppression
31
Alcoholism (chronic ethanol consumption, which is defined as consumption of >_____ g of ethanol per day
> 80 g of ethanol per day
32
Thrombocytopenia attributable to **pure aplasia or hypoplasia of megakaryocytes**
**Antibodies against thrombopoietin (TPO)** have been described to cause the disorder, as have antibodies against the **TPO receptor**.
ACQUIRED PURE AMEGAKARYOCYTIC THROMBOCYTOPENIA
## Footnote
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.
33
Causes of Acquired Pure Megakaryocytric Thrombocytopenia
* **Autoimmune** suppression of megakaryocyte development, either idiopathic, associated with autoimmune disorders such as **systemic lupus erythematosus (SLE) and eosinophilic fasciitis**
* **Infections** such as **hepatitis C**
## Footnote
May achieve durable remission with therapies designed to blunt the autoimmune response, such as **cyclosporine or antithymocyte globulin.**
34
The most common cause of isolated thrombocytopenia in clinical practice
PRIMARY IMMUNE THROMBOCYTOPENIA
35
# 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.
Chidhood ITP
36
# Childhood OR Adult ITP
A chronic disease of **insidious** onset and **rarely resolves spontaneously**.
Adult ITP
37
# TRUE OR FALSE
Most patients with ITP had decreased number of megakaryocytes, and very few of them were producing platelets, so “actual platelet-producing tissue”.
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**.
38
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).**
Integrin αIIb–βIII (~80%)
## Footnote
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.
39
# 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.
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.
## Footnote
Unfortunately, elevated levels of PAIgG later were found in patients with nonimmune thrombocytopenia
40
# TRUE OR FALSE
There is still no specific laboratory test for ITP, the diagnosis of ITP being based on exclusion of other causes.
TRUE
There is still **no specific laboratory test for ITP**, the diagnosis of ITP being based on exclusion of other causes.
41
# 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.
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**.
## Footnote
Increased platelet-associated **C3, C4, and C9** have been demonstrated on the platelets from patients with ITP.
42
**The main regulator of megakaryopoiesis**
Enhances megakaryocyte colony formation and increases the size, number, and ploidy of megakaryocytes, as well as platelet production
Thrombopoietin
## Footnote
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.**
43
TPO is synthesized in greatest quantity in the
LIver
## Footnote
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.
44
This agent,which binds to a region of the TPO receptor that overlaps that bound by authentic TPO
Romiplostim
45
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.
Eltrombopag
## Footnote
Eltrombopag has been approved for use in patients with **aplastic anemia**
46
ITP is classified based: on the absence or presence of other diseases :
**Primary ITP**: absence of any other identified pathology
**Secondary ITP**
## Footnote
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.**
47
# TRUE OR FALSE
Heparin-induced thrombocytopenia (HIT) and alloimmune thrombocytopenias are not classified as ITP and maintain their standard classifications
TRUE
**Heparin-induced thrombocytopenia (HIT) and alloimmune thrombocytopenias** are not classified as ITP and maintain their standard classifications
48
Three phases of ITP:
(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**).
## Footnote
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.
49
Criteria for response to ITP treatment
* **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
50
The IWG proposed that the term **“severe ITP”** only be used for
Patients with clinically **significant bleeding** **requiring additional therapy regardless of platelet count.**
51
Duration of response
Time between first measured CR or R to relapse
52
Corticosteroid dependence
The need for ongoing or repeated glucocorticoid use for at least **two months** to maintain CR or R.
53
Refractory ITP
Relapsed after splenectomy (failure to maintain CR or R) and required therapy
54
On-demand therapy
Therapies used to **temporarily increase the platelet count** in special situations such as **trauma or surgery.**
55
Adjunctive therapies
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.**
56
# TRUE OR FALSE
The overall incidence was higher in women than in men
TRUE
The overall incidence was higher in women than in men
## Footnote
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.**
57
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.
One-third
58
Pattern of bleeding in ITP
Mucocutaneous
## Footnote
**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**
59
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.
Fourfold
60
# 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).
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).
61
# 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.
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.
## Footnote
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.**
62
# TRUE OR FALSE
Patients with ITP are at an approximately twofold increased risk of venous and arterial thrombosis.
TRUE
Patients with ITP are at an approximately **twofold increased risk of venous and arterial thrombosis**.
63
Laboratory Features of ITP
* **Isolated thrombocytopenia** without erythrocyte or leukocyte abnormalities
* Platelet anisocytosis is a common finding as is **large platelet** forms
* **Platelet distribution width is increased**.
## Footnote
The ultrastructure of ITP platelets viewed by electron microscopy is similar to that of normal platelets.
64
Condition wherein **Autoimmune hemolytic anemia with a positive direct antiglobulin (Coombs) test** and reticulocytosis with **ITP**
Evans syndrome
65
# TRUE OR FALSE
Marrow examination, which is always required to make a diagnosis of ITP
FALSE
Marrow examination, which is **not** always required to make a diagnosis of ITP
## Footnote
Reveals a normal or **increased number of megakaryocytes** of normal morphology, although a *decreased number of megakaryocytes does not rule out ITP.*
66
Indications for BMA in ITP
* Patients older than 60 years
* Those with systemic symptoms or other signs
* Those for whom splenectomy is contemplated
## Footnote
*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.*
67
Basis of therapy in ITP
Bleeding signs and symptoms and on the presence of factors that increase the bleeding risk
68
The primary therapeutic goal in ITP
To reach a safe platelet count at which the risk of bleeding is minimal.
## Footnote
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*
69
# ITP
Simple observation is **not recommended** for
* 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
70
Presence of _____ should be regarded as a harbinger of life-threatening bleeding and treated as such
Extensive purpura or hemorrhagic bullae in mucosal tissues (wet purpura)
71
Indications of emergency treatment in ITP
* Patients with **intracranial** or **GI** bleeding, massive **hematuria** or **internal hematoma**
* Those in need of **emergency surgical intervention** or about to go into **labor**
72
Recommended treatment for emergent cases of ITP
IVIG and parenteral glucocorticoids in combination
## Footnote
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.
73
**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.
Aminocaproic acid
## Footnote
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**
74
Can be used in combination with glucocorticoids and IVIG in **older patients.**
Vincristine
75
# TRUE OR FALSE
Plasmapheresis treatment is recommended in current ITP guidelines.
FALSE
**Plasmapheresis** treatment is **not** recommended in current ITP guidelines.
76
Accepted as the standard therapy for initial treatment in adult patients with ITP
Glucocorticoids
## Footnote
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.
77
Dose of steroids
Oral prednisone 1–2 mg/kg per day (or methylprednisolone at equivalent doses)
## Footnote
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.**
78
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.**
<6 weeks
79
Major site both for synthesis of antiplatelet antibodies and for destruction of antibody-coated platelets
Spleen
## Footnote
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.
80
Produces the highest long-term response rates for patients with ITP compared with all other therapies
Splenectomy
## Footnote
***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.
81
Splenectomy can be performed during pregnancy preferably during
Second trimester
82
Splenectomy should be postponed at least _______ months after diagnosis if possible and only after immunization against encapsulated bacterial pathogens
6–12 months
## Footnote
Over the past decade, minimally invasive **laparoscopic splenectomy** has gained preference over open splenectomy.
83
# TRUE OR FALSE
Splenectomy is not recommended in patients with CVID, with chronic infections such as chronic hepatitis and HIV, or with known thrombophilia.
TRUE
Splenectomy is **not recommended** in patients with **CVID, with chronic infections such as chronic hepatitis and HIV**, or with **known thrombophilia.**
84
To minimize the risk of sepsis, patients should be immunized at least _____ weeks before splenectomy with _________________.
2–3 weeks
Polyvalent pneumococcal vaccine, Haemophilus influenzae type B vaccine, and quadrivalent meningococcal polysaccharide vaccine
## Footnote
*Any fever should be carefully evaluated and the patient treated with broad-spectrum antibiotics.*
85
# TRUE OR FALSE
Splenectomy also increases the risk of thrombosis in patients with ITP.
TRUE
Splenectomy also increases the risk of thrombosis in patients with ITP.
86
Accepted as useful predictors of the long-term efficacy of splenectomy
**Time required to reach a normal platelet count** and the **magnitude of platelet recovery**
## Footnote
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**
87
In patients refractory to splenectomy or return to significantly lower level platelet levels than achieved early after splenectomy, _______ should be suspected
Presence of accessory splenic tissue
## Footnote
Particularly if the blood film shows no evidence of splenectomy (ie, pitting and Howell-Jolly bodies are absent in the erythrocytes
88
Screening used to identify residual or accessory splenic tissue
Sensitive radionuclide or magnetic resonance scans
89
The effect of **IVIG** is similar whether or not the patient has undergone splenectomy and is **transient**, generally lasting only
3–4 weeks
## Footnote
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.]
90
The recommended total dose of IVIG
**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**
## Footnote
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.**
91
Dose of IVIG for maintenance therapy
**0.5–1.0 g/kg** as a single dose may be used, administered **every 3–4 weeks**, or **as needed**
92
Anaphylactic reactions in IVIG may occur in patients with
Congenital IgA deficiency
93
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**.
Anti-(Rh)D
## Footnote
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
94
Anti-(Rh)D is not effective in patients
* Who have undergone splenectomy
* Rh-negative patients
* Patients with a positive direct antiglobulin test result
95
Occur in all Rh-positive patients after anti-(Rh)D infusion
A positive direct antiglobulin test result, a decrease in serum haptoglobin levels, and mild and transient hemolysis
| Hemolysis
## Footnote
Generally without requiring a blood transfusion
96
Dose of Anti-(Rh)D
Single dose of 50–100 mcg/kg by IV infusion over 3–5 minutes
## Footnote
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.**
97
A chimeric monoclonal antibody against **CD20**
Depletes B cells in patients with autoimmune diseases, with the effect usually lasting **6–12 months**
Rituximab
## Footnote
Still considered “off label” for ITP
98
Dose of Rituximab
100–375 mg/m2.
weekly infusion for 4 consecutive weeks
## Footnote
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
99
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**
Romiplostim
## Footnote
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
100
Dose of Romiplostim
Weekly subcutaneous injection at doses of 1–3 mcg/kg
## Footnote
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.
101
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
Eltrombopag
## Footnote
**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).
102
Dose of Eltrombopag
25–75 mg
## Footnote
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%
103
An oral, nonpeptide TPO-receptor agonist that binds to the transmembrane domain of TPO receptor, and increases platelet counts.
Lack of significant food interaction
Avatrombopag
104
New TRA found to be effective in patients with ITP **who have not responded to other treatments**, including some who had **failed other TRAs.**
Fostamatinib
105
**Purine analogue** is converted to 6-mercaptopurine after GI absorption and works by suppressing the immune response
**Can be used in pregnancy** if necessary
Azathioprine
## Footnote
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.**
106
This **alkylating drug** can be used in patients with **refractory ITP**.
Cyclophosphamide
## Footnote
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.
107
Synthetic **androgen**, with reduced virilizing effects compared with other androgens, has been used to treat patients with **refractory ITP.**
Danazol
## Footnote
**400–800 mg/day for at least 6 months**
Should **not** be given to pregnant women or patients with liver disease.
108
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
Dapsone
## Footnote
**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
109
Vinca Alkaloids used in ITP
Vincristine and vinblastine
## Footnote
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.**
110
Immune-mediated platelet destruction in the presence of other conditions, including **infections, lymphoproliferative disorders, solid tumors, SLE, or the antiphospholipid syndrome (APS)**
Secondary ITP
111
# 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.
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.**
## Footnote
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.**
112
# TRUE OR FASLE
Among the many potential contributors to thrombocytopenia in patients with SLE, platelet destruction by autoantibodies is the major mechanism.
TRUE
Among the many potential contributors to thrombocytopenia in patients with SLE, **platelet destruction by autoantibodies** is the major mechanism.
## Footnote
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.
Thrombocytopenia in SLE is associated with serious organ pathology, leading to neuropsychiatric disease,renal disease, and APS, and is an ***independent indicator of poor prognosis***.
113
**Infection** can decrease platelet levels in several ways:
* By decreasing production in the marrow
* By increased immune destruction, or
* By inducing microangiopathy as seen in patients with infection induced DIC or HUS
114
Viral infection that is a leading cause of isolated thrombocytopenia in Western countries
HIV
## Footnote
Others: rubella, mumps, and infectious mononucleosis, HCV, HBV
115
# 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.
## Footnote
TRAs may increase the risk of abdominal thrombosis in HCV patients with liver cirrhosis.
IVIG
## Footnote
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**.
116
# 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.
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.
117
The second most common hematologic problem in pregnancy, after **anemia**
Thrombocytopenia
118
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 ________________
Third trimester
## Footnote
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.*
119
# Gestational thrombocytopenia
Platelet counts are usually greater than _____ x109/L and return to normal after delivery.
Greater than 70 x109/L
120
# TRUE OR FALSE
Pregnancy itself may induce ITP or exacerbate preexisting ITP, but generally the platelet count returns to the prepregnancy level after delivery.
TRUE
Pregnancy itself may induce ITP or exacerbate preexisting ITP, but generally the platelet count returns to the prepregnancy level after delivery.
## Footnote
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.
121
# 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
* 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**
122
Preferred initial therapy for ITP in pregnancy
Glucocorticoids
## Footnote
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.
123
Indicated in pregnant patients who do not respond to or tolerate glucocorticoid treatment or when it is necessary to rapidly increase the platelet count.
IVIG
## Footnote
1 g/kg per day for 2 days or 400 mg/kg per day for 5 days alone or combined with low-dose prednisone.
124
# TRUE OR FALSE
The optimal mode of delivery in pregnant patients with ITP has not been determined.
TRUE
The optimal mode of delivery in pregnant patients with ITP has not been determined.
## Footnote
***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.
125
During **vaginal delivery**, the target maternal platelet count should be
50 x 109/L or higher
126
If **cesarean section or epidural anesthesia** is required, the platelet count should be maintained over
70–80 x 109/L
127
Preferred in neonates with severe thrombocytopenia
IVIG
## Footnote
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%.
128
Although there is no defined threshold platelet level for these patients, platelet counts over _________ are considered safe for both anticoagulant and antiplatelet therapy.
50 x 109/L
129
Thrombocytopenia is seen in approximately ____% of women with **preeclampsia**, with the **severity of thrombocytopenia correlating with the severity of the preeclampsia.**
50%
130
This syndrome occurs in the peripartum period and is defined by the presence of microangiopathic hemolytic anemia, elevated liver enzymes, and low platelets.
HELLP Syndrome
## Footnote
In approximately **70% to 80%** of patients, HELLP occurs in the setting of **preeclampsia**
131
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.**
Acute fatty liver of pregnancy (AFLP)
## Footnote
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.
132
**“Swansea criteria”** used for the diagnosis of AFLP
* 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
* Microvesicular steatosis on liver biopsy
## Footnote
**Six or more** of these criteria should be present in a patient who has no obvious reason for hepatic failure.
133
The most effective treatment for preeclampsia, HELLP syndrome, and AFLP
Delivery of the fetus
134
# Acute Fatty Liver of Pregnancy
Indicated if the fetus cannot be delivered or if improvement does not follow delivery
Plasma exchange
## Footnote
**Postpartum day 3** often is considered the limit for supportive therapy in anticipation of a spontaneous recovery.
135
# Acute Fatty Liver of Pregnancy
Indicadted for patients with liver insufficiency, encephalopathy, and coagulopathy may not improve despite immediate delivery and intensive supportive care
Liver transplantation
136
The platelet count in the fetus reaches normal adult levels (>150 x 109/L) after the ___________ trimester and is maintained throughout gestation.
First trimester
137
Caused by the transplacental transfer of maternal alloantibodies against fetal platelet antigens inherited from the father.
Fetal–neonatal alloimmune thrombocytopenia (NAIT)
138
Difference of NAIT and neonatal alloimmune hemolytic anemia (Rh hemolytic disease of the newborn)
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.**
## Footnote
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.
139
Responsible for platelet destruction in NAIT
Maternal alloantibodies against human platelet alloantigens (HPAs)
## Footnote
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.***
140
**HPA alloimmunization** is strongly correlated with the presence of specific class II HLA antigens, with increased risk demonstrated in HPA-1a–negative mothers expressing
HLA-B8, HLADR3, and HLA-DR52a antigens
## Footnote
The presence of the **HLA-DRB3*0101 allele** in HPA-1a–negative women increases the NAIT risk as much as 140-fold.
141
Features that may alert the physician to the possibility of NAIT
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.
## Footnote
Platelet counts recover to normal in **1–2 weeks.**
142
The diagnosis of NAIT usually can be confirmed by
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
143
# TRUE OR FALSE
An infant born with severe thrombocytopenia with no obvious cause such as sepsis should be regarded as having ITP.
FALSE
An infant born with severe thrombocytopenia with no obvious cause such as sepsis should be regarded as having NAIT.
144
The alternatives in the management of affected neonates with NAIT
IVIG, glucocorticoids (alone or combined with IVIG), and platelet transfusions.
## Footnote
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**
145
Treatment options in high-risk NAIT at prenatal
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).
## Footnote
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**
146
**Splenomegaly** may lead to thrombocytopenia by inducing a **reversible** pooling of up to ___% of total body platelets.
90%
147
The most common disorder causing thrombocytopenia because of splenic pooling is
Chronic liver disease with portal hypertension and congestive splenomegaly
## Footnote
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**
148
# TRUE OR FALSE
Thrombocytopenia associated with splenomegaly is often with clinical importance and generally require therapy.
FALSE
Thrombocytopenia associated with splenomegaly is often of no clinical importance and generally does not require therapy.
149
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
Hypersplenism
150
Transient thrombocytopenia occurs during hypothermia, in both animals and humans, when the body temperature falls below ____
25C
## Footnote
In this case, the drop in platelet count likely results from splenic and hepatic pooling and from cold activation and clearance of platelets.
151
Defined as profound thrombocytopenia related to platelet trapping within a vascular tumor, either a Kaposi-like hemangioendothelioma or a tufted angioma
Kasabach-Merritt syndrome
## Footnote
The syndrome presents predominantly during **infancy**, but several adult cases have been reported.
The mainstay of treatment is **eradication of the tumor**
152
A locally aggressive, low-grade malignant tumor characterized by infiltrating sheets or lobules of poorly formed vascular channels and aberrant lymphatic vessels
Kaposi-like hemangioendothelioma
## Footnote
These tumors are composed predominantly of plump, round, oval, and/or spindled endothelial cells with hemosiderin deposits.
153
A lesion characterized by the presence of vascular tufts and aggregates of round dilated capillaries, lymphangiomatosis, microthrombi, and hemosiderin deposits.
Tufted angioma
154
Thrombocytopenia in Kasabach-Merritt syndrome usually is severe and associated with ______.
DIC
## Footnote
Contributing factors include **“platelet trapping” by abnormally proliferating endothelium within the hemangioma and platelet consumption** associated with DIC.
155
A very rare acquired disorder characterized by a periodic decrease in the platelet count, sometimes followed by rebound thrombocytosis without therapy (>500 109/L)
Cyclic thrombocytopenia (CTP)
## Footnote
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.
156
Drugs may cause thrombocytopenia by different mechanisms:
Dose-dependent myelosuppression and immune destruction of the platelets
157
An immune-mediated disorder caused by antibodies that recognize a neoepitope in **platelet factor 4** that is exposed when platelet factor 4 binds heparin.
HIT
158
Most commonly cited drug that cause thrombocytopenia
Quinidine
159
Drugs that may induce **true autoantibodies**
Gold salts and procainamide
## Footnote
Those induced by **gold** being unique in targeting **platelet GPV**.
160
# 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.
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.**
## Footnote
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.**
