Download Dr Mustapha Alfallah – Pediatric Hematologist

Hemostasis
and
Bleeding disorders
Dr Mustapha Alfallah
Pediatric Hematologist-Oncologist
Definitions
• Hemostasis is traditionally defined as a
physiological response to blood vessel injury
and bleeding, which entails a co-ordinated
process involving the blood vessel, platelets,
and blood clotting proteins (i.e. coagulation
factors).
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Hemostasis can be divided into primary and secondary
components.
• The former is characterized by vascular contraction,
platelet adhesion, and formation of a soft aggregate
plug.
• The latter is initiated following the release of tissue
factor and involves a complex sequence of events
known as the blood coagulation cascade,
encompassing serial steps where each coagulation
factor activates another in a chain reaction that
culminates in the conversion of fibrinogen to fibrin.
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Mechanism of Hemostasis
During Hemostasis three steps occur in a rapid sequence.
1. Vascular spasm - Vascular spasm is the blood vessels first response to injury.
2. Platelet plug formation - Platelets adhere to damaged endothelium to form platelet
plug and then degranulate.
As platelets adhere to the collagen fibers of a wound they become spiked and much
stickier. They then release chemical messengers such as adenosine
diphosphate , serotonin and thromboxane A2. These chemicals are released to
cause more platelets to stick to the area and release their contents and enhance
vascular spasms.
The platelet plug formation is activated by the Von Willebrand factor (VWF),
3. Coagulation or blood clotting. Coagulation reinforces the platelet plug with fibrin
threads that act as a “molecular glue”. Once the platelet plug has been formed by
the platelets, the clotting factors begin to form a collagen fiber called fibrin. Once
this begins, red and white blood cells become caught up in the fibrin mesh which
causes the clot to become even stronger
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Number and/or name
Associated genetic disorders
I (fibrinogen)
Congenital afibrinogenemia, Familial renal amyloidosis
II (prothrombin)
Hypoprothrombinemia, Thrombophilia
III Tissue factor
V (proaccelerin, labile factor)
Activated protein C resistance
VII (stable factor, proconvertin)
congenital factor VII deficiency
VIII (Antihemophilic factor A)
Haemophilia A
IX (Antihemophilic factor B or Christmas factor)
Haemophilia B
X (Stuart-Prower factor)
Congenital Factor X deficiency
XI (plasma thromboplastin antecedent)
Haemophilia C
XII (Hageman factor)
Hereditary angioedema type III
XIII (fibrin-stabilizing factor)
von Willebrand factor
von Willebrand disease
Approach
to a patient with
bleeding disorder
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
History.
The clinical history provides the most useful information and should determine
- Site or sites of bleeding,
- Severity and duration of hemorrhage,
- Age at symptom onset.
- Was the bleeding spontaneous or after trauma?
- Was there a previous personal or family history of similar problems
- If there has been previous surgery or significant dental procedures, or
circumcision,
- Delayed or slow healing of superficial injuries may suggest a hereditary
bleeding disorder.
- In postpubertal females, it is important to take a careful menstrual history..
- Medications such as aspirin and other nonsteroidal anti-inflammatory.
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Physical Examination
• The physical examination should focus on whether symptoms
are primarily associated with the mucous membranes or skin
(mucocutaneous bleeding) or the muscles and joints (deep
bleeding).
• Patients with defects in platelet/blood vessel wall
interaction usually have mucous membrane bleeding);
petechiae on the skin and mucous membranes; and small,
ecchymotic lesions of the skin
• Individuals with a clotting factor deficiency have symptoms
of deep bleeding into muscles and joints with much more
extensive ecchymoses and hematoma formation.
• Patients with mild bleeding disorders may have no abnormal
findings on physical examination.
Laboratory Tests
First step evaluation
Platelet count,
Bleeding time,
The bleeding time assesses the function of platelets and their interaction with the vascular wall.
PLATELET FUNCTION ANALYZER.
PTT, and PT.
ACTIVATED" PARTIAL THROMBOPLASTIN TIME (PTT) measures the intrinsic clotting system
PROTHROMBIN TIME (PT) measures the extrinsic clotting system
The PT has been standardized using the International Normalized Ratio (INR) so that values can
be compared from one laboratory or instrument to another.
Thrombin Time (TT) detects the rate of fibrin clot formation after a fixed concentration of
thrombin is added to a sample,
CLOTTING FACTOR ASSAYS.
For most clotting factors the normal range is between 50-150 U/dL (50-150%).
PLATELET AGGREGATION. When a qualitative platelet function defect is suspected,
platelet aggregation testing is usually ordered.
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Defects in Primary Homeostasis
A) Vascular phase :Ex:Henoch Schonlein purpura
B) Platelets phase:
-Quantitative abnormalities of platelets (Thrombocytopenia) Ex I.T.P
-Qualitative abnormalities of platelets (Thrombopathies)
Ex:Glanzmann thromboasthenia
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Defect Coagulation or Plasma Phase
Ex : Hemophilia
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Henoch Schonlein Purpura
1
Definition
Vascular damage occurs from immune complex
deposition within the blood vessel walls
following a viral or bacterial infection
Peak age 2 - 8 years
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Henoch Schonlein Purpura
2
Clinically : various combinations of symptoms and
signs may occur
1- Skin rash : Maculopapular ,erythematous, and
petechial, over legs buttocks, and arms
2- Migratory arthritis
3- Abdominal pain, diarrhea, and GI bleeding
4- Nephritis (Proteinurea, hematurea, azotemia,
hypertension )
5- Others
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Henoch Schonlein Purpura
3
Laboratory findings show no change with normal
platelet count
Treatment : No specific therapy
: Aspirin for arthritis
: Prednisone for GI manifestations
Prognosis : Usually good (but 50% of patients with
nephritis may have persistent abnormal urinary
findings
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Immune Thrombocytopenic Purpura (I.T.P) 1
-The most common bleeding disorder of childhood
-The most common age of diagnosis is between 2
and 10 years of age, with peak age of 4 – 8 years
• There is an equal incidence of ITP in both males
and females
• -Frequently follows viral infections(rubella,
varicella, rubeola)
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Immune Thrombocytopenic Purpura ( ITP )
Clinically : Usually acute onset with
-Spontaneous small hemorrhages into the skin
and mucous membrane (Petechiæ)
-Echymosis
-Epistaxis
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
2
21
Immune Thrombocytopenic Purpura (ITP)
3
Diagnosis
-Presenting platelet count < 20,000/µL,
- The morphology of platelets is typically normal, with varying numbers of
large platelets reflecting the early release of megakaryocytic fragments
into the circulation.
- The typical finding in the bone marrow of patients with ITP is normal or
elevated number of megakaryocytes.
The most serious complication is intracranial hemorrhage (in less than 1 % )
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Immune Thrombocytopenic Purpura (ITP)
4
Treatment
If mild disease = No treatment
In severe cases =
Prednisone or High dose methyl prednisolone,
IVIG or
Anti-Rh immunoglobulin ("anti-D") Only for Rh positive patients
In chronic cases
= Splenectomy
= immunosuppressive drugs (Vincristine,Azathioprine, Rutiximab?)
Prognosis : Remission in 90% of cases
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Hemophilia
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Definition
Hemophilia is caused by a deficiency of coagulation factor VIII (FVIII)
(hemophilia A) or factor IX (FIX) (hemophilia B)
• No ethnic or geographic predisposition has been defined
• Hemophilia A is more common than hemophilia B, representing 80-85% of
the total
• It is inherited in an X-linked recessive manner meaning that males are
affected and females are carriers (mutations of the clotting factor gene on
X chromosome (FVIII=Xq28) (FIX=Xq27))
• Approximately 30% of cases occur because of spontaneous mutations
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Clinical presentation
Spontaneous and post-traumatic hemarthroses and muscle hematomas are the most
frequent injuries that affect hemophiliac patients
• Hemarthroses most commonly occur in the knees, ankles, and elbows, (bleeding
into the shoulder or hip joint are more rare, spinal and wrist joints are very seldom
affected)
•
Joint becomes stiff, swollen, warm, and tender
•
In acute joint bleeds, once the blood has been reabsorbed and the swelling has
diminished, normal joint mobility and function are restored
•
If repeated bleeding episodes there may be damage to joint component which
lead almost inevitably to severe joint damage and disability
Other sites of bleeding are
•
- mouth, gum, nose
•
- Hematuria
•
- CNS bleeding
•
- GIT bleeding
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Diagnosis
When the diagnosis is suspected from clinical grounds or family history the
laboratory tests will include:
1) Complete Blood Count including Hb level and platelet count, these
parameters are normal in hemophilia (If anemia is not present due to
bleeding)
2) Normal prothrombin time (PT)
3) Prolonged activated Partial Thromboplastin Time (aPTT) however in mild
hemophilia this prolongation may be discrete
4) Factor assays for factor level must be done to differentiate between
hemophilia A and B and to classify the hemophilia according to factor level as
- Severe hemophilia if factor level ……...< 1%
- Moderate hemophilia if factor level …..1-5%
- Mild hemophilia if factor level ………..5-25%
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Treatment (General measures):
-Prevention of trauma
-No IM injection
-Aspirin and other drugs that affect platelets
function must be avoided
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Treatment of acute bleeding
1) Factor Replacement
- Fresh Frozen Plasma (FFP)
- Cryoprecipitate (For hemophilia A only)
- Prothrombin complex concentrates (PCC) for Hemophilia B
- Clotting factor concentrates = Plasma derived or recombinant FVIII or FIX
concentrate
*Factor VIII or IX concentration must be increased to at least 25-30% of normal.
* In the case of severe bleeding, or as cover for surgery, it is necessary to increase the plasma factor
concentration to 100%
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Hemophilia
Replacement therapy for hemophilia A :
Every 1unit / Kg increase factor VIII level in the blood
by about 2 %
Repeated every 8 hours if necessary
Replacement therapy for hemophilia B :
Every 1 IU/kg infused, the plasma level of FIX raise by 11.4 %,
Repeated every 12 hours if necessary
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Treatment of acute bleeding
3) Adjuvant therapy
I) Antifibrinolytic drugs
1) Tranexamic (NA in USA) Cyklokapron®
2) Epsilon Aminocaproic acid (EACA) Amicar ®
II) Fibrin sealants
• Can be used for:
Dental extraction
Bleeding from mucous membranes
Circumcision
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist
Primary prophylactic treatment
Although prophylaxis treatment strategies vary greatly, the typical regimen (Malmö
regimen) requires FVIII infused at a dose of 25-40 IU/Kg three time per week in
hemophilia A and 25-40 IU/Kg twice weekly in hemophilia B
• Today the goal is that the child should be able to live as normal live as possible
• Primary prophylaxis is both very demanding (on patients and families) and
expensive.
Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist