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Hemostasis and Bleeding disorders
Haemostasis: is the physiological arrest of hemorrhage at sites of vascular leakage
There are mainly 5 systems which interact together to ensure hemostasis :
1- Platelets .
2- Coagulation Factors .
3- Natural Coagulation inhibitors .
4- Fibrinolytic system .
5- Vascular factors
.
Response to vascular injury
1.Vasoconstriction.
2.Primary hemostasis (platelet reactions and primary hemostasis plug formation),
unstable plug, within few first minute, temporal control .
3.Secondary hemostasis (stabilization of platelets plug by fibrin) fibrin formation by
coagulation factors, within several min .
Coagulation laboratory
Investigation of bleeding tendency cases depending on:
- bleeding history, family history, drug history, and
- physical examination .
- first line investigations (Blood count and blood film examination, Platelets,
beeding time BT, PT, PTT, TT)
- second line investigation accordingly.
Notes:
❖ Platelets count (Normal range 150 000 – 450 000/cmm): a reduced platelets count
is associated with increased liability to bleeding .
❖ A Bleeding time BT : is prolonged if there is reduced platelets count or platelets
dysfunction, or if there is a vascular defect .
❖ Prothrombin Time (PT): this is a test which tests the extrinsic and the common
pathway of the coagulation, normal range is 13-15 sec.
❖ Activated Partial Thromboplastine Time (APTT): This test is used to test for
intrinsic and the common pathway, normal range is 24-38 sec.
❖ Thrombin time: this tests the last step in the coagulation pathway i.e. the
conversion of Fibrinogen (factor I) to fibrin .
د.لقاء محمد مجيد الشريفي
M.B.C.H/F.I .C.M
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Classification of bleeding disorders
1. Platelets disorders: reduction in platelets count (Thromocytopenia) or
dysfunction
2. Coagulation factors disorders: inherited or acquired coagulation factors
deficiency or dysfunction
3. Vascular Purpura: Inherited or acquired
Platelets disorders
Abnormal bleeding associated with platelets disorders is characterize by bleeding from
skin, mucous membrane, post-traumatic
Platelets disorders include:
1. Thromocytopenias (TCP)
2. Thrombocytopathies
1)
Thrombocytopenias (TCP)
I) Reduced production of platelets
- Congenital TCP: e.g. Thrombocytopenia-absent radius syndrome
(TAR syndrome) , Congenital amegakaryocytic thrombocytopenia
syndrome (CAMT syndrome), Wiskott–Aldrich syndrome (WAS)
- Acquired TCP secondary to drugs, chemicals, viral infections
- Acquired TCP as part of BM (Bone marrow) failure: acute leukaemia,
aplastic anemia (AA), Cytotoxic drugs, Marrow infiltration by
malignant disease, Myelofibrosis
II) Increased platelets consumption
• Immune mediated:
- Autoimmune Thrombocytopenic Purpura (AITP)
- Alloimmune thrombocytopenia (NAIT {neonatal alloimmune TCP},
PTP {Post transfusion purpura})
- Drug induced
- Infection induce
• Non immune: DIC, TTP {Thrombotic thrombocytopenic
purpura},HUS{Hemolytic uremic syndrome}, Pre-eclampsia, HELLP
syndrome
III) Abnormal distribution: Hypersplenism
IV) Delusional loss: massive transfusion
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Autoimmune Thrombocytopenic Purpura (ITP)
A relatively common hematological disorder, the main feature of which is bleeding
tendency due to immune thrombocytopenia, and could be classified into:
1. Idiopathic thrombocytopenic purpura: a chronic autoimmune thrombocytopenia,
young adults, without precedent or associated illness.
2. Secondary autoimmune thrombocytopenia: resembles ITP clinically, but
associated autoimmune disorder, or malignancy .
3. Acute Post-viral auto-immune thrombocytopenia: acute usually self-limiting
thrombocytopenic purpura, typically seen in children following acute viral
infection or immunization .
Clinically:
usually with purpura overall the body, may be dry or wet purpura.
Pathogenesis:
Triggering factors induce autoAb production (usually IgG) against GP2b3a or lb.
Removal of platelets by Macrophages of reticuloendothelial mainly in the spleen.
Lifespan of platelets reduce to few hrs. Spleen consider site of destruction and site of
Ab production. In acute ITP in children Ab usually of IgM type.
Haematological findings :
-Blood Picture showing isolated thrombocytopenia (10- 50x10
9
/L), anemia may develop
secondary to bleedingand sometime Evan's syndrome occur in association with
autoimmune hemolytic anemia (AIHA) .
-Findings of associated disease.
-Bone marrow: usually normal cellularity. Increased or normal number of
megakaryocytes .
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Neonatal alloimmune TCP (NAITCP)
Allo-Ab mainly Anti TIPA-la formed in mother due to incompatibility for HPA between
mother and baby, leading to TCP in fetus .Affected 1st baby.
Neonate showing isolated TCP with bleeding manifestation and normal well
motherDiagnosis made by demonstration of maternal platelets alloAb and demonstrate
incompatibility between mother and father for HPA-1a.
Post transfusion purpura (PTP)
Uncommon, serious, sever TCP, sudden, occur after 7- 10 days of transfusion.
Patient is HPA-la negative and formed anti HPAla Ab against transfused platelets HPA-
1a, forming complex that adsorbed on patient platelets causing their destruction.
Drug induce TCP
Many drugs can lead to TCP due to immune mechanism, with platelets usually < 10x
10
9
/L e.g. Quinidine, Quinine, Heparin.
Thrombotic thrombocytopenic purpura (TTP)
Pathogenesis:
congenital or acquired deficiency or dysfunction of enzyme metalloprolease
(ADAMTS-13) which responsible to breakdown HMW (high molecular weight)
multimer of VWF resulting in microthrombous formation in smallblood vessels.
Characteristic signs of the disease are thrombocytopenia, microangiopathic hemolytic
anemia (MAHA), neurological manifestation, fever, mild or no renal manifestation
Lab. findings include TCP, anemia, fragmented RBC, increase retic count, with normal
coagulation tests .Mortality rate up to 90% in untreated cases
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Hemolytic uremic syndrome (HUS)
Pathogenesis:
usually associated with E.coli infection (verotoxin 0157) or other Micro-
Organism(MO)as_shigella.This toxin bind to specific renal cells receptors forming
complex that lead to massive thrombosis in renal microvasculature.
Little or no role of VWF and ADAMTS-13 in HUS.
Familial forms without diarrheal disease may occur ,
Characterize by disease of children, TCP, MAHA, renal impairment, mild or no
neurological manifestation
Lab. findings include TCP, anemia, fragmented RBC, increase retic count, abnormal
renal function, with normal coagulation tests
Prognosis: usually self-limiting , relapse is less, and residual renal dysfunction is
common.
TCP in pregnancy
Second most common hematological abnormality following anemia
Overall incidence is 8%, but decrease to 5.1% if exclude medical and obstetrical
condition ,Causes include: Gestational TCP (75%) ,Hypertensive disorder (21%)
ITP( 3%), Others (1%) .
2)
Platelets dysfunction
Characterize by superficial bleeding with normal platelets count and prolonged BT
Platelets dysfunction may occur at any phase of platelets function which is either due to
hereditary or acquired disorders.
Anti-platelets drugs
Aspirin is the most common type, it irreversibly inhibit cyclo-oxygenase with impair
TXA
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formation .
Dipyridamole inhibit platelets aggregation by blocking reuptake of adenosine.
Clopidogrel inhibit ADP binding to its receptor on platelets.
Abciximab inhibit GP2b3a receptor .
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Others as Antibiotecs, heparin, Dextran, B-blocker
NSAID inhibit cyclo-oxygenase reversibly
Inherited coagulation disorders
Hemophilia A
-Factor VIII, Gene located on long arm of chromosome X.
-Plasma level 50-150% (50-150 u/dl), Plasma half life 10-12 hrs
-Function as cofactor in Tenase complex, synthesis site; mainly from liver, and may be
from lung, spleen and endothelial cells.
Prevalence and Genetic basis
-Most common hereditary clotting factor deficiencies,incidence is (1:10 000) male
birth., life expectancy is now approaching normal .
-A sex linked inherited disorder due to deficiency of factor VIII .
-
Positive family history in 70% of cases and in 30% is due to new mutation .
-The defect is absence or reduce level of factor VIII .
- Carrier of hemophilia A are females with average 50% of plasma factor level, and 50%
of carriers have low factor level. Variable levels in female according to random
inactivation of X chromosome (lionization) .
Clinical features
-
Males are affected. Female can be affected, but usually carrier .
-
Features start usually when the infant starts to crawl, or even during labor or
circumcision.
-
One of the main features is Haemoarthrosis into the bearing joints with subsequent
target joint formation.Other common feature is bleeding into the muscles .
- Painless spontaneous hematuria, gastrointestinal bleeding, CNS bleeding, post
operative hemorrhage , post dental extraction hemorrhage .
-The most impressive feature in hemophilia is not the rate of hemorrhage but its
persistency. The clot is bulk, friable, and break off with rebleeding over days or week .
Correlation of coagulation factor level and severity of disease :
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-Mild Hemophilia A ------------ Level 6-30 U/dl.(post traumatic hemorrhage)
-Moderate Hemophilia A ------------ Level 1-5 U/dl( .)post traumatic and occasional
spontaneous)
-Sever Hemophilia A ------------ Level <1 U/dl.(frequent spontaneous hemorrhage and
joint deformity (
Laboratory findings
-All screenings test (platelets count, bleeding time, PT, TT) are normal except prolonged
APTT .
-Corrected APTT with normal plasma, but not corrected with factor VIII deficient
plasma. ie:
-Normal plasma + Patient Plasma = Normal APTT.
- Factor VIII deficient plasma + Patient plasma (VIII deficient)= Prolonged APTT.
-Factor VIII assay showing reduced Factor VIII concentration .
-Antenatal diagnosis using DNA techniques to chorionic villous biopsy at 8-10 wk or
detection of factor level using fetal blood sampling at 16-20 wk
.
Hemophilia B Factor IX deficiency
Inheritance and clinical features same to hemophilia A
Principle of replacement therapy similar to Hemophilia A, and bleeding treated with F9
concentrate but the dose given single daily due to its longer half life.
Lab findings
Prolonged APTT, which is corrected with normal plasma but not corrected with factor
IX deficient plasma. Ie
- Normal Plasma + Patient Plasma = Normal APTT.
- Factor VIII deficient plasma+ Patient plasma( IX deficient) = Normal APTT
- Factor IX deficient plasma+ Patient plasma (IX deficient) = Prolonged APTT.
- Then measure the concentration of factor IX.
VonWillebrand’s Disease
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-VWF (Von Willebrand’s Factor),Gene located on chromosome 12 .
-Functions are carrier protein of Factor VIII (carrier and protection) and Platelets
adhesion to subendothelium .
-Plasma level 50-150%,Variable half life.Synthesis site; vascular endothelial cells and
Megakaryocytes .
-There are small, intermediate and large MW multimers of VWF with special flanking
bands.Ultra large VWF multimer after secretion is rapidly cleaved by metalloproteinase
(ADAMTS-13).
Prevalence and Genetic basis
-Most common hereditary bleeding disorders.Prevalence is 0.8
.%
-
The defect is absence, reduction or dysfunction in VWF due to point mutation or major
deletion.Majority is AD and rarely AR disease.
Clinical features :
Mucous membrane bleeding, particularly epistaxis and menorrhagia .
Bruising and bleeding after trauma or during surgery are also common .
Haemarthrosis and muscle hematoma are rare except in type 3 .
Classification of VWD :
Type I (75%) Quantitative / Mild deficiency in VWF.
Type III (rare) Quantitative / Absent in VWF.
Type II (15-20%) Qualitative / Dysfunction in VWF.
IIA: absent of high and intermediate multimers
IIB: increase affinity of GPIb for platelets (mutation in GPIb (
IIM: loss of platelets binding activity (mutation in GPIb (
IIN: decrease in F8 binding capacity.
Diagnosis of VWD :
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-
Prolonged Activated Partial thromboplastin time (APTT).
-
Bleeding time classically prolonged .
-
Platelets count normal except in type 2B with low count .
- VWF Ag is reduced.
Acquierd Coagulation Factors Deficiency
Many causes can lead lo acquired coagulation factors deficiency such as:
-DIC
-Vitamin K deficiency
-Liver, renal disease
-Massive transfusion syndrome
-Cardiopulmonary by-pass surgery
-Drugs as anticoagulant, antiplatelets, colloids
-Others: paraproteinemia, hypothermia
DIC (Disseminated Intravascular coagulation):
Definition: widespread intravascular deposition of fibrin with consumption of
coagulation factors and platelets occurs as a consequence of many disorders with
release of pro-coagulant materials into the circulation or widespread endothelial damage
or platelets activation.Either of acute or chronic forms .
Causes:
-Infections: Gram –ve and clostridia septicemia, malaria, viral
-Malignancy: Acute promyelocytic leukemia M3 , disseminated mucin secreting
adenocarcinoma
-Obstetric complications: septic abortion, Abruptio placenta, Placenta previa,
eclampsia, amniotic fluid embolism.
-Widespread tissue trauma: surgery, trauma, burn
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-Hypersensetivity reaction: anaphylaxis, incompatible blood transfusion .
-Vascular abnormalities: cardiac by-pass surgery, Kasabach-Merritt syndrome .
-Others; liver failure, snake venom, hypothermia, heat stroke, acute hypoxia, sever
pancreatitis, pulmonary embolism .
Pathogenesis :
Triggering factors :
*Entering of pro-coagulant materials to circulation (as AML-M3, venom, amniotic
fluid, mucin secreting CA, hypersensitivity reaction) all are associated with increased
activity of TF .
*Release of tissue thrompoblastins into the circulation (as in M3, tissue damage, from
malignant cells, hypersensitivity reaction) .
*Widespread endothelial damage (as in sepsis, burn, hypothermia (.
Clinical features :
Clinical features of underlining disease.Bleeding manifestation (90%) usually mucosal
oozing, GI bleeding, surgical site bleeding .
Thrombotic manifestation (10%) skin lesion, renal failure, gangrene, CNS ischemia .
Acute renal failure from hypovolemia or fibrin deposition, End organ damage
Mortality 30-85%
Lab.findings :
-Anemia with fragmented RBC on blood film (microangiopathic hemolytic anemia) .
- Thrombocytopenia
-Prolonged PT, APTT, TT .
-Low fibrinogen level
-Increase FDP as D-dimer .
Vitamin K deficiency:
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Vitamin K is fat soluble vitamin absorbed in upper small intestine in presence of bile,
and store in liver in only small amount sufficient for few days in deficiency state .
Function: is important cofactor in gamma-carboxylation of glutamic acid residues (Glu)
on coagulation factors 10,9,7,2 with Protein C and Protein S into Gamma-carboxylated
glutamic acid (GLA)
Causes of Vit K deficiency :
-Hemorrhagic disease of newborn .
-Malabsorption: cholestatic disease, Coeliac disease, bowel resection and others .
-Dietary deficiency: poor nutrition, anorexia.
-Sterilization of bowel by broad specrumAb (unclear mechanism) .
-Vitamine K antagonist: warfarin
Hemorrhagic disease of newborn:Newborn is prone to vitamin K deficiency due to :
-Low exchange through placenta .
-Store in the form of K1 of rapid turnover. And there is No gut flora .
-Breast milk of low vitamin contains .
-Liver immaturity .
Clinical Finding : Intracranial hemorrhage, gastrointestinal bleeding, umbilical cord
bleeding .
Forms of disease :
-Early HDN: at 24 hrs due to maternal ingestion of antagonist .
-Classical HDN: usually 1-7 days when vit K prophylaxis not given .
-Late HDN: occur at 2-12 wks, in those not receive prophylaxis and those with
cholestatic liver disease, cystic fibrosis .
Lab. findings :
-Prolonged PT and APTT .Normal TT, Fibrinogen and platelets count .
-Low factors 10,9,7,2 , Low PC, PS.
Liver disease
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Liver synthesis all coagulation factors except VWF, in addition to Antithrombin, Protein
C, Protein S.Hemostatic changes in liver disease may attributed to :
Clotting factors deficiency: vitamin K dependant factors (10,9,7,2) in addition to F5,
will reduce in acute liver disease. So there is prolongation in PT and APTT.In chronic
liver disease there is deficiency in 10,9,7,2, with F5, and some patient may develop
dysfibrinogenemia, while fibrinogen reduce only in end stage liver disease. So there is
prolongation in PT, APTT and then in TT.Thrombocytopenia (low Thrombopoietine
and hypersplenism) and platelets dysfunction.