TBL-Coagulation Disorders Flashcards
Take me through the sequence of events that happen after vascular injury
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.
What are some of the antithrombotic properties of the blood vessels?
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.
What are some of the prothrombotic properties of the blood vessels?
PLATELET EFFECTS: vWF. PROCOAGULANT EFFECTS: TF synthesis. ANTI-FIBRINOLYTIC EFFECTS: PAIs limit fibrinolysis
Bernard-Soulier syndrome
AR deficiency in the complex GpIb-IX, which is essential for platelet adhesion to collagen
Dense platelet granules
ADP, ATP, ionized Ca2+ are important in initiating platelet aggregation and clotting cascade
How does thrombin cause further platelet aggregation and inflammation?
Binding to protease-activated receptors (PARs) on platelet membranes, monocytes, dendritic cells and T-lymphocytes
Glanzmann thrombasthenia
AR deficiency in GpIIb-IIIa, resulting in decreased platelet bridging
Clopidogrel mechanism of action
Inhibition of ADP binding receptor on platelet membranes.
What attracts leukocytes to join up with the fibrin clot?
Chemotactic fibrin split products
Why take a baby aspirin?
Irreversible inhibition of COX blocks TxA2 synthesis and decreases thrombosis. Although PGI2 production is inhibited, endothelial cells can rapidly regenerate COX.
Where do the clotting factors aggregate?
Phospholipid surface and are held together by Ca2+ ions
Vitamin K dependent factors?
II, XII, IX, X, protein C and protein S
Know the clotting cascade
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Why do people with a higher hematocrit have falsely increases PT times?
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.
Factors inactivated by ATIII. What activates ATIII?
IIa, IXa, Xa, XIa, XIIa. ATIII is activated by heparin-like molecules.
Factors inactivated by proteins C and S. What activates protein C?
Va and VIIIa. Protein C is activated by thrombomodulin.
Factors inactivated by TFPI
TF-VIIa complex
Useful indication for DIC, DVT or PE.
D-dimers. These are fibrin split products from plasmin degradation of the fibrin clot.
When is plasminogen most likely to be activated?
When t-PA is bound to fibrin.
Plasminogen activators
t-PA, urokinase and streptokinase
How is plasmin prevented from lysing thrombi all over the body?
Rapid inactivation by alpha2-plasmin inhibitor
How does PAI work?
Prevents binding of t-PA to fibrin, thus preventing t-PA activation and plasminogen will not be activated as a consequence.
What are all of the things thrombin ends up activating?
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Most common inherited cause of hypercoaguability
Factor V gene become resistant to cleavage by protein C
Common cause of hypercoaguable state w/high levels of prothrombin
Prothrombin gene mutation
Enzyme deficiency that causes homocysteinemia
5,10-methylenetetrahydrofolate reductase
What causes HIT syndrome?
Heparin-induced thrombocytopenia caused by antibodies to heparin and PF4. Antibodies cause platelet activation, aggregation and consumption, resulting in thrombocytopenia AND a hypercoaguable state.
Which clotting test will be abnormal in Lupus?
PTT. The antiphospholipid antibody prolongs the test despite causing hypercoaguability in vivo.
Differential for normal PT, PTT and platelet count
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)
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?
Henoch-Shoenlein purpura
Most serious threat to someone with a markedly decreased platelet count
Intracranial bleeding
Differential for normal PT and PTT with thrombocytopenia
1) Decreased production 2) Decreased survival 3) Sequestration 4) Dilution
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?
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
What is a sign of accelerated thrombopoiesis in patients with chronic ITP?
Megakaryocytes in splenic sinuses and increased magakaryocytes in bone marrow
How does acute immune thrombocytopenic purpura differ from chronic ITP?
Acute is a childhood disease, equal in both sexes, follows a viral illness and is self-limited.
Common drugs that induce thrombocytopenia
Quinine, quinidine and vancomycin bind Gp’s and become recognized by antibodies.
What causes HIT?
Antibodies that recognize heparin and platelet factor 4. When antibodies bind to platelets, they activate them and cause thrombosis in the setting of thrombocytopenia.
Why is thrombocytopenia one of the most common presentations in HIV patients?
Megakaryocytes also have CD4 and CXCR4 receptors and get infected with HIV and apoptose.
What is the common trigger for thrombotic thrombocytopenic purpura (TTP)?
ADAMTS13 enzyme deficiency. Normally it degrades vWF. When its gone vWF sticks around causes platelet aggregation, resulting in TTP.
What is the common trigger for hemolytic uremic syndrome (HUS)?
E. Coli O157:H7 infection and production of Shiga-like toxin, which results in platelet activation and aggregation.
Lab values for people with TTP and HUS?
PT and PTT normal
What are the two most significant acquired defects that cause platelet dysfunction?
Aspirin use and uremia
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?
Vitamin K deficiency, parenchymal liver disease and DIC
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?
Factor XII. Thrombin activation of XI and IX compensate for factor XII deficiencies.
vWF test
Ristocetin agglutination test
vWF deficiency labs
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.
What characterizes mild disease in people with hemophilia A?
6-50% VIII function
What are typically absent in hemophilia A?
Petechiae
Why is infection good at causing DIC?
Endotoxins induce release of TNF which induces TF expression on endothelial cells and promotes clotting. Endotoxins can activate factor VII
Common DIC cancers
Acute promyelocytic leukemia and adenocarcinoma
50% of DIC cases
Obstetric related, note typically associated with bleeding
33% of DIC cases
Carcinoma related, note typically associated with thrombosis
Plasmin cleaves fibrin and…
Digests factors V and VIII
