CAUSES AND APROACH TO THROMBOCYTOPENIA

1. APPROACH TO THROMBOCYTOPENIA
Dr.G.Venkata ramana
HOD Family medicine
RDT Hospital,Bathalapalli

2. WHAT IS A LOW PLATELET COUNT?
 Thrombocytopenia is defined as a
platelet count <1,50,000/microL (150 x
109/L).
 Mild thrombocytopenia 1,00,000 to
1,50,000/microL
 Moderate thrombocytopenia 50,000 to
99,000/microL
 Severe thrombocytopenia <50,000/microL

3. WHEN TO WORRY ABOUT BLEEDING?
 Bleeding is a concern in patients with
severe thrombocytopenia
 However, the correlation between
platelet count and bleeding risk is
uncertain
 Clinical predictors of bleeding
 Prior bleeding episodes
 Presence of wet purpura
 Hematuria.

4.  Surgical bleeding -platelet counts <50,000/microL
(<100,000/microL for some high-risk procedures such as
neurosurgery or major cardiac or orthopedic surgery)
 Severe spontaneous bleeding -platelet counts
<20,000/microL, especially <10,000/microL
 Bleeding risk in ITP may be slightly less than that in other
conditions for the same platelet count
 consider other factors that may affect bleeding risk (eg,
platelet function defects, coagulation abnormalities).
 When present, these factors may contribute to bleeding
risk and may be more concerning than the low platelet count.

5. WHEN TO WORRY ABOUT
THROMBOSIS?
 Heparin-induced thrombocytopenia
 Antibodies to a platelet factor 4 epitope induced by heparin
can cause thrombocytopenia and platelet activation, leading to
life-threatening venous and/or arterial thrombosis.
 Vaccine-induced immune thrombotic thrombocytopenia
(VITT) – occurs after vaccination with COVID-19 adenoviral
vector vaccines (AstraZeneca and Janssen [Johnson &
Johnson]). It is associated with life-threatening venous and/or
arterial thrombosis
 Antiphospholipid syndrome Patients may have venous and/or
arterial thrombosis
 Disseminated intravascular coagulation Patients with DIC are at
risk of bleeding or thrombosis, usually venous

6. .
 Thrombotic microangiopathy Thrombocytopenic purpura (TTP),
hemolytic uremic syndrome (HUS), or drug-induced TMA (DITMA)
are associated with small-vessel platelet-rich thrombi. These
microthrombi can occur in any organ and can be life-threatening.
 Paroxysmal nocturnal hemoglobinuria Thrombosis (often involving
unusual locations such as intraabdominal or cerebral veins) can
occur, along with hemolytic anemia and/or bone marrow failure
 ITP with a concomitant thrombotic disorder such as atrial
fibrillation or recent or previous deep vein thrombosis.
 low platelet count is not protective against thrombosis, and
anticoagulation is often indicated

7. PATHOPHYSIOLOGY
 Decreased platelet production bone marrow disorders impair platelet
production (eg, nutrient deficiencies, myelodysplastic syndromes,
aplastic anemia)
 Liver disease Liver is the site of TPO production, and liver disease can
cause thrombocytopenia due to reduced TPO levels
 Platelet destruction/consumption Platelets survive for 8 to 10 days,
removed by monocytes or macrophages of the RES.Accelerated
destruction of platelets can occur due to antibody-mediated clearance.
 Platelet consumption also occurs within thrombi in DIC and TMAs
such as TTP or HUS
 Dilution occurs in the setting of massive fluid resuscitation or massive
transfusion without proportionate transfusion of platelets
 Redistribution/hypersplenism
 Normally approximately one-third of the platelet mass is found in the
spleen, in equilibrium with the circulating platelet pool
 Conditions that increase splenic size and/or cause splenic congestion
through portal HTN (eg, cirrhosis, alcoholic liver disease) can
decrease the platelet count without altering the total platelet mass in
the body

8. CAUSES OF THROMBOCYTOPENIA
 Pseudothrombocytopenia
 Pregnancy
 Gestational thrombocytopenia
 Preeclampsia
 HELLP syndrome (hemolysis, elevated liver enzymes,low platelets)
 Acute fatty liver of pregnancy
 Thrombotic microangiopathy (TMA)
 Thrombotic thrombocytopenic purpura (TTP)
 Hemolytic uremic syndrome (HUS)
 Drug-induced TMA
 Immune thrombocytopenia
 Primary immune thrombocytopenia (ITP)
 Drug-induced immune thrombocytopenia (DITP)
 Infections
 HIV,Hepatitis C
 Sepsis with disseminated intravascular coagulation (DIC)
 Intracellular parasites (eg, malaria, babesia)
 Epstein-Barr virus,Helicobacter pylori
 Dengue,Rickettsial,Brucellosis,Leptospirosis

9.  Hypersplenism
 Alcohol
 Nutrient deficiencies (eg, vitamin B12, folate,
copper)
 Rheumatologic/autoimmune disorders (eg,
systemic lupus erythematosus, rheumatoid arthritis)
 Antiphospholipid syndrome (APS)
 Aplastic anemia
 Paroxysmal nocturnal hemoglobinuria (PNH)
 Myelodysplasia
 Cancer with disseminated intravascular coagulation
 Cancer with bone marrow infiltration or suppression
(eg, lymphoma, leukemia, some solid tumors)

10.  Hereditary thrombocytopenias
 Von Willebrand disease type 2B
 Wiskott-Aldrich syndrome
 Alport syndrome
 May-Hegglin anomaly
 Fanconi anemia
 Bernard-Soulier syndrome
 Thrombocytopenia absent radius syndrome

11. Decreased
production
Increased
destruction
Increased
sequestration
Other
conditions
causing TCP
Congenital bone
marrow failure
(fanconi
anemia,wiskott-
Aldrich syndrome
Immune
thrombocytopenia
(Including
HIV,HCV and drug
related)
Hypersplenism
eg.related to
cirrhosis,lympho
ma,myeloprolifer
ative disorders
Gestational
thrombocytopeni
a
Acquired bone
marrow failure
(aplastic anemia,
myelodysplasia)
HIT,TMA,DIC,Post
transfusion
purpura,hemopha
gocytosis
Pseudo
thrombocytopeni
a
Exposure to
chemotherapy,
irradiation
Neonatal
alloimmune
thrombocytopenia
Bernard-soulier
syndrome,grey
platelet
syndrome
Marrow infiltration
Neoplastic,infectious
Vonwillebrand
disease type 2
May-hegglin
anamoly
Nutritional
deficiency
Mechanical

12. HISTORY
 Onset - new/chronic/relapsing
 History of bleeding
 Pregnancy
 Travel history malaria,dengue,rickettsial
 Risk factors for HIV and HCV
 Recent medication or vaccination
 Recent transfusion -haemodilution
 Ingestion of alcohol
 History of liver disease
 Dietary habit-megaloblastic anemia
 Autoimmune disease/malignancy
 Recurrent pregnancy loss,arterial or venous
thrombosis
 Red/pink/dark urine
 Family history of bleeding disorders and/or thrombocytopenia

13. PHYSICAL EXAMINATION
 Signs of bleeding
 Signs of liver cell disease
 Signs of vitamin deficiencies
 Malar rash,joint deformities
 Anemia,Jaundice,Lymphadenopathy
 Blood pressure
 Hepatosplenomegaly

14. LABORATORY TESTING
Peripheral blood smear
 to exclude pseudothrombocytopenia
 If platelet clumping is observed, the platelet count is repeated using
heparin or sodium citrate as an anticoagulant in the collection tube
 RBC and WBC abnormalities
 Schistocytes microangiopathic process (eg, DIC, TTP, HUS, DITMA).
 Spherocytes immune-mediated hemolytic anemia or hereditary
spherocytosis.
 Leukoerythroblastic findings teardrop cells, nucleated RBCs, or
immature granulocytes suggest an infiltrative process in the bone
marrow.
 Leukocytosis with a predominance of bands (left shift) and/or toxic
granulations suggests infection .
 Immature WBCs (eg, myeloblasts) or dysplastic WBCs suggest leukemia
or myelodysplasia.
 Multi-lobed/hypersegmented neutrophils (ie, >5 lobes) suggest a
megaloblastic process (eg, B12/folate/copper deficiency).
 Giant platelets may suggest a congenital platelet disorder (eg, MYH-9-
related disorders, Bernard Soulier syndrome [BSS])

15. LABORATORY TESTING
 Combined anemia and thrombocytopenia also raises the possibility
of systemic disorders.
 Sepsis with disseminated intravascular coagulation (DIC)
 TTP, HUS, or DITMA
 Autoimmune disorders (eg, Evans syndrome)
 Nutrient deficiencies (eg, folate, vitamin B12, copper)
 Infections
 Bone marrow disorders (eg, myelodysplastic syndromes, leukemia,
bone marrow infiltration by malignancy)
 Combined leukocytosis and thrombocytopenia raise the possibility
of infection, chronic inflammation, and malignancy.
 Pancytopenia raises the possibility of bone marrow
failure/infiltration

16.  HIV, and HCV testing,Rapid urease test
 Blood culture,urine culture,MP,Dengue,weil
felix,scrub IGM,Salmonella IGM etc
 LFT, Coagulation,Usg abdomen
 Vitamin B12,folate levels
 Anti-nuclear antibodies,RA factor,anti CCP
anibodies
 Anti-phospholipid antibodies( aCL, anti
beta2GPI,lupus anticoagulant)
 Microangiopathic changes on the peripheral smear
should prompt coagulation testing (eg, PT, aPTT,
fibrinogen) and measurement of serum lactate
dehydrogenase (LDH) and renal function to evaluate
for DIC, TTP, or HUS

17.  Bone marrow evaluation
 Normal or increased numbers of megakaryocytes suggests
platelet destruction (eg, ITP, drug-induced immune
thrombocytopenia)
 Decreased megakaryocyte numbers, along with overall
decreased or absent cellularity is consistent with decreased
bone marrow production of platelets, as in aplastic anemia
 in rare cases, severe reduction or absence of megakaryocytes
with no other abnormalities (also called acquired
amegakaryocytic thrombocytopenia or acquired pure
megakaryocytic aplasia) may occur.
 Megaloblastic changes in the RBC and granulocytic series
suggest a nutrient deficiency (eg, vitamin B12, folate, copper),
while dysplastic changes suggest a myelodysplastic disorder
 Granulomata, increased reticulin or collagen fibrosis,or
infiltration with malignant cells establishes the diagnosis of
bone marrow invasion, especially when a leukoerythroblastic
blood picture is also present.

19. spleno
megaly
Usg
abdome
n
With
doppler
Macrocyti
c picture
with
hyper
segmente
d
neutrophi
ls
Megalo
blastic
anemia

20. GENERAL MANAGEMENT PRINCIPLES
 Activity restrictions no restrictions are necessary for usual activities or
low-impact exercise.
 individuals with severe thrombocytopenia generally should not participate
in extreme athletics such as boxing, rugby, and martial arts.
 Anticoagulant and anti-platelet medications
 Platelets>50,000-prophylaxis and therapeutic anticoagulation can be
started
 Platelets 25,000-50,000-full dose anticoagulation with platelet support or
half dose anticoagulation
 Platelets <25,000 with hold anticoagulation
 Platelets >50,000 antiplatelets can be continued
 Platelets <50,000 stop all antiplatelet agents
 Nonsteroidal anti-inflammatory drugs are avoided
 Platelet transfusion in case of bleeding or platelet count <10,000-
20000/microL

21. PLATELET PRODUCTS
1. Random donor platelets (RDP)
2. Buffy coat pooled platelets (BCPP)
3. Single donor apheresis (SDP)
1.Random donor platelets (RDP)
◦ The platelets are prepared from whole blood Volume of 40–50 ml and shelf life of 5
days
◦ Depending up on the method of preparation can be classified as PRP platelets or buffy
coat reduced platelets
◦ Raise the platelet count by 5–7 thousand in adults and 20 thousand in paediatric
patients.
2.Buffy coat pooled platelets (BCPP)
◦ Derived from four donations of whole blood (obtained from the buffy coat of ABO
identical donors resuspended in plasma or additive solutions). volume of 160–200 ml.

22. 3.Single donor apheresis (SDP)
◦ A single donation procedure may yield one to three therapeutic doses and
the donation may be split between two or three bags, depending on counts.
◦ SDP are leukocyte reduced
◦ For SDP collection, donors are tested for platelet count, transfusion
transmitted infection (TTI) markers and blood group before collection. The
average volume for SDP is 200–300 ml, and is equal to 5–6 RDP. Thus, it also
often regarded as the jumbo pack.
◦ SDPs are expected to increase a patient's platelet count by 30–50000/ul.
BCPP serves as an alternative choice of SDP in case of emergency.
◦ Compatibility testing is not required for platelet concentrates.

23. RhD-negative platelet concentrates should be given, where
possible, to RhD-negative patients, particularly to women who have
not reached menopause.
◦ If RhD-positive platelets are transfused to an RhD-negative woman
of childbearing potential, it is recommended that anti-D should be
given.
◦ A dose of 300 IU of anti-D should be sufficient to cover six SDP or 30
RDP RhD-positive platelets within a 6-week period.
◦ The standard dose for adults is 5–6 units of random donor platelets
or one unit of apheresis platelets or one unit of BCPP
◦ For neonates/infants- 10-15ml/kg of body weight

24. THERAPIES DIRECTED AT THE CAUSE
 Gestational thrombocytopenia no treatment
 Pre eclampsia,HELLP-steroids controversial role,can
be used for lung maturity
 Therapeutic plasma exchange (TPE) for immune
TTP
 plasma infusion for hereditary TTP
 anti-complement therapy for complement-mediated
TMA (CM-TMA)
 HIT-stop heparin,use non heparin anticaogulant if
needed
 Treatment of infections
 Antibiotics Broad spectrum antibiotics are
appropriate for patients with a presumed infectious
cause of thrombocytopenia
 Antimalarials for malaria
 Antivirals for HIV,HCV

25.  ITP – Glucocorticoids or IVIG
 High-dose dexamethasone (typical dose, 40 mg per day for four
days) and prednisone (typical dose, 1 mg/kg per day for two weeks
followed by a gradual taper) are both effective
 When delivery is not imminent (eg, during early pregnancy and/or
when preterm birth is not expected), prednisone is preferable
 Drug-induced thrombocytopenias – Cessation of drug exposure
 Portal hypertension-propranolol
 Megaloblastic anemia-Vitamin b12 and folate supplementation
 Rheumatologic/autoimmune disorders-Steroids,HCQ
 Antiphospholid syndrome-anticoagulation for thrombosis pts
 Aplastic anemia-triple IST/hematopoietic cell transplantation
 PNH-complement inhibitor
 Malignancies-chemotherapy

26.  1.Rule out pseudothrombocytopenia
 2.identify thrombocytopenic emergencies
requiring immediate action
 3.Identify thrombocytopenia related to
pregnancy
 4.identify and treat infections
 5.palpate for splenomegaly
 6.identify and treat nutritional deficiency
 7.identify and treat RA/SLE,APLA
 8.Identify and treat malignancies,ITP

27. PSEUDOTHROMBOCYTOPENIA
 In vitro platelet clumping
caused by
ethylenediaminetetraacetic
acid (EDTA)-dependent
agglutinins (naturally
occurring antibodies)
 In vitro platelet clumping
caused by an insufficiently
anticoagulated specimen
 In vitro platelet clumping
caused by glycoprotein IIb/IIIa
inhibitors (eg, abciximab)
 Giant platelets counted by
automated counter as white
blood cells rather than
platelets

28. GESTATIONAL THROMBOCYTOPENIA (GT)
 GT is typically characterized by the following:
 Most common at delivery, but can occur at any time during
pregnancy.
 Mild thrombocytopenia. (In 99 percent of women, the platelet
count is ≥100,000 /microL.)
 No increased bleeding or bruising.
 No associated abnormalities on complete blood count (CBC).
 No fetal or neonatal thrombocytopenia.
 GT is a diagnosis of exclusion. No treatment,resolves
postpartum
 Hemodilution,platelet sequestration and consumption in the
placenta plays a role in GT
 Risk of recurrence in subsequent pregnancy

29.  Preeclampsia with severe features
 Severe hypertension
 Severe headache and/or visual symptoms
 Liver function abnormalities
 Epigastric pain
 Thrombocytopenia (platelet count
<100,000/microL)

30. HELLP SYNDROME
 Hemolysis with a microangiopathic blood smear, elevated liver
enzymes, and low platelet count
 Clinical presentation
 Abdominal pain and tenderness in the midepigastrium, right upper
quadrant, or below the sternum.
 Nausea, vomiting,malaise,hypertension and proteinuria
 Diagnosed between 28 and 36 weeks of gestation, but symptoms may
present up to 7 days postpartum
 Diagnosis
 Hemolysis established by at least two of the following:
 Peripheral smear with schistocytes and burr cells
 Serum bilirubin ≥1.2 mg/dL
 Low serum haptoglobin or lactate dehydrogenase (LDH) ≥2 times the
upper level of normal (based on laboratory-specific reference ranges)
 Severe anemia, unrelated to blood loss

31. THE SMEAR SHOWS MULTIPLE
HELMET CELLS (ARROWS)
AND OTHER FRAGMENTED RED
CELLS (SMALL ARROWHEAD);
MICROSPHEROCYTES ARE ALSO
SEEN (LARGE ARROWHEADS).
 Evated liver enzymes:
 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2 times the
upper level of normal due to Parenchymal necrosis of liver
 Low platelets: <100,000 cells/microL.There may be subcapsular hematoma
 formation (which is diagnosed by CT scan) liver may rupture to
 cause sudden hypotension, due to hemoperitoneum
 Differential diagnosis
 acute fatty liver of pregnancy, thrombotic thrombocytopenic purpura, pregnancy-
related hemolytic-uremic syndrome, and systemic lupus erythematosus
 Management-
 Treatment of hypertension,magnesium sulfate for seizure prophylaxis,platelet
transfusion sos.
 Role for steroids-no role
 >34 weeks –delivery after maternal stabilization
 <34 weeks-antenatal steroids and deliver after 48 hrs if mother and fetus stable,if
unstable delivery after maternal stabilization

32. ACUTE FATTY LIVER OF PREGNANCY
 Characterised by maternal liver dysfunction and
microvesicular fatty infilitration of hepatocytes.
 Risk factors:multiple gestation,prior history of
AFLP,and male sex of the fetus
 Pathogenesis:fetal long chain 3-hydroxyacylCoA
dehydrogenase deficiency that results in fetal fatty
oxidation defects.
 LCHAD catalyses a step in beta-oxidation of
mitochondrial fatty acids that forms 3-ketoacyl-CoA
from 3-hydroxyacyl-CoA.
 Accumulation of these metabolites is toxic to the
liver.
 All patients with AFLP and their children should
undergo molecular testing for LCHAD
 AFLP can recur in subsequent pregnancies

33. ACUTE FATTY LIVER OF PREGNANCY
 Swansea criteria
 Signs and symptoms
 Vomiting
 Abdominal pain
 Polydipsia/polyuria
 Encephalopathy
 Laboratory findings
 Elevated bilirubin (>0.8 mg/dL
or >14 micromol/L)
 Hypoglycemia (glucose <72
mg/dL or <4 mmol/L)
 Leukocytosis (>11,000
cells/microL)
 Elevated transaminases (AST
or ALT) (>42 international
unit/L)
 Elevated ammonia (>47
micromol/L)
 Elevated urate (5.7 mg/dL or
>340 micromol/L)
 Acute kidney injury, or creatinine
>1.7 mg/dL (150 micromol/L)
 Coagulopathy or prothrombin
time >14 seconds
 Imaging: Ascites or bright liver
on ultrasound scan
 Histology: Microvesicular
steatosis on liver biopsy
 presence of ≥6 abnormal
variables had positive predictive
value of 85 percent and negative
predictive value of 100 percent
for finding microvesicular
steatosis

34.  Management prompt delivery of the fetus
regardless of gestational age
 Acute liver failure-liver transplantation
 Monitoring for and treatment of
hypoglycemia with 10% Dextrose infusion
 Treatment of coagulopathy-FFP if bleeding
 Platelet transfusion if low
 Magnesium sulfate-to reduce the risk of
cerebral palsy and severe motor dysfunction
in offspring

35. ANTIPHOSPHOLIPID SYNDROME CRITERIA
SYDNEY REVISION OF SAPPORO CRITERIA 2006
 Clinical criteria
 Vascular thrombosis-
arterial or venous
 Pregnancy morbidity
 a) ≥1death of normal
fetus at≥ 10 weeks
 b) ≥1premature birth
at≤34 wks due to
preeclampsia
 c) ≥3 consecutive
abortions at <10wks
 d)placental
insufficiency at<34 wks
 Lab criteria
 Anti-Cardiolipin IgG/IgM
 Anti-beta-2
glycoprotein1
 Lupus anticoagulant
 Medium to high titer
 At least 2 times
 12 weeks apart
 Definite APS:
 1 clinical +1 Lab criteria

36. TREATMENT OF PREGNANT AND POST PARTUM
PATIENTS WITH APS
Ante partum Post partum
APS with prior arterial or
venous thrombosis, with or
without APS-defining
pregnancy morbidity
Therapeutic-dose
LMWH and low-dose
ASA
Warfarin for an indefinite
period of time.
APS based on laboratory
criteria for aPL and APS-
defining pregnancy ≥1 fetal
losses ≥10 weeks of
gestation or ≥3 unexplained
consecutive spontaneous
pregnancy losses <10 weeks
of gestation amorbidityand
NO history of arterial or
venous thrombosis
Prophylactic-dose
LMWH and low-dose
ASA
Prophylactic-dose
LMWH and low-dose
ASA for six weeks,
regardless of route of
delivery.

37. Ante
partum
Post partum
APS based on laboratory
criteria for aPL and APS-
defining pregnancy morbidity of
≥1 preterm deliveries of a
morphologically normal infant
before 34 weeks of gestation
due to severe preeclampsia,
eclampsia, or other findings
consistent with placental
insufficiency and NO history of
arterial or venous thrombosis
Most cases:
Low-dose
ASA
Vaginal delivery: Intermittent
pneumatic compression and
low-dose ASA while in the
hospital. Graduated
compression stockings and
low-dose ASA for six weeks.
Cesarean delivery:
Prophylactic-dose LMWH and
low-dose ASA for six weeks.
Laboratory criteria for APS but
NO clinical criteria for APS (ie,
NO history of venous or arterial
thrombosis and NO history of
APS-defining obstetric
morbidity
Low-dose
ASA
Vaginal delivery: Intermittent
pneumatic compression and
low-dose ASA while in the
hospital. Graduated
compression stockings and
low-dose ASA for six weeks.
Cesarean delivery:
Prophylactic-dose LMWH and
low-dose ASA for six weeks.

38. DISSEMINATED INTRAVASCULAR COAGULATION
 Consumptive
coagulopathy
complicating several
diseases
 Characterised by
 activation of
intravascular coagulation
with microvascular
thrombi
formation,thrombocytope
nia,depletion of clotting
factors,variable bleeding
complications and end-
organ damage
Acute DIC
decompensat
ed
Chronic DIC
compensate
d
Etiology Sepsis
Severe trauma
Obstetric
complications
Malignancy
eg:pancreati
c
Gastric,brain
,
ovarian
Coagulatio
n
studies
prolonged Often normal
Platelets Low Often normal
Fibrinogen Low Often normal
D-dimer High High
Bleeding
risk
Very high Mildly
increased
Thrombo Mildly Very high

39. DIC CAUSES
Obstetric
complications
Infections Neoplasm Massive
tissue injury
miscellaneou
s
Abruptio
placentae
Gram–ve and
+ve sepsis
carcinomas of
pancreas
Traumatic Snake bite
Aminiotic fluid
embolism
Meningo-
coccemia
Acute
promyelocytic
leukemia
Burns Acute
intravascular
hemolysis
Septic abortion Malaria Lung
carcinoma
Extensive
surgery
Giant
hemangioma
Retained dead
fetus
Rocky
mountain
Spotted fever
Carcinomas of
prostrate
Shock
Eclampsia and
severe
preeclampsia
Aspergillosis Carcinomas of
stomach
vasculitis
HELLP
Syndrome,AFL
Histoplasmosis Liver disease

40. PATHOGENESIS OF DIC

41. CLINICAL MANIFESTATIONS AND LABORATORY
DIAGNOSIS
organ Ischemic hemorrhagic
Skin Gangrene
Acral cyanosis
Petechiae
Echymosis
oozing
CNS Delirium/coma/
infarcts
Intracranial
bleeding
Renal Oliguria/azotemia/
cortical necrosis
hematuria
Cardio
vascular
Myocardial
dysfunction
pulmonary Dyspnea/hypoxia
infarct
Hemorrhagic
lung
GI Ulcers,infarcts GI
hemorrhage
Endocrine Adrenal infarcts Adrenal
hemorrhage
Investigations
 Prolonged PT and
aPTT
 Low fibrinogen
 D-dimer is
elevated
 Thrombocytopeni
a
 blood smear-
microangiopathic
hemolytic anemia
with schistocytes

42. ISTH SCORING AND MANAGEMENT OF DIC

43. THROMBOTIC THROMBOCYTOPENIC PURPURA
 An inherited or acquired
deficiency (due to
autoantibodies)of von
Willebrand factor-cleaving
protease known as
ADAMTS13
 Hereditary TTP
 Immune TTP
 Leads to accumulation of
large multimers of VWF which
cause spontaneous platelet
aggregation and thrombi
 Can be induced by drugs like
quinine,tacrolimus,cyclospori
ne,ticlopidine.
 Increased incidence with
pregnancy or HIV

44. TTP-DIAGNOSTIC FEATURES
 Microangiopathic
hemolytic anemia
Elevated LDH,bilirubin
Schistocytes on smear
 Low platelets
 fever
 Neurologic
manifestations-
headache,sleepiness,conf
usion,stupor,stroke,coma,
seizures
 Renal manifestations-
hematuria,proteinuria,elev
ated creatinine,BUN
 PLASMIC SCORE

45.  Diagnosis
 Severe deficiency of
ADAMTS 13
 Inherited TTP has
ADAMTS 13gene
mutation
 Acquired TTP-
ADAMTS13
autoantibody
 Treatment
 Therapeutic pasma
exchange
 Glucocorticoids
 Refractory or relapsing
TTP:rituximab,
vincristine,
cyclophosphamide,
and splenectomy
 Caplacizumab for
severe disease

46. HEMOLYTIC UREMIC SYNDROME
 HUS is characterised
by
 Hemolytic anemia
 Uremia
 Low platelet count
 Predominantly, but
not
exclusively,affects
children
 Types of HUS
 Typical HUS
 Atypical HUS
 HUS due to
complement

47.  Clinical features of
typical HUS
 Acute pallor
 Oliguria
 Diarrhea or dysentery
 Children 1-5years of
age
 5-10 days after onset
of diarrhea
 Hematuria,hypertensi
on,
 pulmonary edema
 hypertensive
encephalopathy
 Management
 Supportive therapy
 Antibiotics
 Plasma therapy

48. IMMUNE THROMBOCYTOPENIA
 Immune
thrombocytopenia (ITP,
also called idiopathic
thrombocytopenic
purpura, immune
thrombocytopenic
purpura) is an acquired
thrombocytopenia
caused by
autoantibodies against
platelet antigens.
 Classification
 Primary
 Secondary
 Post-infectious:HIV,HCV,
CMV,H.Pylori
 Antiphospholipid syndrome
 Autoimmune TCP eg: Evan’s
syndrome
 Lymphoproliferative
disorders:CLL,NHL,HD
 Drug induced ITP

49.  Clinical presentation
 Excessive bleeding
with minor injuries
 Spontaneous bleeding
from mouth and nose
 Petechiae,purpura
 ecchymoses
 Hematuria,epistaxis
 Malena
 Menorrhagia
 Intracranial bleed
 Thrombocytopenia

50. Features Acute ITP Chronic ITP
1 Age Usually 2 to 6 years 20 to 30 years
2 Sex Any Predominant in female
3 Onset Acute chronic
4 Previous infection common unusual
5 Platelet count <20,000 >20,000
6 Spontaneous
remission
common Less <20%
7 Duration 2 to 4 weeks Chronic months to years

51. MANAGEMENT OF ITP

52. DRUG-INDUCED IMMUNE
THROMBOCYTOPENIA
 Thrombocytopenia caused by
drug-dependent, antibody-
mediated platelet destruction.
 DITP is a form of secondary ITP.
 Typically occurs after a period of
initial exposure (median length
21 days), or upon reexposure,
and usually resolves in 7–10
days after drug withdrawal
 DRUGS
 Acetaminophen
 Aspirin
 Beta-lactam antibiotics
(penicillins, cephalosporins,
flucloxacillin)
 Carbamazepine
 Ethambutol
 Furosemide
 Heparin
 Ibuprofen
 Aceclofenac
 Valproic acid
 Vancomycin
 Trimethoprim-sulfamethoxazole
 Sulfonamides
 Oseltamivir
 Naproxen
 Linezolid
 Tirofiban
 Quinine
 Ondansetron
 Rifampin
 Levofloxacin
 Piperacillin
 Pyrazinamide
 Phenytoin

53.  DITP is a clinical diagnosis
made by excluding other
causes of thrombocytopenia
and documenting resolution
of thrombocytopenia upon
drug discontinuation.
 Laboratory testing for drug
dependent antiplatelet
antibodies is often helpful but
not required.
 Drug discontinuation is
essential in patients with
suspected DITP
 Treatment of bleeding
 platelet transfusions
 IVIG if bleeding is severe and
primary ITP is a possible
diagnosis
.
 When bleeding other than
petechiae/purpura is present
but not severe, glucocorticoids
are often given
 Recovery – The platelet count
will increase, often beginning
one to two days after drug
discontinuation, with return to
the patient's normal range in a
week.
 All drug-induced
thrombocytopenia should be
communicated to the patient
and documented in the medical
record.

54. HEPARIN INDUCED THROMBOCYTOPENIA
 Decreased platelet
count during or
following heparin
therapy
 Onset may be rapid or
delayed
 Types of HIT
 Type 1 HIT
 Benign form,small
decrease in platelet
count occuring 2days
after starting heparin
platelet counts returns
to normal with
continued heparin
therapy
 Type 2 HIT
 More serious form
 Occurs 5-10 days after
exposure of heparin
 formation of antibodies
against heparin-P4
complex
 Risk of thrombosis

55. PATHOPHYSIOLOGY
 Neo antigen
Heparin+platelet
factor 4
 HIT autoantibody
(IgG) to Neo antigen
 Immune mediated
activation of platelets
 Thrombocytopenia
 Thrombosis

56.  Clinical manifestations
 Thrombocytopenia
plts<1.5lakh,>50%
decline from baseline
 Thrombosis venous
>arterial
 Skin necrosis
 Limb gangrene
 Organ
ischemia/infarction
 timing 5-10days after
exposure
 Laboratory testing
 Immunoassay
 Detects presence of
HIT antibodies in
serum
 EIA
 Functional assay
 Detects ability of HIT
antibody from patient
serum to activate
platelets
 Serotonin release
assay

57.  Management
 Stop all forms of heparin
 Anticoagulate with non
heparin agent if high risk
of thrombosis
 Argatroban, Lepirudin
 Fondaparinux,Bivalirudi
n
 platelet transfusions if
bleeding
 Evaluate for thrombosis
 Do not give warfarin
until the platelet count
returns to its baseline
level
 Avoid heparin for life
 HIT during or
immediately preceding
pregnancy if requires
anticoagulation-use
Fondaparinux,Argatroba

58. ITP VS TTP VS DIC
PARAMETER ITP TTP DIC
Pathogenesis Antiplatelet
antibodies
Endothelial defect Thrombin excess
Clinical condition Not sick Sick sick
Redcells Normal schistocytes Schistocytes +/-
PT (INR) Normal N/Slightly increased Increased
aPTT Normal N/Slightly increased Increased
Fibrinogen Normal Normal Decreased
Fibrin monomers Normal Slightly increased Increased
Fibrin degradation Normal Slightly increased Increased
D-dimers Normal Slightly increased Increased
Therapy Steroids,IVIG,
splenectomy
Plasma
exchange/vincristine
FFP/Platelets

59. INFECTION-INDUCED THROMBOCYTOPENIA
 Dengue,HIV,Hepatitis C
 Sepsis with disseminated
intravascular coagulation
(DIC)
 Intracellular parasites (eg,
malaria, babesia)
 Epstein-Barr virus
 Helicobacter pylori
 Rickettsial
 Brucellosis,
 Leptospirosis
 Infections can affect both
platelet production and
platelet survival
 RxTreatment of the
underlying infection

61. MEGALOBLASTIC ANEMIA
 Deficiencies of vitamin B12 and/or
folate can cause megaloblastic
anemia
 Causes of folate deficiency
 Inadequate dietary intake
 Increased requirements
 Intestinal malbsorption
 Medications
 Genetic disorders
 Presentation
 macrocytic anemia,jaundice,
 neuropsychiatric changes
 Treatment of folic acid
deficiency
 Folic acid 1-5mg for 1-4
months
 Chronic hemolytic anemia-
indefinitely

62. VITAMIN B12 FUNCTIONS AND ABSORPTION

63. CAUSES AND CLINICAL MANIFESTATIONS OF VIT
B12 DEFICIENCY

64.  Lab investigations
 Low serum vitamin b12
 Methylmalonic acid and
homocysteine elevated
 PS:macrocytic
RBC,mild leukopenia
and thrombocytopenia
 Hypersegmented
neutrophils
 Low reticulocyte count
 Management
 Inj.vitb12 1000mcg im od
for 1 week f/b
 Inj.vitb12 1000mcg im
once a week for 4 weeks
 f/b inj.vit b12 1000mcg
once a month for 6
months

65. APLASTIC ANEMIA
 Bone marrow failure (BMF)
disorder characterized by
pancytopenia with bone marrow
hypoplasia/aplasia due to loss of
hematopoietic stem cells
 TYPES
 Inherited
 Acquired
 Inherited AA Causes
 Fanconi anemia
 Shwachman-Diamond syndrome
 Abnormal thrombopoietin or its
receptor
 Dyskeratosis congenita and
other telomere abnormalities
 Acquired AA causes
 Idiopathic
 Cytotoxic drugs and radiation
 Cancer treatment (anticipated
effect)
 Toxic chemicals
 Benzene
 Solvents
 Drug reaction
 Anti-seizure agents:
carbamazepine, phenytoin
 Antibiotics: sulfonamides,
chloramphenicol
 NSAIDs: phenylbutazone,
indomethacin
 Anti-thyroid drugs methimazole,
propylthiouracil
 Gold
 Arsenicals
 Viral infections
 Epstein-Barr virus
 HIV
 Other herpes viruses
 Immune disorders
 Eosinophilic fasciitis
 Systemic lupus erythematosus
 Graft-versus-host disease
 Miscellaneous
 Paroxysmal nocturnal
hemoglobinuria
 Thymoma
 Pregnancy
 Anorexia nervosa

66. CLINICAL FEATURES AND BONE MARROW FINDINGS
 Presentation
 fatigue, dyspnea, fever,
infections, or
bleeding/bruising
 Hypocellular/aplastic
bone marrow biopsy,
morphologically normal
residual hematopoietic
cells, and no infiltration
with malignant cells or
fibrosis.
 The marrow space is
mostly composed of fat
cells and marrow stroma

67. CLASSIFICATION AND MANAGEMENT OF APLASTIC ANEMIA
 Severe AA
 Bone marrow cellularity <25 percent
(or 25 to 50 percent if <30 percent
of residual cells are hematopoietic)
 At least two of the following:
 Peripheral blood absolute neutrophil
count (ANC) <500/microL
 Peripheral blood platelet count
<20,000/microL
 Peripheral blood reticulocyte count
<60,000/microL
 Very severe AA
 criteria for SAA (above) and ANC is
<200/microL
 Non-severe AA
 Hypocellular bone marrow (as
described for SAA)
 Peripheral blood cytopenias not
fulfilling criteria for SAA or vSAA
(see abo

68. PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
 Acquired disorder in which
hematopoietic stem cells and
their cellular progeny have
reduced or absent
glycosylphosphatidylinositol
(GPI)-anchored proteins on
the cell surface
 Loss of the GPI-linked
complement inhibitors, CD55
and CD59, on red blood cells
(RBCs) leads to chronic
and/or paroxysmal
intravascular hemolysis and a
propensity for thrombosis,
organ dysfunction, and
hypocellular or dysplastic
bone marrow
 Clinical manifestations
 Hemolysis-related Fatigue,
dyspnea, hemoglobinuria
(red/pink/cola-colored urine)
 Thrombosis of abdominal veins,
cerebral veins, or dermal veins
 Smooth muscle dystonia
 Caused by depletion of
intravascular nitric oxide (NO)
due to free hemoglobin
 Abdominal pain, erectile
dysfunction, pulmonary
hypertension, and/or renal
insufficiency.

69. PATHOPHYSIOLOGY OF PNH

70. CLASSIFICATION,DIAGNOSIS AND MANAGEMENT OF PNH
 Classification
 Hemolytic (classical)
PNHintravascular hemolysis, but no
bone marrow failure
 Subclinical PNH PNH granulocytes
and/or erythrocytes are present, but
no substantial intravascular
hemolysis or BMF
 PNH with bone marrow failure PNH
clone size and LDH are variablebone
marrow cellularity and morphology
meet criteria for severe AA or high-
risk MDS
 Diagnosis
 Flow cytometry PNH-affected
granulocytes and erythrocytes is
demonstrated by loss of GPI-
anchored proteins (eg, CD55, CD59)
Bone marrow examination –
Microscopy and cytogenetics to
evaluate for BMF and MDS.
 Management
 hemolytic PNH without bone marrow
failure
 complement inhibitor
 Ravulizumab
 eculizumab
 Subclinical PNH
 watchful waiting
 PNH with severe BMF
 allogeneic HCT
 PNH in pregnancy
 C5i
 Thrombosis prophylaxis
 low molecular weight heparin during
the last trimester and continue
treatment for 8 to 12 weeks postpartum