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Flashcards in Coagulation Deck (46)
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1. rapid formation of a clot to stop bleeding from a damaged vessel (vessel wall, platelets, coagulation cascade)
2. prevent out of control clot formation (counter-regulatory mechanisms)


site of synthesis of most of the proteins involved in coagulation

•Vitamin K is required to produce active forms of several of the coagulation factor proteins and anticoagulants (protein C and protein S)


hemostastis sequence of events

damage to vessel!
Primary Hemostasis
1. vasoconstriction - reduces blood flowing to the area
2. damaged endothelium exposes collagen, which is normally hidden from the blood
-von Willebrand factor bins to this collagen
3. platelets adhere to vWF to form an initial hemostatic plug
-this activates the platelets and they release granules that recruit additional platelets and play a role in the coagulation cascade

Secondary Hemostasis
4. during damage to the vessels wall, tissue factor is also exposed to circulation
-TF plus the activated platelets initiate the coagulation cascade
5. insoluble fibrin is formed, a cement that holds the platelets together to form a stable hemostatic plug
6. counter regulatory mechanisms are set in action
-protein C, protein S and antithrombin


coagulation cascade

•extrinsic - initiates
•intrinsic - amplifies
•cascade takes place on the phospholipid surface of activated platelets, localizing the cascade


extrinsic pathway



intrinsic pathway



common pathway

•PTT and aPTT


counter regulatory mechanisms

1. antithrombin, after activation by heparin-like molecules on the endothelium, inhibits thrombin and other coagulation factors; this results in inhibition of teh coagulation cascade
2. activated protein C (APC) with its cofactor protein S, inhibits clotting by inactivating factors Va and VIIIa; protein C is activated by a complex of thrombin and thrombomodulin (expressed on the endothelium)
3. tissue plasminogen activator (t-PA), produced by endothelial cells, promotes fibrinolysis to clear fibrin deposits from the endothelial surface


prothrombin time (PT)

•clot formation is initiated by thromboplastin (phospholipid and tissue factor) that is mixed with patient plasma and calcium - time to clot formation is measured
•evaluates extrinsic (VII) and common (X, V, II and fibrinogen) pathways
•used to monitor Vitamin K antagonist therapy
•PT may vary between labs because thromboplastins vary in sensitivity - international normalized rayio (INR) to calibrate


activated partial thromboplastin time

•aPTT reagent (phospholipid with and intrinsic pathway activator) and calcium are added to patient plasma and time to clot formation is measured
•no tissue factor! = "partial thromboplastin"
•evaluates intrinsic (XII, XI, IX, VIII) and common (X, V, II) pathways
•used to monitor unfractionated heparin therapy


D-dimers and fibrin degradation products (FDPs)

•fibrinolysis is mediated by plasmin, which degrades fibrin clots into D-dimers
•if plasmin degrades fibrinogen, FDPs are generated but not D-dimers
•part of a panel of tests in evaluating for disseminated intravascular coagulation (DIC)
•also assist in evaluation of patients suspected of having DVT and/or PE
•D-dimers and FDPs can become elevated whenever the coagulation and fibrinolytic systems are activated (DIC, DVT/PE, malignancy, post-operative states, liver cancer patients, significant bleeding, etc...) therefore this test is not specific for any one diagnosis!


mixing studies and factor assays

•causes of prolonged clotting times include factor deficiencies, factor inhibitors and anticoagulation therapy
•mixing studies are performed to differentiate between them
•normal plasma is mixed with patient plasma and the clotting time is measured again
•factor deficiency? then clotting time should normalize
•factor inhibitor? then clotting time will remain prolonged
•factor deficiencies - factor assay to determine which factor


evaluation of platelet function

•numerous tests available
-platelet aggregometry
-platelet function analyzer
-cutting someone and waiting for them to stop bleeding



•fragments of megakaryocyte cytoplasm shed directly into teh circulation
•life span is 8-10 days, after which they are removed from circulation by the monocyte-macrophage system
•approx 1/3 of the total platelet mass is sequestered in the spleen and in equilibrium with circulating platelets



•low platelets
•most common cause of abnormal bleeding
•in general, severity of hemorrhage correlates with the platelet count
•surgical bleeding <50,000/uL
•clinical or spontaneous bleeding <10,000/uL
•>10,000/uL may be asymptomatic unless challenged with trauma or surgery


platelet type bleeding

•mucocutaneous bleeding
-small ecchymoses


thrombocytopenic patients

•bleeding usually involves small vessels of the skin or mucous membranes


patients with clotting factor deficiencies

•constitute the vast majority of patients with inherited coagulation disorders
•rarely bleed from superficial cuts - initial platelet plugs are enough
•deep hematomas and hemoarthroses, bleeding tends to be delayed after the initial insult


thrombocytopenia classifications

1. decreased production
-drugs, marrow disorders, vitamin deficiency, infection
2. decreased survival
-immune (antibody mediated) ITP, SLE, post-transfusion, HIV, drugs (HIT)
-nonimmune (mechanical) DIC, TTP, cardiac bypass, prosthetic valves
3. splenic sequestration
4. dilution
-massive transfusion - RBC products do not contain significant numbers of viable platelets
5. artifactual


artifactual thrombocytopenia

• consider with cases of unexpected thromocytopenias
•falsely low platelets - not counted due to platelet clumping or platelet satellitism (platelets stick to WBC)
•caused by EDTA (anticoagulant present in blood collection tubes used for CBCs) and anti-platelet antibodies --> clumping or satellism
•repeat sample collected into an alternative anticoagulant necessary


thrombocytopenias due to decreased platelet survival

1. heparin induced thrombocytopenia (HIT) - coagulation
2. immune thrombocytopenic purpura (ITP)


thrombotic microangiopathies

1. hemolytic uremic syndrome (HUS) - coagulation
2.thrombotic thrombocytopenic purpura (TTP) - coagulation
•spectrum of syndromes with widespread formation of thrombi in the microcirculation
•triad: thrombocytopenia, renal failure, microangiopathic hemolytic anemia (fragmented RBCs formed as they traverse the microvascular thrombi - anemia and schistocytes)


disorders of platelet function

1. acquired
2. congenital
-Bernard-Soulier Syndrome
-Glanzmann's Thrombasthenia

•symptomatic patients wil present with platelet-type bleeding but will usually have a normal or only mildly decreased platelet count


inherited coagulation protein abnormalities

1. Hemophilia A
2. Hemophilia B
3. von Willebrand disease


acquired coagulation factor deficiencies

1. Vitamin K deficiency
2. severe liver disease


heparin induced thrombocytopenia (HIT)

•decreased platelet survival
•Type I: occurs rapidly after starting heparin, likely due to direct platelet-aggregating effects of heparin, usually clinically insignificant
•Type II: potentially devastating
-5-14 days after starting heparin
-less common than Type I
-pathogenesis: IgG to heparin-platelet factor 4 ---> platelet activation and aggregation, thrombosis! aggregates are removed from the circulation leading to thrombocytopenia
-clinical features: DVT, PE, severe thrombocytopenia with bleeding rare - usually thrombosis, unfractionated heparin, surgical patients, exclude other causes
-laboratory diagnosis: platelet count <150,000 or 40-50% of pre-heparin count, immunoassay or functional studies that detect platelet activation in the presence of heparin (not available many places)
-treatment: discontinue use of heparin, avoid warfarin in aute stage


immune thrombocytopenic purpura

•decreased platelet survival
•clinical features: isolated thrombocytopenia, common cause in both children and adults, petechial and mucosal hemorrhages, aka idiopathic thrombocytopenic purpura
•pathogenesis: acquired autoimmune disorder that causes platelet destruction, IgG coat platelets which are removed by mononuclear phagocytic system, ineffective production by megakaryocytes may also play a role
•laboratory diagnosis: diagnosis of exclusion
-no specific test
-blood smear evaluation - normal or large platelets, normal RBC, WBC (rules out other causes)
-bone marrow biopsy - normal or increased megakaryocytes (not performed unless clinical history and course point to ITP)

•acute (childhood)
-abrupt onset, preceded by viral illness
-self limited, 80% spontaneous resolution
-treatment: restricted activity, nothing else if >10,000-20,000/uL and no risk of bleeding; steroid therapy and or IVIG if severely low counts or severe bleeding or risk of bleeding

•chronic (adult)
-<40 yo females
-not associated with preceding illness
-chronic, relapsing course
-treatment: depend on platelet count and risk of bleeding; no treatment, glucocorticoids, IVIG, splenectomy, if severe - transfusion

DON'T TREAT in the absence of bleeding or really low counts! Quality of life and preventing bleeding episodes


hemolytic uremic syndrome (HUS)

•thrombotic microangiopathies
•clinical features: in children, typically begins after an episode of bacterial or viral gastroenteritis with bloody diarrhea, renal failure more severe than in TTP
•pathogenesis: cytotoxin released from E.Coli (O157:H7) or other bacteria causes endothelial damage and platelet activation
•diagnosis: clinical, look for schistocytes
•treatment: supportive, dialysis, and/or plasma exchange


thrombotic thrombocytopenic purpura (TTP)

•thrombotic microangiopathies
•adult females
•flulike symptoms
•40% of patients
-neurologic abnormalities
-microangiopathic hemolytic anemia (schistocytes)
-renal failure
•pathogenesis: deficiency of vWF protease (ADAMTS13) --> platelet aggregates; acquired (antibody to ADAMTS13) and inherited (less common) forms
•diagnosis: measure ADAMTS13 (not available everywhere), schistocytes on blood smear
•treatment: once fatal, now 90% complete recovery with plasma exchange



•disorder of platelet function
-acquired qualitative platelet disorder
•pathogenesis: incompletely understood; impaired platelet adhesion and aggregation
•clinical: mucocutaneous bleeding
•laboratory: impaired platelet aggregation
•treatment: correct anemia, dialysis, estrogen treatment (mechanism not well understood)