| Bleeding

Hematology
438 teamwork disorders 1

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| Introduction to Vascular Bleeding disorders
Definition: Heterogeneous (different) group of conditions characterized by easy bruising and spontaneous
bleeding from the small vessels. With normal coagulation tests. Usually the underlying abnormality is either in the
vessels themselves or in the perivascular connective tissues.
Causes of bleeding disorders:
● Vascular disorders, Thrombocytopenia, Defective platelet f unction, Defective coagulation.

Vascular defects

Acquired vascular defects Inherited vascular defects

● Simple easy bruising (in young healthy women with unknown cause) is a common benign ● Hereditary hemorrhagic telangiectasia 2: Autosomal
disorder which occurs in otherwise healthy women, especially those of
dominant , Rare.
child-bearing age.
● Connective tissue disorders e.g.:
● Senile purpura caused by atrophy of the supporting tissues of cutaneous blood
vessels. The most common acquired vascular defect Seen in old adults (Considered normal) -Ehlers–Danlos syndrome 3: There are hereditary
● Henoch-schönlein purpura is usually seen in children and often follows an collagen abnormalities, with purpura resulting from
acute upper respiratory tract infection. defective platelet adhesion.
| Bleeding disorders
Bleeding disorders

Congenital/ Inherited bleeding disorders

Acquired bleeding disorders
(coagulation or clotting factor disorders)

1- Liver disease. 2- Vitamin K deficiency 1- Haemophilia A (factor VIII) A looks like ٨ so its factor ٨ deficiency.
3- DIC 4- Acquired hemophilia. 2- Haemophilia B (factor IX) B for benign so it is factor 9 deficiency.
5- Drugs (heparin, warfarin, tPA, rivaroxaban, dabigatran) 3- Von Willebrand disease
NOTE: Single deficiencies of factors other than VIII and IX are rare.
All factors deficiency give rise to bleeding disorders of varying
degrees of severity, except contact factor (plasma kallikrein-kinin
| Haemophilia A inherited in an X-linked recessive pattern
system) (e.g. factor XII and XI, and plasma prekallikrein (PK))

Definition: Deficiency of factor VIII results from a mutation in the factor VIII gene, which lies at the the long arm of the
X-chromosome. It ranges form single-point mutations to large deletions.

In the plasma, factor VIII is only

1 ● The prevalence of this disorder is about one per
10 000 males. 2
Prenatal diagnosis of
haemophilia can be made 3 found complexed with VWF,
which acts as a carrier and prolongs
● Females with haemophilia have been observed by analysis of fetal DNA, which
its plasma half-life.
extremely rarely and these are either can be obtained either by
homozygotes 4 for the abnormal gene or are chorionic villus sampling
heterozygotes in whom the normal between 11.5 and 14 weeks of Genetic mutational analysis allows
X-chromosome has not produced sufficient gestation or by amniocentesis 4 carriers to be identified with accuracy
and is the method of choice.
quantities of factor VIII due to lyonization 5. after 16 weeks.
| Haemophilia A cont.
Clinical features:

01 Infants may develop prof use post‐circumcision

haemorrhage or joint and soft tissue bleeds and
excessive bruising.
02 Recurrent painful hemarthrosis and muscle
haematomas dominate the clinical course of severely
affected patients

03 If inadequately treated, lead to progressive joint

deformity and disability. 04 Intracranial bleeding is the most common cause of
death from the disease itself.

Diagnosis Treatment
● Treatment should be given at the earliest sign of spontaneous or post-traumatic bleeding, which consists of intravenous
● The possibility of injections of factor VIII concentrate.
haemophilia is ● Guidelines exist for the plasma level to be achieved for different types of haemorrhage.
suggested by the finding ● A controlled trial has proven that regular prophylaxis is far superior to on‐demand treatment. Approximately 25% of patients
of a normal PT and a with haemophilia, usually after treatment with factor VIII on 10-20 occasions, develop antibodies that inhibit its functional
activity.
prolonged APTT. ● Haemorrhage in patients with high-titre inhibitors may require treatment with ‘bypassing agents’ such as recombinant factor
● Confirmation is by a VIIa or FEIBA (factor eight inhibitor bypassing activity; that is, a plasma-derived activated prothrombin complex
specific assay of factor concentrate), which activate the coagulation cascade below the level of factor VIII.
VIII coagulant activity ● The administration of factor VIII may be avoided in mild to moderate haemophilia by using the vasopressin analogue
with normal VWF. desmopressin (DDAVP), which causes a temporary increase in factor VIII and VWF by provoking the release of these factors
from endothelial cells. DDAVP is used intravenously, subcutaneously or intranasally.
| Haemophilia B (Factor IX deficiency, Christmas disease) inherited in an
X-linked recessive pattern

Characteristics:
01 The clinical features and inheritance
of factor IX deficiency are identical to
02 The factor IX gene is located on
the long arm of the 05 Plasma-derived factor IX concentrate
or recombinant factor IX is available
those in factor VIII deficiency. X-chromosome. and should be administered
intravenously as soon as spontaneous or
post-traumatic bleeding starts.

03 Factor IX deficiency affects about 04 The APTT is prolonged and

the PT normal. The diagnosis 06 Factor IX has a longer half -life in the
1 in every 50 000 males. plasma (18-24 hours) than factor VIII
can be made by assay of the and hence can be given at less frequent
factor IX level. intervals.

| Correlation of coagulation factor activity and disease severity in haemophilia A or B

Coagulation factor activity
Clinical manifestations
(percentage of normal)

● Severe disease with Frequent spontaneous bleeding into joints, muscles, internal organs from
<1 early life Joint deformity and crippling if not adequately prevented or treated.

1–5 ● Moderate disease, Bleeding after minor trauma, Occasional spontaneous episodes.

>5 ● Mild disease, Bleeding only after significant trauma, surgery.

| Von Willebrand disease
Definition: It is an autosomal disorder characterized by mild(most are undiagnosed), moderate or severe bleeding. The bleeding results
from either a qualitative abnormality or a quantitative deficiency of VWF. It’s the most common inherited bleeding disorder with prevalence
of up to 1%.
What are the functions of VWF?
● Binds platelets to subendothelial tissues.
● It acts as a carrier for factor VIII.
The reduction in VWF results in a reduction in factor VIII concentration (can be misdiagnosed as hemophilia A).

● Spontaneous bleeding is usually confined

to mucous membranes and skin most The laboratory findings include:
Types of Prolonged PFA closure time.
commonly epistaxis and ecchymoses. ●
VWD ● Bleeding into joints and muscles is rare ● Usually a prolonged APTT.
except in type 3 disease. Diagnosis ● Reduced factor VIII clotting activity
● Reduced levels of VWF antigen or activity.
Type 1 (most frequent): partial ● Impaired ristocetin-induced platelet
reduction, AD (Autosomal dominant) aggregation.

Type 2: There are qualitative

abnormalities, AD or AR (Autosomal ● For type 1 disease, desmopressin (DDAVP) is the first
line treatment. DDAVP increases plasma levels of both
recessive) VWF and factor VIII.
Treatment ● Very high purity VWF concentrate may be used.
Type 3: There is nearly complete ● The antifibrinolytic drug (tranexamic acid) may be used
for treating epistaxis or menorrhagia.
absence of VWF molecules, AR
| Acquired bleeding disorders
Vitamin K deficiency DIC

Liver disease Drugs Acquired hemophilia

(heparin, warfarin, tPA, rivaroxaban, dabigatran)

| Vitamin K deficiency
➔ Fat‐soluble obtained from green vegetables and bacterial synthesis in the gut
➔ Hemorrhagic disease of the newborn:
- usually on the second to fourth day of life, but occasionally during the first 2 months.
- PT and APTT are both prolonged.
- Caused by:

lack of gut bacterial synthesis low quantities in breast

liver cell immaturity
of the vitamin milk
 | Disseminated intravascular coagulation (DIC)
➔ Generalized activation of the clotting system followed by marked activation of the fibrinolytic system
➔ Acute DIC may be associated many serious/lifethreatening diseases

Clotting system Fibrinolytic system

Clotting cascade is activated in various

Widespread
activation of
coagulation As a consequence of the fibrin
ways (tissue damage, collagen exposure, CLOTTING formation, the fibrinolytic
release of TF and other procoagulants)
Microthrombi FACTORS

Endothelial
damage
in the
circulation
PLATELETS
mechanism is activated, resulting in
high concentrations of FDPs,
FIBRINOLYSIS
+FDPs

Generalized
platelet
aggregation including D-dimers

Activation of the cascade leads to the

generation and dissemination of large
amounts of thrombin in the circulation, the
activation of platelets and the formation of
intravascular microthrombi
 01: 02: 03:
Infections Malignancy Obstetric
Viral infection: Widespread mucin‐secreting Obstetric complications
Causes of DIC

-Gram‐negative
-varicella adenocarcinoma Amniotic fluid embolism
-meningococcal septicaemia
Premature separation of placenta
-Clostridium welchii septicaemia -HIV
-Severe falciparum malaria -hepatitis Acute promyelocytic Eclampsia; retained placenta
-cytomegalovirus leukaemia Septic abortion

04: 05: 06: 07:

Hypersensitivity Mechanical Vascular Miscellaneous
-Liver failure
- Anaphylaxis -Pancreatitis
Widespread tissue damage -Vascular abnormalities
-Snake and invertebrate venoms
Following surgery or trauma. Kasabach–Merritt syndrome
-Hypothermia
-Incompatible blood transfusion After severe burns
-Leaking prosthetic valves
-Heat stroke
-Cardiac bypass surgery
-Acute hypoxia
-Vascular aneurysms
-Massive blood loss
| Clinical manifestation of DIC
Acute DIC Chronic DIC

➔ The haemorrhagic manifestations ➔ the haemorrhagic tendency may be mild or moderate

may be so severe as to lead to death ➔ Some patients with chronic DIC are asymptomatic because
the activation of the clotting and fibrinolytic systems is
finely balanced and the production of clotting factors and
platelets is sufficiently increased to compensate for their
increased consumption.

1-The platelet count is low

2-Fibrinogen concentration is low Treatment is aimed at preventing further
3-High levels of fibrin degradation coagulation by removal of the initiating cause
Diagnosis products ( D‐dimers)
Treatment
4-The PT and APTT are prolonged Supported with transfusions of blood,
5-RBCs fragments in blood smear. fresh-frozen plasma and platelet concentrates
in order to restore blood volume and replace
-Compensation by the liver may render clotting factors and platelets.
some of the coagulation tests normal.
| Acquired haemophilia
➔ Acquired hemophilia is a rare but life-threatening condition
➔ Caused by the development of autoantibodies (inhibitors) directed against plasma coagulation factors, most
frequently factor VIII (FVIII)
➔ Could be idiopathic or secondary to underlying condition (autoimmune disease, infection, malignancy,…)
➔ More common in the elderly
➔ Treated with ‘bypassing agents’ such as recombinant factor VIIa or FEIBA and immune suppression

| Massive transfusion syndrome

Some protocols include

reduced levels of: Further dilution of these 1 : 1 : 1 for red cells, platelet
-platelets factors occurs packs and FFP
Blood loss -coagulation factors during replacement with red
and inhibitors cells
1-The cause of bleeding disorders is one of these defects: a-vascular
disorder, b-thrombocytopenia, c-problems in platelet function or
1-Bleeding is more commonly caused by Acquired vascular defects
d-coagulation factors (most common cause).
2-In platelets defect we will have: mucocutaneous hemorrhage,
2-this disease leads to abnormal blood vessel formation in the skin, mucous
In coagulation cascade defect we will have: deep joint and deep tissue
membranes, and often in organs such as the lungs, liver, and brain.
hemorrhage
Telangiectasias are small dilated blood vessels that can occur near the surface
3-Prolonged thrombin time is only seen in:
of the skin or mucous membranes.
A- patient taking heparin
3-since collagen is abnormal in this disease , when injury happens platelets
B- defected fibrinogen
wouldn't be able to bind to this abnormal collagen.
4-Normal Coagulation factor activity of factor VIII is about 55
4-an individual having two identical alleles of a particular gene or genes and
5-Hemophilia B is less common than Hemophilia A
so breeding true for the corresponding characteristic.

Dr.
5-is a process by which one of the copies of the X chromosome is inactivated
in female mammals (In this case the normal X is inactivated)

Notes
 Key answers:
| Quiz 1-D 2-C 3-D 4-A 5-B 6-B

1-Hemophilia B caused by deficiency of factor: 3-Which of these findings is related with hemophilia 5-Where is factor IX gene located?
A?
A. VI A. Short arm of chromosome X
B. VII A. Shortened APTT B. Long arm of chromosome X
C. VIII B. Decreased PT C. In both arms of chromosome X
D. IX C. Increased PT D. Has no specific locus
D. Prolonged APTT
2-Factor VIII is found complexed with : 6-The most frequentlY factor involved in Acquired
4-The complete absence of VWF is seen in: hemophilia is:
A. Factor IX
B. Albumin A. Type 3 VWD A. VII
C. VWF B. Type 2 VWD B. VIII
D. Factor X C. Type 1 VWD C. IV
D. None D. X
THANKS | TEAM MEMBERS

● Amirah Alzahrani ● Abdullah Alghamdi

● Deema Almaziad ● Hashem Bassam
| TEAM LEADERS ● Jude Alotaibi ● Mashal Abaalkhail
● Njoud Almutairi ● Moath Aljehani
| Abdulaziz Alghamdi ● Nouf Albraikan ● Mohammed Alasmari
● Mohammed H.Alshehri
● Noura Almazroa Mohammed Alkhamees
| Elaf Almusahel
●
● Razan Alzohaifi ● Mohammed Alshalan
● Rema Almutawa ● Naif Alsolais
● Renad Alhaqbani ● Raed Alojayri
● Renad Almutawa ● Saud Bin Queid
● Wejdan Alnufaie
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