Approach to thrombocytopenia

APPROACH TO
THROMBOCYTOPENIA
Presenter : Dr. Sukriti Azad
PG 2nd year

NORMAL PHYSIOLOGY
• Platelets are normally made in the bone marrow from progenitor cells
known as megakaryocytes likely under the influence of flow in capillary
sinuses.
• The major regulator of platelet production is the hormone
thrombopoietin (TPO) , which is synthesized in the liver, kidney and
smooth muscle cells.
• Synthesis is increased with inflammation and specifically by
Interleukin 6.
• Normal platelet lifespan is 7-10days. Every day, 1/10 of platelet pool is
replenished.

THROMBOCYTOPENIA
• Thrombocytopenia may be defined as a subnormal number of platelets
in the
circulating blood. It is the most common cause of abnormal bleeding.
• Despite the number and diversity of disorders that may be associated
etiologically, thrombocytopenia results from only four processes:
1. Artifactual thrombocytopenia
2. Deficient platelet production
3. Accelerated platelet destruction
4. Abnormal distribution or pooling of the platelets within the body

CLASSIFICATION
• Thrombocytopenia can be classified based on pathophysiologic criteria .
• It should be recognized that multiple pathogenetic factors may simultaneously
or sequentially play a role in the production of thrombocytopenia.
• Measurement of serum thrombopoietin concentrations or reticulated platelets
may both elucidate the pathophysiology of thrombocytopenia.
• Measurement of the percentage of reticulated platelets identifies platelets that
have recently been released from the bone marrow.
• There is an increased percentage of reticulated platelets in patients with
thrombocytopenia caused by increased destruction and a normal to reduced
percentage of reticulated platelets in patients with deficient production.

ARTIFACTUAL THROMBOCYTOPENIA
• Falsely low platelet counts, occurs ex vivo when platelets are not counted
accurately.
• This mechanism should be considered in patients who have
thrombocytopenia but no petechiae or ecchymoses.
• Although inaccurate counting may occur in the presence of giant platelets
or with platelet satellitism,the most common cause of artifactual
thrombocytopenia is platelet clumping (pseudothrombocytopenia).

• Platelet clumping in
pseudothrombocytopenia appears
to be caused by anticoagulant-
dependent platelet agglutinins that
are immunoglobulins (Igs) of IgG,
IgA, or IgM subtypes.
• Clumping is most seen when blood
is collected into
(EDTA)anticoagulant
• There is evidence that the
autoantibodies bind to
glycoprotein IIb/IIIa.
• In such patients , a blood smear
should be evaluated, and a repeat
platelet count determined in blood
collected in sodium or heparin vial.

ACCELERATED PLATELET DESTRUCTION
• Accelerated platelet destruction is the most
common cause of thrombocytopenia.
• It leads to stimulation of thrombopoiesis
and, consequently, to an increase in the
number, size, and rate of maturation of the
precursor megakaryocytes.
• When the rate of platelet destruction
exceeds this compensatory increase in
platelet production, thrombocytopenia
develops.
• “Compensated” platelet destruction without
thrombocytopenia may also occur in
patients with prosthetic heart valves and
idiopathic thrombocytopenic purpura after
• Platelet destruction may result from both
intracorpuscular defects and
extracorpuscular abnormalities.
• Intracorpuscular defects are rare but have
been demonstrated in certain forms of
hereditary thrombocytopenia, such as
Wiskott-Aldrich syndrome.
• In such disorders, the survival of affected
platelets is shortened in the circulation of
both the patient and normal recipients.
• Platelet destruction most often is the result of
extracorpuscular factors ; various
immunologic phenomena are the most
common.

Increased Platelet Destruction
• Caused by immunologic
processes
1. Autoimmune
I. Idiopathic
II. Secondary: infections,
pregnancy, collagen vascular
vascular disorders,
lymphoproliferative disorders,
disorders, drugs,
miscellaneous
2. Alloimmune
I. Neonatal thrombocytopenia
II. Post-transfusion purpura
• Caused by nonimmunologic
processes
1. Thrombotic
microangiopathies
I. Disseminated intravascular
coagulation
II. Thrombotic
thrombocytopenic purpura
III. Hemolytic-uremic syndrome
• Platelet damage by abnormal
vascular surfaces
1. Miscellaneous
I. Infection
II. Massive blood transfusions

DEFICIENT PLATELET PRODUCTION
• Those that depopulate the stem cell or
megakaryocyte compartments are the most
common, such as marrow injury by
myelosuppressive drugs or irradiation and
aplastic anemia.
• Deficient platelet production may also be
the consequence of disordered proliferation
within a precursor compartment of normal
or even increased size. For example, in
disorders characterized by megaloblastic
hematopoiesis, hypertrophy of the
precursor compartment occurs in response
to thrombopoietic stimuli, but
thrombopoiesis is ineffective, and platelet
production is insufficient.
Rarely, abnormalities of the processes
that normally regulate thrombopoiesis
appear to underlie deficient platelet
production, such as deficiency of
thrombopoietin and cyclic
thrombocytopenia
CAUSES
• Hypoplasia of megakaryocytes
• Ineffective thrombopoiesis
• Disorders of thrombopoietic control
• Hereditary thrombocytopenias

ABNORMAL POOLING
• Abnormal pooling or abnormal in vivo
distribution of an essentially normal
total platelet mass may produce
thrombocytopenia.
• This type of thrombocytopenia is seen in
the various disorders associated with
splenomegaly , in which platelet
production is normal or even increased,
but most of the platelets are sequestered
in the vastly enlarged extravascular
splenic pool.
• Thrombocytopenia may also be caused
by dilution of platelets when patients
are massively transfused during blood
loss.
CAUSES
• Disorders of the spleen (neoplastic,
congestive, infiltrative, infectious, of
unknown cause)
• Hypothermia
• Dilution of platelets with massive
transfusions

IMMUNE THROMBOCYTOPENIA
• Immune thrombocytopenia (ITP) occurs when platelets undergo
premature
destruction as a result of autoantibody or immune complex deposition on
their membranes.
• Although this disorder was previously known as idiopathic
thrombocytopenic purpura, it is now correctly termed ITP because this
nomenclature more clearly reflects the immune-mediated mechanism of
the
disease.

• A diagnosis of exclusion, because currently available clinical assays for
platelet-associated antibodies or serum antiplatelet antibodies/immune
complexes are neither specific nor sensitive enough for routine clinical
use.
• These disorders are characterized by peripheral thrombocytopenia
(confirmed by examination of the peripheral smear), with a normal or
increased number of megakaryocytes present on bone marrow
examination, and absence of splenomegaly.
• Those patients who have no identifiable underlying cause, which might
include infections, collagen vascular diseases, lymphoproliferative
disorders (chronic lymphocytic leukemia or lymphoma), or drugs, are
diagnosed as primary ITP.

PRIMARY IMMUNE THROMBOCYTOPENIA
• Platelet count of less than 1,00,000/μL in the absence of other causes or disorders
that may be associated with thrombocytopenia.
• Primary ITP refers to thrombocytopenia in which apparent exogenous etiologic
factors are lacking and in which diseases known to be associated with secondary
thrombocytopenia have been excluded.
Immune Thrombocytopenia
1. Primary
2. Secondary
• Infections
• Collagen vascular diseases
• Lymphoproliferative disorders
• Solid tumors
• Drugs
• Miscellaneous

ACUTE v/s CHRONIC ITP
Feature Acute ITP Chronic ITP
Peak age of incidence Children 2-6 y Adults 31-64 y
Sex predilection None 3:1 female to male
Antecedent infection Common 1-3 week(s) before Unusual
Onset of bleeding Abrupt Insidious
Hemorrhagic bullae in mouth Present in severe cases Usually, absent
Platelet count <20 000/μL 30 000-80 000/μL
Eosinophilia and lymphocytosis Common Rare
Spontaneous remissions Occurs in 80% cases Uncommon
Duration 2-6 week, rarely longer Months to years

PATHOPHYSIOLOGY OF ITP
• The syndrome of ITP is caused by platelet-specific autoantibodies that
bind to
autologous platelets, which are then rapidly cleared from the circulation
by the
mononuclear phagocyte system via macrophage Fcγ receptors
predominantly in
the spleen and liver.
• An array of diverse immunologic perturbations involving T and B
lymphocytes, dendritic cells, plasma cells, and macrophages may
contribute to different extents to the pathophysiology of primary
immune thrombocytopenia.

• As such, the pathogenesis of childhood ITP or ITP that follows viral infections such
as cytomegalovirus (CMV), varicella zoster, or Helicobacter pylori infections is less
complex and affects primarily peripheral immune tolerance in the setting of
immune stimulation in response to a transient antigenic stimulus. It is more likely
to respond more readily to therapy or remit spontaneously.
• In contrast, ITP pathogenesis involving a differentiation block or loss of central
tolerance (e.g., in hematologic malignancies or autoimmune disease) is
multifaceted, involving a largely autoreactive lymphocyte repertoire that can
reconstitute quickly after therapy, and therefore often refractory or only transiently
responsive to treatment.
• In these cases, combination therapy that targets more than one aspect of the faulty
immune response may be effective because additional cell types are involved in
disease pathogenesis.

ITP IN PEDIATRIC AGE GROUP
Acute ITP in pediatric patients is generally self-limited, and at least two-
thirds
of patients will achieve a complete remission (defined as a platelet count
greater
than 150 × 109/L within 6 months of initial diagnosis and without need
for
ongoing platelet-directed therapy)

ITP IN ADULTS
• In adults, the onset of the chronic form of the disorder is usually
insidious.
• A long history of hemorrhagic symptoms of mild to moderate severity is
often described by the patient, but antecedent infections or fever is
uncommon.
• Patients with chronic ITP usually have a fluctuating clinical course.
Episodes of
bleeding may last days or weeks and may be intermittent or even cyclic.
• Spontaneous remissions are very uncommon in adults, with an
estimated
occurrence of <5%.
• One common manifestation that is reported in 22% to 39% of surveyed

CLINICAL MANIFESTATIONS
• Bleeding
- Petechiae
- Purpura : Dry(cutaneous) Vs
Wet(mucosal bleed)
- Epistaxis
- Severe hemorrhage : ICH , UGI bleed,
menorrhagia
 Predictors of severe bleeding
- Degree of thrombocytopenia
(<20,000)
- Previous minor bleeding, and
- Chronic ITP (i.e., diagnosis >12
months prior)

History : A stitch in time saves nine!!

MANAGEMENT
• Physical examination
- Look esp. for wet bleed : poor prognosis, catastrophe
- Lymphadenopathy
- Hepatosplenomegaly
• Laboratory testing
- PBS : r/o thrombocytopenia and atypical cells
- HIV and HCV testing
- H.pylori testing
- TFT
- ANA,RF , APLA
- Vitamin B12 and folate level
- Coomb’s test : 1 % have co-existing autoimmune hemolytic anemia
( Evans syndrome )

What is the role of Bone marrow
examination?
• Not required for typical ITP
• Atypical presentations
• Unexplained cytopenias (anemia, leukopenia), dysplasia on PBS
• Pts. whose platelet counts do not respond to ITP therapy : MDS ?
Hereditary ? Acquired ?
• Age > 60 years ( to r/o MDS ) : no longer an indication
 Antiplatelet antibody testing : Not recommended
• Low sensitivity
• Lack of inter-lab reproducibility

Definition of response to treatment of
ITP
• Complete response(CR) :
Platelet count > 1 lakh measured on 2 occasions > 7 days apart
and absence of bleeding
• Response(R):
> 30,000 or more than 2-fold increase in platelet count from
baseline on 2 occasions > 7 days apart and absence of bleeding
• Nonresponse :
< 30,000 or less than 2-fold increase in platelet count from
baseline or presence of bleeding . Platelet count must be
measured on 2 occasions more than a day apart .

• Loss of complete response :
< 1 lakh measured on 2 occasions more than a day apart or presence of
bleeding.
• Loss of response :
< 30,00 or less than 2-fold increase in platelet count from baseline or
presence of bleeding measured on 2 occasions more than a day apart.
• Corticosteroid dependence :
Need for ongoing or repeated administration of corticosteroid to maintain
maintain platelet count > 30,000.
• Refractory ITP :
Failed to respond to (or relapsed after) splenectomy and is severe

WHO DO WE TREAT ?
• All patients who present with
bleeding and those with platelet
counts less than 20,000 / cu mm .
• Immediate therapy is not required
for patients with platelet counts
between 20,000 and 50,000 /cu mm
in the absence of bleeding or
predisposing comorbid conditions
such as uncontrolled HTN, active
PUD, anticoagulation, recent surgery,
or head trauma.
Hospitalization and emergency
therapy : which patient ??
• Patients with profound muco-
cutaneous or internal bleeding
• Platelet counts of less than 20,000/cu
mm and a history of significant
bleeding.

What is the target platelet count ?
• > 30,000 in pts without co-morbidities and drugs interfering with
platelet function.
• Above 40,000 to 50,000/cu mm for patients requiring aspirin, NSAIDs
, warfarin, or other anti- thrombotics.
• Minor surgery : > 50,000/cu mm
• Major surgery ( including neurosurgery ) : > 80,000/ cu mm

INITIAL THERAPY
• Emergency treatment :
IV methylprednisolone (1.0 g/d for 1-3 consecutive days)
combined with IVIG.
• Non-emergent therapy :
High-dose dexamethasone, typically administered as 40 mg
orally per day for four days with no taper for 1-3 cycles, or oral
prednisone at 1 mg/kg daily for 2-3 weeks followed by a gradual
taper.

Prednisolone Vs Dexamethasone
Compared with prednisone, dexamethasone was associated
with:
• A better overall response (platelet count >30,000/microL)
• A better complete response (platelet count >100,000/microL) at
two weeks.
• Fewer bleeding events during the first 10 days
• Fewer toxicities

IVIG
• Raise the platelet count within 24 to 48
hours
• The effect of IVIG usually persists for 2-6
weeks.
• 1 g/kg OD for 1-2 days.
• Most adverse reactions are mild and
transient.
• Serious reactions can occur : Headache,
hypertension, chills, allergic reactions,
vomiting, and hypotension .
• Other rare adverse reactions include
anaphylaxis, hemolytic anemia, acute
kidney injury, and thrombosis
Anti-D
• Alternative to conventional IVIG for
patients whose RBCs are Rh(D)
positive.
• The usual dose of anti-D is 50 to 75
mcg/kg intravenously.
• Common adverse effects of anti-D include
infusion reactions like IVIG.
• Anti-D should be avoided in patients with
pre-existing hemolysis or a high risk of
hemolysis

TPO Receptor agonists
• Romiplostim (Nplate) : once-
weekly subcutaneous injection.
• Eltrombopag (Promacta, Revolade)
: once-daily pill.
• Stimulate the production of
megakaryocytes and ultimately
platelets in the bone marrow by
binding to and activating the TPO
receptor.
• Indication : Failed one line of
therapy such as corticosteroid or
IVIG and who have not had
splenectomy.
• A TPO-RA may also be used as a
temporizing measure in a patient
who requires an increase in platelet
count for a period of time.
• Generally used as maintenance
therapy for ITP because, except in
the rare patient, they do not induce
remission.
• Risk : BM reticulin formation and
thrombosis

SPLENECTOMY
• Indication : Failed corticosteroid therapy
• Single best option to convert a patient with ITP into a “nonpatient” .
• IVIG, IV anti-D, or pulse doses of corticosteroids are used in known
responders
to boost the platelet count prior to splenectomy.
• Approximately 85% of patients attain a hemostatic response after
Splenectomy.
• Immunize with polyvalent pneumoccocal, H influenzae type b, and
quadrivalent meningococcal polysaccharide vaccines at least 2 weeks
prior to

RITUXIMAB
• Indication : Patients in whom splenectomy fails
• Anti-CD20 monoclonal antibody
• Dose : 375 mg/m2 IV every week for 4 weeks
• Responses are usually noted within 4 to 8 weeks after the first infusion
but may
occur as late as 4 months.
• A complete or partial remission occurs in 25% to 50% of Patients.
• Side effects are mostly related to the first infusion (fever, chills,
hypotension,
bronchospasm).

Experimental Therapy
• Thrombopoietic factor
• AMG 531
– Thrombopoietin receptor agonist
– Phase 2 placebo-controlled trial

Hepatitis-C with ITP
• Antiviral therapy should be
considered in the absence of
contraindication.
• T/t of ITP =IVIG
• Corticosteroids may increase viral
load
• Platelet count should be closely
monitored
HIV with ITP
• Antiviral therapy should be considered
before any other treatment
• Treatment: Corticosteroid , IVIG or
anti D
• Those who fail above treatment :
Splenectomy

Management of patient with severe bleed
• Platelet transfusion.
• IVIG : 1g/kg, repeated the following day
if the platelet count remains
<50,000/microL).
• Glucocorticoids (e.g.,
methylprednisolone, 1 g IV , repeated
daily for 3
doses; or dexamethasone, 40 mg orally
or intravenously, repeated daily for
four days).
• Romiplostim, 500 mcg subcutaneously
Other hemostatic agents in severe bleeding
that does not respond to platelet
transfusions:
Tranexamic acid
• Antifibrinolytic agent
• Orally (1 to 1.5 g three to four times daily)
or intravenously (1 g over 10 minutes,
followed by 1 g over the next eight hours).
EACA (Epsilon Amino-Caproic Acid)
• Antifibrinolytic agent
• Doses in the range of 4 to 12 g/day,
administered orally or intravenously for
several days up to several months
Activated factor VII (factor VIIa)

Thrombocytopeni
a In Pregnancy
• Most common
hematological
abnormality

GESTATIONAL THROMBOCYTOPENIA
• For the thrombocytopenia to be consistent with gestational
thrombocytopenia :
Women should have no history of thrombocytopenia (except
during a previous pregnancy).
The thrombocytopenia resolved spontaneously within 1-2
months
after delivery.
The foetus/new-born baby should not have had
thrombocytopenia
 GTP is unlikely if platelet count < 50,000.

Gestational Thrombocytopenia Vs ITP

ITP in Pregnancy
• ITP occurs in 1 per 1000 to 1 per 10,000
pregnancies, accounting for
approximately 3% of women who are
thrombocytopenic at delivery.
• ITP should be suspected any time during
pregnancy with isolated
thrombocytopenia of less than
50,000/cu mm , esp. during the first 2
trimesters.
• In the absence of symptoms or treatment
: monitor platelet counts at least
monthly through the first 2
trimesters, biweekly in the third,
weekly as term approaches and more
often, if indicated.
• Ideally, maternal platelet counts should
be maintained above 20,000/cu mm
throughout pregnancy and above
50,000/cu mm near term to minimize
the
need for platelet transfusions in the event
• Use corticosteroids as initial therapy,
but this can induce or exacerbate GDM,
bone loss, HTN , and perhaps abruption
and prematurity
• For this reason, we tend to rely more on
IVIG together with low-dose prednisone
(20 mg every day).
• Splenectomy should be avoided if
possible, and deferred to the second
trimester when necessary.
•Use of danazol, cyclophosphamide, anti-
CD20, vinca alkaloids, and other
potentially teratogenic therapy is avoided.
• Mode of delivery is based entirely on
obstetric indications

DRUG INDUCED ITP
• Antibody against new epitopes
of platelet glycoprotein.
• Moderate to severe
thrombocytopenia.
• Drop in platelet count within 2-
3 days up to 1-3 weeks.
• Recovery in 5-10 days after drug
stoppage
• Should be suspected when
patient has recurrent episodes
of thrombocytopenia with
prompt recovery.

MANAGEMENT
• Investigations
Drug dependent anti Platelet antibody by
 Flow cytometry
 Platelet Immunofluorescence test
 ELISA and
 Western blotting
• Treatment:
If a patient’s platelets fall, all unnecessary drugs need to be stopped.
Give platelet transfusions , IVIg is particularly helpful in quinine-
induced ITP.

Thrombocytopenia in the Cardiac
Patients
Several mechanisms in patients undergoing open heart surgery:
• Cardiopulmonary bypass may result in mechanical destruction of platelets
• Hemodilution in the bypass circuit
• Drug-induced platelet destruction
• Sepsis
• Post-transfusion purpura
 The nadir platelet count is typically seen on the second or third day after
surgery, with a rapid recovery thereafter.
Severe thrombocytopenia is observed in 0.1%-2% of patients after exposure
to GPIIb/IIIa inhibitors (e.g., abciximab, tirofiban, eptifibatide) during
percutaneous coronary intervention.

HEPARIN INDUCED
THROMBOCYTOPENIA(HIT)
• Differs from other DIT in two major ways.
o The thrombocytopenia is not usually
severe, with nadir counts rarely
<20,000/μL.
o HIT is not associated with bleeding and,
in fact, markedly increases the risk of
thrombosis.
• Mechanism of thrombocytopenia :
Antibody formation to a complex of
the PF4 and heparin.
• A fraction of those who develop antibodies
will develop HIT, and a portion of those (up
to 50%) will develop thrombosis (HITT).
• HIT more common with UFH than
LMWH.
• Most patients develop HIT after 5-14 days
of LMWH exposure.
• 4 Ts in the diagnostic algorithm for HIT
1) Thrombocytopenia (≤1,00,000/μL or
decrease by≥50%)
2) Timing of platelet drop within 5-14
days of heparin exposure
3) Thrombosis (venous more common
than arterial)
4) Other causes of Thrombocytopenia
ruled out

TREATMENT OF HIT
• Prompt discontinuation of heparin.
• Give alternate anticoagulants such as Fondaparinux,
Rivaroxiban, Bivalirudin, Argatroban and Lepirudin
• Do not give platelet transfusions
• Do not give Warfarin until the platelet count returns to baseline
level. If Warfarin was administered ,give Vitamin K to restore
INR to normal.
• Evaluate for thrombosis, particularly DVT.

THROMBOTIC THROMBOCYTOPENIC
PURPURA
• An inherited or acquired deficiency (due
to autoantibodies) of von Willebrand
factor-cleaving protease known as
ADAMTS13.
• Leads to accumulation of large
multimers of VWF which cause
spontaneous platelet aggregation and
thrombi.
• Can be induced by drugs, including
ticlopidine, quinine, cyclosporine,
tacrolimus, mitomycin C.
• Increased incidence with pregnancy or
HIV

TTP - Diagnostic Features
• Microangiopathic Haemolytic Anaemia
(MAHA)
Elevated LDH, elevated bilirubin
Schistocytes on the peripheral smear
(MUST BE PRESENT)
• Low platelets - MUST BE PRESENT
• Fever
• Neurologic Manifestations - headache,
sleepiness, confusion, stupor, stroke, coma,
seizures
• Renal Manifestations - haematuria,
proteinuria, elevated creatinine, BUN
• CBC normal or slightly elevated WBC.
• Hb is moderately depressed at 8-9 g/dL.
Platelet count ranges from 20,000-50,000
per microliter.
• PBF : Red blood cells are fragmented and
appear as schistocytes.
• Certain schistocytes have the appearance
of helmet cells .
• Spheroidal cells often are present .
• Occasional nucleated erythroid precursors
may be present.
• Decreased haptoglobin
• Increased reticulocyte count
• Negative direct antiglobulin test

TTP- Course and Prognosis
• Treatment relies on Plasma Exchange.
• Plasma exchange is superior to plasma infusion, but if PLEX is
delayed, give FFP.
• Remove all inciting agents.
• Platelet transfusions contra-indicated.
• Multiple case reports of stroke and/or death during or immediately
after platelet transfusion.
• Can consider giving if life-threatening haemorrhage is present but
avoid routine platelet transfusions.
• Secondary measures if no response to plasma exchange include
splenectomy, vincristine , rituximab , cyclophosphamide.

HUS-HEMOLYTIC UREMIC SYNDROME
• HUS, is a disease characterized by :
1. Hemolytic anemia
2. Uremia
3. Low platelet count
• It predominantly, but not exclusively, affects children.
• Types of HUS:
1. Typical HUS
2. Atypical HUS
3. HUS due to Complement abnormalities

CLASSIFICATION OF HUS / TTP ACCORDING
TO ETIOPATHOGENESIS

Typical/Diarrhea associated/Shiga Toxin
associated HUS
• Enterohaemorrhagic E. coli
• Shigella dysenteriae type 1
• Rarely, HUS can occur with E. coli UTI
• The common serotype of E coli:0157:H7
• However, only about 10-15% patients with E. coli 0157:H7 infection will
develop HUS
• Sources of infection are :
 Milk and animal products (incompletely cooked beef, pork, poultry,lamb)
 Human feco-oral transmission
Vegetables, salads and drinking water may be contaminated by bacteria
shed in animal wastes

Atypical/Non-Diarrhea Related HUS
• Pneumococcal HUS
• HUS due to Complement abnormalities
• Miscellaneous Causes of HUS / TTP
Abnormalities in intracellular vitamin B12 metabolism
 HIV
Systemic lupus erythromatosus
Malignancies
Radiation
Certain drugs

Other infections associated with HUS
• Include viruses like :
Influenza
Cytomegalovirus
Infectious mononucleosis
• Bacteria like:
Streptococcii
Salmonella

PATHOPHYSIOLOGY
• The typical pathophysiology involves the shiga-toxin binding to
proteins on the surface of glomerular endothelium and inactivating a
metalloproteinase called ADAMTS13, which is also involved in the
closely related TTP.
• The arterioles and capillaries of the body become obstructed by the
resulting complexes of activated platelets which have adhered to
endothelium via large multimeric vWF.
• The growing thrombi lodged in smaller vessels destroy RBCs as they
squeeze through the narrowed blood vessels, forming schistocytes, or
fragments of sheared RBCs.
• The consumption of platelets as they adhere to the thrombi lodged in
the small vessels typically leads to mild or moderate
thrombocytopaenia
• However, in comparison to TTP, the kidneys tend to be more
severely affected in HUS, and the central nervous system is less

CLINICAL FEATURES
• The commonest clinical presentation of HUS is :
Acute pallor
 Oliguria
 Diarrhea or dysentery
• It occurs commonly in children between 1-5 years of age.
• HUS develops about 5-10 days after onset of diarrhea.
• Hematuria and hypertension are common.
• Complications of fluid overload may present with:
 Pulmonary edema
Hypertensive encephalopathy
• Despite thrombocytopenia, bleeding manifestations are rare
• Neurological symptoms like:
Irritability
Encephalopathy
Seizures

INVESTIGATIONS
• CBC
• Peripheral blood smears
• Reticulocyte count
• LDH
• Bili unconjugated
• Cr & BUN
• Urine analysis
 Haemoglobinuria
Hematuria
Proteinuria

INVESTIGATIONS TO IDENTIFY CAUSE
• In patients with dirrhea, the identification of pathogenic EHEC or Shigella is
performed by:
Stool culture
Further serotyping by agglutination or enzyme immunoassay
• Rarely HUS can occur with E. coli UTI:
• Urine cultures are indicated in non-diarrheal patients
• Bacteriological cultures of body fluids are indicated in suspected
pneumococcal disease.
Sputum
 CSF
 Blood
 Pus

DIAGNOSIS
• Clinically, HUS can be very hard to distinguish from TTP
• The laboratory features are almost identical, and not every case of
HUS is preceded by diarrhea
• HUS is characterized by the triad of:
1. Hemolytic anemia
2. Thrombocytopenia
3. Acute renal failure
• The only distinguishing feature is that in TTP fever and
neurological symptoms are often present, but this is not always the
case
• A pericardial friction rub can also sometimes be heard on
auscultation

MANAGEMENT
1. Supportive Therapy
2. Antibiotics
3. Plasma Therapy
4. Miscellaneous

SUPPORTIVE THERAPY
• In all patients, supportive treatment is primary.
• Close clinical monitoring of :
 Fluid status
 Blood pressure
 Neurological
 Ventilatory parameters
 Blood levels of glucose, electrolytes, creatinine and hemogram need
frequent monitoring
• The use of antimotility therapy for diarrhea has been associated with a
higher risk of developing HUS
• With the onset of acute renal failure :
Fluid restriction
 Diuretics

ANTIBIOTICS
• E. coli
• Shigellosis
• Pneumococcal HUS

PLASMA THERAPY
• In aHUS due to :
 complement factor abnormality
 ADAMTS13 deficiency
The replacement of the deficient factor with FFP
• Daily plasma infusions (10 to 20 mL/kg/day)
• Exchange of 1.5 times plasma volume ( 60 to 75 mL/kg/day) using
FFP

MISCELLANEOUS
• In patients with persistent ADAMTS13 antibodies and poor response
to plasma exchange:
• Immunosuppressive therapy with high dose
steroids/cyclophosphamide/ cyclosporin/rituximab
• Splenectomy

DISSEMINATED INTRAVASCULAR
COAGULATION
• DIC is a clinicopathologic syndrome characterized by
widespread intravascular fibrin formation in response to
excessive blood protease activity that overcomes the natural
anticoagulant mechanisms.

PATHOPHYSIOLOGY
1. Increased thrombin generation: Mediated predominantly by tissue
factor/factor VIIa pathway
2. Impaired function of physiological anticoagulant pathway
a) Reduction of antithrombin levels -- The result of a combination of increased
consumption, enzyme degradation, impaired liver synthesis and vascular leakage
b) Depression of protein C system -- The result of a combination of increased
consumption, impaired liver synthesis, vascular leakage and down- regulation of
thrombomodulin
c) Insufficient tissue factor pathway inhibitor (TFPI)
3. Impaired fibrinolysis: Mediated by release of plasminogen activators from
endothelial cells immediately followed by an increase in the plasma levels of
plasminogen activator inhibitor type 1 (PAI-1)
4. Activation of inflammatory pathway: Mediated by activated coagulation
proteins and by depression of the protein C system

HISTORY
The symptoms of disseminated intravascular coagulation (DIC) are often
those of the underlying inciting condition
1. Bleeding
• GI bleed
• Petechiae and ecchymosis,
• Intravenous (IV) lines and catheters bleed
• Surgical sites, drains, and tracheostomies and within serous cavities.
2. Renal Failure
3. Pulmonary involvement
• Dyspnea, hemoptysis, and cough
4. Jaundice

SYMPTOMS
Circulatory signs include the
following:
1. Signs of spontaneous and life-
threatening hemorrhage
2. Signs of subacute bleeding
3. Signs of diffuse or localized
thrombosis
4. Bleeding into serous cavities
Central nervous system signs
include the following:
1. Nonspecific altered consciousness
or stupor
2. Transient focal or neurologic
deficits
Cardiovascular signs include
the following:
1. Hypotension
2. Tachycardia
3. Circulatory collapse
Respiratory signs include the
following:
1. Pleural friction rub
2. Signs of acute respiratory distress
syndrome (ARDS)

GI signs include the following:
1. Hematemesis
2. Hematochezia
Genitourinary signs include the following:
1. Signs of azotemia and renal failure
2. Acidosis
3. Hematuria
4. Oliguria
5. Metrorrhagia
6. Uterine hemorrhage
Dermatologic signs include the following:
1. Petechiae
2. Jaundice (liver dysfunction or hemolysis)
3. Purpura
4. Hemorrhagic bullae
5. Acral cyanosis
6. Skin necrosis of lower limbs (purpura
fulminans)
7. Localized infarction and gangrene
8. Wound bleeding and deep subcutaneous
hematomas
9. Thrombosis

DIFFERENTIAL DIAGNOSIS
1. Atypical hemolytic-uremic syndrome
2. Hemolytic-Uremic Syndrome
3. Heparin-induced thrombocytopenia and thrombosis syndrome
4. Idiopathic Thrombocytopenic Purpura
5. Liver disease
6. Primary hemostatic disorders (eg, dysfibrinogenemias;
inhibitors
to factors II, V, X)
7. Thrombotic Thrombocytopenic Purpura

DIAGNOSIS
•Platelet -- moderate-to-severe thrombocytopenia is present in DIC.
•Activated partial thromboplastin time [aPTT] and prothrombin
time [PT]) are typically prolonged.
•Protein C and antithrombin are 2 natural anticoagulants that are
frequently decreased in DIC.
•Elevated levels D-dimer and FDPs
•Thrombomodulin is elevated in DIC, a marker for early
identification
and monitoring of DIC.
•Chronic DIC diagnosis when the schistocytes are seen in concert
with
normal coagulation values and increased D-dimer levels.

TREATMENT
1) Replacement therapy - Fresh-
frozen plasma
2) Anticoagulants
- Unfractionated and low-molecular-
weight heparin
- Danaparoid sodium
- Recombinant hirudin
- Recombinant tissue factor pathway
inhibitor
- Recombinant nematode
anticoagulant protein c2
3) Restoration of anticoagulant
pathways
- Antithrombin
- Recombinant human activated
protein C
4) Other agents
- Recombinant activated factor VII
- Antifibrinolytic agents
- Anti-selectin antibodies
- Recombinant interleukin-10
- Monoclonal antibodies against TNF
and CD14

Management of Underlying Disease
•The management of acute and chronic forms of disseminated intravascular coagulation (DIC) should primarily
primarily be directed at treatment of the underlying disorder.
Administration of Blood Components and Coagulation Factors
•Platelet transfusion may be considered in patients with DIC and severe thrombocytopenia in patients with
with bleeding or in patients at risk for bleeding
•The PT (>1.5 times the normal) Replacement with FFP is indicated
•Low levels of fibrinogen (<100 mg/dL) or brisk hyperfibrinolysis will require infusion of cryoprecipitate. The
cryoprecipitate. The replacement of 10 U of cryoprecipitate for every
2–3 U of FFP is sufficient to correct the hemostasis.
•In case of a (relative) vitamin K deficiency in the face of consumption, administration of vitamin K may be
may be required.
Anticoagulation
•Experimental studies have suggested that heparin can at least partly inhibit the activation of coagulation in
coagulation in cases of sepsis and other causes of DIC . However, a beneficial effect of heparin on clinically
clinically important outcome events in patients with DIC has not yet been demonstrated in controlled clinical
clinical trials.
•Therapeutic doses of heparin are indicated in cases of obvious thromboembolic disease or where fibrin
fibrin deposition predominates
(e.g., purpura fulminans or acral ischemia).
• A dose of 4-5 U/kg constant infusion without an 80-U/kg bolus is a safe means to deliver heparin to the DIC
the DIC without increasing the bleeding risk.

Restoration of Anticoagulant Pathways
•Antithrombin concentrate, recombinant human APC(Activated Protein C),
Protein C), tissue factor (TF)
pathway inhibitor (TFPI) and recombinant thrombomodulin (rTM)
• Antifibrinolytic treatment
In the coagulopathy associated with acute promyelocytic leukemia
(AML-M3) and in some cases of DIC secondary to malignancies (e.g.
prostate carcinoma) lysine analogues such as tranexamic acid can be
utilized
Investigational Treatments
Tissue factor (TF)-VIIa complex include inactivated factor VII and
recombinant nematode anticoagulant peptide (NAPc2)

Approach to thrombocytopenia

Recomendados

Recomendados

Mais conteúdo relacionado

Mais procurados

Mais procurados (20)

Semelhante a Approach to thrombocytopenia

Semelhante a Approach to thrombocytopenia (20)

Último

Último (20)

Approach to thrombocytopenia