116 Thrombocytopenia Flashcards
One-third of the platelets are stored in the _________, and the remaining two-thirds circulate in _____________ human
Spleen: one-third
Blood vessels: two-thirds
Platelets have a mean lifespan in the circulation of ______ days
7–10 days
Approximately 1 × 10 11 platelets are produced per day
Every day approximately ________% of circulating platelets are removed by the mononuclear phagocyte system, primarily by macrophages in the ____________.
10% to 12%
spleen and liver
The normal platelet count
150–400 × 10 9 /L
Classically thrombocytopenia is defined as platelet count less than __________
less than 150 × 10 9 /L
Throbocytopenia
Severe:
Moderate:
Mild:
Severe (platelet count <20 × 10 9 /L)
Moderate (platelet count 20–70 × 10 9/L)
Mild (>70 × 10 9/L)
The blood-to-anticoagulant ratio should be as recommended. The International Council for Standardization in Hematology recommends the use of ____________ as the anticoagulant.
Ethylenediaminetetraacetic acid (EDTA)
Conditions associated with pseudo thrombocytopenia
- Use of EDTA as an anticoagulant
- Platelet cold agglutinins
- Myeloma
ANTIBODY-INDUCED PLATELET AGGLUTINATION
The antibodies usually are of the Immunoglobulin ________ type.
Immunoglobulin (Ig) G type
IgM and IgA antibodies also have been described
ANTIBODY-INDUCED PLATELET AGGLUTINATION
In most cases, the antibodies are directed against the __________
Integrin αIIbβIII (also termed glycoprotein [GP] IIb/IIIa)
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 ______________
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.
Some antiplatelet antibodies from patients with pseudothrombocytopenia cross-react with negatively charged phospholipids and may exhibit _______________ activity.
Anticardiolipin activity
Thrombocytopenia has been described in patients with acute coronary syndromes treated with the ___________ and other _________________
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.
TRUE OR FALSE
Pseudothrombocytopenia may be accompanied by pseudoleukocytosis
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.
How can platelet clumping be prevented
- 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.
Patients with IPD usually present witH
Mucocutaneous bleeding
Spontaneous life-threatening bleeding is rare.
TRUE OR FALSE
Majority of IPDs are inherited as autosomal dominant traits.
FALSE
Majority of IPDs are inherited as autosomal recessive traits.
Laboratory PBS findings of a potential IPD
- 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).
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.
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.
Gold standard in diagnosing IPDs
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
Test recommended in patients with platelet granule deficiencies
Platelet nucleotide content and release
Test that can be used in patients with platelet surface glycoprotein deficiencies such as Bernard-Soulier syndrome
Flow cytometric analysis
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.
Electron microscopy
TRUE OR FALSE
Isolated thrombocytopenia is common in patients with nutritional deficiencies.
FALSE
Isolated thrombocytopenia is rare in patients with nutritional deficiencies.
Iron-deficiency anemia (IDA) generally develops after acute or chronic bleeding and is usually accompanied by (thrombocytosis OR thrombocytopenia)
Thrombocytosis
Thrombocytopenia associated with IDA is relatively rare, reported in only 2.3% and 2.4% of pediatric and adult IDA patients, respectively.
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
Various other autoimmune disorders can coexist with pernicious anemia, including autoimmune vitiligo and autoimmune thyroiditis.
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
May be misdiagnosed as having MDS because increased ring sideroblasts and dysplastic precursor cells can be seen in on bone marrow smears
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)
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.
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
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.
Mechanisms of thrombocytopenia in chronic ethanol consumption
- Alcoholic liver cirrhosis (both splenomegaly and thrombopoietin deficiency)
- Folic acid deficiency
- Alcohol-induced marrow suppression
Alcoholism (chronic ethanol consumption, which is defined as consumption of >_____ g of ethanol per day
> 80 g of ethanol per day
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
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.
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
May achieve durable remission with therapies designed to blunt the autoimmune response, such as cyclosporine or antithymocyte globulin.
The most common cause of isolated thrombocytopenia in clinical practice
PRIMARY IMMUNE THROMBOCYTOPENIA
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
Childhood OR Adult ITP
A chronic disease of insidious onset and rarely resolves spontaneously.
Adult ITP
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.
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%)
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.
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.
Unfortunately, elevated levels of PAIgG later were found in patients with nonimmune thrombocytopenia
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.
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.
Increased platelet-associated C3, C4, and C9 have been demonstrated on the platelets from patients with ITP.
The main regulator of megakaryopoiesis
Enhances megakaryocyte colony formation and increases the size, number, and ploidy of megakaryocytes, as well as platelet production
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.
TPO is synthesized in greatest quantity in the
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.
This agent,which binds to a region of the TPO receptor that overlaps that bound by authentic TPO
Romiplostim
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
Eltrombopag has been approved for use in patients with aplastic anemia
ITP is classified based: on the absence or presence of other diseases :
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.
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
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).
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.
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
The IWG proposed that the term “severe ITP” only be used for
Patients with clinically significant bleeding requiring additional therapy regardless of platelet count.
Duration of response
Time between first measured CR or R to relapse
Corticosteroid dependence
The need for ongoing or repeated glucocorticoid use for at least two months to maintain CR or R.
Refractory ITP
Relapsed after splenectomy (failure to maintain CR or R) and required therapy
On-demand therapy
Therapies used to temporarily increase the platelet count in special situations such as trauma or surgery.
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.
TRUE OR FALSE
The overall incidence was higher in women than in men
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.
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
Pattern of bleeding in ITP
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
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
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).
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.
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.
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.
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.
The ultrastructure of ITP platelets viewed by electron microscopy is similar to that of normal platelets.
Condition wherein Autoimmune hemolytic anemia with a positive direct antiglobulin (Coombs) test and reticulocytosis with ITP
Evans syndrome
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
Reveals a normal or increased number of megakaryocytes of normal morphology, although a decreased number of megakaryocytes does not rule out ITP.
Indications for BMA in ITP
- 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.
Basis of therapy in ITP
Bleeding signs and symptoms and on the presence of factors that increase the bleeding risk
The primary therapeutic goal in ITP
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
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
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)
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
Recommended treatment for emergent cases of ITP
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.
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
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
Can be used in combination with glucocorticoids and IVIG in older patients.
Vincristine
TRUE OR FALSE
Plasmapheresis treatment is recommended in current ITP guidelines.
FALSE
Plasmapheresis treatment is not recommended in current ITP guidelines.
Accepted as the standard therapy for initial treatment in adult patients with ITP
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.
Dose of steroids
Oral prednisone 1–2 mg/kg per day (or methylprednisolone 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.
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
Major site both for synthesis of antiplatelet antibodies and for destruction of antibody-coated platelets
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.
Produces the highest long-term response rates for patients with ITP compared with all other therapies
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.
Splenectomy can be performed during pregnancy preferably during
Second trimester
Splenectomy should be postponed at least _______ months after diagnosis if possible and only after immunization against encapsulated bacterial pathogens
6–12 months
Over the past decade, minimally invasive laparoscopic splenectomy has gained preference over open splenectomy.
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.
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
Any fever should be carefully evaluated and the patient treated with broad-spectrum antibiotics.
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.
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
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
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
Particularly if the blood film shows no evidence of splenectomy (ie, pitting and Howell-Jolly bodies are absent in the erythrocytes
Screening used to identify residual or accessory splenic tissue
Sensitive radionuclide or magnetic resonance scans
The effect of IVIG is similar whether or not the patient has undergone splenectomy and is transient, generally lasting only
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.]
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
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.
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
Anaphylactic reactions in IVIG may occur in patients with
Congenital IgA deficiency
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
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
Anti-(Rh)D is not effective in patients
- Who have undergone splenectomy
- Rh-negative patients
- Patients with a positive direct antiglobulin test result
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
Generally without requiring a blood transfusion
Dose of Anti-(Rh)D
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.
A chimeric monoclonal antibody against CD20
Depletes B cells in patients with autoimmune diseases, with the effect usually lasting 6–12 months
Rituximab
Still considered “off label” for ITP
Dose of Rituximab
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
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
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
Dose of Romiplostim
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.
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
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).
Dose of Eltrombopag
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%
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
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
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
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.
This alkylating drug can be used in patients with refractory ITP.
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.
Synthetic androgen, with reduced virilizing effects compared with other androgens, has been used to treat patients with refractory ITP.
Danazol
400–800 mg/day for at least 6 months
Should not be given to pregnant women or patients with liver disease.
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
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
Vinca Alkaloids used in ITP
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.
Immune-mediated platelet destruction in the presence of other conditions, including infections, lymphoproliferative disorders, solid tumors, SLE, or the antiphospholipid syndrome (APS)
Secondary ITP
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.
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.
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.
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.
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
Viral infection that is a leading cause of isolated thrombocytopenia in Western countries
HIV
Others: rubella, mumps, and infectious mononucleosis, HCV, HBV
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.
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.
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.
The second most common hematologic problem in pregnancy, after anemia
Thrombocytopenia
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
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.
Gestational thrombocytopenia
Platelet counts are usually greater than _____ x109/L and return to normal after delivery.
Greater than 70 x109/L
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.
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.
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
Preferred initial therapy for ITP in pregnancy
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.
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
1 g/kg per day for 2 days or 400 mg/kg per day for 5 days alone or combined with low-dose prednisone.
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.
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.
During vaginal delivery, the target maternal platelet count should be
50 x 109/L or higher
If cesarean section or epidural anesthesia is required, the platelet count should be maintained over
70–80 x 109/L
Preferred in neonates with severe thrombocytopenia
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%.
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
Thrombocytopenia is seen in approximately ____% of women with preeclampsia, with the severity of thrombocytopenia correlating with the severity of the preeclampsia.
50%
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
In approximately 70% to 80% of patients, HELLP occurs in the setting of preeclampsia
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)
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.
“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
Six or more of these criteria should be present in a patient who has no obvious reason for hepatic failure.
The most effective treatment for preeclampsia, HELLP syndrome, and AFLP
Delivery of the fetus
Acute Fatty Liver of Pregnancy
Indicated if the fetus cannot be delivered or if improvement does not follow delivery
Plasma exchange
Postpartum day 3 often is considered the limit for supportive therapy in anticipation of a spontaneous recovery.
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
The platelet count in the fetus reaches normal adult levels (>150 x 109/L) after the ___________ trimester and is maintained throughout gestation.
First trimester
Caused by the transplacental transfer of maternal alloantibodies against fetal platelet antigens inherited from the father.
Fetal–neonatal alloimmune thrombocytopenia (NAIT)
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.
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.
Responsible for platelet destruction in NAIT
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.
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
The presence of the HLA-DRB3*0101 allele in HPA-1a–negative women increases the NAIT risk as much as 140-fold.
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.
Platelet counts recover to normal in 1–2 weeks.
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
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.
The alternatives in the management of affected neonates with NAIT
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
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).
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
Splenomegaly may lead to thrombocytopenia by inducing a reversible pooling of up to ___% of total body platelets.
90%
The most common disorder causing thrombocytopenia because of splenic pooling is
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
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.
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
Transient thrombocytopenia occurs during hypothermia, in both animals and humans, when the body temperature falls below ____
25C
In this case, the drop in platelet count likely results from splenic and hepatic pooling and from cold activation and clearance of platelets.
Defined as profound thrombocytopenia related to platelet trapping within a vascular tumor, either a Kaposi-like hemangioendothelioma or a tufted angioma
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
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
These tumors are composed predominantly of plump, round, oval, and/or spindled endothelial cells with hemosiderin deposits.
A lesion characterized by the presence of vascular tufts and aggregates of round dilated capillaries, lymphangiomatosis, microthrombi, and hemosiderin deposits.
Tufted angioma
Thrombocytopenia in Kasabach-Merritt syndrome usually is severe and associated with ______.
DIC
Contributing factors include “platelet trapping” by abnormally proliferating endothelium within the hemangioma and platelet consumption associated with DIC.
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)
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.
Drugs may cause thrombocytopenia by different mechanisms:
Dose-dependent myelosuppression and immune destruction of the platelets
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
Most commonly cited drug that cause thrombocytopenia
Quinidine
Drugs that may induce true autoantibodies
Gold salts and procainamide
Those induced by gold being unique in targeting platelet GPV.
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.
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.
