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HEMOSTASIS
1. VASCULAR PHASE
2. PLATELET PHASE
3. COAGULATION PHASE
4. FIBRINOLYTIC PHASE
Lab Tests
Hemostasis
BV Injury
Tissue Factor
CBC-Plt
BT,(CT)
PT
PTT
Neural
Blood Vessel
Constriction
Platelet
Aggregation
Coagulation
Cascade
Platelet
Activation
Blood flow
Fibrin
formation
Plt Study
Stable Hemostatic Plug
Morphology
Function
Antibody
NORMAL CLOTTING
Response to vessle injury
1. Vasoconstriction to reduce blood flow
2. Platelet plug formation (von willebrand factor binds
damaged vessle and platelets)
3. Activation of clotting cascade with generation of fibrin
clot formation
4. Fibrinlysis (clot breakdown)
CLOTTING CASCADE
Normally the ingredients, called factors, act like a row of
dominoes toppling against each other to create a chain
reaction.
If one of the factors is missing this chain reaction cannot
proceed.
VASCULAR PHASE
WHEN A BLOOD VESSEL IS
DAMAGED, VASOCONSTRICTION
RESULTS.
PLATELET PHASE
PLATELETS ADHERE TO THE
DAMAGED SURFACE AND FORM A
TEMPORARY PLUG.
COAGULATION PHASE
THROUGH TWO SEPARATE
PATHWAYS THE CONVERSION OF
FIBRINOGEN TO FIBRIN IS
COMPLETE.
EXTRINSIC
Collagen
Tissue Thromboplastin
XII
XI
VII
IX
VIII
X
FIBRINOGEN
(I)
V
PROTHROMBIN
(II)
THROMBIN
(III)
FIBRIN
FIBRINOLYTIC PHASE
ANTICLOTTING MECHANISMS ARE
ACTIVATED TO ALLOW CLOT
DISINTEGRATION AND REPAIR OF
THE DAMAGED VESSEL.
HEMOSTASIS
DEPENDENT UPON:
Vessel Wall Integrity
LABORATORY EVALUATION
PLATELET COUNT
BLEEDING TIME (BT)
PROTHROMBIN TIME (PT)
PARTIAL THROMBOPLASTIN TIME (PTT)
THROMBIN TIME (TT)
PLATELET COUNT
NORMAL
< 100,000
Thrombocytopenia
50,000 - 100,000
Mild Thrombocytopenia
< 50,000
Sev Thrombocytopenia
BLEEDING TIME
PROVIDES ASSESSMENT OF PLATELET
COUNT AND FUNCTION
NORMAL VALUE
2-8 MINUTES
PROTHROMBIN TIME
Measures Effectiveness of the Extrinsic
Pathway
Mnemonic - PET
NORMAL VALUE
10-15 SECS
NORMAL VALUE
25-40 SECS
THROMBIN TIME
Time for Thrombin To Convert
Fibrinogen
Fibrin
A Measure of Fibrinolytic Pathway
NORMAL VALUE
9-13 SECS
VESSEL DEFECTS
VITAMIN C DEFICIENCY
PLATELET DISORDERS
THROMBOCYTOPENIA
THROMBOCYTOPATHY
THROMBOCYTOPENIA
INADEQUATE NUMBER
OF PLATELETS
THROMBOCYTOPATHY
ADEQUATE NUMBER BUT
ABNORMAL FUNCTION
THROMBOCYTOPENIA
DRUG INDUCED
BONE MARROW FAILURE
HYPERSPLENISM
OTHER CAUSES
OTHER CAUSES
Lymphoma
HIV Virus
Idiopathic Thrombocytopenia Purpura (ITP)
THROMBOCYTOPATHY
UREMIA
INHERITED DISORDERS
MYELOPROLIFERATIVE DISORDERS
DRUG INDUCED
FACTOR DEFICIENCIES
(CONGENITAL)
HEMOPHILIA A
HEMOPHILIA B
von WILLEBRANDS DISEASE
FACTOR DEFICIENCIES
HEMOPHILIA A (Classic Hemophilia)
80-85% of all Hemophiliacs
Deficiency of Factor VIII
Lab Results - Prolonged PTT
FACTOR DEFICIENCIES
VON WILLEBRANDS DISEASE
Deficiency of VWF & amount of Factor VIII
Lab Results - Prolonged BT, PTT
OTHER DISORDERS
(ACQUIRED)
ORAL ANTICOAGULANTS
COUMARIN
HEPARIN
LIVER DISEASE
MALABSORPTION
BROAD-SPECTRUM ANTIBIOTICS
INHIBITORS
30% of people with haemophilia develop an antibody to the
clotting factor they are receiving for treatment. These
antibodies are known as inhibitors.
These patients are treated with high does of FVIIa for bleeds or
surgery. This overrides defect in FVIII or FIX deficiency.
Longterm management involves attempting to eradicate
inhibitors by administering high dose FVIII (or FIX) in a
process called immune tolerance
Bleeding Disorders
Coagulation
disorders
factor disorders
Site of bleeding
Skin
Mucous membranes
(epistaxis, gum,
vaginal, GI tract)
Petechiae
Yes
No
Ecchymoses (bruises)
Small, superficial
Large, deep
Extremely rare
Common
Yes
No
Immediate,
usually mild
Platelet
Petechiae, Purpura
Coagulation
Petechiae
(typical of platelet disorders)
Hemarthrosis
Hematoma
Petechiae
Purpura
Ecchymosis
Senile Purpura
Petechiae in patient
with Rocky Mountain
Spotted Fever
Henoch-Schonlein purpura
Ecchymoses
(typical of coagulation
factor disorders)
Inherited bleeding
disorders
Hemophilia
A and B
vonWillebrands disease
Other factor deficiencies
Acquired bleeding
disorders
Liver
disease
Vitamin K
deficiency/warfarin
overdose
DIC
Hemophilia A and B
Coagulation factor deficiency
Inheritance
Incidence
Severity
Complications
Hemophilia A
Hemophilia B
Factor VIII
Factor IX
X-linked
recessive
X-linked
recessive
1/10,000 males
1/50,000 males
Hemophilia
Clinical manifestations (hemophilia A & B are
indistinguishable)
Hemarthrosis (most common)
Fixed joints
Hemarthrosis (acute)
Treatment of hemophilia A
treated
May contain von Willebrand factor
treated
No functional von Willebrand factor
Mild bleeding
Target:
Major bleeding
Target:
Adjunctive therapy
-aminocaproic acid (Amicar) or DDAVP (for mild disease only)
Complications of therapy
Viral infections
Hepatitis
B
Hepatitis C
HIV
Human parvovirus
Hepatitis A
Other
Hepatitis serology
Negative
Hepatitis B virus only
Hepatitis C virus only
Hepatitis B and C
Blood 1993:81;412-418
HIV -positive
(n=382)
53%
% positive
HIV-negative
(n=345)
47%
% negative
1
1
24
74
20
1
45
34
Treatment of hemophilia B
Agent
High
purity factor IX
Recombinant human factor IX
Dose
Initial
dose: 100U/kg
Subsequent: 50U/kg every 24 hours
Incidence - 1/10,000
Laboratory evaluation of
von Willebrand disease
Classification
Type 1
Type 2
Type 3
Diagnostic tests:
Assay
vWF antigen
vWF activity
Multimer analysis
Normal
vonWillebrand type
2
Normal
Normal
Absent
Cryoprecipitate
Source
inactivated product
Vitamin K deficiency
Source of vitamin K
Green vegetables
Synthesized by intestinal flora
Causes of deficiency
Malnutrition
Biliary obstruction
Malabsorption
Antibiotic therapy
Treatment
Vitamin K
Fresh frozen plasma
Sepsis
Obstetrical complications
Trauma
Head injury
Fat embolism
Malignancy
Vascular disorders
Immunologic disorders
Intravascular
deposition of fibrin
Thrombosis of small
and midsize vessels
with organ failure
Depletion of platelets
and coagulation factors
Bleeding
Pathogenesis of DIC
Release of
thromboplastic
material into
circulation
Coagulation
Fibrinolysis
Fibrinogen
Plasmin
Thrombin
Fibrin
Monomers
Fibrin
Clot
(intravascular)
Consumption of
coagulation factors;
presence of FDPs
aPTT
PT
TT
Fibrinogen
Presence of plasmin
FDP
Fibrin(ogen)
Degradation
Products
Plasmin
Intravascular clot
Platelets
Schistocytes
Platelet transfusion
Quantitative disorders
distribution
Dilution effect
Decreased production
Qualitative disorders
Abnormal
Inherited
disorders (rare)
Acquired disorders
Medications
Chronic renal failure
Cardiopulmonary bypass
Increased
destruction
Thrombocytopenia
Immune-mediated
Idioapthic
Drug-induced
Collagen vascular disease
Lymphoproliferative disease
Sarcoidosis
Non-immune mediated
DIC
Microangiopathic hemolytic anemia
2.
3.
Dysfibrinogenemia
4.
5.
DIC
6.
Management of Hemostatic
Defects in Liver Disease
Treatment
Treatment
Treatment
Replacement therapy
Guidelines
INR therapeutic-5
Guidelines
Omit warfarin
Vitamin K 10 mg slow IV infusion
FFP or PCC (depending on urgency)
Repeat vitamin K injections every 12 hrs as needed
Omit warfarin
Vitamin K 10 mg slow IV infusion
PCC ( or recombinant human factor VIIa)
Repeat vitamin K injections every 12 hrs as needed
Preexisting abnormality
Special cases (e.g. Cardiopulmonmary bypass)
Platelet count
RBC and platelet morphology
Thrombocytopenia
TTP, DIC, etc.
Coagulation
Prothrombin time
Partial thromboplastin time
Coagulation factor assays
50:50 mix
Fibrinogen assay
Thrombin time
Extrinsic/common pathways
Intrinsic/common pathways
Specific factor deficiencies
Inhibitors (e.g., antibodies)
Decreased fibrinogen
Qualitative/quantitative
fibrinogen defects
Fibrinolysis (DIC)
FDPs or D-dimer
Platelet function
Prothrombin time
(PT)
Thromboplastin
Tissue factor
Phospholipid
Calcium
Intrinsic pathway
Extrinsic pathway
Thrombin time
Common pathway
Thrombin
Fibrin clot
Thrombin Time
Procedure:
Add
Variables:
Source
Heparin
Hypofibrinogenemia
Dysfibrinogenemia
Elevated FDPs or paraprotein
Thrombin inhibitors (Hirudin)
Thrombin antibodies
Classification of thrombocytopenia
thrombocytopenic
purpura
Heparin-associated
thrombocytopenia
Trousseaus syndrome
DIC
thrombocytopenia (ITP)
Most others
Drugs
Treatment Approaches to
the Bleeding Patient
Peri-operative
management
CMV-negative patients
Prevent CMV
transmission
Irradiated RBCs
Prevent GVHD
Leukopoor
Previous non-hemolytic
transfusion reaction
CMV negative patients
Prevents reaction
PNH patients
IgA deficient recipient
Prevents hemolysis
Prevents anaphylaxis
Washed RBC
Prevents transmission
RBC incompatibility
Usually unknown; rarely against IgA
Antibody to neutrophils
Antibody to donor plasma proteins
Donor antibody to leukocytes
Volume overload
Bacterial contamination
Hypocalcemia
Massive transfusion
Transfusion-transmitted disease
Infectious agent
Risk
HIV
Hepatitis C
Hepatitis B
Hepatitis A
HTLV I/II
CMV
Bacteria
Creutzfeld-Jakob disease
Others
~1/500,000
1/600,000
1/500,000
<1/1,000,000
1/640,000
50% donors are sero-positive
1/250 in platelet transfusions
Unknown
Unknown
Platelet transfusions
Source
Platelet
Target level
Bone
Transfusion reactions
Higher
DIC
Warfarin
reversal
Coagulation deficiency (factor XI or VII)
ml/kg
Note
Viral
screened product
ABO compatible
Cryoprecipitate
Indications
Fibrinogen
deficiency
Uremia
von
Willebrand disease
Hemostatic drugs
Aminocaproic acid (Amicar)
Mechanism
Dose
50mg/kg po or IV q 4 hr
Uses
Primary menorrhagia
Oral bleeding
Bleeding in patients with thrombocytopenia
Blood loss during cardiac surgery
Side effects
GI toxicity
Thrombi formation
Hemostatic drugs
Desmopressin (DDAVP)
Mechanism
Dose
Uses
Side effects
Mechanism
Use
Dose
90
g/kg IV q 2 hr
Adjust as clinically indicated
~$5,000/dose or $60,000/day