What is the definition of hemostasis?

Proper balance of anti-coagulant and pro-coagulant factors to maintain blood flow and protect from hemorrhage.

In what ways does the endothelium normally exert anti-thrombotic effects?

·        Prevents platelet aggregation

o   Intact endothelium

o   Prostaglandin I2

o   Nitric oxide

·        Anti-coagulant effects

o   Heparin

o   Thrombomodulin

·        Fibrinolytic effects

o   tPA

In what ways does the endothelium normally exert pro-thrombotic effects?

·        Promotes platelet aggregation

o   VWF

·        Pro-coagulant effects

o   Tissue factor (r/t cytokines like TNF and interleukin-1, or to bacterial endotoxin exposure)

·        Antifibrinolytic effects

o   Plaminogen activator inhibitor

Which two substances released by the endothelial cells have anti-platelet effects?

1.    Prostaglandin I2 (protacyclin): vasodilates and decreases platelet aggregation

2.   Nitric oxide: vasodilates

What is the mechanism of heparin?

It is a cofactor of antithrombin III that inactivates thrombin and factor Xa.

What does thrombomodulin do?

Activates protein C

What does plasminogen do?

Clot (fibrin) lysis

When a clot is formed, large amounts of plasminogen are trapped in the clot. Slow release of tissue plasminogen activator (t-PA) from injured tissues and vascular endothelium converts plasminogen to plasmin, which digests the fibrin strands, causing the clot to dissolve.

What does Von Willebrand factor do?

Attaches platelets to the subendothelial extracellular matrix forming a bridge between the platelets and the collagen.

What does tissue factor do?

Tissue Factor and Tissue thromboplastins activate the extrinsic clotting pathway

Which factor initiates the extrinsic clotting pathway?

Factor VII

Which factor initiates the intrinsic clotting pathway?

Factor XII

Which factor initiates the final common clotting pathway ?

Factor X

What is Virchow’s triad?

1.    Endothelial injury

2.   Abnormal blood flow

3.   Hypercoagulability

Where is turbulence of blood flow more important to promote clotting?

Arteries

Where is stasis of blood flow more important to promote clotting?

Veins

What are primary hypercoagulable disorders?

Inherited diseases

More common:mutations in the factor V and prothrombin gene.

More rare:antithrombin III, Protein C, Protein S defficiency.

What are secondary hypercoagulable disorders?

Acquired diseases – mnemonic – D-A-M-M-E-D P-H-L-O  

DIC

Atrial Fibrillation

MI

Malignancy

Estrogen excess (pregnancy)

Damaged tissue 

Prolonged immobilization

Heparin induced thrombocytopenia

Lupus anticoagulant syndrome (antiphospholipid antibody d/o)

Oral contraceptives

Examples of endothelial injury that result in thrombosis formation are:

Examples of stasis and turbulence that create Abnormal blood flow and results in thrombosis formation:

• atherosclerotic plaques
• arterial aneurysms
• AMI
• ventricular aneurysms of the heart
• mitral stenosis which leads to atrial dilatation
• Turbulence may cause arterial and cardiac thrombi.

What is the most common primary hypercoagulable disorder?

Factor V leiden disease

 This glutamine for arginine mutation is resistant to degradation causing more clotting and thrombosis, it commonly presents in young adulthood.

Why is the pro-coagulant antiphospholipid antibody called lupus anti-coagulant?

Because it causes a falsely high PTT

True or False

Primary antiphospholipid syndrome is a autoimmune disorder.

False

Only secondary antiphospholipid syndrome is due to autoimmune disease such as SLE.

What is the quantitative definition of thrombocytopenia?

< 100,000 platelets on CBC

Below what platelet count does spontaneous bleeding occur?

< 20,000 platelets on CBC

What test assesses the functional ability of platelets?

Bleeding time

What are the four mechanisms that cause thrombocytopenia?

1.    Decreased production

2.   Increased consumption

3.   Sequestration from hypersplenism

4.   Dilutional from massive transfusion

What is the mechanism of thrombocytopenia in ITP?

Antiplatelet antibody leading to destruction of platelets in the spleen

Who is affected most often with chronic ITP?

Women ages 18-40

What is found on bone marrow biopsy in chronic ITP?

Increased numbers of megakaryocytes

What is the treatment of ITP?

1.      Glucocorticoids

2.   Surgical splenectomy

Who is affected most often with acute ITP?

Children under the age of 5

What is the treatment of acute ITP?

Self-limited; steroid therapy for severe cases

What are causes of secondary immune mediated thrombocytopenia?

·        SLE

·        AIDS

·        Hepatitis C

·        Drugs

What is the time frame of the two types of heparin induced thrombocytopenia?

Which is more serious? Why

1.    Immediate

2.   5-14 days

The delayed reaction at 5-14 days is more serious. The immediate type of heparin induced thrombocytopenia is reversible when the heparin is stopped. The delayed thrombocytopenia is associated with thrombosis.

Antiphospholipid antibody syndrome signs/symptoms include:

1. Recurrent venous & arterial thrombosis

2. Repeated miscarriages

3. Cardiac valve vegetations

4. Thrombocytopenia

What is the mechanism of action of heparin induced thrombocytopenia associated with thrombosis?

Heparin dependent anti-platelet antibodies cause platelet activation and thrombosis with MI, stroke, DVT, and PE.

What is one alternative in patients with a history of heparin induced thrombocytopenia associated with thrombosis that require anticoagulation?

Low molecular weight heparin (Lovenox)

What is the pentad of signs and symptoms associated with thrombotic thrombocytopenic purpura?

1.    Fever

2.   Central nervous system involvement (headache, 

    confusion, stroke)

3.   Acute renal failure

4.   Thrombocytopenia

5.   Microangiopathic hemolytic anemia

What are precipitating causes of TTP?

·        Drugs (quinine, ticlopidine)

·        Pregnancy

·        Infection (with dysentery)

What is the treatment for thrombotic thrombocytopenic purpura?

Plasmapheresis

How is thrombotic thrombocytopenic purpura distinct from DIC?

Thrombotic thrombocytopenic purpura does not activate the coagulation cascade – even though platelet count is low the problem is with diffuse thrombosis as platelets are consumed

What are two congenital disorders that cause platelet dysfunction with mechanism?

1.    Bournard-Soulier syndrome: Abnormal platelet receptor for von Willebrand factor

2.   Glanzmann’s thrombasthenia: Inability to form cross bridges between platelets and fibrin

What are two means of acquired platelet dysfunction with mechanism?

1.    NSAID use: inhibits COX production of thromboxane A2.

2.   Uremia: cause for platelet dysfunction unknown.

What are acquired disorders affecting coagulation factors?

·        Cirrhosis (causes decreased synthesis)

·        Vitamin K deficiency (decreased synthesis of vitamin K dependent factors)

·        DIC (from clotting factor consumption)

Which coagulation factors is vitamin K dependent for their production?

·        VII

·        IX

·        X

·        Prothrombin (aka II)

Impairment to the flow of bile or malabsorption of fat soluble vitamins in GIT will lead to vit K deficiency. 

What is the genetics of hemophilia A?

X-linked recessive

What is the pathophysiology of hemophilia A?

Factor VIII deficiency

Which coagulation pathway is affected in hemophilia A?

Intrinsic pathway

Which lab test that assesses coagulation is abnormal in hemophilia A?

PTT elevated

What is the treatment for hemophilia A?

Factor VIII replacement

Where is von Willebrand factor synthesized?

In the endothelium (as opposed to the other factors that are synthesized in the liver)

What is the genetics variants of von Willebrand deficiency most often?

Autosomal dominant

What are the two roles of von Willebrand factor?

1.    Stabilize factor VIII

2.   Binds to platelet receptor (Gplb) to bridge platelets together and facilitate platelet adhesion

Which two coagulation pathways are abnormal in von Willebrand deficiency?

1.    Intrinsic pathway

2.   Platelet function

Which two lab tests that assess coagulation are abnormal in most genetic variants of von Willebrand deficiency?

1.    PTT elevated

2.   Bleeding time prolonged

What is the treatment for von Willebrand deficiency?

Factor VIII products that contain von Willebrand factor

What is the platelet count in patients with either hemophilia A or von Willebrand deficiency?

Normal

What is the pathology of DIC?

1.    Microinfarcts with tissue hypoxia due to pathologic clotting.

2.   Bleeding from consumption of clotting factors and activation of fibrinolytic pathway.

What are underlying causes of DIC?

·        Obstetrical complication (50% cases of DIC)

o   Abrupted placenta

o   Amniotic fluid embolization

o   Retained dead fetus

o   Septic abortion

o   Toxemia

·        Cancer (33% cases of DIC)

o   Solid organs: pancreas, lung, stomach

o   Promyelocytic leukemia (chronic low grade DIC)

·        Sepsis

o   Gram negative sepsis with circulating endotoxin

o   Meningococcus

·        Massive tissue injury

o   Trauma

o   Burns

o   Extensive surgery

·        Miscellaneous

o   Snake bite

o   Heat stroke

Which causes of DIC are typically acute/abrupt and what is the usual presenting feature?

·        Obstetrical & Gram negative sepsis with circulating endotoxin

·        Bleeding complications

Which cause of DIC is typically chronic/insidious and what is the usual presenting feature?

·        Cancer

·        Thrombotic complications

What are the two mechanisms that precipitate DIC?

1.    Tissue injury that activates the extrinsic pathway.

2.   Endothelial injury that activates the intrinsic pathway.

What is the underlying pathophysiolgic result that perpetuates DIC common to both pathways?

Thrombin generation

What three phenomena observed in DIC result from thrombin generation?

1.    Intravascular fibrin deposition – microinfarcts/tissue hypoxia

2.   Plasminogen activation – bleeding

3.   Platelet consumption – microinfarcts/tissue hypoxia where platelets are consumed & bleeding where platelets are deficient

What lab abnormalities are seen in DIC?

·        Prolonged PT: from coagulation factor consumption

·        Prolonged PTT: from coagulation factor consumption

·        Elevated fibrin split products: from activation of coagulation pathways

·        Thrombocytopenia: from platelet consumption

·        Anemia: from hemolysis

What clinical complications are seen in DIC?

Depends on organs involved:

·        Respiratory failure

·        Renal failure

·        Coma

·        Circulatory collapse

·        Ecchymosis and petechiae

What is the treatment of DIC?

Heparin administration – for clotting

FFP administration – for bleeding