TBL-Coagulation Disorders

Question 1

Take me through the sequence of events that happen after vascular injury

Answer 1

1) Neurological & endothelin-induced vasoconstriction 2) Platelet GpIb adheres to exposed ECM vWF 3) Platelets change shape and release ADP & TxA2 4) ADP & TxA2 recruit and activate surrounding platelets, TxA2 vasoconstricts 5) ADP activates platelet GpIIb/IIIa receptor 6) Fibrinogen binds GpIIb/IIIa 7) Primary hemostatic plug is formed 8) TF-VIIa initiate clotting cascade and activate thrombin 9) Fibrin polymerization occurs and secondary hemostatic plug is formed 10) Release of t-PA and thrombomodulin for antithrombotic effects.

Question 2

What are some of the antithrombotic properties of the blood vessels?

Answer 2

ANTI-PLATELET EFFECTS: PGI2 and NO = vasodilation, adenosine diphosphatase to get rid of prothrombotic ADP. ANTI-COAGULANT EFFECTS: thrombomodulin binds thrombin and causes it to activate protein C, which inhibits Va and VIIIa and stops clotting. TFPI inhibits tissue factor-VIIa and Xa. Both thrombomodulin and TFPI enhance ATIII activity. Finally, t-PA activates plasmin and fibrinolysis.

Question 3

What are some of the prothrombotic properties of the blood vessels?

Answer 3

PLATELET EFFECTS: vWF. PROCOAGULANT EFFECTS: TF synthesis. ANTI-FIBRINOLYTIC EFFECTS: PAIs limit fibrinolysis

Question 4

Bernard-Soulier syndrome

Answer 4

AR deficiency in the complex GpIb-IX, which is essential for platelet adhesion to collagen

Question 5

Dense platelet granules

Answer 5

ADP, ATP, ionized Ca2+ are important in initiating platelet aggregation and clotting cascade

Question 6

How does thrombin cause further platelet aggregation and inflammation?

Answer 6

Binding to protease-activated receptors (PARs) on platelet membranes, monocytes, dendritic cells and T-lymphocytes

Question 7

Glanzmann thrombasthenia

Answer 7

AR deficiency in GpIIb-IIIa, resulting in decreased platelet bridging

Question 8

Clopidogrel mechanism of action

Answer 8

Inhibition of ADP binding receptor on platelet membranes.

Question 9

What attracts leukocytes to join up with the fibrin clot?

Answer 9

Chemotactic fibrin split products

Question 10

Why take a baby aspirin?

Answer 10

Irreversible inhibition of COX blocks TxA2 synthesis and decreases thrombosis. Although PGI2 production is inhibited, endothelial cells can rapidly regenerate COX.

Question 11

Where do the clotting factors aggregate?

Answer 11

Phospholipid surface and are held together by Ca2+ ions

Question 12

Vitamin K dependent factors?

Answer 12

II, XII, IX, X, protein C and protein S

Question 13

Know the clotting cascade

Answer 13

*

Question 14

Why do people with a higher hematocrit have falsely increases PT times?

Answer 14

They have less plasma and therefore the concentration of citrate is higher in their plasma. Higher citrate concentration requires higher Ca2+ to activate the clotting cascade.

Question 15

Factors inactivated by ATIII. What activates ATIII?

Answer 15

IIa, IXa, Xa, XIa, XIIa. ATIII is activated by heparin-like molecules.

Question 16

Factors inactivated by proteins C and S. What activates protein C?

Answer 16

Va and VIIIa. Protein C is activated by thrombomodulin.

Question 17

Factors inactivated by TFPI

Answer 17

TF-VIIa complex

Question 18

Useful indication for DIC, DVT or PE.

Answer 18

D-dimers. These are fibrin split products from plasmin degradation of the fibrin clot.

Question 19

When is plasminogen most likely to be activated?

Answer 19

When t-PA is bound to fibrin.

Question 20

Plasminogen activators

Answer 20

t-PA, urokinase and streptokinase

Question 21

How is plasmin prevented from lysing thrombi all over the body?

Answer 21

Rapid inactivation by alpha2-plasmin inhibitor

Question 22

How does PAI work?

Answer 22

Prevents binding of t-PA to fibrin, thus preventing t-PA activation and plasminogen will not be activated as a consequence.

Question 23

What are all of the things thrombin ends up activating?

Answer 23

*

Question 24

Most common inherited cause of hypercoaguability

Answer 24

Factor V gene become resistant to cleavage by protein C

Question 25

Common cause of hypercoaguable state w/high levels of prothrombin

Answer 25

Prothrombin gene mutation

Question 26

Enzyme deficiency that causes homocysteinemia

Answer 26

5,10-methylenetetrahydrofolate reductase

Question 27

What causes HIT syndrome?

Answer 27

Heparin-induced thrombocytopenia caused by antibodies to heparin and PF4. Antibodies cause platelet activation, aggregation and consumption, resulting in thrombocytopenia AND a hypercoaguable state.

Question 28

Which clotting test will be abnormal in Lupus?

Answer 28

PTT. The antiphospholipid antibody prolongs the test despite causing hypercoaguability in vivo.

Question 29

Differential for normal PT, PTT and platelet count

Answer 29

Meningococcemia (vasculitis), hypersensitivity vasculitis (drug-induced immune complex deposition), weak vessel walls (Scurvy, Ehlers-Danos, Cushing’s, AL amyloidosis), immune complex deposition (Henoch-Shonlein purpura), tortuous blood vessels that bleed easily (Hereditary hemorrhagic telangiectasia)

Question 30

A patient comes to see you complaining of a purpuric rash, colicky abdominal pain, polyarthralgia and acute glomerulonephritis. Labs show normal PT, PTT and platelet count. What is your diagnosis?

Answer 30

Henoch-Shoenlein purpura

Question 31

Most serious threat to someone with a markedly decreased platelet count

Answer 31

Intracranial bleeding

Question 32

Differential for normal PT and PTT with thrombocytopenia

Answer 32

1) Decreased production 2) Decreased survival 3) Sequestration 4) Dilution

Question 33

An adult woman under the age of 40 has an insidious onset of petechiae, epistaxis, gum bleeding, hematuria, melena and excessive menstrual flow. She has also had one previous subarachnoid hemorrhage that almost killed her. Physical exam does not reveal splenomegaly or lymphadenopathy. Labs reveal thrombocytopenia and large platelets on blood smear. There were increased megakaryocytes on bone marrow biopsy. Her PT and PTT were normal. What is causing her condition and how do you treat her?

Answer 33

She is presenting with symptoms of chronic immune thrombocytopenic purpura (ITP). This is most often due to a secondary cause (HIV, Lupus or B-cell neoplasm) and is a diagnosis of exclusion after assessing primary causes. This happens when IgG autoantibodies against GpIIb-IIIa or Ib-IX causes platelet destruction. This can be treated by splenectomy or corticosteroids. If it comes back after splenectomy you give rituximab

Question 34

What is a sign of accelerated thrombopoiesis in patients with chronic ITP?

Answer 34

Megakaryocytes in splenic sinuses and increased magakaryocytes in bone marrow

Question 35

How does acute immune thrombocytopenic purpura differ from chronic ITP?

Answer 35

Acute is a childhood disease, equal in both sexes, follows a viral illness and is self-limited.

Question 36

Common drugs that induce thrombocytopenia

Answer 36

Quinine, quinidine and vancomycin bind Gp’s and become recognized by antibodies.

Question 37

What causes HIT?

Answer 37

Antibodies that recognize heparin and platelet factor 4. When antibodies bind to platelets, they activate them and cause thrombosis in the setting of thrombocytopenia.

Question 38

Why is thrombocytopenia one of the most common presentations in HIV patients?

Answer 38

Megakaryocytes also have CD4 and CXCR4 receptors and get infected with HIV and apoptose.

Question 39

What is the common trigger for thrombotic thrombocytopenic purpura (TTP)?

Answer 39

ADAMTS13 enzyme deficiency. Normally it degrades vWF. When its gone vWF sticks around causes platelet aggregation, resulting in TTP.

Question 40

What is the common trigger for hemolytic uremic syndrome (HUS)?

Answer 40

E. Coli O157:H7 infection and production of Shiga-like toxin, which results in platelet activation and aggregation.

Question 41

Lab values for people with TTP and HUS?

Answer 41

PT and PTT normal

Question 42

What are the two most significant acquired defects that cause platelet dysfunction?

Answer 42

Aspirin use and uremia

Question 43

A patient presents with oozing blood days after tooth extraction and hemarthrosis after minor stress on his knee. What are 3 acquired factor deficiencies he could have?

Answer 43

Vitamin K deficiency, parenchymal liver disease and DIC

Question 44

A patient presents with oozing blood days after tooth extraction and hemarthrosis after minor stress on his knee. What factor deficiency would not cause this?

Answer 44

Factor XII. Thrombin activation of XI and IX compensate for factor XII deficiencies.

Question 45

vWF test

Answer 45

Ristocetin agglutination test

Question 46

vWF deficiency labs

Answer 46

Normal platelet count, normal PT, prolonged PTT because the vWF-VIII complex is decreased, VIII degrades faster and you get an intrinsic clotting factor deficiency.

Question 47

What characterizes mild disease in people with hemophilia A?

Answer 47

6-50% VIII function

Question 48

What are typically absent in hemophilia A?

Answer 48

Petechiae

Question 49

Why is infection good at causing DIC?

Answer 49

Endotoxins induce release of TNF which induces TF expression on endothelial cells and promotes clotting. Endotoxins can activate factor VII

Question 50

Common DIC cancers

Answer 50

Acute promyelocytic leukemia and adenocarcinoma

Question 51

50% of DIC cases

Answer 51

Obstetric related, note typically associated with bleeding

Question 52

33% of DIC cases

Answer 52

Carcinoma related, note typically associated with thrombosis

Question 53

Plasmin cleaves fibrin and…

Answer 53

Digests factors V and VIII