What does Factor V do in the coagulation cascade?
- activated factor V forms a complex with activated factor Xa
- this complex cleaves prothrombin into thrombin which forms fibrin - initiating platelet aggregation
- factor V is inactivated by activated Protein C
What is Factor V Leiden?
Factor V Leiden is a mutation at position 506 on the factor V gene. The mutation causes a Glutamic Acid residue to replace an Arganine residue. Position 506 is the place where factor V is normally cleaved into 2 fragments by activated Protein C. If factor V cannot be inactivated then there is increased risk for clotting.
Name some factors that can lead to vasoconstriction.
- compression due to obesity
- prior sites of a thrombus
- chemical factors such as nicotine and vasoconstriction agents
Name some modifiable risks for coagulation.
- obesity
- sedentary lifestyle
- travel
- pregnancy
- elective surgery - especiall ortho with its associated immobilization
- smoking
- prior DVT
- use of birth control pills
Name some un-modifiable risk factors for coagulation.
- Factor V Leiden
- prothrombin gene mutation
- malignancy
- emergent surgery
- chronic illnes
- Lupus anticoagulant
If you have a couple risk factors or have the Factor V Leiden mutation does that mean you will clot?
Not necessarily, you have to overwhelm the coagulation system. Even with the presence of risk factors it would take at least 4 risk factors at once to ensure abnormal clotting.
For acute thrombogenesis, why do patients require 7-10 full days of heparinization even with adequate coumadinization?
Coumadin basically causes vitamin K depletion which is required for the vitamin K dependent cofactors - factors II, VII, IX, X and protein C. The liver will continue to make these factors and some of them will already be carboxylated. These carboxylated factors will be inactivated according to their half lives but this takes time - so 7-10 days is needed for the Coumadin to work.
Can Coumadin be initiated at the same time as heparin?
Yes, because its effects will not be seen right away.
What is Lupus Anticoagulant?
LA is an acute phase reactant. If present then will see at time of an acute clot. It is called an anticoagulant because in vitro it caused a prolonged PTT but it is actually a procoagulant. If present then it is considered a risk factor for clotting.
What is recommended before making long-term therapeutic coumadin decisions when Lupus anticoagulant is present?
A repeat serology is recommended 3 months after an acute thrombotic event.
Describe the two types of Heparin induced thrombocytopenia.
- Type 1 - modest, transient decrease in platelets secondary to heparin induced platelet agglutination. Is self-limited, platelet counts can return to normal even while heparin is continued
- Type 2 - a drug induced, immune mediated response secondary to antibodies directed against Heparin-Platelet factor 4 complex that results in a 50% or greater drop in platelet counts. Severe thrombocytopenia with bleeding is rare.
- Type 2 is most common in the setting of major surgery where large volumes of heparin are required coronary artery bypass grafting.
How is Type II HIT diagnosed?
Measure radiolabeled 5-HT.
When should HIT be on the differential diagnosis?
Should be considered in all recently hospitalized patients returning with acute thrombosis within 1-2 weeks of their hospital stay. Clinically you will see thrombocytopenia and thrombosis. The thrombosis is treated with direct thrombin inhibitors.
Name some clinical characteristics of HIT.
- incidence is 10X greater than patients treated with unfractionated heparin than in those receiving LMWH
- incidence higher among surgical patients
- uncommon among pediatric, obstetrical, and hemodialysis patients
- thrombosis with declining platelets is seen in about 50% of patients with recent hospitalization
What are the direct thrombin inhibitors?
- Dabigatran
- Argatroban
- Ximelagatran
What drug can reverse the effects of too much Heparin?
Protamine Sulfate.
What is the pathophysiology of DIC?
Widespread activation of the clotting cascade causing a consumption of clotting factors and platelets with resultant bleeding. The microvascular compromise secondary to thrombin formation results in tissue ischemia with result an end organ damage particularly of the liver and kidneys.
What are some diseases or conditions that promote expression of tissue factor and thus promote DIC?
- gram pos or neg septicemia
- damaged cerebral tissue
- APL
- placental tissue from obstetric catastrophes
- snake venoms
- acute hemolytic transfusion reactions
- hypotension from any cause that results in endothelial cell damage
- massive tissue injuries such as trauma, burns and hypothermia
Why does sepsis cause activation of coagulation?
Endotoxin, IL-1, TNF-a and other cytokines trigger the release of tissue factor and this causes activation of coagulation.
What are the characteristic lab findings of DIC?
- prolonged PT/PTT or both
- thrombocytopenia
- decreased fibrinogen levels
- increased D-dimer
What is the primary treatment for DIC?
- treat the underlying condition - treat bacterial infection with broad spectrum, empiric antibiotics until microbe can be identified
- supportive care, including maintaining platelets at greater than 100,000 and maintaing fibrinogen at greater than 100.
What kinds of conditions can lead to hypocoagulative states and bleeding?
- trauma
- infections
- drugs
- disorders of the coagulation system such as platelets and congenital or acquired factor disorders - platelet disorders are common but not often associated with clinically relevant bleeding
- disorders of organ systems such as liver failure, renal failure, CABG surgery, myeloproliferative syndromes
What are some drugs that can cause bleeding?
- GP IIb/IIIa inhibitors such as Plavix
- COX I inhibitors such as aspirin
- Heparin
- Coumarins
- ginko and ginseng
Renal failure can lead to acquired platelet dysfunction. What is one of the treatments for this condition?
DDAVP or Desmopressin. This drug works by limiting the amount of water excreted by the kidney and it also causes release of vWF from Weibel Palade bodies. vWF binds to platelets and also increases the half life of Factor VIII.
