Flashcards in Coagulation Part I Deck (65):
What 2 things does endothelial cell wall injury cause?
1. platelet activation
What will platelets do upon activation?
form a platelet plug (primary hemostasis) as the primary defense against a tear, but they have to be reenforced by coagulation (secondary hemostasis).
What are the two systems of secondary hemostasis that lead to FIBRIN formation?
1. intrinsic system
2. extrinsic system
Where do the extrinsic and intrinsic pathways meet in the coagulation cascade?
at the formation of factor X (10)= start of the combined pathway.
What single factor makes up the intrinsic pathway?
Factor VII (7).
What 4 factors make up the extrinsic pathway?
Factors XII (12), XI (11), IX (9), VIII (8)
What 5 factors make up the common pathway?
Factors X (10), V (5), prothrombin, which is converted to thrombin, and then it converts fibrinogen into fibrin!
What factor is not really active in the coagulation cascade?
Factor XII (12). So a person with a factor 12 deficiency will not have any clinical problems (despite the coagulation test done outside of the body indicating that it should be a problem) since it really has no role in blood clotting, when inside the body :)
What is the role of factor XIII (13)?
It is activated by thrombin to cross-link fibrin, forming a stable clot over the platelet plug.
Will a person with factor 13 deficiency be detected by the standard tests (PT or PTT)?
NO. So in this case the person would have a clinical problem, but the coagulation tests would not detect it.
What are the two clotting tests used?
1. partial thromboplastin time (PTT)= intrinsic pathway
2. prothrombin time (PT)= extrinsic pathway
What type of surface does the PTT test require to initiate coagulation in the intrinsic system?
What initiates the PT test in the extrinsic system?
**If a patient has a prolonged PTT, but a normal PT in what system would you find the defect?
What is the international normalized ratio (INR)?
gives a value that can be interpreted internationally based on the clotting times of the prothrombin time (PT).
What are the most common bleeding disorders?
Coumadin and heparin overdoses followed by thrombocytopenia, liver disease, and surgical complications.
What is Coumadin (Warfarin)?
blocks the utilization of vitamin K on the vitamin K dependent coagulation factors.
What are the vitamin K dependent coagulation factors?
10, 9, 7, and 2 (prothrombin). All of these proteins are synthesized in the liver, but are not biologically active. Vitamin K allows the carboxylation of glutamine residues to form Gla residue (biologically active).
What could cause a greater than expected response to Coumadin (increased INR or increased PT time)?
- suppression of GI flora ability to synthesize vitamin K by antibiotics (low vitamin K and thus more unopposed Coumadin= greater coagulation effect).
- malabsorption of vitamin K
What could cause a lower than expected response to Coumadin (decreased INR or decreased PT time)?
- increased ingestion of leafy vegetables, broccoli, liver, kale (increases vitamin K ).
- genetic variation and hereditary warfarin resistance.
What should you do in the case of Coumadin overdose?
discontinue use and can also give vitamin K, fresh frozen plasma, or prothrombin complex concentrates.
What is Heparin?
negatively charged (anionic) glycosaminoglycan (straight chain of mucopolysaccharides) that binds to and activates ANTITHROMBIN, which leads to inactivation of thrombin and factor 10a, as well as factors 9, 11, and 12.
How do we manage heparin overdose?
withhold heparin (short half life) or give protamine sulfate (not effective for low molecular weight heparins).
What is low molecular weight heparin?
affects thrombin and factor 10a, and has longer half life. Can also be given subcutaneously, thus can be given in outpatient setting. The problem is that there is not a good way to monitor levels, and thus overdose becomes an issue.
How do we monitor heparin dose?
partial thromboplastin time (PTT)
What are the global effects of liver disease?
- thrombocytopenia (low platelets) due to alcoholism or hypersplenism (uses platelets)
- decreased synthesis of coagulation factors
- accelerated fibrinolysis
How do you manage liver disease?
manage underlying liver disease, fresh frozen plasma, cryoprecipitate, and vitamin K
What is fibrinolysis?
normal process that occurs to reduce to amount of fibrin if it is in excess. At the end of the process, you produce PLASMIN from plasminogen, which degrades fibrin. Thus, you reduce clotting.
What is an activator of plasminogen?
tissue plasminogen activator (tPA) which is a thrombolytic agents that "busts" the clots in strokes or MIs :)
What could cause abnormal fibrinolysis?
trauma, infection, or liver disease
How do you diagnose abnormal fibrinolysis?
measure the fibrinogen degradation products (will not see D-dimers because this is the result of excessive cleavage of serum fibrinogen and NOT fibrin thrombi split products).
What is disseminated intravascular coagulation (DIC)?
bleeding state caused by the rapid inappropriate activation of coagulation factors via tissue factor leading to the subsequent consumption of platelets and factors 5 and 7.
What are the predisposing conditions for DIC?
sepsis, trauma, obstetric complications, acute pancreatitis, malignancy, nephrotic syndrome, or transfusion.
To what does DIC lead?
- microangiopathic hemolytic anemia
- multi-organ failure (from clumps of platelets)
- secondary fibrinolysis and fibrinogenolysis (triggered by presence of too many clotting factors).
What diagnoses can DIC cause?
- microangiopathic hemolytic anemia
- evidence of secondary fibrinolysis and fibrinogenolysis (use fibrinogen degradation products= d-Dimers).
What are d-Dimers?
cross-linked fibrin degradation products.
How do you manage DIC?
- maintain hydration to avoid multiorgan failure
- replacement therapy (platelets, FFP, cryoprecipitate)
- judicious heparin anticoagulation if there is a risk for thromboembolisms (BE VERY CAREFUL BC THIS COULD MAKE IT WORSE).
What is thrombotic thrombocytopenia purpura (TTP)?
- inhibition of ADAMTS 13 (vWF metalloprotease) decreasing degradation of vWF multimers, causing extensive microscopic clots to form in the small blood vessels throughout the body. It can be hereditary or occur due to pregnancy, medication or infection.
How does TTP present clinically?
as a pentad:
1. Thrombocytopenia (platelet deficiency)
2. Heomolytic anemia (RBC degradation)
3. Neurologic signs
5. Renal impairment
How do you treat TTP?
plasmapheresis and steroids
Will you have normal coagulation tests with TTP?
What are the hereditary bleeding disorders?
vWD= vWF and is the most common
hemophilia A= factor 8
hemophilia B= factor 9
hemophilia C= factor 11 (Ashkenazi Jews)
What are the clinical features of hemophilia A and B?
- hemarthrosis (joint bleeding) and delayed bleeding (ex. hours after a dental procedure you start to bleed and cannot stop).
- males have disease and females are usually carriers (X-linked recessive for both hemophilia A and B).
What are the clinical features of hemophilia C?
generalized bleeding and is autosomal dominant.
What are the clinical features of von Willebrand disease?
mucocutaneous bleeding, immediate bleeding, and has autosomal inheritance
How do you diagnose hemophilia?
measure the coagulant level:
- decreased factor 8c for hemophilia A
- decreased factor 9c for hemophilia B
- decreased factor 11c for hemophilia C
How do factor 8 and vWF interact?
- Factor 8 (large protein made in the liver) binds to vWF (largest protein, synthesized in endothelial cells), stabilizing factor 8allowing it to more efficiently operate.
- vWF also binds to platelets via Gp1b platelet receptor to activate them.
What is von Willebrand disease?
intrinsic pathway coagulation defect= decrease in vWF, which normally acts to carry/protect factor 8. This also leads to defect in platelet plug formation due to decrease in platelet-to-vWF adhesion. There are types 1-3.
What happens in type 1 vWD?
This type is the most common (80%).
There is an equal reduction in both low and high-molecular-weight vWF multimers
What happens in type 2 vWD?
The low-molecular-weight vWF multimers are present, but the high-molecular-weight multimers are absent.
What happens in type 3 vWD?
There is a total absence of both low and high-molecular-weight vWF multimers.
What is acquired vWD?
antibodies against vWF
How do we test for vWD?
- bleeding time to test platelet function
- quantitate factor 8 activity
- quantitate vWF cofactor activity using Ristocetin
- quantitate vWF antigen (protein)
- study multimer pattern
What would lab results be for type 1 vWD?
concordant results= vWF activity/vWF antigen
What would other types of wVD other than type 1 show for their lab results?
discordant results= vWF activity/vWF antigen >0.7
Is bleeding time normal for hemophilia A when diagnosing in the lab?
How do we manage hemophilia A?
- using DDAVP (desmopressin)= vasopressin (ADH) analog. Use this for minor injuries or minor surgeries.
- for major surgeries give factor 8 concentrates
How do we manage hemophilia B?
using factor 9 concentrates
How do you manage hemophilia C?
fresh frozen plasma
How do you manage vWD?
DDAVP for mild injuries or minor surgery.
For large surgeries you must use plasma derived factor 8 concentrates (that already has vWF) but NOT recombinant concentrates because these don't have vWF.
How are the platelet plugs formed?
when the platelets become activated, they through out pseudopods that help to form the plug.
Do platelets have nuclei?
NO, but they do have granules, a microtubule network, and mitochondria.
How do platelet disorders present clinically?
history of easy bruising, mucocutaneous bleeding, petechiae, and purpura.
What is thrombocytopenia?
platelet counts less than 150,000/uL