MHD - Lec#2 - Abnormal Hemostasis I & II

Question 1

Alterations in bone marrow results in an increased or decreased platelet count?

What are the following examples of:

• May Hegglin anomaly (autosomal dominant),

Wiskott-Aldrich syndrome,

absent radius syndrome, Fanconi’s anemia

Answer 1

Decreased

• Marrow hypoplasia, aplasia, replacement by neoplastic cells, marrow fibrosis, radiation injury, leukemia, paroxysmal nocturnal hemoglobinuria (PNH).
  2. Hereditary thrombocytopenia

Question 2

What is a normal platelet count?

Answer 2

200-500 thousand mm3

Question 3

What is an example of acquired abnormal hematopoiesis?

What drugs often induce thrombocytopenia?

How does hemodialysis affect the number of platelets?

Answer 3

B12/Folate deficiency, pre-leukemia*

• Heparin, gold, quinine, quinidine, sulfonamides, GP IIb/IIIa Inhibitors

2. DECREASE
   = thrombocytopenia

Question 4

What is the main mechanism of Heparin induced thrombocytopenia?

Answer 4

1. Heprin forms a complex with PF-4
2. Antibodies form against this complex and decrease the number of platelets

• PF-4 comes from LIGHT GRANULES (alpha)

Question 5

What is ITP?

What is TTP?

Answer 5

ITP: Immune thrombocytopenic purpura
- IgG antibodies made to GpIIb/IIIa
= IMMUNE response

TTP: thrombotic thrombocytopenic purpura

• abnormal vwf multimers which cause arterial thrombi in micro vessels
• result in organ failure etc..

Question 6

State the following for
Glanzmann’s thrombasthenia

1. dominant/recessive/sex or autosomal
2. Which receptor is defective
3. Activation, adhesion, or aggregation defect
4. Bleeding time change or not

Answer 6

Glanzmann’s thrombasthenia

Autosomal recessive,
GPIIb/IIIa defect,
aggregation defect (decreased) ,
bleeding time increased

Question 7

State the following for
Bernard- Soulier Disease

1. dominant/recessive/sex or autosomal
2. Which receptor is defective
3. Activation, adhesion, or aggregation defect
4. Bleeding time change or not

Answer 7

Autosomal recessive,
GP Ib defect,
adhesion defect* (not aggregation)
bleeding time increased

Question 8

What is a storage pool disease?

What is polycethemia vera?

Answer 8

decrease dense granule content (ADP, serotonin, histamine, Ca)

no aggregation

2. Acquired disorder of platelets
   - cancer of RBCs which hematocrit increases tremendously

Question 9

What is normal in vascular disorders that are NON THROMBOCYTOPENIA purpuras?

Answer 9

Platelet function and coagulation are normal.

• Easy bruising, bleeding from mucosa, purpura, vasculitis.

Question 10

What are the following examples of:

1. Ehler Danlos Syndrome (Hypermobile joints. Hyperflexible skin, osteogenesis imperfecta, drugs, infections, amyloidosis)
2. Purpura simplex, amyloids, drugs, steroid purpura (prednisone), Cushing’s syndrome (steroid excess), Henoch-Schonlin purpura (usually drug induced).

Answer 10

1. CONGENITAL SUBENDOTHELIAL disorder
   = ehler danlos
2. Acquired SUBENDOTHELIAL disorder

Question 11

What is the most common congenital endothelial disorder ?

What are examples of acquired endothelial disorders?

Answer 11

Hereditary hemorrhagic Telangiectasia (HHT)

Inflammation, vasculitis (drugs, viruses, Rickettsia)

Question 12

The following are examples of what?

• Orthostatic purpura
• Mechanical purpura (mechanical pressure)
• Increased transluminal pressure

What is a nutritional disorder of the vasculature?

Answer 12

Mechanical disorder

2. Scurvy (vit C deficient)

Question 13

What occurs in Factor V leiden (aka APC - activated protein C deficiency)?

What is the function of protein C?

Answer 13

Protein C cannot digest and inactivate Factor 5

• cofactor in final pathway activating 10 to 10a & 2 to 2a
• point mutation results in enhanced 5 activity and no inactivation by protein Ca
• protein C and S are anti-coagulant and vitamin K dependent and are carboxylated by gamma-carboxyl glutamic acid

**If activated protein C cannot regulate factor 5 then the coagulation cascade is not controlled and THROMBOSIS occurs!

PROTEIN C - digests factor 5 & 8

Question 14

What is released by heparin and capable of inhibiting TF and the TF/Factor 7 complex?

Answer 14

tissue Factor Pathway Inhibitor!

• Intrinsic pathway: PTT, heparin, hemophilia

Extrinsic: PT, warfarin/coumadin

Question 15

What are the most common coagulation defects in the intrinsic pathway?

Answer 15

Hemophilia A (Factor VIII)
-8

Hemophilia B (Factor IX) -9

Question 16

What factors are involved in 12 to 12a conversion?

Answer 16

Fischer Factor & Fletcher factor (kallikrein)

• Kallikrein can act on HMWK collagen and release KININS

= the most potent vasodilating mechanisms
which is why some patients with coagulation (DIC) will also have hypotension due to decreased BP as a result of kallikrein conversion

Question 17

PT & warfarin/coumadin are most part of which pathway?

Answer 17

EXTRINSIC

Question 18

What stabilizes fibrin and leads to cross-linking?

Answer 18

Factor 13 a transamidase

Question 19

What are the vitamin K dependent proteins?

Answer 19

2,7,9,10 C & S

• Protein C and Protein S
  vitamin K dependent proteins just like 2,7,9,10
  protein C and S have anti-coagulant function
  protein C to Ca by thrombin-thrombomodulin
  protein S is a REQUIRED COFACTOR for the transformation of protein C to Ca

Question 20

What substances are measured by PT?

APTT?

Answer 20

2.5.7.10 and fibrinogen

8,9,10,12

( all except 7, 13 and protein C and S)

Question 21

State the following for Hemophilia A & B:

1. Transmission
2. APTT
3. Platelet count

Answer 21

1. sex linked recessive
2. APTT IS ELEVATED!
3. No effect on platelet number

Question 22

How are Type 1 and 3 vWf diseases different from type 2?

Describe vwf disease.

Answer 22

1 & 3 = decrease in circulating level of factor

2 = QUALITATIVE defect in the protein

vWF
= cementing protein made by the endothelium and able to bind vWF to collagen in subendothelium and then to paltelets GpIb  if this binding doesn’t occur there is NO adhesion (lack of first step of coagulation)

Qualitative defect - protein is not binding

Quantitative defect - less production

Question 23

How would you distinguish hemophilias vs. Von willebrand’s disease using the following?

1. APTT
2. Platelet
3. Bleeding time

Answer 23

Hemophilias:
APTT prolongation
 (45s, normal is 30s)
Platelet function-normal
Bleeding time - no effect

Von Willebrand’s Disease

• APTT slightly elevated due to mild reduction in factor VIIIc (almost no change)
• Hemostatic function impaired due to impaired adhesion of platelets to collagen in-vivo. (PLATELETS)
• Bleeding time ELEVATED!!!.

Question 24

TPP is due to a defect in what enzyme?

Answer 24

ADAMS13

Pathogenicity of TPP:
overexpression of VWF multimers trapping platelets and causing occlusion of small vessels = MICROANGIOPATHIC occlusion
ADAMS13 enzyme is deficient and cannot cut down the VWF into small monomers!!!
bleeding due to deficiency of vWF

Question 25

A decrease in the fibrinogen concentration and an increase in degradation product formation contribute to what?

Answer 25

BLEEDING - Excessive activation of the fibrinolytic system can cause bleeding.

Question 26

How is primary fibrinolysis different from secondary? What causes each?

Answer 26

Primary: - fibrinogen is converted into FDP only by plasmin (fibrinogen degradation products) Ex: Dead Baby Syndrome ( Abruptio Placenta) - snake bite Overdosage of thrombolytic agents can result in a primary fibrinolytic state and cause bleeding Secondary: DIC - both fibrin & fibrinogen are digested by plasmin (create Fibrinogen DP and Fibrin DP) - Secondary fibrinolysis is also associated with digestion of clotting factors and consumption of platelets. ***D- Dimer is a hallmark for diagnosis of DIC usually due to SEPSIS

Question 27

What is the hallmark of DIC?

Answer 27

D- dimer formation

Question 28

Deficiency of a2-antiplasmin results in what?

Answer 28

Results in increased fibrinolysis (Bleeding) anti-plasmin is an inhibitor of plasmin (fibrinolytic enzyme) - Plasmin is a SERINE PROTEASE alpha 2 antiplasmin complex will form inactivating PLASMIN to measure this complex use ELISA method to find out the amount of the complex and the extent of fibronolysis in the patient

Question 29

How does heparin induced thrombocytopenia occur? How can drug induced bleeding by heparin be controlled?

Answer 29

1. PF-4 forms a complex with heparin, antibodies attack the complex and degrade it - thrombocytopenia 2. Heparin Protamine Sulfate!

Question 30

How are bleeding disorders diagnosed?

Answer 30

1. Bleeding time 2. Platelet count 3. platelet function Adhesion Aggregation * (most used) Activation - Aspirin treated patients will not respond to Arachinodic Acid (inhibits COX2) test over-ingestion with arachinodic acid aggregation Collagen can also activate platelets by binding to vWF and GpIb - collagen induced aggregation is also used

Question 31

How are the following Thrombophilias diagnosed? 1. Factor V leidein 2. prothrombin 20210 3. Hyperhomocysteinemia

Answer 31

1. Factor V Leiden (APC resistance) - PCR method to see if a patient is Factor 5 deficient - 30% of patients who develop DVT 2. Prothrombin 20210 - overproduction of pro-thrombin resulting in thrombosis - measure with PCR 3. Hyperhomocysteinemia - homocystein was usually measured in urine, but this defect is due to a methionine transformation meth-THF reductase enzyme is responsible for the transformation and is defective - test for MTHFR (methotrexate inhibits MTHFR - used in tx of leukemia and lymphomas) - some patients develop excessive thrombosis due to inhibition of MTHFR

Question 32

______ can be increased in diabetes, cancer, inflammation What is the normal fibrinogen level? What is the D-dimer test used to diagnose?

Answer 32

1. Plasminogen activator inhibitor (PAI) Most basic tests are PT, PTT, fibrinogen level, platelet count, and then PCR for molecular diagnosis 2. Fibrinogen normally 400ml/dl DIC= 200 or 100 ml/dl 3. D - dimer used to diagnose DIC

Question 33

Which of the blood clotting tests is commonly used for the diagnosis of Hemophilias? ``` Activated partial thromboplastin time Prothrombin time/INR Thrombin time Bleeding time Fibrinogen levels ```

Answer 33

APTT - slight increase of 3-5 seconds Which is used to monitor Heparin = APTT Which of blood clotting test is used for monitoring of WARFARIN = PT /INR

Question 34

A patient was admitted to the hospital with a urinary tract infection. Two days later he developed fever and his coagulation parameters and platelet count became abnormal. Additional test showed D-dimer positive and positive blood cultures for E. Coli. What is the likely diagnosis of this patient ``` DIC Hemophilia Hypercoaguable state APC Resistance Von Willebrand disease ```

Answer 34

DIC

Question 35

1. Splenectomy results in thrombocytopenia or thrombocytosis? 2. NSAIDS & Aspirin results in quantitative or qualitative changes in platelets?

Answer 35

Thrombocytosis - platelets are functioning normally and released into circulation 2. QUALITATIVE changes - function is impaired