Wake Disorders Of Hemostasis

Front 1

Thrombocytopenia

Back 1

<150,000 /uL (Normal 150,000 – 350,000/uL)

Spontaneous bleeding <20,000 /uL
Usually involves small vessels of skin, mucous membranes GI/GU tracts
Intracranial bleeding can be serious problem too!

Front 2

Thrombocytopenia
Causes

Back 2

- Decreased platelet production
- Bone marrow problems, e.g. aplastic anemia, MDS, vitamin deficiency, tumors
- Decreased platelet survival
- Immunologic, i.e. circulating anti-platelet antibodies to GpIIb/IIIa or GpIb
- ITP, HIV, drugs
- Mechanical destruction/consumption, e.g. MAHA, prosthetic heart valves
- Sequestration
- Dilutional

Front 3

Thrombocytosis
Complications

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- THROMBOTIC episodes, due to the increased number of active platelets
- BLEEDING episodes, as platelet function may also be defective

Front 4

Thrombocytosis
Secondary/Reactive

Back 4

Infections
Iron deficiency anemia
Inflammatory disorders
Acute/chronic blood loss
Drugs (steroids)
Malignancies (Classical Hodgkin Lymphoma)
Splenectomy

Front 5

Primary Thrombocytosis

Back 5

Essential Thrombocytosis
CML
Polycythemia Vera
Chronic Idiopathic Myofibrosis

Front 6

PTT
Reference Range

Back 6

21 – 31

Front 7

PT
Reference Range

Back 7

10.8 – 13.9

Front 8

Fibrinogen
Reference Range

Back 8

180 – 363

Front 9

D-Dimer
Reference Range

Back 9

<230

Front 10

Immune Thrombocytopenic Purpura
Dx

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- Peripheral Blood: Thrombocytopenia
- Bone Marrow: Normal/increased numbers of megakaryocytes
- No known exposure to thrombocytopenic agents

Labs: normal PT, aPTT

Front 11

Immune Thrombocytopenic Purpura
Acute

Back 11

children, self-limiting (acute viral infection)

Front 12

Immune Thrombocytopenic Purpura
Chronic

Back 12

adults (autoimmune syndromes, infections, drugs, HIV)

Front 13

Immune Thrombocytopenic Purpura

Back 13

- Antiplatelet antibodies to GPIIb/IIIa or GpI/IX
Coat and damage platelets, which are then selectively removed from circulation by spleen
- May be secondary or primary (idiopathic)

Front 14

Platelet Phase Tests

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- Bleeding Time (BT)
- Platelet Enumeration
- Aggregation Studies

Front 15

Bleeding Time (BT)

Back 15

- Normal: 2-9 minutes
- Non-specific, very difficult to standardize
- Diagnoses: thrombocytopenia, VWD, primary hemostasis problems

Front 16

Platelet Enumeration

Back 16

- Normal: 150-350 K
- Usually requires < 50K before bleeding occurs
- Diagnoses: thrombocytopenia vs. thrombocytosis

Front 17

Aggregation Studies

Back 17

- Addition of platelet aggregators, e.g. ADP
- Diagnoses: Platelet function defects

Front 18

Activated Partial Thromboplastin Time (aPTT)

Back 18

Normal: 21 - 35 seconds
Diagnoses:
- increased aPTT Sensitive to Intrinsic Pathway abnormalities: XII, XI, IX, VIII, X, V
- Less sensitive to II, fibrinogen

Front 19

Prothrombin Time (PT)

Back 19

Normal: 10-14 seconds
Diagnoses:
- increased PT: Sensitive to Extrinsic Pathway abnormalities: VII, X, V, II, fibrinogen
- Useful in Vitamin K deficiency: II, VII, X

Front 20

Fibrinogen Degradation Products (FDPs)

Back 20

Measures presence of fibrin or fibrinogen degradation products
- Antibodies to FDPs are bound to latex particles, which clump in the presence of antigen
- False positive and negatives are common
- Sample procurement techniques (in vitro clotting)
- Liver disease, rheumatoid arthritis
- D-dimer test preferred
- More specific for fibrinolysis
- Normal < 200 ng/mL

Front 21

Fibrinogen Degradation Products (FDPs)
When it is useful?

Back 21

- DIC, level usually very elevated
- DVT, post-operative, acutely ill level elevated, not as high as seen in DIC

Front 22

If you have an:
eleveated PT
elevated aPTT
decreased platelets
then you suspect?

Back 22

DIC

Front 23

Linitis plastica

Back 23

- 'leather-bottle' stomach
- due to poorly differentiated adenocarcinoma infiltrating gastric wall.
- this type of gastric carcinoma does not ulcerate or protrude into the gastric lumen.

Front 24

Microangiopathic hemolytic anemias (MAHA)

Back 24

Endothelial damage in microvasculature
- Disseminated intravascular coagulation
- Thrombotic thrombocytopenic purpura
- Hemolytic uremic syndrome

Front 25

Mechanical/Vascular hemolysis

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Direct mechanical trauma from hemodynamic defect and/or extreme turbulence
- Prosthetic heart valves, vascular malformations
- Malignant hypertension
- Severe burns
- “March hemoglobinuria", karate, bongo drumming

Front 26

Reasons for RBC Fragmentation Syndromes?

Back 26

Mechanical/Vascular hemolysis
Microangiopathic hemolytic anemias

Front 27

Disseminated Intravascular Coagulation (DIC)
(systemic activation of

Back 27

I. Coagulation system: widespread expression of tissue factor (TF)
- Intravascular THROMBUS formation (compromising blood supply to various organs)
- Exhaustion of platelets and coagulation factors resulting in HEMORRHAGE.

II. Fibrinolytic system: Plasmin degrades fibrinogen and fibrin, producing fibrin degradation products (FDPs), exacerbating bleeding

Front 28

Disseminated Intravascular Coagulation (DIC)

Back 28

A secondary condition in which microthrombi develop throughout the bloodstream, blocking small blood vessels and depleting platelets and clotting factors needed to control bleeding.

Front 29

Disseminated Intravascular Coagulation (DIC)
Clinical Features

Back 29

- Bleeding is usually severe 
- Petechiae and ecchymoses of skin and mucous membranes 
- Shock
- Signs of the underlying disease are usually present 
- Organ(s) involved with accompanying signs/clinical effects must also be taken into consideration.

Front 30

Disseminated Intravascular Coagulation (DIC)
Laboratory Diagnosis

Back 30

- Increase PT/aPTT
- Thrombocytopenia
- Increase D-dimers (FDPs)

also...
- Schistocytes in blood smears
- Decreased concentrations of coagulation factors V/VIII

Front 31

Malignancies Associated w/ DIC

Back 31

solid tumors, hematologic

Front 32

Obstetric Emergencies Associated w/ DIC

Back 32

amniotic fluid embolism, abruptio placentae

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Organ Destruction Associated w/ DIC

Back 33

severe pancreatitis, severe hepatic failure

Front 34

Sepsis/Severe Infection Associated w/ DIC

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(any microorganism)

Front 35

Severe toxic or immunologic reactions Associated w/ DIC

Back 35

snake bites, recreational drugs, transfusion reactions, transplant rejection

Front 36

Vascular abnormalities associated with DIC

Back 36

Kasabach-Merritt syndrome, large vascular aneurysms

Front 37

Thrombotic Thrombocytopenic Purpura
Laboratory Dx

Back 37

- Deficiency of vWF metalloproteinase ADAMTS13
- Enzyme deficiency results in accumulation of very-high-molecular weight multimers of vWF, promoting platelet aggregation.
- Acquired (antibody inhibitor) or inherited
- Consumptive thrombocytopenia
- Schistocytes in blood smears

Front 38

Hemolytic Uremic Syndrome
Clinical Features

Back 38

MAHA
Thrombocytopenia
Renal Insufficiency
Bloody Diarrhea

Front 39

Hemolytic Uremic Syndrome
Laboratory Dx

Back 39

- E. COLI INFECTIOUS GASTROENTERITIS
- E.coli strain 0157:H7 elaborates Shiga-like toxin absorbed by GI tract and binds to endothelial cells, initiating platelet activation
- Consumptive thrombocytopenia
- Schistocytes in blood smears

Front 40

How do you get E.coli strain 0157:H7?

Back 40

eating uncooked meat...food poisoning

Front 41

aPTT mix

Back 41

to rule out possible coag inhibitor substances in blood, e.g. heparin

Front 42

TT
(Thrombin Time)

Back 42

- thrombin time measures activity of thrombin in the conversion of fibrinogen into fibrin by thrombin. Useful for diagnosis of dysfibrinogenemia

Front 43

vWF Ag

Back 43

- vonWillebrand Factor Antigen measures the serum level of vWF

Front 44

If you are still clinically concerned about a bleeding disorder but your baseline bleeding tests look fine, then what do you order?

Back 44

- aPPT mix
- Factor VIII
- Factor IX
- Thrombin Time
- vWF Ag

Front 45

Von Willebrand’s Factor
Functions

Back 45

- CARRIER PROTEIN FOR VIII Stabilizes VIII, increasing serum half life
- BINDS TO GpIb RECEPTOR on platelets adhesion to damaged endothelium

Front 46

Von Willebrand’s Factor
Endothelium Pro-thrombotic properties

Back 46

- Endothelial production of von Willebrand Factor (vWF)
- Synthesis of Tissue Factor, activating extrinsic cascade

Front 47

Von Willebrand’s Disease
Mild Forms

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TYPE1, TYPE 2
- Many patients asymptomatic
- Cutaneous/mucosal bleeding: epistaxis, ecchymoses, menorrhagia, GI

Front 48

Von Willebrand’s Disease
Severe Forms

Back 48

TYPE 3
- Usually with concomitant low levels of Factor VIII
- Severe bleeding: Hemarthroses, dissecting hematomas

Front 49

Von Willebrand’s Disease

Back 49

Bleeding Disorder
- Characterized by mucocutaneous bleeding episodes
- Most common bleeding disorder - 1% of general population
- Autosomal Dominant or Recessive
- Multiple genetic mutations
- Results in either a quantitative or qualitative deficiency of vWF

Front 50

Von Willebrand’s Disease
Diagnostic Approach

Back 50

- Hematologic evaluation of peripheral blood
- Screening for hemostasis
- I.e. platelet count, PT, aPTT, etc.
- vWD panel
- Factor VIII activity – decreased in vWD
- vWF antigen – decreased in vWD
- Ristocetin cofactor activity – decreased in vWD
- vWF multimeric analysis – qualitative test of vWF

Front 51

How is vWF secreted?

Back 51

in multimers of themselves

Front 52

Multimeric Analysis of vWF
Type 1

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- generalized decrease in all sizes of multimers

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Multimeric Analysis of vWF
Type 2

Back 53

- loss of high molecular weight multimers

Front 54

Multimeric Analysis of vWF
Type 3

Back 54

multimer absence

Front 55

Hemophilia A

Back 55

- 2nd most common inherited coagulation disorder, 1:5,000 male births
- Sex-Linked (X-Linked) Recessive - Xq28
- Sporadic gene mutations very common
- 30% cases with negative family history
- Spectrum of bleeding manifestations
- Recurrent hemarthroses, severe hemorrhagic diathesis
- Exsanguinating hemorrhage from trivial trauma
- Deep muscle (psoas)/joint hematomas, easy bruising, post-surgical oozing

Front 56

Suspect Hemophilia A if

Back 56

1. . Birth of infant to mom with family history
2. Appearance of bleeding in neonatal period
3. Pattern of bleeding (joint/muscle), easy bruising

Front 57

Factor VIII

Back 57

- Synthesized in liver
- Circulates bound to von Willebrand Factor as stable complex
- Activated by IIa (and Xa!): Enhances activation of X by IX 200,000 fold
- Inactivated by Protein C

Front 58

Factor IX

Back 58

Plasma thromboplastin, Christmas factor
- Vitamin K dependent
- Activated by XIa and VIIa

Front 59

Hemophilia B

Back 59

- X-linked recessive, 1:30,000 male
- Most families have unique mutation
- Spectrum of bleeding manifestations
- Exsanguinating hemorrhage from trivial trauma
- Deep muscle (psoas)/joint hematomas, easy bruising, post-surgical oozing

Acquired
- Liver disease, vitamin K deficiency
- Warfarin/coumadin therapy

Front 60

Hemophilia B
Therapy

Back 60

Administration of Factor IX

Front 61

Liver Disease
as an Acquired Coagulopathy

Back 61

- Hepatitis/Cirrhosis
- Major site of clotting factor synthesis: all factors but vWF
- Usually results in bleeding diathesis

Front 62

Vitamin K Deficiency
as an Acquired Coagulopathy

Back 62

- Biliary obstruction, malabsorption syndromes, nutritional deficiencies, drugs (affecting gut flora)
- Vitamin K-dependent factors: II, VII, IX, X, Proteins C/S
- Results in bleeding diathesis

Front 63

Disseminated Intravascular Coagulopathy
as an Acquired Coagulopathy

Back 63

- Tissue Factor expression - cancers, tissue injury, burns, infections, toxins, drugs
- Uncontrolled generation of thrombin/microthrombi - “consumes” platelets/factors
- Subsequent thrombolysis adds to bleeding tendency - increase fibrin split products
- Usually results in purpuric manifestations

Front 64

Westermark sign

Back 64

Pulmonary Angiogram Sign
Dilatation of
pulmonary vessels proximal to
embolism along with collapse of distal vessels, often with a sharp cut off.

Front 65

APC Mix

Back 65

PTT performed in the presence and absence of exogenously supplied activated protein (APC). In normal patients, the APC degrades the patient's factor Va and VIlla, and on that basis, prolongs the PTT. In patients with a factor V Leiden mutation, the degradation of factor Va does not occur to the same extent and, therefore, the PTT does not become as prolonged. The ratio of the PTT + APC versus PTT without is calculated. Normal individuals typically have ratio of 2.0 or greater, and individuals with factor V Leiden typically had a ratio less than 2.0.

Front 66

Factor V Leiden

Back 66

Most common inherited thrombotic disorder
- Accounts for 20-50% of thrombotic disorders
- Autosomal Dominant, point substitution mutation at nucleotide 1691 resulting in Arg506 --> Gln
- MUTATION IN Factor V RENDERS THE COFACTOR RESISTANT TO PROTEOLYSIS BY ACTIVATED PROTEIN C
- Recurrent venous thromboembolism, may be asymptomatic

Front 67

Factor V Leiden
Dx

Back 67

DNA mutational Analysis

Front 68

Factor V Leiden
Treatment

Back 68

prophylaxis anticoagulation (warfarin)

Front 69

Hypercoagulability
Primary Genetic

Back 69

(see venous thrombi)
- Mutation in Factor V gene
- Mutation in Prothrombin gene 20210A
- Antithrombin III, protein C/S deficiencies
- Fibrinolysis defects

Front 70

Antiphospholipid Antibody Syndrome

Back 70

Prothrombotic disorder
- Autoantibodies directed against a number of antigens complexed to phospholipids
- Autoimmune syndromes - Lupus anticoagulant, anticardiolipin antibody
- Direct platelet activation, interference of protein C activity
- Recurrent venous and arterial thromboembolism, fetal loss (multiple spontaneous abortions), thrombocytopenia, variety of neurological manifestations
- Most often diagnosed because of incidental paradoxical elevated aPTT
- In vitro artifact caused by interaction of the antibodies with the phospholipid reagant used in the test assay

Front 71

List the Hereditary Thrombophilias

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- Factor V Leiden
- Prothrombin 20210A transition
- Methylene tetrahydrofolate reductase mutation (MTHFR C6771T)
- Protein C/S deficiencies
- Antithrombin deficiency

Front 72

Thrombophilic Disorders

Back 72

- Hereditary Thrombophilias
- Antiphospholipid Antibody Syndrome
- Disseminated Intravascular Coagulation (DIC)
- Heparin-induced Thrombocytopenia syndrome (HIT).