platelet disorders & coagulation defects

when an injury happens, what do platelets do?
platelets are activated (which appear as small structural matters w/out a nucleus), they respond very rapidly to injury, sending out pseudopods that cling to each other. the coagulation system is also enhanced
what does the intrinsic coagulation system consist of? exstrinsic?
intrinsic: factors 12, 11, 9, & 8 and 8 is the one involved with hemophilia. extrinsic: tissue factor and factor 7
what does the extrinsic system do?
stimulates the intrinsic system factor 9 and the common pathway (formation of fibrin)
will people with severe factor 12 deficiency bleed?
no, not abnormally
what are the coagulation tests?
platelet counts, partial thromboplastin time, prothrombin time (INR: international normalized ratio), mixing studies, thrombin time, 5M urea solubility, bleeding time
what is the aPTT?
this is initiated by a negative surface, a particle stimulates and activates factor 12 -> intrinsic system to fibrin. factor 12 is important in the test, people w/ a deficiency in it will have abnormal aPTT tests but not necessarily bleeding problems
what is PT?
tissue factor is added and factor VII is stimulated, then the common pathway and fibrin
what is the endpoint of both the intrinsic and extrinsic coagulation systems? what is needed at this endpoint? can PT or aPTT test for this?
fibrin, but not crosslinked fibrin. factor 13 is needed here, but cannot be tested for using aPTT or PT
what are the common aquired bleeding disorders?
coumadin/heparin (anticoag rx), thrombocytopenia (low platelets), liver disease, GYN/GI/sx complications. DIC is NON-common aquired bleeding disorder
why are anticoagulation drugs risky? what are they?
it is a real balance because have to give enough anticoagulation to prevent patients from having heart attacks and strokes and to prevent bleeding; so walking on a tight rope. the drugs are either warfarin or heparin
what is coumadin? what is it affected by?
originally a rat poison it is a warfarin derived drug. it is affected by diet, antibx, and other drugs
what is heparin?
an anticoagulant given IV or subcu as LMW (low molecular weight)
what is the number 1 cause for losses in vascular problems?
issues with coagulation
what biological process is vit K a part of?
vit K -> carboxylation of glutamine residues -> Gla residue (biologically active gamma carboxyglutamate residues)
how does warfarin/coumadin’s blockage of vit K affect coagulation?
vit K is not able to activate factors X, IX, VII and prothrombin as well as blocking the formation of proteins C and S (it doesn’t synthesized them, just adds a carboxyl group to the glutamic residues on them)
when would you get a greater than expected response with warfarin/coumadin?
accidental OD/suicide, antibx killing off vit K producing bacteria so less K to block in total system and coumadin’s effect is increased, malabsorption problems (vit K drops as a result, coumadin has a greater effect)
when would you see a less than expected response to coumadin?
increased ingestion of green leafy vegetables, broccoli, liver, kale (increases vit K intake) or genetic variation/hereditary warfarin resistance
what is done in the case of a coumadin OD? how is a decision made?
administer vit K (takes 3-4 hrs to work), fresh frozen plasma, or prothrombin concentrates (if very sever). INR levels/PT time help make the desicion, the higher the PT: the more aggressive the response. bleeding in different areas is also treated differently (GI more important that hematuria).
what is heparin?
a negatively charged mucopolysaccharide that activates antithrombin and and inactivates factor 10, 9, 12 (LMW just affects thrombin and factor 10) (OD is usually iatrogenic)
what is done in the case of a heparin OD?
nothing (has short half life) or give protamine sulfate
what is a problem with LMW heparin?
there is not a good test for it, factor 10 assay is no reliable. fortunately, bleeding complications and death are very low with LMW heparin but when they occur, it can be devastating because have no way of monitoring level and no antidote
would a pt on heparin or warfarin have an abnormal thrombin time? what can this be used to dx?
heparin, b/c it is directly antithrombin (as well as an abormal fibrin). warfarin only affects factors upstream from thrombin. this can thus be used to dx whether pts have had either a warfarin or coumadin OD
would antibx cause a greater than expected response to coumadin? green leafy vegetables?
antibx: yes, green leafy vegetables: no
would protamine sulfate be effective in treating a coumadin overdose?
no, it is the antidote to heparin OD
what are the predisposing conditions for disseminated intravascular coagulation (DIC)?
infection, cancer, shock, pregnancy
what happens in DIC?
rapid coagulation with consumption of platelets and coagulation factors (platelets are the first to be consumed), then platelets clump/coagulate and get stuck in filters, kidneys, other organs and cause irreversible tissue damage. RBCs are sheared and bleeding in other places occurs b/c all clotting factors are used up and the body tries to break up the original clots (secondary fibrinolysis): making the new bleeding worse -> bad cycle
what is diagnostic for DIC? treatment?
thrombocytopenia, microangiopathic hemolytic anemia, evidence of secondary fibrinolysis. it should be treated with hydration in the early phase to lessen permanent damage. 80% of the time PT is increased due to fibrin split end products
what is the fibrinolytic pathway?
plasminogen is converted to plasmin which breaks down fibrin into fibrin degradation products -> one of the most important of which are D-dimers
when does abnormal primary fibrinolysis occur?
it is rare, but seen with liver disease infections
what is diagnostic for abnormal fibrinolysis?
increased PT (split products are anti-thrombin) or fibrinogen degradation products (mainly D-dimers)
can D-dimers be used for dx of pulmonary embolism of DVT?
yes
is fibrinolysis ever induced in pts?
yes, it can be used to lessen the effects of strokes using tissue plasminogen activator (TPA) or urokinase
how are pts with DIC managed?
1) manage predisposing condition (pregnancy) 2) maintain hydration to avoid multiorgan failure 3) replacement therapy (platelets, cryoprecipitate which is rich in fibrinogen) 4) judicious anti-coagulation (heparin) if there is a risk for thromboembolism 5) activated protein C if there a risk of purpura fulminans (gram – sepsis)
what are the global effects of liver disease?
thrombocytopenia (alcohol, hypersplenism), lack of synthesis of coagulation factors, decreased intravascular coagulation (most coagulation factors are synthesized in the liver), DIC (liver normally removes activated coagulation factors and if it doesn’t do its job, can get DIC)accelerated fibrinolysis, and dysfibrinogenemia (abnormal fibrinogen produced)
how are coagulation problems associated with liver disease treated?
manage underlying liver disease, fresh frozen plasma, cryoprecipitate, and vit K
what is the most common bleeding disorder? what does it affect?
vWD, which affects the intrinsic system (b/c it is needed to protect factor 8), and platelet function (causes moremucocutaneous bleeds, nose/GYN) pts usually just bleed a little more than normal (but can be severe)
what is hemophilia A? how does it present?
factor 8 functional deficiency, and is X-linked recessive. usually presents with joint problems and delayed bleeding (intrinsic system is the back up after the extrinsic system goes in first)
what is hemophilia B? how does it present?
factor 9 deficiency, and is X-linked recessive. usually presents with joint problems and delayed bleeding (intrinsic system is the back up after the extrinsic system goes in first)
what is hemophilia C? how does it present?
a factor 11 deficiency, autosomal recessive. do not realize they have the deficiency; can bleed during surgery so it is important to get an accurate history
how will the aPTT respond to pts with hemophilia A/B/C? PT?
they should all be increased b/c 8,9, & 11 are in the intrinsic system and for the same reason the PT test would be normal
can vFD be detected via bleeding time?
yes
what are the 2 functions of vWF?
1)bind factor 8 and stabilize it 2)promote adhesion w/platelets – this is why platelets are abnormal in pts with vWF disease.
what are the different types of vWD?
type 1: decrease in all multimers, type 2: missing high MW multimers (rare), type 3: total absence of multimers
what is common between vFD type I and hemophila A?
both will have a deficiency in factor 8 function, vFD type I b/c vWF is not there to protect it, and hemophilia A b/c of genetics
in hemophilia A, why is the test for factor VIII antigen positive? why is it negative with vFD type I?
b/c the factor is there, its just non-functional. with vWD type I, vFD is not there to protect it, so factor VIII is actually gone
is the bleeding time abnormal in hemophila A or vFD type I?
bleeding time is normal in hemophilia A, but abnormal with vFD
of hemophilia A,B and C what can DDAVP (derivative of vasopressin which releases endogenous vWF and factor 8) be used to treat?
hemophilia A, vFD
of hemophilia A,B and C what can human derived factor conc. be used to treat?
hemophilia A,B, vFD, (doesn’t contain enough factor XI)
of hemophilia A,B and C what can recombinant factor conc. be used to treat?
hemophilia A,B, (no need to used it for hemophilia C and you can’t use it for von Willebrand Disease because you need vWF and recombinant doesn’t have it)
of hemophilia A,B and C what can fresh frozen plasma be used to treat?
hemophilia C, b/c it contains enough factor XI
what happens to pts who have had a lot of replacement therapy for factor VIII? can this also happen to pts w/out hemophila/factor 8 therapy? how do pts w/this present and how is this tested for?
they can develop antibodies to factor VIII. this can also happen w/pts with other immune problems like RA or during pregnancy (baby can be foreign and stimulate antibodies). pts with this have massive bleeding, an elevated PTT and low factor VIII
what is a mixing study? how is it used to determine the difference between hemophilia and factor VIII inhibitor?
a mixing study is done to determine if an elevated PTT is due to a factor VIII inhibitor (antibody) or hemohilia (type I). the pt’s plasma is mixed with normal plasma and then factor VIII is tested for and the PTT is run again. if the PTT is normal (above 40%) then the pt has hemophilia, if the PTT result is still abnormal they have antibody that is attacking the factor VIII in the normal plasma.
how is high titer factor VIII treated?
recombinant activated factor VII, but there is a side effect of thrombosis
how is low titer factor VIII treated?
the pts system is overwhelmed with factor VIII concentrates
what would a hx/lab results (except mixing studies) look like for a pt with factor VIII inhibitor who aquired it during pregnancy?
one day post partum developed multiple bruises and cutaneous bleeding. No history of bleeding aPTT- 83 sec (normal <32 sec), PT – normal, Platelets – normal.
how are hemophilia A and B aquired?
X-linked recessive
if a pt has normal coagulation tests, but a history of bleeding, what could be at fault?
factor XIII, which is not testable by any coagulation tests (which can test for fibrin clot capability, but not crosslinking)
how can a factor XIII deficicency be tested for?
the 5M urea test: a clot is placed in 5M urea, and if it dissolves, the clot was not cross-linked
what is the clinical presentation of platelet disorders?
mucocutaneous bleeding, petechiae and purpura
what is the definition of thrombocytopenia?
platelets are <140,000
what is pseudothrombocytopenia?
if the pt has nothing wrong with them and the platelet count comes out low. this can be due to a machine error or platelet clumping, giving the impression of the count being lower than it actually is (this can be checked for by looking at a peripheral smear to check blood count)
what are secondary problems that can cause thrombocytopenia?
bone marrow aplasia, bone marrow infiltration (leukemia), hypersplenism, DIC, TTP, blood loss and transfusions. if none of these are the case you are left with drugs or idiopathic thrombocytopenic purpura (ITP)
what is the first step in initial management of thrombocytopenia? what is the next step?
risk assessment: if the platelet count is above 10,000, the pt isn’t in danger BUT it should be raised to >80,000 if they are going into sx. the next step that should be taken is calling the pharmacy and seeing if any of the medications the pt is on can cause thrombocytopenia.
why are corticosteroids given to pts presenting with thrombocytopenia?
b/c it reverses any immunological processes as well as stabilizing the vessel wall.
how quickly should platelet counts bounce back if their thrombocytopenia is a result of drugs and they are taken off of whatever drug is causing the problem?
1-2 wks
if the pt’s platelet count is 5-8,000 what tx is administered?
this is considered an emergency and they are given IV IgG, IV RhIG which block the removal of platelets (should last a week or two)
when are platelet transfusions usually given?
platelet transfusions are usually given to pts w/aplastic anemia (cannot produce platelets)
what is the most common source of platelets for transfusion?
random donor platelets (RDP) usually a mix of platelets from 6 donors
why would single donor platelets be given to a pt with thrombocytopenia?
this decreases the chance of infection and the platelets are more viable as the aphereisis machine selects for platelets, but it is also more expensive than RDP
why would HLA-matched platelets be given to a pt with thrombocytopenia?
if the pt has had previous blood transfusions and is alloimmunized. and apheresis machine is used to select cells
what is a likely cause of ITP (idiopathic thrombocytopenic purpura)? what is the most common target of attack on platelets?
autoimmune platelet destruction, possibly related to HIV. the gpIIb/IIIa is the most frequent target of destruction
what are 2 treatments for ITP if the immune system is thought to be involved?
corticosteroids can work in the short term, but will cause vascular fragility and cushing syndrome eventually. if no improvement is seen a splenctomy can be performed, since that is the major site for platelet removal (60% of pts respond to this). if ITP does not respond to a splenectomy is is considered refractory ITP and immunotherapies are next in line.
what platelet level is gestational thrombocytopenia usually?
rarely <100,000
how can platelet production be augmented?
a variety of cytokines including thrombopoietin are effective in stimulating release of platelets from megakaryocytes. thrombopoietin mimicing agents (receptor agonists), or cytokines IL-3, KL, IL 6, IL 11 or LIF can also stimulate platelet production
what is heparin induced thrombocytopenia (HIT) related to? how is it diagnosed? how is it treated?
a platelet factor 4 (stored in platelets and important for platelet function) antibody. what is diagnostic for HIT? skin lesions, a decrease of 50% and the 4 T’s: thrombocytopenia, timing (7-13 days), thrombosis, other causes of thrombocytopenia not present; these = 85% chance of HIT. in which tx is discontinuation of heparin and or LMWH and administration of anti-thrombin agents.
if a pt is put on heparin and coumadin and their platelet count drops, what should be done?
get them off heparin and start anti-thrombin agents
what is thrombotic thrombocytic purpura (TTP)? how does it compare with DIC? how is it treated?
it is similar to DIC, b/c it occurs with pregnancy and infections – but it also is associated with renal impairment, fever, neurological signs, hemolytic anemia, and thrombocytopenia. it also has severe clumping that does not occur with DIC which affects kidney function. TTP coagulation tests are usually normal and DIC shows increases in d-dimers and PT. plasmapheresis is the tx for TTP
what is the clinical pentad for TTP? what causes this?
thrombocytopenia, hemolytic anemia, neurological signs, fever, and renal impairment. problems with ADAMTS-13 cause TTP
what is seen in the hx when diagnosing platelet dysfunction?
lifelong hx of bruising in hereditary disorders, family hx of bleeding, mucutaneous bleeding and medications possibly responsible.
what is seen in the physical exam when diagnosing platelet dysfunction?
petechiae
what is seen in clinical lab studies when diagnosing platelet dysfunction?
platelet count and morphology (pts can have normal platelet counts), bleeding time is checked (best available bedside test for platelet function – but not done on pts w/thrombocytopenia), and platelet aggregation and secretion studies
what are physical characteristics of platelets that allow them to perform their functions?
platlets are circular disks with microtubles (allow the platelet to contract). they have alpha granules (dark bodies) that help squeeze out the ADP, serotonin, and platelet factor 4. they first adhere then secrete; initiating aggregation (followed by clotting)
what causes a problem with adhesion in platelets? what clinical disorders will this lead to?
if GpIb and vWF are abnormal, this will cause a problem with adhesion and either bernard soulier or vW disease can result
what defects in platelets can cause problems with secretion (and thus aggregation)?
if there are problems in the platelet with: the dense bodies, alpha granules, GpIIb/IIIa, or fibrinogen – secretion (of ADP, serotonin, and proteins) and aggregation can be abnormal and lead to storage pool disease, grey platelet syndrome and thrombasthenia
when platelets are subjected to collagen/shear stress/thrombin what do they do?
release TXA2 (thromboxane) and ADP as well as express GpIIb/IIIb which all lead to aggregation
what does aspirin do in terms of platelets? reopro/abciximab? plavix?
ASA blocks release of thromboxane (TXA2). reopro/abciximab blocks expression of GpIIb/IIIb. plavix blocks ADP release
what are commonly aquired platelet disorders?
ASA, uremia, hepatic cirrhosis, myeloma and related disorders (bad if platelets get Ig coated), & cardiopulmonary bypass
how are aquired platelet disorders managed?
the underlying condition is managed, DDAVP, and corticosteroids
is platelet GpIIb/IIIb absent in thrombasthenia/glanzmann’s? is it also a fibrinogen receptore?
yes to both
what are the major risk factors for venous thrombositic events (VTE)?
malignancies, sx, age, immobilization, pregnancy, oral contraceptives, and hormonal replacement therapy. (also can be caused by: lupus anticoags, thrombophilia (hereditary hypercoag stat), rx’s: aspariginase/immune modulation in mult. myeloma)
what is antiphospholipid lupus? how is it diagnosed? how is it treated?
this may be seen in pts with a hx of miscarriages, arterial and venous thrombosis in unusual sites (mesentery), slightly elevated PTT but not corrected by mixing, **but no hx of bleeding. it is diagnosed via demonstration of phospholipid dependence and an antilipid IgG/IgM such as cardiolipin. they are given anti-coagulation therapy only if the pt is at risk for thrombosis.
what are the regulatory steps in the coagulation pathway?
tissue factor inhibitor, protein C & S (activated by thrombin+thrombomodulin), antithrombin and the fibriogenolysis/fibrinolysis pathways
what is factor V leiden?
a mutant variation of factor V which cannot be inactivated by protein C
what is warfarin related skin necrosis? how are pts treated?
this results if a pt with a protein C deficiency is put on warfarin (paradoxical effect with these pts and thrombosis occurs). pts are put on heparin first, or coumadin and heparin.
what is the risk of thrombosis in factor V leiden?
very low
what are clues for underlying thrombophilia?
family hx of VTE, cerebral/hepatic/mesenteric/renal venous/arterial thrombosis, miscarriages & VTE at a young age
what does the combination of any aquired or hereditary risk factors for thrombosis mean?
the risk of thrombosis is greatly increased (if someone has factor V deficiency and breaks a hip it is a good reason to prophylactically anti-coagulate)
what is activated protein C resistance? if a pt is suspected to have it, what tests should be run?
when factor V does not react to normal APC. 95% of the time, this is factor V leiden, but first a coagulation test should be ordered before a factor V leiden test – just to screen for other deficiencies
what are indications for long-term anticoagulation therapy in pts w/thrombophila or hypercoagulability?
recurrent and idiopathic thrombosis (with or without and underlying thrombophilia or risk factor for thrombosis) are indications
what are NOT indications for long-term anticoagulation therapy in pts w/thrombophila or hypercoagulability?
single events (even pulmonary embolism) or unprovoked thrombosis
what is the increase of risk for a venous thrombosis event in pregnancy? is there a timeframe with a higher risk? how is it managed?
5-10%, which is even greater with a hx of VTE and/or during the 6 week post partum period. LMW heparin is administered b/c coumadin is a teratogen and can enter breast milk
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