This lecture is prepared for postgraduate students in Internal medicine. It presents a physiologic and basic background of the process of homeostasis followed by a practical approach to diagnosis and brief information of different causes of bleeding disorders
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Platelet and coagulation post graduate lecture
1. Platelets & Coagulation:
Bleeding Disorders
Dr. Monkez M Yousif
Professor of Internal Medicine
Faculty of Medicine
Zagazig University
2018
2. Case Study-Presentation
ï” 18 year old male presented to the ED after 3 weeks of
nosebleeds and increasing levels of severe fatigue.
ï” No medical history, born at term, all developmental
milestones achieved.
ï” No family history of bleeding or thrombosis.
ï” No medications, denies recreational drugs/alcohol.
ï” Physical exam finds blood clots in both nostrils and
petechial hemorrhages in mouth and lower extremities.
ï” Bleeding subsided but lab results were monitored closely
during hospitalization while blood products were
administered.
7. HEMOSTASIS
ï”Primary Hemostasis
â Blood vessel contraction
â Platelet Plug Formation
ï”Secondary Hemostasis
â Activation of Clotting Cascade
â Deposition & Stabilization of Fibrin
ï”Tertiary Hemostasis
â Dissolution of Fibrin Clot
â Dependent on Plasminogen Activation
8. Process- primary hemostasis
ï”Platelets immediately form a hemostatic plug at the
site of injury. This is called primary hemostasis.
ï”In a normal individual, coagulation is initiated within
20 seconds after an injury occurs to the blood vessel
damaging the endothelial cell.
10. a TPO binds to the MPL receptor on the surface of
megakaryocytes and platelets and is not recycled.
b The regulation of platelet production through hepatic clearance
of deâsialylated platelets which attach to the AshwellâMorell
hepatic receptor. This initiates a signal via JAK2 for further
thrombopoietin (TPO) and hence platelet production. GAL,
galactose.
17. Secondary hemostasis
ï” Secondary hemostasis then followsâplasma components
called coagulation factors respond (in a complex cascade) to
form fibrin strands which strengthen the platelet plug.
ï” Coagulation is initiated by platelets adhering to and
activated by collagen in the blood vessel endothelium.
ï” The activated platelets then release the contents of their
granules, these contain a variety of substances that stimulate
further platelet activation and enhance the hemostatic process.
18. Coagulation cascade
ï” The coagulation cascade of secondary hemostasis has two
pathways, the Contact Activation pathway (formerly
known as the Intrinsic Pathway)
ï” And the Tissue Factor pathway (formerly known as the
Extrinsic pathway) that lead to fibrin formation.
Responsible for initiation of blood coagulation.
19.
20. XIIa
Coagulation cascade
IIa
Intrinsic system (surface contact)
XII
XI XIa
Tissue Factor
IX IXa VIIa VII
VIII VIIIa
Extrinsic system (tissue damage)
X
V Va
II
Fibrinogen Fibrin
(Thrombin)IIa
Vitamin K dependant factors
Xa
Ca+ Pl (Tenase )
Ca+ Pl (Prothrombinase)
PC PS
21. The actions of thrombin in the coagulation pathway. It
also activates platelets and inflammation
30. Diagnosis of Bleeding Disorders
Laboratory testing
Physical examination
Bleeding history
31. Bleeding history: what to look for ?
ï”Frequency of bleeding
ï”Severity of bleeding
ï”Sites of bleeding
ï”Age of appearance
ï”Positive family history
ï”Surgical and post-operative bleeding (early vs.
late bleeding)
ï”Spontaneous or after trauma (post partum)
50. Laboratory Evaluation of Bleeding
Overview
CBC and smear Platelet count Thrombocytopenia
RBC and platelet morphology TTP, DIC, etc.
Coagulation PT Extrinsic/common pathways
APTT Intrinsic/common pathways
Coagulation factor assays Specific factor deficiencies
50:50 mix Inhibitors (e.g., antibodies)
Fibrinogen assay Decreased fibrinogen
TT Qualitative/quantitative
fibrinogen defects
FDPs or D-dimer Fibrinolysis (DIC)
Platelet function von Willebrand factor vWD
Bleeding time In vivo test (non-specific)
Platelet function tests Qualitative platelet disorders
51. Assessment of Primary Hemostasis
Platelets in circulation
ï¶ 150,000 to 450,000 cells/mm3
ï¶ 70% in circulation; 30% in spleen
ï¶ Life span ~ 7 to 10 days
ï¶ Removed by reticuloendothelial system : liver, spleen
52. Platelet count Symptoms
50-100,000 Prolonged bleeding following trauma
< 50,000 Easy bruising
Purpura following minor trauma
< 20,000 Spontaneous bleeding
Petechiae
May suffer spontaneous internal and
intracranial bleeding
Thrombocytopenia
55. Classification of platelet disorders
ï” Quantitative disorders
â Failure of platelet production
â Increased consumption
â Abnormal distribution
â Dilutional loss
ï” Qualitative disorders
â Inherited disorders (rare)
â Acquired disorders
» Medications
» Chronic renal failure
» Cardiopulmonary bypass
56. Causes of thrombocytopenia
I. Failure of platelet production
A. Selective megakaryocyte
depression
â Rare congenital defects
â Drugs, chemicals, viral infections
B. Part of general bone marrow
failure
â Cytotoxic drugs
â Radiotherapy
â Aplastic anemia
â Leukemia
â Myelodysplastic syndromes
â Myelofibrosis
â Marrow infiltration (e.g. carcinoma,
lymphoma, Gaucherâs disease)
â Multiple myeloma
â Megaloblastic anemia
â HIV infection
II. Increased consumption of platelets
A. Immune
â Autoimmune
â Idiopathic (ITP)
â Associated with SLE,
â CLL or lymphoma;
â Infections: Helicobacter pylori, HIV,
other viruses, malaria
â Drugâinduced, e.g. heparin
â Postâtransfusional purpura
â Fetoâmaternal alloimmune
thrombocytopenia
B. DIC
C. TTP
III. Abnormal distribution of platelets
â Splenomegaly (e.g. liver disease)
IV. Dilutional loss
â Massive transfusion of stored blood
57. Thrombocytopenia as a result of drug or toxin
Bone marrow suppression
ï” Predictable (doseârelated)
â ionizing radiation,
cytotoxic drugs, ethanol
ï” Occasional
â chloramphenicol,
coâtrimoxazole,
penicillamine,
â organic arsenicals,
benzene, etc.
Immune mechanisms
ï” Analgesics, antiâinflammatory drugs
â gold salts
ï” Antimicrobials
â penicillins, rifamycin, sulphonamides,
trimethoprim, paraaminosalicylate
ï” Sedatives, anticonvulsants
â diazepam, sodium valproate, carbamazepine
ï” Diuretics
â acetazolamide, chlorathiazides, furosemide
ï” Antidiabetics
â chlorpropamide, tolbutamide
ï” Others
â digitoxin, heparin, methyldopa, quinine, quinidine
58. Features of Acute and Chronic ITP
Features Acute ITP Chronic ITP
Peak age Children (2-6 yrs) Adults (20-40 yrs)
Female: male 1:1 3:1
Antecedent infection Common Rare
Onset of symptoms Abrupt Abrupt-indolent
Platelet count at presentation <20,000 <50,000
Duration 2-6 weeks Long-term
Spontaneous remission Common Uncommon
59. Initial Treatment of ITP
Platelet count Symptoms Treatment
(per ”l)
>50,000 None
20-50,000 Not bleeding None
Bleeding Glucocorticoids
IVIG
<20,000 Not bleeding Glucocorticoids
Bleeding Glucocorticoids
IVIG
Hospitalization
61. TTP
a Platelet thrombus in a
small cardiac vessel with
minor endothelial and
inflammatory reaction.
b Peripheral blood film
showing red cell
fragmentation.
62. The platelet distribution between the circulation and
spleen in normal individuals (left), and in patients with
moderate or massive splenomegaly (right).
63. Intrinsic pathway abnormalities
Hemophilia A (FVIII)
Hemophilia B (FIX)
severe FXI def.
severe (type 3) VWD
BLEED ING
Contact factor def.
Inhibitors
Heparins
mild coagulation factor def.
N ON BLEED ING
PT - normal
PTT abnormal
platelets - normal
FXII, PK, HMWK
66. Coagulation disorders
ï” Hereditary coagulation disorders
â Hemophilia A
â Factor IX deficiency
â Von Willebrand disease
â Hereditary deficiency of other coagulation factors
ï” Acquired coagulation disorders
â Disseminated intravascular coagulation
â Massive transfusion
67. A typical family tree in a
family with hemophilia.
Note the variable levels
of factor VIII activity in
carriers (*) because of
random inactivation of
X chromosome
(Lyonization). The
percentages show the
degree of factor VIII
activity as a percentage
of normal.
68. Hemophilia A: acute
hemarthrosis of the right knee
joint with swelling of the
suprapatellar region. There is
wasting of the quadriceps
muscles, particularly on the left.
Hemophilia A showing severe disability. The
left knee is swollen with posterior
subluxation of the tibia on the femur. The
ankles and feet show residual deformities of
talipes equinus, with some cavus and
associated toe clawing. There is generalized
muscle wasting. The scar on the medial side
of the left lower thigh is the site of a
previously excised pseudotumour.
69. (a) Hemophilia A: massive hemorrhage in the area of the right
buttock. (b) 15âyearâold boy with sudden left hip pain and
hemophilia A. Magnetic resonance imaging (MRI) axial image,
T2âweighted, revealing large left spontaneous hematoma (yellow
arrow) in left gluteus maximus muscle compared with normal right
side (red cross).
70. Hemophilia A:
Xâray of the
knee joints
shows
destruction
and narrowing
of the left joint
space.
72. vonWillebrand Disease
von Willebrand factor
Synthesis:
In vascular endothelium and megakaryocytes
Function:
ï¶Carrier of factor VIII
ï¶Anchors platelets to subendothelium
ï¶Bridge between platelets
73. VWF VWF VWF VWF
VIII
t1/2 = 12-20 h
Normal Blood Clotting
Normal level of VIII
t1/2 †2 h
Bleeding
VIII
†10% of normal VIII
VWF and Factor VIII Survival
74. Von Willebrand Disease
Clinical Features:
â Prevalence â 100 per million
â Female : male â 2:1
â Bleeding of platelet dysfunction and/or FVIII
deficiency
75. Laboratory evaluation of VWD
Classification (major types):
â Type 1, partial quantitative deficiency (â70%)
â Type 2, qualitative abnormalities (â 25%)
â Type 3, complete deficiency (< 5%)
Diagnostic tests:
vonWillebrand type
Assay 1 2 3
vWF antigen ï Normal ïï
vWF activity ï ï ïï
Multimer analysis Normal Normal Absent
76. Laboratory Tests in VWD
âą VWF Antigen (VWF: Ag)
âą Ristocetin Cofactor Activity (VWF: RCo)
âą Factor VIII (FVIII: Ag or FVIII:C)
77. Treatment of VWD
1) DDAVP (Desmopressin)
Vasopressin analog with no vasoconstrictive activity
âą Releases intracellular VWF and factor VIII
âą Effective for type 1
2) Factor VIII/VWF Complex
âą Cryoprecipitate: Unacceptable infection risk
âą Factor VIII/VWF concentrates: Low infection risk
3) Purified Factor VIII
âą Plasma or Recombinant: Cannot stabilize factor VIII. Inappropriate
78. Main clinical and laboratory findings in hemophilia A, factor
IX deficiency (hemophilia B, Christmas disease) and vWD
79. The acquired coagulation disorders
Deficiency of vitamin Kâdependent factors
âHemorrhagic disease of the newborn
â Biliary obstruction
â Malabsorption of vitamin K (e.g. tropical sprue, gluten-induced
enteropathy)
â Vitamin Kâantagonist therapy (e.g. coumarins, indandiones)
â Liver disease â complex dysregulation with synthetic failure of
proâ and anticoagulant factors
â DICâ consumption of all clotting factors
and platelets
Inhibition of coagulation
â Specific inhibitors (e.g. antibodies against factor VIII)
â Nonâspecific inhibitors (e.g. antibodies found in SLE, RA which
paradoxically cause thrombosis)
Miscellaneous
âDiseases with Mâprotein production that interfere with hemostasis
âTherapy with heparin, defibrinating agents or thrombolytics
80. The action of vitamin K in Îłâcarboxylation of glutamic acid in
coagulation factors which are then able to bind Ca2+ and attach to the
platelet phospholipid. Warfarin inhibits vitamin K reductase. It is
metabolized in the liver and genetic variations in the reductase enzyme
VKORCâ1 and in the cytochrome CYP2C9 largely account for wide
variations in warfarin sensitivity of individuals.
82. Disseminated intravascular coagulation
ï Systemic thrombo-hemorrhagic disorder
ï Characteristic features:
â Activation of coagulation system
â Defective fibrinolytic system
â Consumption of clotting factors
â Consumption of natural inhibitors
â Tthrombocytopenia
83. Disseminated intravascular coagulation:
characteristics
ï”Widespread activation of coagulation
ïź intravascular formation of fibrin
ïź thrombotic occlusion of small vessels
ïź contributes to multiple organ failure in conjunction
with hemodynamic and metabolic consequences
ï”Depletion of platelets and clotting factors
ïź severe bleeding
84. Systemic activation of coagulation
Intravascular
deposition of fibrin
Depletion of platelets
and coagulation factors
Thrombosis of small
and midsize vessels
and organ failure
Bleeding
90. DIC and Infectious Disease
ï Severe sepsis is the most common clinical
condition associated with DIC
ï Bacterial infection
ï Occurs in 30 - 50% of Gram -ve sepsis
â Lipopolysaccharide (endotoxin)
ï Gram positive sepsis
â exotoxin (e.g. staphylococcal a-hemolysin)
91. DIC and severe trauma
ï Especially seen after brain trauma
â release of fat and phospholipid
ï Cytokine activation
â similar pattern to severe sepsis
ï âSystemic inflammatory response syndromeâ
after trauma
â 50 - 70% associated with DIC
92. DIC and Cancer
ï Solid tumors
â metastatic cancer 10 - 15%
ï Hematological cancer
â acute leukemia 15%
ï Acute promyelocytic leukemia
â DIC and hyperfibrinolytic state
93. DIC and Obstetrical Disorders
ï Abruptio placentae,
ï amniotic fluid embolism,
ï fetal death in utero,
ï septic abortion,
ï pre-eclampsia
oRelease of thromboplastin-like material
oUsually short-lived and self-limiting
94. DIC and Giant Hemangioma
ï Local activation of coagulation system ïź
systemic depletion of locally consumed
clotting factors and platelets
ï Activated coagulation factors ïź reach
systemic circulation ïź DIC
95. Microangiopathic hemolytic anemia
ï Peripheral blood picture:
â Anemia
â Thrombocytopenia
â Fragmented red cells (schistocytes)
ï A feature common to several conditions:
â DIC
â Thrombotic thrombocytopenic purpura
â Hemolytic Uremic Syndrome
97. Pathogenesis of DIC
ï Increased thrombin generation
ï Depression of physiologic anticoagulation
mechanism
ï Delayed removal of fibrin due to impaired
fibrinolysis
102. Diagnosis of DIC
ï Clinical setting
ï Laboratory tests
ï Criteria
â Underlying disease known to be associated
â Initial platelet count < 100 X 109/L, or rapid decline in platelet
count
â Prolongation of clotting times (PT & APTT)
â Presence of fibrin degradation products
â Low levels of coagulation inhibitors (e.g. antithrombin)
â Low fibrinogen level in severe cases
105. Clinical features of disseminated intravascular coagulation:
(a)Indurated and confluent purpura of the arm;
(b)Peripheral gangrene with swelling and discoloration of the skin of
the feet in fulminant disease.
106. Disseminated intravascular coagulation
ï Laboratory results:
â Prolonged PT, APTT and TT
â Reduced fibrinogen level
â Increased D-Dimers
â Thrombocytopenia
â Microangiopathic changes in blood film
108. Management of DIC
ï Treatment of underlying disorder
ï Anticoagulants
â low dose heparin
â low molecular weight heparin
â new thrombin inhibitors (ATIII independent)
â useful for clinically overt thromboembolism or
extensive deposition of fibrin
109. Management of DIC
ï Platelets and Plasma
â to treat bleeding tendency
â to cover an invasive procedure for patients with a high
risk of bleeding
ï Clotting factor concentrates
â overcomes large volumes of plasma
â but not advocated because: 1) contains small amount
of activated factors, and 2) DIC results in deficiency
of multiple factors
110. Concentrates of coagulation inhibitors
ï Antithrombin concentrate
â reduces sepsis related mortality
â improvement of DIC and organ function
ï Supportive therapeutic option in severe DIC
111. Antifibrinolytic agents
ï Generally not recommended
â fibrinolysis is already impaired in DIC
â may enhance fibrin deposition
ï For bleeding in DIC associated with primary or
secondary hyperfibrinolysis
â e.g. acute promyelocytic leukaemia
112. New therapeutic options
ï Nematode anticoagulant protein c2
â specific inhibitor of tissue factor-VIIa-Xa complex
ï Recombinant TFPI
ï Protein C concentrate
113. Hemostasis tests: typical results in acquired bleeding
disorders.
TTAPTTPTPlatelet count
Normal (Rarely
prolonged
ProlongedProlongedLowLiver Disease
Grossly
prolonged
ProlongedProlongedLowDIC
NormalProlongedProlongedLow
Massive
transfusion
NormalProlongedGrossly ProlongedNormal
Coumarin
anticoagulants
ProlongedProlongedMildly Prolonged
Normal
(Rarely low)
Heparin
NormalProlonged
Normal or
prolonged
Normal
Circulating
anticoagulant
114. Everything is OK
FXIII def.
Alpha 2 antiplasmin def.
D ysfibrinigenemia
Bleeding time
NORMAL
Hereditary or acquired platelet defect
mild VWD
Bleeding time
ABNORMAL
PT - normal
PTT - normal
platelets - normal
Abnormal vascular integrity
115. Hereditary Hemorrhagic Telangiectasia
(Osler-Weber-Rendu)
ï” AD disorder
ï” Pathogenesis â Defect in development of some blood
vessels (venules &arterioles), forming:
- telangiectases
- arteriovenous malformations or fistulas (AVM /
AVF)
- other vascular lesions
ï” Clinical: Telangiectasia of the nose, face, skin, lung,
brain, GIT leading to bleeding
ï” Coagulation tests â normal
ï” Treatment: Hexacaprone (Tranexamic acid)
118. Senile purpura
ï”Very common among elderly people
ï”Results from loss of peri-vascular fat and
connective tissue
ï”No treatment
119. Normal phenomena
ï¶Easy bruising â âpurpura simplexâ
ï¶Mainly- young females
ï¶Sometimes â cyclical pattern
ï¶Confined to limbs
ï¶Occasionally painful â âdevilâs pinchâ
ï¶No treatment
120. Case
24 old female complains
about blue marks that
appear on her legs from
time to time.
Diagnosis: Purpura
Simplex
121. Case Study-Presentation
ï” 18 year old male presented to the ED after 3 weeks of
nosebleeds and increasing levels of severe fatigue.
ï” No medical history, born at term, all developmental
milestones achieved.
ï” No family history of bleeding or thrombosis.
ï” No medications, denies recreational drugs/alcohol.
ï” Physical exam finds blood clots in both nostrils and
petechial hemorrhages in mouth and lower extremities.
ï” Bleeding subsided but lab results were monitored closely
during hospitalization while blood products were
administered.
124. Case StudyâDiagnosis and Therapy
ï”reticulocytosis, and increased mean corpuscular
volume (MCV), decreased platelets with increased
mean platelet volume (MPV), numerous
promyelocytes, High D-dimer, with PT/APTT
correcting on mixing study, along with low
fibrinogen indicate disseminated intravascular
coagulation (DIC) secondary to acute myelogenous
leukemia (AML); most likely acute
promyelocyticleukemia (APL).
125. ï”DIC due to TF release by APL blasts.
ï”Molecular studies of PML-retinoic acid receptor-
alpha (RARA) gene fusion was positive; occurs
in >95% of APL cases.
ï”Transfusions to replace factors, along with
platelets and RBCs during APL treatment