7/16/2007

Case 3‐01‐01
• 21 year old female

Coagulation and  Hemostatic  • CC:  multiple ecchymoses

Problems • (+)
(+) gum bleeding
bl di
• Menstrual hx: ↑ flow of menses for
the last 2 cycles
Section of Hematology‐Oncology • PE: pale
Department of Medicine (+) petechiae and ecchymoses on BLE
(‐) hepatosplenomegaly

Clinical manifestations of Disorders of 1° &  2° hemostasis

Case 3‐01‐01
MANIFESTATIONS 1°
DEFECTS IN 1° 2°
DEFECTS IN 2°
HEMOSTASIS HEMOSTASIS
• What other questions would you ask to  (PLATELET) (COAGULATION
DEFECTS)
provide clues as to the nature of the problem? ONSET OF Immediate Delayed – hours to
BLEEDING AFTER days
• What laboratory examinations will you  TRAUMA
request? SITES OF BLEEDING Superficial – skin, Deep – joints,
mucous membrane, retroperitoneum
nose, GIT, GUT
FAMILY Hx +/-
+/- Autosomal or X-
X-linked
Autosomal dominant recessive
RESPONSE TO Tx Immediate, local Requires sustained
measures effective systemic therapy
Back to Questions

Diagnostic Examinations:  
Laboratory Examinations Primary Hemostatic system
Platelet count
• Platelet count • Correlates with propensity to bleed
• Bleeding time • 50,000‐100,000 causes mild prolongation of bleeding 
time, bleeding occurs with severe trauma or stress
• Prothrombin time
• <50,000 is associated with easy bruising
<50,000 is associated with easy bruising
• Activated partial thromboplastin time • <20,000 associated with high incidence of spontaneous 
bleeding
Bleeding time
• Reliable & sensitive test for platelet function
• Any patient with BT >10’ has an ↑ risk of bleeding but the 
risk does not become great until >15‐20’

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Diagnostic Examinations:  
Plasma coagulation 
Activated partial thromboplastin Intrinsic limb of coagulation
time system

Patients with qualitative platelet Adequacy of factors XII, HMWK,

PK, XI, IX, VIII
abnormalities have a normal Common coagulation pathway
after conversion of F X
platelet count and a prolonged Prothrombin time Extrinsic or tissue factor
factor--
bleeding time.
time. dependent pathway
Common coagulation pathway
after conversion of F X
Thrombin time Conversion of fibrinogen to fibrin
Fibrinogen level

Specific coagulation factors

LOW PLATELET COUNT

Case 3‐01‐01 Splenomegaly N spleen

• CBC : Hgb = 9 g/dl Hct  = 28 mg% N marrow Abn marrow N marrow Abn marrow

WBC = 8500 u/L  segs =  72% lymphos = 28% Congestive hema d/o hema d/o
splenomegaly leukemia aplasia
platelet = 40,000 liver disease lymphoma refractory
storage diseases myeloid anemia
• Bleeding time = 12 minutes
Bleeding time = 12 minutes tumor metaplasia
p preleukemia
p
metastatic CA
excess
• Prothrombin time = 12.3 seconds destruction
normal control = 11.2 seconds Abn sequestration combined d/o prodn defect

IMMUNE NON IMMUNE

• Activated PTT = 39.8 seconds drug sepsis/DIC
normal control = 39.1 seconds idiopathic vasculitis
prosthesis

Thrombocytopenia:  Causes
• ↓ marrow production of megakaryocytes
Qualitative Platelet Dysfunction
‐ marrow infiltration (tumor, fibrosis) • Defects of platelet adhesion
‐ marrow failure ( hypoplastic, aplastic anemias, drug effects)
• Splenic sequestration of circ platelets
vWd uremia
‐ splenic enlargement due to tumor infiltration Bernard Soulier syndrome
‐ splenic congestion due to portal HPN • Defects of platelet aggregation
• ↑ destruction of circ platelets
Glanzmann’s thrombasthenia
‐ non immune destruction 
o u e des uc o
– DIC Drugs uremia
– Sepsis • Defects of platelet release
– Vasculitis
– vascular prosthesis ↓ cyclooxygenase activity
‐ immune destruction drug induced (ASA, NSAIDS)
– Antibody to platelet Antigens
– Drug associated Antibodies congenital
– Circulating  immune complexes  granule storage pool defects
• SLE
• viral agents • Defect of platelet coagulation activity
• bacterial sepsis Scott’s syndrome uremia

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Evaluation  of Platelet Function Idiopathic Thrombocytopenic Purpura

• Bleeding time
• Acquired disease w/ no clinically apparent 
• vWF assays associated conditions or other causes of 
thrombocytopenia
• Platelet aggregometry
• Acute vs chronic ITP
• Membrane glycoproteins

• Platelet granule content

Clinical Features of ITP in children & adults
Treatment for ITP
CHILDREN ADULTS • Glucocorticoids
Peak age 2-4 yo 15
15--40 yo
• IV Ig
Sex (F:M) Equal 2.6:1
• Anti Rh(D) immune globulin
Onset Acute Insidious (>2mos) • Splenectomy
(<1wk)
(<1 k)
symptoms Purpura (<10% Purpura (typically Chronic ITP
w/severe bleeding not • Cyclophosphamide
bleeding) severe)
• Vinca alkaloids
Spontaneous CR 83% 2% • Danazol
Chronic dse 24% 43% • Observation
Eventual CR 89% 64%

Thrombocytopenia due to 
Splenic Pooling (Sequestration)
Von Willebrand Disease
• Displacement of majority of platelets from   • Most common inherited bleeding disorder 
peripheral circulation to a slowly exchangeable  • Von Willebrand factor
splenic pool. 
‐ facilitates platelet adhesion by linking platelet 
membrane receptors to vascular 
• s/s
s/s related to the 1
related to the 1° d/o; bleeding is primarily the 
d/o; bleeding is primarily the
result of coagulation abnormalities caused by the 1° endothelium
d h li
liver disease ‐ plasma carrier for F VIII
• s/s may be mild to moderate bleeding episodes, 
• Platelet transfusions rarely needed & does not  depending on type of vWD
produce significant ↑ in peripheral platelet count  • Treatment: F VIII concentrates
since as many as 90% of the transfused platelet is 
sequestered into the spleen.   desmopressin

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Case 3‐02‐01 Case 3‐02‐01
• 52 year old male • What other questions will ask in the history?
• What laboratory examinations will you 
• CC:  hematemesis request?

• PE:  BP = 90/60 PR = 112/min
(+) spider angioma, chest
(+) palmar erythema
Traube’s space obliterated

Diagnostic Examinations in patients 
Case 3‐01‐01
with liver disease
• PT, PTT • Thrombin Time • CBC:  Hb:  80 g/dL  Hct:  0.24
• Platelet count • D – dimer WBC count:  3.5 x 109/L, 50 % segmenters, 45% 
• fibrinogen • Fibrin degradation  lymphocytes, 2% eosinophils, 3% monocytes
products 
products Platelets:  90 x 109/L
• Whole blood or
Whole blood or 
euglobin clot lysis time  • Prothrombin time:  patient:  24 sec
Normal control:  12 secs
Results of above tests will allow one to establish Prothrombin activity:  50%
whether thrombocytopenia, fibrinolysis, DIC,
or deficiency of coagulation factors is present.
• APTT:  patient 56 secs
Normal control:  35 secs
Back

XII
PK, HK
XIIa
INTRINSIC Pathway
Interpretation? HK
XI XIa
• Normochromic normocytic anemia
• Thrombocytopenia IX IXa
EXTRINSIC Pathway
• Prolonged prothrombin time VIIIa
VIIa,, TF
X X
Xa X
• Prolonged activated partial thromboplastin 
time Va XIII

prothrombin Thrombin

XIIIa

Fibrinogen Fibrin

cross linked fibrin

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Causes of Bleeding in patients with Liver Disease
Anatomic factors
• Portal HPN
splenomegaly & 2° thrombocytopenia
varices
• Peptic ulceration
• Gastritis
Hepatic Function abnormalities
• ↓ synthesis of procoagulant proteins (fibrinogen, 
prothrombin, FV, VII, IX, X, XI)
• ↓ synthesis of coagulation inhibitors (protein C, S, AT III)
• Impaired absorption & metabolism of Vit K
• Failure to clear activated coagulation proteins leading to DIC, 
systemic fibrinolysis

Therapy
Disseminated Intravascular Coagulation
• Treatment strategy based on careful clinical 
evaluation of causes of bleeding and assessment of 
• Widespread intravascular coagulation is induced by 
the major hemostatic abnormalities involved.   procoagulants introduced or produced in the blood 
• In patients who bleed spontaneously, following  circulation which overcomes the natural 
trauma, or predicted to bleed following surgery, the  anticoagulant mechanisms.
1° goal of treatment is correction of hemostatic 
1 goal of treatment is correction of hemostatic
defects. • Diffuse multi‐organ bleeding, hemorrhagic necrosis, 
thrombus formation in blood vessels
• FFP
• Prothrombin Complex concentrates
• Clinical manifestations attributable to the DIC, 
• Vit K
underlying cause, or to both.
• Platelet transfusion
• Cryoppt
• Antifibrinolytic agents

Infection, burns Trauma, burns

Multiorgan dysfunc CA
Autoimmune d/o Obstetric cx
Hemorrhagic shock
Clinical Manifestiations:  DIC
Intravasc generation Aneurysm, vasculitis
Of TF by monocytes, Heat stroke
SIRS Endothelial cells • Bleeding
TRIGGERING OF
Exposure
TF COAG PATHWAY • Thrombosis & thromboembolism
Failure of Of bld to
Control Tissues w//
Th
Thrombin
bi generation
ti
mechanisms TF
• Shock
Consumption Consumption of
DIC
Of AT III, Prot C Plts, F V & VIII,
fibrinogen
BV obs • Renal, liver, CNS, pulmonary dysfunction
Ischemia
Compensatory FDP Inhibition of:
Microangio fibrinolysis D-dimer thrombin
Pathic HA plt aggreg
BV patency

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Diagnostics:  DIC  Treatment:  DIC
• Platelet count • Manage underlying disease
• fibrinogen level
• PT, PTT, TT
• FDP,   D Dimer • Blood component therapy
• fragmented RBCs
fragmented RBCs

• Will reflect extent of consumption of hemostatic components • Heparin administration 
• In most instances, changes in > 3 parameters in addition to ↓
platelet count are consistent with DIC • Antithrombin III concentrate 

PT N, PTT ↑, PLT N
Hemophilia 
Bleeding No Bleeding
↓ F XII, HK, PK • X‐linked hereditary d/o due to defective or 
INJURY REL Lupus anticoag deficient Factor VIII molecule (Hemophilia A) 
Severe def F XI heparin
Mild to mod or IX (Hemophilia B)
Hemophilia A/B

UNPROVOKED • A:  1:10,000 live male births
Minor Major B:  1:25,000‐30,000 live male births 
vWD Severe Hemophilia A/B
Severe (type 3) vWD
Acquired inhibitor to FVIII
Acquired vWD

Clinical Classification of  Hemophilia
Factor level
Treatment of Hemophilia A
Class Clinical Features
Severe < 1% spontaneous hemorrhage from • Factor replacement therapy 
infancy – Factor concentrate
Frequent spontaneous – Cryoppt (will only achieve 20% F VIII level max)
hemarthroses/hemorrhages, requiring
clot factor replacement • Desmopressin
• A ifib i l i
Antifibrinolytic agents
Mod 1-5% 2° to trauma or surgery
Hemorhage 2°
Occ spontaneous hemarthroses
• Fibrin glue
• Supportive:
Mild 6-30% 2° to trauma or surgery
Hemorhage 2° – Avoidance of ASA, NSAIDs
Rare spontaneous hemarthroses – Avoidance of IM injections

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Treatment of Hemophilia B
• Factor replacement therapy 
– Factor concentrate
– Fresh Frozen Plasma

• Fibrin glue

• Supportive:
– Avoidance of ASA, NSAIDs
– Avoidance of IM inections

PT ↑, PTT ↑, PLT N
PT ↑, aPTT N, PLT N
Bleeding No Bleeding
Afibrinogenemia Hypofibrinogenemia
Bleeding No bleeding Severe def F II, V, X Mild def F II, V, X
Combined F V & VIII
Severe FVII def mild F VII def
def
use of oral Combined def of
anticoagulants Vit K dep factors
Acquired inhibitors
to F II & V
Acquired F X def

Case 3‐03‐01 Case 3‐03‐01
• 72 year old male was recently admitted to the hospital 
Neurology ward  • What other questions would you ask during history 
– drooling of saliva from the left side of his mouth taking?
– slurring of speech 
– right sided upper and lower extremity weakness
• What other aspects of the physical examination 
• past history of hypertension, hypercholesterolemia and  should you pay attention to?
di b
diabetes mellitus type 2
lli 2 • Wh f
What factors put this patient at risk for a 
hi i i kf
• medications include:  Felodipine, Simvastatin, Gliclazide and  thrombotic complication?
Metformin
• PE admission: drowsy, but responds to verbal stimuli • What are the differential diagnosis?
• bedbound with no bathroom privileges • What laboratory  examinations are important to 
• fifth hospital day:  swelling of his right lower extremity with  arrive at the diagnosis?
erythema
• How can thrombotic complications be prevented?
• 6th hospital day: difficulty of breathing and had to be 
intubated because of hypoxemia.

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Virchow’s triad: hypercoagulability (acquired,

Virchow’s triad: the three risk factors inherited)
• Advanced age • Malignant disease
• Pregnancy and puerperium
• History of DVT • Infection
• Acute myocardial infarction • Stroke
• Nephrotic syndrome
• Myeloproliferative disorders
ed
Inherite

• Antiphospholipid
A ti h h li id resistance
i t
Venous
thrombosis

Inherited
• Activated protein C resistance

• Protein C deficiency

• Protein S deficiency
Vascular injury
• Other congenital conditions

Acquired

Rosendaal FR. Lancet 1999; 353: 1167–1173.

Rosendaal FR. Lancet 1999; 353: 1167–1173.

Virchow’s triad: stasis (acquired) Virchow’s triad: vascular injury

A range of acquired factors is known to increase the
(acquired)
risk of venous thrombosis by inducing stasis.
• Surgery (anesthesia, immobilization)
• Obesity Vascular injury
• Paralysis
• Congestive heart failure Acquired
• Prolonged immobilization
• Infection
• Malignancy
• History of DVT
• Pregnancy • Surgical damage
• Acute myocardial infarction • Trauma
• Advanced age
• History of DVT
• Varicose veins
• Advanced age
• Chemotherapy

Rosendaal FR. Lancet 1999; 353: 1167–1173. Rosendaal FR. Lancet 1999; 353: 1167–1173.
Back to Questions

Diagnosis of DVT Diagnosis of DVT

Patients with suspected DVT
Ultrasonography
Ultrasonography

Abnormal
Normal Abnormal

Cli i l score
Clinical Clinical Score

Low Intermediate High

Low Intermediate High
Repeat
No DVT Ultrasonography Venography
at 1 week Venography DVT DVT

No DVT DVT No DVT DVT

No DVT DVT

Adapted from Lensing AWA, Prandoni P, Prins MH, Butler HR, Lancet, 1999. Adapted from Lensing AWA, Prandoni P, Prins MH, Butler HR, Lancet, 1999.

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Normal Doppler Ultrasound

Abnormal Doppler Ultrasound

Diagnosis of PE Diagnosis of PE

Ventilation/Perfusion CUS for DVT

Scan
POSITIVE Negative
Normal
o a Abnormal
b o a
Low Clinical Suspicion Low Clinical Suspicion
TREAT & & Other Combinations
High/Moderate High Probability Scan Low Probability Scan
Clinical Suspicion
PE Excluded &
Other combinations
Pulmonary
High probability Lung Scan PE EXCLUDED Serial CUS
Angiogram

TREAT

Adapted from Kearon C. ASH. 1999 Adapted from Kearon C. ASH. 1999

Normal V/Q Scan High probability V/Q Scan

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Key Elements of Natural History of VTE DVT and PE: two expressions of the
same disease
VTE usually starts as DVT including the
calf The PE
PE––DVT relationship 1–2% of patients with
Frequent sources of PE DVT die as a result of
When DVT causes symptoms, over 80% include: PE.
involves the p
popliteal
p or more p proximal „ proximal leg DVT 75% of these deaths occur
during initial hospital
veins „ isolated calf vein
thrombosis admission: detection of
VTE at an earlier stage
Of patients with isolated calf (‘distal”) DVT, „ pelvic thrombosis would allow more deaths
to be prevented.
about 20% extend into proximal veins „ renal/inferior vena cava
thrombosis.
A recent study showed that
usually within one week of presentation 82% of patients with acute PE
had detectable DVT at the
same time PE was diagnosed.

From Kearon C, ASH, 1999 Girard P et al. Chest 1999; 116: 903–908.
Hirsch J et al. Circulation 1996; 93: 2212–2245.
Perrier A et al. Arch Int Med 1996; 156: 531–536.
Pesavento R et al. Minerva Cardioangiol 1997; 45: 369–375.

Clinical Model for Determining Clinical Suspicion of DVT

If Present, Score Clinical Model for Determining Clinical

Active cancer (treatment ongoing or within previous 6 1 Suspicion of DVT
months or palliative
Paralysis, paresis or recent plaster immobilization of lower 1
extremities Pre--test
Pre Total Points Prevalence of
Recently bedridden > 3 days or major surgery within 4 1
weeks
Probability DVT
Locali ed tenderness along distrib
Localized distribution
tion of deep venous
eno s 1
system High >3 85%
Entire leg swollen 1

Calf swelling 3 cm > asymptomatic side (10 cm below tibial 1 Moderate 1 or 2 33%
tuberosity)
Pitting edema confined to symptomatic leg 1
Low <0 5%
Dilated superficial veins (non varicose) 1

Alternative diagnosis as likely or greater than that of DVT -2

TOTAL POINTS Wells PS, Hirsch J, Anderson DR et.al., J Intern Med, 1998
Wells PS, Hirsch J, Anderson DR et.al., J Intern Med, 1998

Risk Assessment Model (6th ACCP Consensus, 2001) Guidelines for Anticoagulation
RISK LEVEL DESCRIPTION Calf vein Proximal
vein throm
Clinical
PE
Fatal PE Unfractionated Heparin
Throm
bosis bosis Suspected VTE
„ Obtain baseline APTT, PT, CBC
Low Uncomplicated minor surgery in 2 0.4 0.2 0.002
patients <40 yr with no clinical risk „ Check for contraindication for heparin Rx
factors „ Give heparin 5000 U IV
Moderate Any surgery in pts. 40 to 60 yr with 10 to 20 2 to 4 1 to 2 0.1 to „ Order imaging study
no additional risk factors; major 0.4
surgery in
i pts
t < 40 yr with
ith no addl
ddl Confirmed VTE
risk factors; minor surgery in pts „ Rebolus with heparin 80 U/kg IV, start maintenance infusion at
with risk factors 18 U/kg/h
High Major surgery in pt > 69 yr w/o addl 20 to 40 2 to 4 1 to 2 0.1 to „ Check APTT at 6 hour, to maintain a range corresponding to a
risk factors or 40 to 60 yr with addl 0.4 therapeutic level
risk factors; pts with MI; medical pts
with risk factor „ Check platelet count daily
Highest Major surgery in pts > 40 yr with 40 to 80 10 to 20 4 to 10 1 to 5 „ Start warfarin therapy on day 1 at 5 mg, adjust subsequent daily
previous VTE, malignant disease or dose accdg to INR
hypercoagulable state; pt with „ Stop heparin after 4 to 5 days of combined therapy, when INR is
elective major LE orthopedic surgery,
hip fracture, stroke, multiple trauma
> 2.0 (range 2-
2-3)
or SCI

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Guidelines for Anticoagulation

Guidelines for Anticoagulation Low Molecular Weight Heparin
Low Molecular Weight Heparin
Confirmed VTE
„ Give LMWH

Enoxaparin 1 mg/kg SC q 12 h
Suspected VTE
Dalteparin 200 anti-
anti-Xa U/kg once daily
„ Obtain baseline APTT, PT, CBC Nadroparin 90 anti-
anti-Xa U/kg twice daily
„ Check for contraindication for heparin Rx Reviparin 90 anti-
anti-Xa U/kg twice daily
Tinzaparin 175 anti-
anti-Xa U/kg once daily
„ Give heparin 5000 U IV „ Start warfarin therapy on day 1 at 5 mg, adjust subsequent daily

„ Order imaging study dose accdg to INR

„ Check platelet count on days 3 & 5.

„ Stop LMWH after at least 4 to 5 days of combined therapy, when

INR is > 2.0 for two consecutive days

6th ACCP Consensus, Chest, 2001
6th ACCP Consensus, Chest, 2001
Lensing AWA, Prandoni P, Prins MH, Butler HR, Lancet, 1999.

Treatment of VTE

Vena cava filter

Surgical interruption
Thrombectomy
Fibrinolytic therapy

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