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Lec # 23

Thrombocytopenia

Thrombocytopenia (TCP) is the presence

of low platelets in the blood (< 150 x 109/L).
it could be : mild, moderate, severe.

Dr. Mahmoud 3ayesh

Thues 17/11/2009

Normal plt count is

150,000 and 450,000
per mm3 ,
if < 150,000 then its
TCP

If Plt count > 150 x 109/L , then we can perform any surgery except
brain surgery.

Spontaneous bleeding occurs if the pt was febrile at Plt count of
20 x 109/L ,if no fever then bleeding occurs at 10 x 109/L Plt count.

Pts with low Plt count are more prone to have bleeding , or usually
purpuric rash.

If associated with recurrent joints bleeding , then its factor VIII
deficiency ( Haemophilia Type A).

Haemophilia A is a recessive X-linked genetic disorder involving

a lack of functional clotting Factor VIII and represents 90% of
haemophilia cases.
Haemophilia B is a recessive X-linked genetic disorder involving
a lack of functional clotting Factor IX.
IX It is similar to but less
common than haemophilia A.
Haemophilia C is an autosomal genetic disorder involving a
lack of functional clotting Factor XI.
XI

OSCE
Ques.

If pt has pinpoint rash the most appropriate investigation

 Plt count.
count

OSCE
Ques.

A picture of a patient with large ecchymosis on the

thigh, if PT and PTT are normal, what is the
cause?
Answer Thrombocytopenia
Thrombocytopenia

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Its v.imp. to differentiate between purpuric rash & vasculitis :
- If the rash blanches with pressure >>> then its erythema.
- If doesnt >>> either TCP or Vasculitis (in vasculitis its
Slightly elevated & usually history of joint pain).
Thrombocytopenia
Pseudo?

True?
Fragmented RBCs

(Perform smear)

TMA?

No need to
work up

High WBC

v.imp

Low
WBC/Hb
MCV-N

WBC, Hb
PT/PTT
Physical
examination

PTT
Splenomegaly

MCV

Leukemia?

Normal

ITP?

DIC?

Vitamin B12
deficiency?
MDS?

Hypersplenism?

(consider
bone marrow
aspiration)

(look for cause)

Types of TCP :
Artefactual /false/ pseudo
TCP
 Sm ppl have Plt that stick
together due to the presence of
prts in the blood (Abs) that bind
to the Plt.
These Abs also bind to a
chemical in blood that is tested in
the lab, giving a falsely low Plt
count.
The platelet count can also be
reduced if the blood sample is
difficult to take and the blood
clots (forming Clumps).

 It is helpful to repeat the
sample in different tubes with
different chemicals.

 True TCP :
 Low Plt count could be: isolated
(ITP) or part of pancytopenia
(Systemic dis.: leukaemia,
hypersplenism), the pathogenesis
involves:
 Reduced Plt production.
- Bone marrow infiltration/malignancy.
- Chemo-/Radiotherapy, alcohols.
- Viral infection (HIV, CMV, hepatitis).
- Megaloplastic / aplastic anemia.
- Leukemia.
- Congenital TCP.
 Increased Plt destruction.
- Immune: ITP, Drug-induced.
- Non-immune: TMA, DIC,TTP ,

microangiopathic HA.
 Plt sequestration in the spleen
 So imp. to check the spleen.

Any pt has low Plt count, if with splenomegaly then its

neither ITP nor aplastic anemia.

Hypersplenism
Type of disorder which causes
the spleen to rapidly and
prematurely destroy blood cells.
 Has 4 cardinal signs
1. Splenomegaly
Splenomegaly is must.
2. Pancytopenia.
3. Normal or hyperplastic bone
marrow.
4. Respond to splenectomy
so Plt count back to normal.
 some causes of congestion
include : Haemolytic anemia ,
portal hypertension, leukemia
and lymphoma.

Splenomegaly:
Causes divided into :
1.Infections.
2. inflammation: RA, SLE,
sarcoidosis.
3. Haematological : Haemolytic
anemia,
anemia hemoglobinopathy ,
leukaemia, lymphoma,
myeloproliferative
myeloproliferative diseases.
4. Portal Hypertension:
Hypertension: liver
diseases.
5. Miscellaneous: storage diseases,
amyloid , 10& 20 neoplasia ,
tropical splenomegaly.

TCP is usually associated with bleeding tendency, except:

1. Anti-phospholipid syndrome (APS).

Disorder of coagulation that coz thrombosis in BV as well as

Pregnancy-related complications: miscarriage, stillbirth..etc

Could be primary or secondary to other dis. As SLE.

More Common in females.

Pt with low Plt count presented with CVA,DVT, PE.

APTT is prolonged .

2. Heparin- induced TCP ( HIT).

pt receive heparin may counter sudden drop of Plt

(250,000- 5000)  So pt usually presented with
Mesentric vascular ischemia or PE.

3. TTP ( discussed later).

ITP
[idiopathic /immune thrombocytopenia purpura ]

Is the condition of having a low platelet count (thrombocytopenia) of no

known cause (idiopathic).

Most causes appear to be related to antibodies (IgG) against Plts.

Isolated low plt count & low Hg if bleeding occurs without splenomegaly

Most common in females, so they come with purpuric rash or heavy
menses, or even asymptomatic & discovered incidentally

Causes:
1. Primary with unknown cause.
2. Secondary: autoimmune diseases (SLE), Haemolytic anaemia,
Viral infection (e.g. starts as rhinitis then spread down, HIV)
Lymphoma, Graft vs. host dis. (GVHD).

Presentation of the pt
Depends on the Plt count:
1- Petechial rash /doesnt blanch with pressure.
2- Bleeding : Epistaxis, Hematuria, Hematemesis,
Melena, Heavy menses.
3- Asymptomatic.

 In the Hx, its important to ask about:

(GVHD)
common complication of
allogeneic bone marrow
transplantation in which
functional immune cells in
the transplanted marrow
recognize the recipient as
"foreign" and mount an
immunologic attack. It can
also take place in a blood
transfusion.

- Purpuric rash & bleeding diathesis/tendency:

(Many sites of bleeding). Or spontaneous bleeding: epistaxis,
Gum bleeding, skin bleeding, heavy menses, prolonged bleeding after
surgery.
- ask for drugs which may cause haemolysis.
- Other autoimmune diseases.
- Family history of bleeding.

 In physical exam, every thing is normal except for

.

evidence of bleeding, No Splenomegaly or lymphadenopathy

 Investigations/ Lab results:

1. CBC: Thrombocytopenia, normal WBC count, normal or low Hg if bleeding.

Make sure thats low Plt count is not lab error, no clumps /clots in the tube.
2. Peripheral smear/ blood film: large platelets, no blasts or
fragmentation .

Blasts + RBCs fragmentation  TTP.

3. Bone marrow exam: increased megakaryocyte count;

imp to roll out leukaemia.

4. Coagulation screen to roll out DIC & TTP .

In ITP: normal PT, APTT, fibrinogen, D-dimer.

In DIC: low Plt, prolonged PT, low fibrinogen.

Management:
If u make sure about causes of low PLT count, then weve 3 lines for
treatment of ITP & Haemolytic anaemia :

 Steroids: (Prednisone)
Prednisone)
given orally or IV for (2,3 mos) then make tapering for it.

Intravenous g-globulin (IVIg) :

isolated IgG extracted from the plasma of over 1000 blood donors
raise Plt count quickly but effects last ( 2 weeks - 3 months )only.
Its very expensive, used in
- acute severe stages of TCP
- active bleeding
- Preparation for splenectomy
- If pts ( specially pregnant females) resistant to steroids.
But may cause anaphylactic shock.

If failed then
 Splenectomy
tt of choice for all adult steroid-dependent/ Resistant pts.
Complete remission of Low Plt 85% (15% dont respond).

Post-splenectomy changes , include :

1. Raised Plt count, increased risk of potentially fatal clot formation
2. High incidence of infections (encapsulated MO: pneumococcal,
N.meningitis, H.Influenza )  v.imp to give vaccines 3weeks before
splenectomy & take oral penicillin.

If failed then


Look for accessory spleen & give other drugs as: Rituximab.

Accessory spleen:
Small nodule of splenic tissue found apart from the main body of the spleen.
They are medically significant in that they may result in interpretation errors in
diagnostic imaging or continued symptoms after therapeutic splenectomy.

 ITP in Pregnancy 

DDx of TCP in pregnancy:

1. Gestational (3rd semester, usually Plt > 75,000).
2. Chronic ITP.
3. Preeclampsia (include. HELLP syndrome)
4. von Willebrand disease (vWD) .

 Plt > 30,000

sufficient for delivery

#  Plt > 50,000 are

required for cesarean
section

HELLP synd.
A variant of Pre-eclampsia (pregnancy HTN & PrtUria). Occurs during
the later stages of pregnancy.
Its an abbreviation of the main findings:

H
Hemolytic anemia

E
Elevated Liver enzymes

L
Low Plt count

Management : giving steroids , IVIg, splenectomy (should be

avoided unless necessary).

Plt transfusion is contraindicated in all cases of ITP , coz they will

have destruction due to Ag-Ab rxn.

TTP
[Thrombotic Thrombocytopenic Purpura]
A rare disorder of the blood-coagulation system, causing extensive
microscopic thrombosis to form in small blood vessels throughout the
body (thrombotic microangiopathy/ TMA), pts usually have skin rash.

Von willbrabd factor [vWF

[vWF]
vWF] is a large multimeric
glycoprotein present in blood plasma and produced constitutively in
endothelium , megakaryocytes, and subendothelial connective tissue.

Exceedingly potent in supporting platelet aggregation, acts like glue

to help the platelets stick together and form a blood clot, most
apparent in tissues having high blood flow in narrow vessels.

The biological breakdown of vWF is largely mediated by the

protein ADAMTS13, It is a metalloproteinase which cleaves vWF.

If large vWF multimers persist tendency for  coagulation.

Types of TTP:
1. Idiopathic TTP: inhibition of the enzyme ADAMTS13 by antibodies
(IgG), rendering TTP an autoimmune disease.
2. Secondary TTP, due to : Cancer, bone marrow transplantation,
pregnancy, medications, HIV.

Here the activity of the enzyme is depressed.

3. Hereditary TTP (Upshaw-Schlman syndrome) this is generally due to
inherited deficiency of the enzyme.

In all types of TTP , large circulating vWF , will occlude small blood
vessels & coz aggregation of Plt  thrombosis.
Findings & lab results:
1. Microangiopathic hemolytic anemia
(Microangiopathic/ microvascular subgroup
of hemolytic anemia caused by factors in the
small BV. It is identified by the finding of
anemia and schistocytes(fragmented RBCs)
on microscopy of the blood film.
2.Anemia & Thrombocytopenia -quite severe
Schistocytes , seen in MHA
& pts who have prosthetic
(< 20,000), bleeding at presentation is common.
valves with normal Plt.
3. Neurological impairment
(dizziness, headache, confusion, convulsions, coma)
4. Renal failure (impaired KFT ,  creatinine)
5. Fever.

 LDH is constantly elevated;

(Tissue breakdown elevates levels of LDH, and therefore a measure of it
indicates e.g. hemolysis & ischemia. Other disorders indicated by elevated
LDH include: cancer, meningitis, encephalitis, acute pancreatitis & HIV.)

 Coagulation tests are normal (normal PT , APTT).

Management of TTP:
1. Plasmapheresis to remove large vWF & replace the enzyme.
2. if not available then > infusion of fresh frozen plasma (FFP),
Even though Plt transfusions are CONTRAINDICATED???
(This makes sense if the condition is autoimmune TTP coz of Abs).

HUS
[Hemolytic uremic syndrome]

Occurs in pediatrics , Equivalent to TTP in adults.

Induced by infection with Verotoxin-producing E.Coli and Shigella,

causing  endothelial damage, secondary platelet activation
& formation of thrombi in renal microvasculature.

[TTP has more neurological Sx, while HUS has more renal Sx].

Pt comes with : diarrhea, vomiting, impaired kidney functions

+ drop in Plt & RBCs count.

Without logical complications.

Management:
1. Acute disease is usually selflimited.
2. Plasmapheresis is treatment of choice even its not effective in
preventing renal damage.
3. Renal dialysis.

DIC
[Disseminated intravascular coagulopathy]
consumptive coagulopathy : pathological activation of coagulation (blood
clotting) mechanisms  formation of small blood clots inside the blood
vessels throughout the body.

As the small clots consume all the available coagulation proteins and
platelets, normal coagulation is disrupted and abnormal bleeding occurs.

The affected person is often acutely ill and shocked with widespread
haemorrhage (common bleeding sites are mouth, nose and venipuncture
sites), extensive bruising, renal failure and gangren, or it may be insidious
and chronic, as in cases of cancer.

Pt comes with
 purpuric rash with low Plt count  (so not vasculitis).
 diagnosed as ITP ,when hes given steroids & IVIg >>
no improvement.
On physical exam : splenomegaly  (so not ITP).
In endoscopy: Portal HTN, esophageal varices .
 Bone marrow study shows large megakaryocytes.
 Improved when given fresh frozen plasma.
DDx of the condition is :
 Gaucher dis.( genetic disease in which lipid accumulates in cells
and certain organs: spleen, liver, kidneys, lungs, brain and bone
marrow)
 liver cirrhosis( 1st presentation is TCP, portal HTN,
splenomegaly)

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 Its imp.to think of the setting of the condition , for example:

If Pt with liver cirrhosis , comes with hemaemesis varices not PU.
If Pt uses OCS , comes with SOB PE.
If Pt with APS , comes with CVA  stroke or thrombosis.

Definitive diagnosis depends on the result of:

 Thrombocytopenia.
 Prolongation of PT and APTT  high INR.
 A low fibrinogen concentration.
 Increased levels of fibrin degradation
products (FDP : D-dimer).
 Fragmentation of the RBCs.

Test

Result

Prothrombin Time

Slightly to grossly prolonged

aPTT

Variable

Fibrinogen

Usually low

Thrombin time

Usually prolonged

Factor levels

Variable

Platelet Count

Usually low

RBC fragmentation

Sometimes present

Fibrin split products

Usually present

V.Imp

The reference range for prothrombin time is usually around 1215 seconds.
the normal range for the INR is 0.81.2.
for people on warfarin therapy, 2.03.0
 A high INR level such as INR=5 indicates that there is a high chance of
bleeding, whereas if the INR=0.5 then there is a high chance of having a clot.

APTT : Values below 25 seconds or over 39 s (depending on local normal

ranges) are generally abnormal.
fibrinogen Normal levels are about 1.5-3.0 g/L
D-Dimer.Most sampling kits have blood reference ranges of 0-300 ng/ml as
normal range.

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Here the dr. talked about a case he was working on:

** A female pt known to have acute promyelocytic leukaemia:
- Her Plt count dropped over afew days :
- PT raised to 2.5 then 3 then 4.
- Fibrinogen decreases from 500 to 200 then 100
- She suffered from bleeding in the sites of BM biopsy & venipunctures.
- Then she developed DIC & intraventricular hemorrhage.
** Also pts with G-ve sepsis in ICU, they may develop DIC:
- bleeding in site of the IV line, hematuria when applying Foley
catheter, depletion of the clotting factors, thrombosis, reduced level
of consc.

Commonest causes include:

Cancers of lung, pancreas, stomach, prostate.

Obstetrical problems.

Massive tissue injury: Trauma, burns, extensive surgery

Infections: virusus, Gram-negative sepsis, Neisseria meningitidis,
Streptococcus pneumoniae, malaria

Miscellaneous: Liver disease, snake bite, giant hemangioma, shock, heat
stroke, vasculitis, aortic aneurysm, Serotonin syndrome.

Treatment :

OSCE
Ques.

Depends on primary manifestation

Thrombosis - Anticoagulant therapy
Bleeding - Replacement therapy
Primary treatment
TREAT UNDERLYING DISEASE
Replacement
Cryoprecipitate Fibrinogen ( at low tempreture)
Fresh frozen plasma (factors II, VII, IX, X).
Platelets
Heparin ( Rarely indicated, just if theres thrombosis).

A lab result with low platelets, anemia, low WBC's, fibrinogen low, PTT
prolonged, INR increased
What is the most likely diagnosis? DIC
Give 2 causes ( go up).

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Before ending , the dr. talked briefly about warfarin & heparin toxicity , & here
what he said :

Warfarin:
 Used as anticoagulant for DVT, PEetc.
Target INR ( 2.5-3.5).
 half life : 36 hrs.
 used as rodenticides for controlling rats and mice in residential,
industrial, and agricultural areas. Warfarin is both odorless and tasteless,
and is effective when mixed with food bait, because the rodents will
return to the bait and continue to feed over a period of days until a lethal
dose is accumulated
 Complications of tt : Bleeding, skin necrosis , Protien C deficiency,
teratogenicity.
 In cases of toxicity : stop the drug , give FFP & Vit.K.

Heparin :
 Half life of conventional heparin : 1.5 hrs
 Half life of LMW heparin : 4-6 hrs.
 Complications of tt: bleeding, osteoporosis, HIT.

 In TT of DVT, we start with warfarin , then replace it with Heparin

( warfarin coz prt C deficiency & skin necrosis).

Sry for the delay & for any mistake, the lecture was totally disoriented, I
tried to make it Make sense & understandable.
I didnt attach the pics (dr said they wont come in OSCE) & part of
slides (go back to them).

Wish u all AD7

AD7A MOBARK & JOYFUL VACATION

REHAM NAWAF
www.Shifa2006.com