4. Von willebrand factor
• large multimeric glycoprotein -endothelial
cells and megakaryocytes
Storage –weibel-palade bodies[endothelium],
alpha granules[platelets]
Function-
1.carrier for factor VIII[degrades rapidly when
not bound ]
2.Acts as a ligand binds to platelet gpIb
• Cleavage -[ADAMTS13]-upshaw schulman
syndrome
5. PLATELETS
• -Platelets from megakaryocytes ,
- normal – 1.5 to 4.5 lakhs
• life span of 7 to 10 days.
• Thrombopoeitin – liver .
-glycoproteins-
• GpIIb-IIIa –receptor of fibrinogen[glanzmanns
thrombasthenia]
• GpIb-receptor of vWF[bernard-soulier
syndrome]
10. Factors preventing coagulation.
Physiological – anticogulant mechanism-
• Anti-thrombin III-inhibits factor II,X
• Protein C-inactivates factor V,VIII
• Protein S-Cofactor for activated protein C
• Protein Z-degrades factor X
• Tissue Factor Pathway Inhibitor[TFPI]-neutralizes
factor X
• Thrombomodulin-thrombin,once bound to
thrombomodulin ,deactivates it.
11. HOW EXTENSION - CONTROLLED
• A process that solubilises fibrin in the
bloodstream by proteolytic action of plasmin.
• Plasmin is the major fibrinolytic protease
synthesized in liver.
• Plasminogen (PLG), a circulating plasma
zymogen, can be converted to plasmin by
both tissue PLG activator (tPA) as well as by
urokinase (uPA).
14. THROMBOTIC DISORDER
• Inappropriate activation of normal
haemostatic process in uninjured
vasculature or thrombotic occlusion of a
blood vessel after relatively minor injury
15. Disorders of thrombosis
• Risk – genetic and enviromentl factors
• Mc – arterial is atherosclerosis
• Mc – venous – immobility , surgery and
underlying medical condition like malignancy
16.
17.
18. Arterial thrombosis
• Seen in coronary arteries,
circle of Willis, small
arteries of limbs and
digits.
• Common in aorta due to
atherom a or
arteriosclerosis
• Due to high pressure and
rapid flow , these are
often platelet variety .
19. Venous thrombosis
• Common - slower flow, lower pressure with easy
compressibility and eddy formation around valves
• Usually start in the deep veins of the calf, frequently
a propagating thrombus extending in to femoral
and iliac veins.
• Common in patients who are immobilized
20. Sites of venous
thrombosis
• Leg veins:immobiliity, post surgery,
hypercoagulability
• Pelvic veins: pueperal sepsis,post
partum, pelvic surgery,
• IVC: Tumour, extension from leg
• Renal vein: Tumour compression
• Portal/hepatic vein: Local sepsis,
tumour
• Cavernous sinus: Facial sepsis
• SVC:Mediastinal tumour
• Axillary vein: Rucksac, surgery
21.
22. Effects of thrombosis
• Arterial:
• Infarction
• Ischaemia
• No effects if there are adequate anastomoses
• Venous:
• Anastomoses developed frequently to by pass the
obstruction
25. Antiphospholipid antibodies
• ABS to phospholipids ( cardiolipin ) or
phospholipidsbinding protein
(b2microglobulin) - detected by ELISA.
• If -interfere with phospholipids dependent
coagulation tests – LUPUS ANTICOAGULANT
• Not only APTT prolongation ( reagent
dependent ) , not corrected after mixing
studies.
26. Patient approach
• History
– major surgical procedures
– Trauma
– Recent hospitalization[within 90 days]
– Pregnancy
– smoking
• Drug history
– Oral contraceptives
– Hormone replacement therapy
27. • History of i.v drug abuse
• Obstetric history- recurrent fetal loss/late fetal
loss
• Family history of venous thrombosis
• History suggestive of malignancy
• Diet history – strict vegetarian –
hyperhomocystinemia .
32. Physical examination
• Homans' test Dorsiflexion of foot elicits pain in
posterior calf. Warning: it must be noted that it is of
little diagnostic value and is theoretically dangerous
because of the possibility of dislodgement of loose
clot.
• Pratt's sign: Squeezing of posterior calf elicits pain.
• Superficial thrombophlebitis:palpable tender,cord
venous segment
• Phlegmasia cerulea dolens/alba dolens
33. Total of Above Score
>3High probability
1 or 2Moderate probability
< 0Low probability
Wells score
34.
35. TREATMENT
• LMW Heparin is usually used as a bridging
agent
• Warfarin start dose is 5mg
• Target INR 2.0-3.0
• Duration:
– Isolated DVT:3 months
– for VTE:3-6 months
– For cancer and VTE:Until the patient is cancer free
36. • Rivaroxoban[factor X inhibitor]:approved as
monotherapy ,without parenteral bridging
anti-coagulant,no need for INR monitoring
start dose:15mg b.d x 3wks followed by
20 mg o.d
• Fondaparinux[anti Xa]:once daily,s.c inj
• Direct thrombin inhibitors:argatroban and
bivalirudin
37. FDP AND D-DIMER
• FDP- ( from breakdown of fibrinogen ).
1. DIC , liver disease , inherited or acquired
disorders of fibrinogen
• D-DIMER ( specific for actual clot ).
1. ongoing thrombosis and fibrinolysis , DIC ,
primary hyperfibrinolysis .
39. 1. Functional deficiency in the procoagulant
mechanism.
a. The platelets and blood vessels
b. The procoagulant plasma components
2. Functional excess in anticoagulant
mechanisms.
a. Anticoagulant drugs
b. Natural anticoagulants
3. Functional excess in the fibrinolytic
mechanism.
41. 1. Spontaneous / induced
- at risk situations
- response to past surgeries
2. Symptoms –
-prolonged bleeding with surgery/tooth
extraction
-menorrhagia , PPH , large bruises following
trauma .
42. 3. EPISTAXIS – lack of seasonal variation and that
require medical evaluation and treatment .
43. Hemoptysis- never a bleeding disorder
and is rare even in patients with serious
bleeding disorders.
but, blood-tinged sputum in association with
upper respiratory tract infections may be
more common in patients with hemostatic
disorders.
44. 4. Bleeding with eruption of primary teeth .
5.Menorragia (>80ml blood /cycle )
- resulting in I.D.A
- clots >1cm
- changing pad more than hourly
45. 6. GI bleeding – vWD type 2 and 3 associated
with angiodysplasia of bowel .
7. Hemarthrosis and spontaneous muscle
hematoma – clotting factor deficiency .
Spontaneous hemarthrosis – severe vWD
with factor 8 levels <5% (rare in other
disorders )
48. 10. Nutrition history –
(a) vitamin K deficiency- if the patient also is
taking broad-spectrum antibiotics,
(b) vitamin C deficiency, - if the patient has
skin bleeding consistent with scurvy
(perifollicular purpura).
(c) general malnutrition and/or
malabsorption.
49. 11. A family history is particularly important
when hereditary disorders are considered.
-consanguinity,
-any similar compliants .
50. Physical Examination
50
• Is it bleeding? e.g. fixed drug eruption, erythema nodosum,
viral exanthem and mosquito bites The examination should
determine the presence of petechiae, ecchymoses,
hematomas, hemarthroses, or mucous membrane
bleeding.
52. 1/4/2018 approach to pediatrics bleeding disorders 52
Look for hepatosplenomegaly
Do a rectal exam for evidence of GI bleeding
Look for physical signs and symptoms of diseases related to
capillary fragility,
53. • Localized cyanosis is differentiated from
ecchymosis by the momentary blanching
pallor (with cyanosis) occurs after pressure
54. Color of the bruise
Red bruises - extensor surfaces of the arms
and hands indicate loss of supporting tissues,
as occurs in Cushing syndrome, glucocorticoid
therapy, senile purpura, and damage from
chronic sun exposure.
Jet-black bruises-warfarin induced skin
necrosis.
55. • Easy bruising can also occur in patients with
Ehlers-Danlos syndrome manifested by
distensible skin or extraordinary ligament
laxness, and in patients with hyperflexibility of
the thumb.
56. Finding Disorders of Coagulation Disorders of Platelets or
Vessels
Petechiae Rare Characteristic
Deep dissecting
hematomas
Characteristic Rare
Superficial ecchymoses Common; usually large and
solitary
Characteristic; usually small
and
multiple
Hemarthrosis Characteristic Rare
Delayed bleeding Common Rare
Bleeding from
superficial cuts and
scratches
Minimal Persistent often profuse
Sex of patient 80–90% of inherited forms
occur only in male patients
Relatively more common in
females
Positive family history Common Rare (exc. vWF , hereditary
hemorr.
telangiectasia)
62. METHODS
• Disposable standardized devices have been
developed that control the length and depth
of the skin incision.
• Blood pressure cuff -the upper arm and
inflated to 40 mm Hg for children and adults-
to maintain the venous pressure .
63. • IVY METHOD
- incision 10mm length , 1mm depth ,
- every 30 sec blood removed by filter paper
- normal- 3 to 9 minutes
• Duke method
- Pricked with lancet or needle,3 to 4 mm deep.
- Every 15 sec blood wiped by filter paper
- Normal 2-5 minutes
64. Causes of prolonged BT
Thrombocytopenia.
VWD.
Platelet function disorder-uremia
DIC
Disorder of blood vessels.
66. Platelets function assays
• PFA – platelet function analyser – membrane
of catridage are coated with – ADP
/COLLAGEN
and EPINEPHRINE/COLLAGEN .
depends on – platelet function
- plama vWF
- platelet number and hematocrit
67.
68.
69. Normal COL/EPI closure time (<120 sec)
Can detect 1. NSAID induced platelet
dysfunction
2.functional defect
Affected by anemia and thrombocytopenia .
70. Significance
Reflects overall activity of the Extrinsic Pathway.
Most sensitive to changes in Factor V,VII,X.(vit k )
Lesser to Factor I & II.
Standardisation by INR .
Normal Range
11 to 16 seconds(with rabbit thromboplastin)
10-12 seconds(with human thromboplastin)
Prothrombin Time(PT)
71. Significance
Reflects efficiency of Intrinsic Pathway.
Sensitive to changes in Factor VIII,IX,XI,XII.
Also sensitive to heparin & circulating anticoagulants.
measures the clotting time of plasma after the
activation of contact .
Indicates the overall efficiency of the Intrinsic
pathway.
Normal range
26 to 40 seconds.
Activated Partial Thromboplastin Time
72. Causes of prolonged aPTT
1. Deficiency of Factor VIII(Hemophilia A).
2. Deficiency of Factor IX(Hemophilia B).
3. Heparin therapy.
4. Circulating anticoagulants.
5. Liver disease.
73. Relevant 2nd line investigations are carried out with
each of the patterns of abnormalities in first line tests.
2nd Line Investigation
74. Mixing study
PRINCIPLE
• Unexplained prolongation of aPTT and rarely PT
• Mixed with normal plasma 1:1 ratio
• Correction (should be within few seconds) indicates a
possible factor deficiency, whereas failure to correct
suggests the presence of an inhibitor.
METHOD
• Perform a PT and/or aPTT on control, patient`s,and a 50:50
mixture of the control and pt`s plasma.
76. Prolongation indicates
- presence of specific inhibitor
- lupus anticoagulant
- interfering substance ( heparin ,
paraproteins and fibrin split products )
77. Significance
Asses the final step of coagulation
Bypasses Extrinsic & Intrinsic pathway.
Principle
Thrombin is added to plasma and the clotting time-measured.
TT is affected by the concentration and reaction of fibrinogen
and by the presence of inhibitory substances.
Normal range
TT should be within 2 s of the control
(i.e. 15–19 sec). Times of 20 s and longer are definitely abnormal.
Thrombin Time(TT)
78. Causes of prolonged TT
1. Disorders of fibrinogen-
Afibrinogenaemia.
Hypofibrinogenaemia.
Dysfibrinogenaemia.
2. Liver disease.
3. heparin therapy.
.
79. Modification of standard test using PL, thus
increasing the senstivity to antiboby interfering with
coagulation
Snake venom is not inhibited by heparin
more sensitive for lupus anticoagulant .
Dilute russel venom viper test
80. Automated coagulation methods
• Thrombo elasto graph(TEG)- demonstrates
changes during blood coagulation and
fibrinolysis. Used in surgical settings.
• Tell about platlet function also.
81. SCURVY
CUSHING’S SYNDROME,EHLER’S DANLOS SYNDROME,RENDU-
OSLER- WEBER SYNDROME(HHT) etc.
Inflammatory and metabolic – HIT , vasculitis , henonch scholein
purpura .
88. • Classic hemophilia (A) and hemophilia B-
indistinguishable
• Phenotype depends on factor 8/9 activity
- severe < 1%
- moderate 1 to 5%
- mild 6 to 30%
89. • Bleeding first noticed usually in early years
• 5 Hs:
– Hemarthroses
– Hematomas
– Hematochezia
– Hematuria
– Head hemmorhage
90. Treatment
• Without treatment – life expectancy is limited –
and is mainly by factor replacement .
• Treat should begin as soon as possible
- symptoms often precedes objective evidence of
bleeding .
- classic symptoms often require lab investigation
and prompt replacement
• Avoid drugs – like NSAIDS
91. Dosing
• DOSED in units , and defined as
• 1 unit = amount of factor 8 ( 100ng/ml) or
factor 9 ( 5ug/ml) in 1 ml of normal plasma .
• 1U fac 8 per kg increases factor level by 2%
92. Requirement
• Factor 8 dose = twice a day inj ( 8-12hrs)
(target level-patient level ) ×body wt× 0.5unit/kg
• Factor 9 dose = once a day inj ( 24 hr)
(target level-patient level ) ×body wt× 1unit/kg
93. • Cryoprecipitate – factor 8-80IU/bag
• Mild bleeding – uncomplicated hemarthrosis ,
sup hematoma –initial therphy with factor
level of 30-50%
- & to maintain levels of 25-15% in next 2-3
days
• Large hematomas , deep bleed – levels 50% or
even higher , replacement may require for 1
week .
94. • Severe life threatning bleeds- CNS , RP ,
oropharyngeal space – sustained levels of 50-
100% for > 7-10 days .
• Prophylactic replacement in surgery –aimed at
achieving 100% , for 7 to 10 days .
95. Non transfusion theraphy
1.DESMOPRESSIN
- only in hemophilia A
- not in severe disease (no stores available )
- 0.3ug/kg over 20min increase factor 8 level by 2-
3foldwithin 30 to 60min ( to determine response )
2.ANTIFIBRINOLYTIC
- GI/gums/ORAL surgery bleed – T.A ,EACA for 1 week
- not for hematuria
96. Complications- to note .
3. Inhibitor formation
- severe deficiency of factors> 80%
- gross gene rearrangements
Suspect
- do not respond to factor replacement at
therapeutic doses .
- early detection require to eradicate AB and
avoid bleeding.
-annual screeing for inhibitors .
97. • Low level AB- high dose fac. human/porcine
• High level AB-
- prothrombin complex concentrate (2,7,9,).
- recombinant factor 7a (bypass agent).
• Antibody eradication by
- ITI, immune tolerance induction ( infusion of
missing protein till inhibitor disappears , >year.
- Anti CD20 rituximab with ITI.
98. Should carriers be treated
• Factor level of 50% normal – considered not
at risk .
• Factor 8/9 level decreases following delivery
- maintain 50-70% activity for3 days – vaginal
- for 5 days if cesarean .
• Mild cases - use desmopressin or
antifibrinolytic .
104. • Acquired vWD – rare
- a/o with lymphoproliferative disease.
- Heyde syndrome : AS+GI bleed
- Aortic stenosis vWF- shear stress – susceptible
to proteases and develop functional TYPE 2
vWD – reverses also .
105. Treatment of vwd
• Type 1 – desmopressin ( IV / Nasal spray )
• Dose – 0.3ug/kg IV
- 2 inhalation one in each nostril(1.5mg/ml)
• Major side effect – hyponatremia (fluid
retention ) so – fluid restriction for 1 day .
106. • Type 2A , 2M – responds to Desmopressin .
• Type 3 ,2 b, 2N – VWF replacement ,
cryoprecipitate .
• Antifibrinolytic theraphy – useful
107. D.I.C
• Exposure of blood to phospholipids from
damaged tissue ,hemolysis , endothelium all
contributes .
• Mortality 30 t0 80% depends on underlying
disease , age and severity .
108.
109.
110. • DIC – unlikely diagnosis in presence of normal
FDP.
111. Chronic DIC
• Low grade compensated DIC in conditions like
–giant hemangioma , malignacy ,dead fetal
syndrome
• PT/aPTT, platelet may within normal range
• FDP, D-Dimer are elevated , red cell
fragmentation might present .
112. Treatment
• Morbidity and mortality - underlying disease
than complication .
1. HEMORRHAGIC SYMPTOMS
-FFP/PRP if with active bleeding or high risk.
114. ACQUIRED INHIBITORS
• Most commonly – fac 8 (acquired hemophilia)
& fact 5,9,10,11
• Older adults
• 50% =no cause , 50%= underlying malignancy ,
pregnancy , autoimmune disease
115. • Lupus anticoagulant – may cause bleeding –
hypoprothrombinemia ( ab to prothrombin)
• Management
- steroid or steroid + cytotoxic therapy
- eradicate inhibitors >70% cases
- no established guidelines .
116. LIVER RELATED FACTS
• Factor 5 only from hepatocytes – low level
may indicate – hepatic failure
• Normal factor 5 and low factor 7 indicates –
vit k deficiency
• Dysfibrinogenimia is common
117. Also at increased risk of thrombosis
- esp portal and mesentric vein
- DVT , and P.E
Even if PT and aPTT are elevated , thrombosis is
possible
125. HYPERCOAGULABLE
STATE
ACUTE THROMBOSIS HEPARIN THERAPHY WARFARIN
THERAPHY
1. ANTITHROMBIN
DEFICIENCY
AFFECTED AFFECTED RARELY AFFECTED
2.ANTIPHOSPHOLIPI
D ANTIBODIES
NOT CHANGED NOT CHANGED NOTCHANGED
3.FACTOR V LEIDEN NOT CHANGED NOT CHANGED NOT CHANGED
4.FACTOR 8 LEVEL AFFECTED AFFECTED AFFECTED
5.LUPUS
ANTICOAGULANT
NOT AFFECTED AFFECTED AFFECTED
6.PROTEIN C AFFECTED NOT AFFECTED AFFECETED
7.PROTEIN S AFFECTED NOT AFFECTED AFFECTED
8.PROTHROMBIN
GENE MUTATION
NOT AFFECTED NOT AFFECETED NOT AFFECTED
126. Warfarin associated supratherapeutic
INR – ACCP guidelines
1. Less than 5 – lower warfarin dose ,
-omit a dose and resume warfarin at lower dose
-no dose reduction if minimally elevated.
2. >5 to < 9
- omit a dose and administer vit k 1 to 2.5mg
- omit 1-2 doses and monitor INR frequently and
resume warfarin at lower dose .
127. 3.More than 9
- hold warfarin and adminster 2.5 to 5 mg oral vit
k . Monitor INR frequently
- resume warfarin at lower dose after reaching
the range
4. Supratherapeutic INR with bleeding
- hold warfarin
- 10mg vit k by slow iv.
- FFP/ 4 factor prothrombin complex concentrate.