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Cardio > Coagulation > Flashcards

Coagulation Flashcards

1
Q

hemostasis

A
  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)
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2
Q

site of synthesis of most of the proteins involved in coagulation

A
  • liver
  • Vitamin K is required to produce active forms of several of the coagulation factor proteins and anticoagulants (protein C and protein S)
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3
Q

hemostastis sequence of events

A

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

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

coagulation cascade

A
  • extrinsic - initiates
  • intrinsic - amplifies
  • common
  • cascade takes place on the phospholipid surface of activated platelets, localizing the cascade
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5
Q

extrinsic pathway

A
  • PTT
  • TF
  • VII
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6
Q

intrinsic pathway

A
  • aPTT
  • XII
  • XI
  • IX
  • VIII
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7
Q

common pathway

A
  • PTT and aPTT
  • X
  • V
  • II
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8
Q

counter regulatory mechanisms

A
  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
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9
Q

prothrombin time (PT)

A
  • 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
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10
Q

activated partial thromboplastin time

A
  • 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
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11
Q

D-dimers and fibrin degradation products (FDPs)

A
  • 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!
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12
Q

mixing studies and factor assays

A
  • 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
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13
Q

evaluation of platelet function

A

•numerous tests available

  • platelet aggregometry
  • platelet function analyzer
  • cutting someone and waiting for them to stop bleeding
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14
Q

platelets

A
  • fragments of megakaryocyte cytoplasm shed directly into teh circulation
  • 150,000-450,000/uL
  • 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
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15
Q

thrombocytopenia

A
  • 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
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16
Q

platelet type bleeding

A

•mucocutaneous bleeding

  • petechiae
  • purpura
  • small ecchymoses
  • menorrhagia
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17
Q

thrombocytopenic patients

A

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

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18
Q

patients with clotting factor deficiencies

A
  • 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
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19
Q

thrombocytopenia classifications

A
  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
    - splenomegaly
  4. dilution
    - massive transfusion - RBC products do not contain significant numbers of viable platelets
  5. artifactual
20
Q

artifactual thrombocytopenia

A
  • 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
21
Q

thrombocytopenias due to decreased platelet survival

A
  1. heparin induced thrombocytopenia (HIT) - coagulation

2. immune thrombocytopenic purpura (ITP)

22
Q

thrombotic microangiopathies

A
  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)
23
Q

disorders of platelet function

A
  1. acquired
    - uremia
  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

24
Q

inherited coagulation protein abnormalities

A
  1. Hemophilia A
  2. Hemophilia B
  3. von Willebrand disease
25
Q

acquired coagulation factor deficiencies

A
  1. Vitamin K deficiency

2. severe liver disease

26
Q

heparin induced thrombocytopenia (HIT)

A

•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
-adults>children
-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

27
Q

immune thrombocytopenic purpura

A

•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

28
Q

hemolytic uremic syndrome (HUS)

A
  • 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
29
Q

thrombotic thrombocytopenic purpura (TTP)

A

•thrombotic microangiopathies
•adult females
•flulike symptoms
•40% of patients
-fever
-neurologic abnormalities
-microangiopathic hemolytic anemia (schistocytes)
-thrombocytopenia
-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

30
Q

uremia

A

•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)

31
Q

Bernard-Soulier Syndrome

A
  • congenital qualitative platelet disorder
  • pathogenesis: rare, deficiency of platelet glycoprotein Ib (GPIb) which mediates adhesion of platelets, via vWF, to subendothelial collagen
  • clinical: mucocutaneous bleeding
  • laboratory: variable platelet count with large platelets; for diagnosis, platelet aggregation studies, flow cytometry and molecular testing
  • treatment: platelet transfusion may be indicated, avoid aspirin and other anti-platelet drugs
32
Q

Glanzmann’s Thrombasthenia

A
  • congenital qualitative platelet disorder
  • pathogenesis: deficiency of a platelet glycoprotein IIb/IIIa (GPIIb/IIIa) that mediates platelet-platelet interaction (aggregation)
  • clinical: mucocutaneous bleeding at birth or early infancy
  • laboratory: normal platelet count and morphology; for diagnosis, platelet aggregation studies, flow cytometry and molecular testing
  • treatment: platelet transfusion may be indicated, avoid aspirin and other anti-platelet drugs
33
Q

Hemophilia A

A

•inherited coagulation protein abnormalities
•pathogenesis: x-linked, VIII
•clinical features: easy bruising, massive hemrrhage after surgery/trauma and spontaneous hemorrhage into joints (hemarthrosis)
-severe <1% FVIII activity, usually diagnosed before 1 yo - spontaneous bleeding or bleeding after minimal injury
-moderate 2-5% residual FVIII activity
-mild 6-30% FVIII activity, may present in adulthood after surgery or trauma
-delayed bleeding after procedures
•long term complications: infectious disease (HIV, HBV, HCV), factor inhibitors - antibodies made causing inhibition to FVIII replacement
•laboratory: decreased FVIII, abnormal aPTT
•treatment: FVIII replacement (prophylactic or therapeutic)

34
Q

Hemophilia B

A
  • congenital qualitative platelet disorder
  • pathogenesis: x-linked, frequency 1/6 that of Hemophilia A
  • clinical features: indistinguishable from Hemophilia A
  • laboratory: decreased FIX, abnormal aPTT
  • treatment: FIX replacement
35
Q

von Willebrand Disease

A

•congenital qualitative platelet disorder
•pathogenesis: autosomal dominant, rare variants are recessive, decrease or impaired function in vWF —> secondary abnormalities in platelet adhesion and clot formation
•clinical features: most common inherited bleeding disorder, platelet-type bleeding: mucocutaneous bleeding but can also present with spontaneous soft tissue bleeding from minor trauma or wound bleeding
•laboratory:
-abnormal platelet function, normal platelet count
-prolonged aPTT due to decrease in FVIII (vWF is chaperone and carrier!)
-electrophoresis - abnormal or decreased vWF multimers
-vWF level and function required to direct therapy
•treatment: DDAVP (releases vWF and FVIII from endothelial cells) or vWF concentrates

36
Q

Vitamin K deficiency

A
  • acquired coagulation factor deficiencies
  • Vitamin K is an active coenzyme in the carboxylation of glutamic acid residues required for the function of factors II, VII, IX, and X.
  • malnutrition, impaired intestinal absorption, antimicrobial inhibition of the gut flora that provide Vitamin K
  • clinical features: easy bruising, GI bleeding, hematomas
  • laboratory: prolonged PT early, both Pt and aPTT will be prolonged in severe deficiency
  • treatment: Vitamin K, plasma in severe bleeding
37
Q

severe liver disease

A

•acquired coagulation factor deficiencies
•hemostatic defects are numerous:
-decrease synthesis of clotting factors
-thrombocytopenia due to splenomegaly, platelet antibodies and/or decreased marrow production
•clinical features: patients bleed from extensive impairment of their hemostatic mechanisms, high risk for bleeding from esophageal varices, gastritis, and peptic ulcers
•laboratory: prolongation of PT and aPTT, thrombocytopenia
•treatment: fresh frozen plasma, platelets and/or Vitamin K

38
Q

thrombotic disorders

A 
•include DVT, PE and arterial thrombosis
•1 per 1,000 per year
•Virchow's Triad
1. stasis
2.endothelial injury
3.hypercoagulability
•risk of recurrence and length of anticoagulation
39
Q

inherited thrombophilias

A

•when to suspect
-first thrombosis at a young age <50yo
-recurrent thrombosis
-thrombosis at an unusual site (mesenteric, portal or cerebral veins)
-life threatening thromboembolism
-family history of thrombosis
•don’t test when patients are in the setting of a major transient risk factor, check if they are on anticoagulant therapy

  1. abnormalities of the protein C system
  2. prothrombin gene mutation
  3. antithrombin deficiency
40
Q

abnormalities of the protein C system

A

•inherited thrombophilia
•with cofactor PS, inactivates FVa and FVIIIa
1. APC resistance
-glutamine for arginine = Factor V Leiden mutation
-renders FV resistant to inactivation by APC
-autosomal dominant
-clotting based or DNA studies
2. protein C deficiency
-autosomal dominant
-measure of PC activity and antigen level
3. protein S deficiency
-autosomal dominant
-measure of PS activity and antigen level

41
Q

prothrombin gene mutation

A
  • inherited thrombophilia
  • point mutation in nucleotide 20210
  • increased levels of prothrombin that promote clot formation
  • molecular studies
42
Q

antithrombin deficiency

A
  • inherited thrombophilia
  • antithrombin is an inhibitor of XIIa, XIa, IXa, Xa and IIa (thrombin)
  • pateinst are heterozygous, homozygous is lethal in utero
  • mesure AT level and antigen level
43
Q

acquired thrombotic disorders

A
  • tissue injury
  • prolonged bedrest or immobilization
  • disseminated intravascular coagulation
  • antiphospholipid antibody syndrome
  • pregnancy and postpartum
  • heparin induced thrombocytopenia
  • oral contraceptive use
  • smoking
  • myeloproliferative disorders (polycythemia vera, essential thrombocytosis)
  • malignancy
44
Q

malignancy

A

•acquired thrombotic disorders
•may precede diagnosis of malignancy
•pathogenesis:
-stasis: bed rest, vascular compression
-endothelial injury: vascular invasion, catheters, chemotherapy
-hypercoagulability: substances released from neoplasm may activate the coagulation cascade

45
Q

antiphospholipid antibody syndrome/lupus anticoagulant

A

•acquired thrombotic disorders
•pathogenesis: APAs are directed against protein-phospholipid complexes
-in vivo: procoagulant effects on PC. platelets and fibrinolysis, exact pathogenesis unknow
-in vitro: interfere with phospholipid dependent coagulation tests (aPTT) resulting in increased clotting times, one of the most common causes of a prolonged aPTT
•clinical features: autoimmune disease (SLE) or as reactions to drugs or infections, or in the absence of any known disease (primary)
•lupus anticoagulant is a double misnomer as most patients don’t have lupus and they present with clotting, not bleeding
•antiphospholippid syndrome (APS): defined by 1. APA in serum and at least one clinical feature of the disease, including thrombosis or pregnancy morbidity; repeat test in 12 weeks
•laboratory: APA and prolonged aPTT by an inhibitor (lupus anticoagulant), the antibody alone in the absence of clinical symptoms is not sufficient for diagnosis of APS
•treatment: heparin followed by coumadin, lifelong anticoagulation has to be considered

46
Q

disseminated intravascular coagulapathy (DIC)

A

•acquired thrombotic disorders
•pathogenesis: excessive activation of coagulation results in formation of microvascular thrombi and secondary consumption of platelets, coagulation factors and natural anticoagulants
•triggers include
1. release of thromboplastic substance into teh blood (TF and other substances)
2. widespread endothelial injury

•acute

  • exposure to massive amounts of TF
  • overwhelms control mechanisms and compensatory mechanisms (liver, bone marrow) don’t have time to respond resulting in consumption of platelets and coagulation factors (“consumptive coagulopathy”)
  • sever bleeding, tissue ischemis (microthrombi) and microangiopathic hemolytic anemia

•chronic

  • compensated DIC
  • when blood is exposed intermittently to TF and the compensatory mechanisms in teh liver and bone marrow are able to replenish depeleted coagulation factors and platelets
  • malignancy
  • not a primary disease
  • clinical features: in acute, bleeding due to consumptive coagulopathy, ischemia and multiorgan failure; in chronic, asymptomatic, develop thrombosis or have minor bleeding
  • laboratory: acute - thrombocytopenia, hypofibrinogenemia, microangiopathic hemolytic anemia (schistocytes), prolonged PT and aPTT and elevated D-dimers; chronic - these labs are variable, platelet count may be only mildly decreased, fibrinogen is often normal or increased and the PT and aPTT may be normal
  • management: treat the underlying cause, with serious bleeding plasma and/or paltelet transfusion is indicated, heparin is limited to patients with predominantly thrombotic complications

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