ABnormal Hemostasis I&II

Question 1

What can cause thrombotic and bleeding disorders?

Answer 1

abnormal function of platelets and vascular endothelial

Question 2

What are the different types of QUANTITATIVE platelet pathology?

Answer 2

DECREASED platelet count results in bleeding, known as THROMBOCYTOPENIA
INCREASE platelet count
a. THROMBOCYTOSIS-benign
b. THROMBOCYTHEMIA-clonal proliferation (neoplastic)

Question 3

THROMBOCYTOPENIA

Answer 3

• alteration in bone marrow: marrow hyperplasia, aplasia, replacement by neoplastic cells, marrow fibrosis, radiation injury, leukemia, paroxysmal nocturnal hemoglobinurea (PNH)
• hereditary (not very common): May Hegglin anomaly (autosomal dominant), Wiskott-Aldricj syndrome, absent radius syndrome, Fanconi’s anemia
• abnormal hematopoiesis (acquired): B12/folate deficiency, pre-leukemia
• drug-induced (direct or INdirect with platelet antibodies): Heparin**, gold, quinine, quiinidine, sulfonamides, GP2b/31 inhibitors
• dilutional: hemodialysis, heart lung machine
• ITP and TTP
• –ITP=immune thrombocytopenic purpura (IgG mediated); endogenous aggregation of platelets
• –TTP: thrombotic thrombocytopenic purpura (abnormal vWF multimers), arterial thrombi (platelet rich); aggregates sans trigger
• HUS: hemolytic uremic syndrome

Question 4

THROMBOCYTOSIS

Answer 4

• splenectomy-platelet function is normal (spleen=filter)

- reactive thrombocytosis-due to cancer, infection, drugs

Question 5

THROMBOCYTHEMIA

Answer 5

-autonomous thrombocytosis, clonal disorder 
platelets INCREASE (>1,000,000 µl): clusters of -platelets in circulation, may occlude small vessels, bleeding may occur

Question 6

QUALITATIVE DISORDERS

Answer 6

• platelet NUMBERS usually NORMAL, platelet FUNCTION is IMPAIRED
• 1. disease induced platelet defects: liver disorders, paraproteinemia; (adhesion, activation aggregation)
• 2. drug induced platelet defects: aspirin (COX2 inhibitor), NSAID
• 3. diet induced platelet defects: omega-3 fatty acids (ocean fish)–>blocks generation of thromboxane

Question 7

INHERITED disorder of platelets

Answer 7

• congenital disorders resulting mostly in bleeding diathesis
  1. Glanzmann’s thrombasthenia-autosomal recessive, GP2b/3a defect, aggregation defect, INCREASED bleeding time
  2. Bernard-Soulier disease-autosomal recessive, GP 1b defect, adhesion defect, INCREASED bleeding time
  3. Storage pool disease-DECREASES dense granule content, no aggregation
  4. other disorders-purpura of unknown origin-gray (instead of white) platelet syndrome. lack of alpha granules

Question 8

OTHER acquired disorders of platelets

Answer 8

• metabolic disorders-uremia (bleeding)
• myeloproliferative disorders-polycythemia vera (high hematocrit [60 instead of 45], cancer of the red cells, , granulocytic leukemia, myelofibrosis

Question 9

General: Vascular disorders

Answer 9

• NON-THROMBOCYTOPENIC PURPURAS, do NOT result in severe bleeding diathesis
• platelet function and coagulation are NORMAL
• easy bruising, bleeding from mucosa, purpura, vasculitis (inflammation of the blood vessels)

Question 10

SUBendothelial Disorders

Answer 10

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

Question 11

ENDOTHELIAL DISORDERS

Answer 11

1. CONGENITAL-MOST COMMON, hereditary hemorrhagic, telangiectasia (HHT), arteriovenous malformation; giant hemangioma (Kasaback-Merritt syndrome)
2. ACQUIRED-inflammation, vasculitis (drugs, viruses, Rickettsia)

Question 12

Mechanical and Nutritional Disorders

Answer 12

C. MECHANICAL DISORDERS 
1. Orthostatic purpura 
2. mechanical purpura 
3. *increased transluminal pressure 
D. NUTRTITIONAL DISORDERS 
scurvy (vit C deficiency)

Question 13

BLEEDING DISORDERS due to COAGULATION FACTOR ABNORMALITIES: Intro and Labs

Answer 13

Intro: specific defects in clotting factors: 8 (Hemophilia A), 9 (Hemophilia B)
Lab Diagnosis:
1. PT (EXtrinsic): 2, 5, 7, 10,, and fibrinogen (7 is uncommon)
2. APTT (INtrinsic): 8, 9, 11, 12 (measure ALL factors, BUT: 7, 13, protein C & S)

Question 14

BLEEDING DISORDERS due to COAGULATION FACTOR ABNORMALITIES: Hemophilias and vW

Answer 14

• Hemophilia A and B
• –defects due to coagulation factors…most result in bleeding
• –both transmitted as sex-linked recessive; APTT ELEVATED, no effect on platelets
• –Hemophilia A (classical)-F8 coagulant deficiency
• –Hemophilia B (Christmas disease)-F9 deficiency
• von Willenbrand’s disease
• –hemostatic defect due to vWF (ristocetin co-factor, F8 antigen) defect.
• —–vWF binds to platelet receptors (GP 1b, 2b, 3a) and to collagen and SUBendothelium
• –Type 1 and Type 3 vW: DECREASE in circulating level of the factor
• –Type 2 vW: QUALITATIVE (molecular structural defect) defect in the protein

Question 15

BLEEDING DISORDER due to ABNORMALITIES of the FIBRINOLYTIC SYSTEM-Intro

Answer 15

• excessive activation of fibrinolytic system can cause bleeding
• REDUCTION in [fibrinogen] and an INCREASE in fibrinogen degradation products contribute to bleeding

Question 16

BLEEDING DISORDER due to ABNORMALITIES of the FIBRINOLYTIC SYSTEM-PRIMARY

Answer 16

• fibrinogen is converted into fibrinogen degradation products
• seen in dead fetus syndrome (Abruptio Placenta)
• fibrinogen degradation products can also produce anticoagulant effects
• overdosage of thrombolytic agents can result in a primary fibrinolytic state and cause bleeding

Question 17

BLEEDING DISORDER due to ABNORMALITIES of the FIBRINOLYTIC SYSTEM-SECONDARY (DIC-disseminated intravascular coagulation)

Answer 17

• BOTH fibrin and fibrinogen are digested by plasmin=simultaneous digestion of clotting factors and consumption of platelets
• complex syndrome/consumption coagulapathy

Question 18

What is the pathogenesis of DIC?

Answer 18

massive tissue destruction, sepsis, and endothelial injury lead to release of TF ( endothelial injury also leads to platelet aggregation)
release of TF leads to widespread microvascular thrombosis which leads to three things:
1. activation of plasmin
fibrinolysis–>fibrin split products–>inhibition of thrombin, platelet aggregation, and fibrin polymerization
proteolysis of clotting factors
2. vascular occlusion–>ischemic tissue damage–>microangiopathic hemolytic anemia
3. consumption of clotting factors and platelets
eventually all lead to BLEEDING

Question 19

What happens when there is a deficiency of alpha-2 antiplasmin?

Answer 19

• results in increased fibrinolysis (bleeding)

- alpha 2-AP-plasmin complex, alpha 2-AP binds plasmin at the serine site

Question 20

What are drug-induced bleeding disorders?

Answer 20

A. bleeding with thrombolytic drugs
B. bleeding with anti-coagulants (heparin**)
C. bleeding with drugs
–antiplatelet drugs
–thrombolytic drugs
D. drug-induced thrombocytopenia
E. **Heparin Induced Thrombocytopenia (HIT)

Question 21

What are HIV associated bleeding disorder mostly due to?

Answer 21

Thrombocytopenia

Question 22

How do you diagnose bleeding disorders?

Answer 22

A. Bleeding Time 
B. Platelet Count 
C. Platelet Function Studies (triple A) 
---adhesion 
---aggregation 
---activation

Question 23

What is the molecular diagnosis of bleeding disorders?

Answer 23

Factor V Leiden
Prothrombin 20210
Hyperhomocysteinemia