Blood Disorders

Introduction :

Normal hemostasis:

is the active process that clots blood in areas of blood vessel injury, and limits the clot to the areas of injury.

The main components of the hemostatic process are:

1. Vasoconstriction (vascular phase)

2. Platelet plug formation (primary hemostatic – platelet phase)

3. Fibrin thrombus formation (secondary hemostatic coagulation phase).

4. Fibrinolysis (clot breakdown) 


A. Differential diagnosis of bleeding

1-Hemophilia (factor 8 or 9 deficiency)


2. von Willebrand disease

3. Acquired clotting factor deficiency: disseminated intravascular coagulation (DIC), vitamin K deficiency,
and liver failure

4. Acquired thrombocytopenia: DIC, idiopathic thrombocytopenic purpura (lTP)

B. Historical findings

Establish sites of bleeding:

a.Distinguish between mucosal bleeding and deep tissue or joint bleeds

-*Vascular and platelet dysfunction usually present with:

o Subcutaneous or mucus membrane bleeding (Superficial bleeding) : purpura, petechiae, epistaxis.

o Coagulation factors deficiency (Deep bleeding) :


Usually occur deep into joins, muscles, retroperotineal space.

b. Bleeding limited to single site suggests systemic or inherited bleeding disorder

2. duration and severity

3. Severe inherited bleeding disorders typically present in infancy.

4. Bleeding complications associated with injury or procedures (e.g., circumcision), if extensive, can
imply inherited bleeding tendency

5. History of recent infection can be associated with autoimmune-mediated

6. Bleeding from unusual site as joint or internal organ.



o Symptoms: epistaxis, gingival bleeding, easy bruising, menorrhagia, hematuria, neonatal bleeding,
gastrointestinal bleeding, hemarthrosis, prolonged bleeding after lacerations

o Response to hemostatic challenge: circumcision, surgery, phlebotomy, immunization/intramuscular
injection, suture placement/removal, dental procedures

o Underlying medical conditions: known associations with hemostatic defects (liver disease, renal failure)
Liver disease = Most of coagulation factors coming from live ; vit K independent factor.

Medications:

o Antiplatelet drugs (Aspirin)

o Anti-coagulants (warfarin, heparin, LMW)


o Prolonged use of antibiotics causing vitamin K deficiency


Family history: siblings, parents, aunts, uncles, grandparents:

1- sex linked recessive (hemophilia A&B,WAS)


2-autosomal recessives disease (Clotting factors deficiency 2,5,7,10,11,13)

3- Autosomal dominant( VWF, qualitative platelet disorders)

C. Physical examination findings

1.Petechiae

2. Purpura

3. Ecchymoses

4.Hepatosplenomegaly :

a.Hematologic malignancies can present with bleeding and are often associated with enlarged liver and/or
spleen

b.Splenomegaly can also result in consumptive thrombocytopenia that can lead to bleeding

5.Hematomas

6.Hemarthrosis

7-Hemangiomas

8-  Significant lymphadenopathy

9-Active and playful vs. Ill looking

10-Dysmorphic features

11- Café-au-lait spots 




D. Diagnosis

Tests to evaluate bleeding disorders:

1.Platelet counts:150-450x103/mm3

2.Prothrombin time(PT):Measures the extrinsic and common coagulation pathways 10-15 second

3.Activated Partial thromboplastin time(aPTT): Measures the intrinsic and common coagulation pathways
the normal range is 30 – 50 second

4.Thrombin time:Time for thrombin to convert fibrinogen to fibrin9-13second 


5.Bleeding time: 2-9minutes .Prolonged in platelet disorder. 


- Some bleeding disorders might not be associated with any abnormalities in the screening tests like:

a. Mild factors deficiency

b. Factors 13 deficiency.

c. HSP. “Henoch-Schonlein purpura”

d. Ehler danlos syndrome . “vascular problem”

e. Scurvy. 

What causes bleeding disorders:
Vessel defects.

Platelet disorders.

Clotting factor deficiencies.

Vessel defects: Vascular causes:

Vasculitis – Henoch-Schonlein Purpura affect girls

Age 4-6
years
Present as = Purpuric rash in lower limb
Pathologic = buttock rash and commonly associated with abdominal
pain + hematuria .. It is autoimmune process
Treated by: supportive care / steroid in severe
cases long time complication: renal failure

Hemangiomas- Kassalback-Merritt big hemangioma start to consuming the platelet and coagulation and
syndrome cause bleeding problems .. Manage by surgical or laser.

Platelet disorders:

Platelet physiology:
Platelets Production: Hematopoietic stem cell
Platelet circulation:
Normal count is 150,000- 450,000
Normal life span 7-10 days.
About 1/3 are trapped in the spleen.
Causes of thrombocytopenia: Low platelets count
1.Bone marrow disorders “production problem”
Hypoplasia
Idiopathic
Drug-induced (cytotoxic, alcohol)
Infiltration
Tumors (leukemia, lymphoma, neuroblastoma)
2.Increased consumption of platelets:

Immune thrombocytopenic purpura “commonest cause of thrombocytopenia in children “
Disseminated intravascular coagulation (DIC)

Viral infections (HIV, Epstein-Barr virus) ITP :
Bacterial infections (gram-negative septicemia) Affect 2-10 years
History of infection or
3,Hypersplenism
vaccination 2-3 weeks before
Primary
presentation
Thalassemia (most common)
ITP well children
Liver disease
Malaria In exam : stable vital
sign / no
hepatosplenomegly
Clinical presentation of thrombocytopenia: Inves: only
Petechiae thrompocytopenia
Purpura Under mictoscope : No
Gum bleeding abnormality PT and
Epistaxis PTT : normal
Manage: platel more that 20 =
Excessive bleeding after surgery
do nothing .. Check after 2-3
Gastrointestinal bleeding (Fresh blood or melena) days
Hematuria
Serious complication :


intercranial hemorrhage ( less
than 20 ) .. Treat with cortisone
(short course – low cost, oral )
4mg/ 4dividied doses/ 4 days
Other med: IVIG for 2 days
( faster response )
Acquired disorders of platelet function:
Drugs:
Best example is ASPIRIN which is the MOST COMMON cause of acquired platelet
function disorder.
Aspirin irreversibly affect the cyclo-oxygenase enzyme, the effect last 4-7 days . Presents as elevated bleeding
time but purpura is unusual.


Factor deficiencies (congenital):

Hemophilias
Caused by lack of coagulation factors
Von willebrand’s disease
Caused by lack of von willebrand´s factor

Types of hemophilia:
Hemophilia A: Absence or deficiency of Factor VIII.
Hemophilia B (Christmas Disease): Absence or deficiency of Factor IX.
Hemophilia C: Absence or deficiency of Factor XI ,Very rare and mild.
von Willebrand Disease: deficiency or abnormality of VWF

Hemophilia inheritance:
Hemophilia is an X-linked gene disease.
Afather with the X-linked gene will pass it to all his daughters resulting in heterozygous
carriers.
A mother who is a carrier of the mutant gene will pass the gene on to half her sons and half her
daughters. All her sons will have hemophilia and all her daughters will be heterozygous carriers.
Females are carriers
Males have the disease
Hemophilia A:
Occurrence: 85% Haemophilia A; 15% Haemophilia-B
Clinical manifestations :
Hemarthrosis (most common):
Most common problem in haemophilia
Symptoms include, pain and disabled joints
Repeated joint bleeding leads to synovial inflammation and increased vascularity and
thickening of the synovium.
Soft tissue hematomas (e.g., muscle)
Muscle atrophy
Shortened tendons
Other sites of bleeding
Urinary tract
CNS, neck (may be life-threatening)
Prolonged bleeding after surgery or dental extractions

Severity of hemophilia depends upon the level at which factor VIII is deficient:

Factor VIII levels <1% 1% - 5% 5% - 25%

Type Severe hemophilia Moderate hemophilia Mild hemophilia

Symptoms Severe hemorrhage, Bleeding after mild Bleeding after severe

deep tissue bleeding. trauma. trauma and surgery.
Present within first Present during Present during
year of life. childhood. adulthood.

Investigations:
APTT prolonged
PT is normal
Factor VIII (or IX) is low (<40%)

Aim of therapy:
Prevention of bleeding episodes
Treatment of bleeds
Preservation of joint function
Complete social integration & Quality of Life
Precautions:
Aspirin is strictly contraindicated .
NSAID’s (used for the treatment of arthritic pain) should be prescribed with caution
Intramuscular injections are contraindicated because they may provoke severe intramuscular
bleeding

Childhood immunisations can be given after FVIII prophylaxis
Activities and sports are encouraged to maintain a healthy musculoskeletal system which
reduces risk of bleeding
Only sports with high risk of head& neck injury i.e. boxing should be avoided

Treatment:
Treating the patient after a bleed is known as “on demand” or “crisis” therapy
It is crucial to treat as soon as possible after bleeding
The dose of factor required depends on the site and severity of bleeding and is calculated
according to the following formula:
1 IU FVIII/ kg raises FVIII levels
by 2% therefore:
required units= body weight(kg) x desired FVIII: rise x 0.5

Hemophilia B:
Factor IX deficiency
Factor IX half-life = 18- 36h
Incidence: 1 : 30.000 males
20% severe
50% moderate
30% mild
World-wide 70,000 people with severe Haemophilia B
Clinically indistinguishable from haemophilia A
Treatment:
1 IU FIX:C /kg increases FIX
levels by 1% therefore:
Required dose= body weight (kg) x
desired FIX increase(%)
 Prevention
”Preventative treatment is known as “prophylaxis
Only for severe Haemophilia
FVIII is administered by the patient or suitably trained relative x 3 /week, starting soon after
diagnosis
Dosage: 20-50 IU / kg / x 3/week
Aim: to maintain trough levels of FVIII > 1 % i.e. converting patient from severe to moderate
disease and preventing spontaneous bleeds

- Prophylaxis:
20-30 IU / kg body weight x 2/ week

Hemophilia A (More common) Hemophilia B

Short half life 8-12 hrs
1 of the factor = increase by 2
Give more frequent with low
doses
required units= body weight(kg) x
desired FVIII: rise x 0.5
16-18 hrs
1 of the factor = increase by 1
Once a day with high dose
Required dose= body weight (kg) x desired
FIX increase(%)

Desired level for both factor 8 & 9

Von willebrand’s disease:
Autosomal inheritance disease
Males and females are equally affected
Most frequent inherited bleeding disorder
Incidence - 1/10,000
Very wide range of clinical manifestations
Clinical manifestations:
Epistaxis
Easy bruising / hematomas
Menorrhagia
Gingival bleeding
GI bleeding
Dental extraction bleeding
Trauma/wound bleeding
Post-partum bleeding
Post-operative bleeding
Types:
o Type 1 (60-80%)
5-30% quantitative reduction in vWF
o Type 2 (10-30%)
Qualitative defect in vWF
Sub-types 2a, 2b,2m, 2n
Type 3 (1-5%) most sever
Absent vWF
This type may also present with a clinical picture of hemophilia A
 Treatment:

Acquired bleeding disorders:

Vitamin K deficiency:
Source of vitamin K :Green vegetables,Synthesized by intestinal flora
Required for synthesis: Factors II, VII, IX ,X
Causes of deficiency: Inadequate intake, Biliary obstruction, Mal-
absorption, Antibiotic therapy


Liver disease and hemostasis:

Decreased synthesis of II, VII, IX, X, XI, and fibrinogen
Vitamin K deficiency
Dysfibrinogenemia
Enhanced fibrinolysis (Decreased alpha-2-antiplasmin)
DIC
Thrombocytoepnia due to hypersplenism

Disseminated intravascular coagulation (DIC):

Is an acquired bleeding disorder
Is not a disease entity but an event that can accompany various disease processes
In DIC, a systemic activation of the coagulation system simultaneously leads to :
Inadequate fibrin removal (inhibition of fibrinolysis ) and increase fibrin deposition (results in
thrombus formation).
Exhaustion of platelets and coagulation factors (results in bleeding).

Is a Paradoxical Clinical Presentation “clotting and hemorrhage”

Common clinical conditions associated with DIC:
Sepsis
Trauma
Head injury
Fat embolism
Malignancy
leukemias
Obstetrical complications
Amniotic fluid embolism
Abruptio placentae
fetal death syndrome

Vascular disorders
Reaction to toxin (e.g. snake venom, drugs)
Liver disease, pancreatitis
Immunologic disorders
Severe allergic reaction
Transplant rejection

Signs and symptoms of DIC: Most common signs of DIC are bleeding
and thrombosis
Manifested by ecchymosis, petechiae and purpura
Bleeding from multiple sites either oozing or frank bleeding
Cool and or mottled extremities may be noted
Thrombosis leads to tissue ischemia and infarction
Dyspnea and chest pain if pleura and pericardium involvement
Hematuria
Diagnosis and lab findings:
Test Abnormalit
y
Platelet Decreas
count e d
Bleeding Increas
time PT e d
Activated Prolong
PTT e d
Thrombin Prolong
time e d
Fibrinogen Prolong
Fibrin degradation product e d
(FDP) Decreas
ed
Increased

MCQs
Deficiency in hemophilia A in which factor?

Factor IX

Hb & WBC normal- clorring =me normal- bleeding =me prolonged?

ITP
Hemophilia lap finding is?

Normal PT and prolonged APTT

Bleeding =me is a screening test for evalua=ng possible bleeding disorders. Of the following, the results of this test are
BEST correlated with
A. Factor VIII an-genic ac-vity
B. Factor VIII coagulant ac-vity
C. Fibrin clot forma-on
D. Platelet func-on

In which of the following organs is erythropoie=n primarily produced?

Bone marrow.
Liver.
Kidney
Spleen.
Hemophilia B deficiency in factor?IX
Diagnos=c feature of HSP? Rash
Girl with menorrhagia with +ve FHx of bleeding disorders? vWD
True about Hemophilia? X-linked recessive
Most organ affected in hemophilia? Joints
-Which of the following medica=on cause platelet dysfunc=on? Aspirin

-Which of the following is the most common cause of thrombocytopenia in children?

Immune thrombocytopenic purpura
-Which of the following is the mode of inheritance of Hemophilia A ? X-linked recessive
-Hemophilia B cause by deficiency of which of the following factor ? IX
-Which of the following is the most common site of bleeding in Hemophilia ? Joints
-A 10-year old male has an erythematous rash shown below. Laboratory: CBC, differential, Platelet
count, PT, PTT are normal. Which of the following is the most likely diagnosis?

. Henoch-Schönlein Purpur

-Newborn male with Physical anomalies shown below

CBC: WBC 50,000; Hb: normal. Platelet: 15000 .. Which of the following is the
most likely diagnosis?
TAR syndrome (thrombocytopenia absent radius syndrome)

-A 3- year old boy is admitted with a day history of a painful, swollen right knee slide
shown below. His mother gives a history of easy bruising since he started crawling.
He is the only child, but according to his mother one of his nephews also has a
bleeding tendency. White
9
cell count1: 12.5 x 10 /l [5.1 -13.9]. Hemoglobin: 11.8g/dl [11.14 -15.46]
9
Platelet count: 300 x 10 /l [152.5 - 397.5] INR : 0.96 [0.94 - 1.33] PTT: 72 sec [26.62 - 40.38]
Thrombin Time: 15 sec [13 -15] Fibrinogen: 325 mg/dl [117.72 -
384.28] Which of the following is the most likely diagnosis ?
Hemophilia

-A 6-year old male has severe hemophilia A (FVIII deficiency) present to the ER after
head trauma his weight is 20 kg. Head CT scan shown below.. Which of the following
is the most appropriate dose of recombinant factor VIII?
1000 units
-A 13-year old female is referred for easy bruising and mennorrhagia. Her father has a
life long history of easy bruising and bleeding after dental extraction. Which of
the following is the most likely diagnosis in this family?
Von Willebrand disease.

-A woman takes her three year old child to the general practitioner with a history of a
skin rash of 3 days duration. Ten days before the onset of the rash the child had mild
upper respiratory symptoms with cough and fever. The mother managed this
symptomatically without consulting a doctor.
On examination the child appears well with no temperature and no signs of an upper
respiratory infection. There is a fine peticheal rash on the skin and mucous
membranes. No lymphadenopathy or hepatosplenomegaly is found
9 9
WBC: 10.1 x 10 /l [5.1 - 13.9] Haemoglobin:11.5g/dl [11.14 -15.46] Platelet count: 4.0 x 10 /l
[152.5 -397] MCV:75.1 fl [73.1 - 88.8] MCH: 28.9 pg/l [24.05 -29.9] Normal
differential white cell count ..What do you think is the possible diagnosis?

Immune thrombocytopenic purpura [ITP]