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                                                           Tests for lysis of clots (fibrinolytic activity). Test is
  Systematic Approach to                                       monoclonal Ab to cross linked D regions of
    Bleeding Disorder                                          degraded fibrin.
                                                              1st Cross linking: Thrombin generation cross-
Is there a problem with the pts platelets?
                                                               linking of fibrin clot via thrombin activation of
    Thrombocytopenia or platelet functional defect            Factor XIII.
    Platelet count, bleeding time
                                                              2 Degradation of fibrin: Fibrinogen degradation by
Does the pt have an inherited coagulopathy, single             plasmin  Fibrin
     factor deficiency?                                    PPP or Plasma Protamine Paracoagulant: Measures
    Factor VII, VIII, X, V, XI, fibrinogen.                   monomer when clots are present. Was used
    PT, PTT                                                   originally as test for DVT.
Does the pt have a deficiency of several of the Vit-K      Anti-Thrombin III: Produced in liver. Measured as %
     dependent Coagulation factors?                            of Nl.
    Vit-K deficiency, liver dz, warfarin therapy          DIC: Antithrombin III < 60% of Nl. < 10-30 %  DIC
    PT, PTT, TT and Fibrinogen assay                      -2 Antiplasmin: Produced in liver.
Is there a Circulating Anti-coagulant present?             Rapidly inactivates plasmin irreversibly. Test for rate of
    Heparin, factor VIII or IX Ab, lupus anti-coagulant       plasmin generation in fibrinolysis.
    PTT with 1:1 mix, TT, Reptilase time                  Severe liver dz:  production of -2 Antiplasmin  
Does the pt have a consumptive coagulopathy?                   inhibition of plasmin  
    TTP, HUS, vasculitis, sepsis, OB complications,       DIC:  in alpha antiplasmin.
     trauma, liver dz.
    DIC screen: Plt count, PT, PTT, TT, fibrinogen,
     antithrombin III, -2 antiplasmin, d-Dimer assay,            Platelet Dysfunction
     blood film, PPP                                       Acquired Abnormalities of Platelet Function
                                                           Medications: ASA, other NSAIDS, clopidogrel,
      Clinical Approach to                                     penicillins
                                                           Systemic Disorders
       Bleeding Disorders                                  1) Chronic renal failure and uremia: Uncleared
Platelet Tests                                                 metabolic byproducts act as inhibitors of platelet
                                                               function.  BT. Corrected by hemodialysis.
Platelet count: Inspected by Wright’s smear. 1 platelet    2) Cardiopulmonary bypass surgery: Aggregation
    per 20 RBC. Normal between 150,000 and
                                                               response to ADP  and loss of  granule contents.
    300,000. False low levels can occur because of
                                                           3) Antiplatelet antibodies
    poor anticoagulation of sample, or presence of
                                                           Hematologic Dz
Bleeding Time: To detect significant defect in Plt         1) CML
    function. Direct relationship between Plt # and BT.    2) Leukemias and myelodysplastic disorders: BT. Also
    Used to detect a functional defect in a pt w/Nl plt
                                                              defects in epinephrine-induced aggregation and
    count. Uremia and ASA therapy prolong BT. Also            dense alpha granule function.
    to detect pts w/vWD.                                   3) Multiple myelomas and other dysproteinemias:
Coagulation Tests:                                         Congenital Disorders of Platelet Function
Partial Thromboplastin Time: Intrinsic and common          1) Deficiencies of agonist receptors: ADP, epi,
    pathways: XII, XI, IX, VIII, X, and V.                    collagen.
Normal: 25 to 38 sec.                                      2) Deficiency of structural abnormalities of adhesion
Prolonged by lack of any of the factors in the int or         receptor.
    common pathway. Factor deficiencies must be            3) Signaling for proteins required for platelet
    severe to affect the assay.                               aggregation
More sensitive to heparin, and anti-phospholipid           4) Deficiency of platelet procoagulant activity
INTRINSIC PATHWAY                                       Storage pool deficiencies:
                                                  PaTTI Has
XII  XI  IX  VIII     Prothrombin Bernard-Soulier syndrome: deficiency of GP Ib-V-IX,
                                         giant platelets, thrombocytopenia.
                    X  Xa + V   Glanzmann thrombasthenia: Autosomal recessive.
           II  VII         Thrombin     Moderate bleeding. Lacks IIb/IIIa (no fibrinogen
EXTRINSIC PATHWAY                                 PeTE’s Car binding).  PLA-1. Aggregates with ONLY
Prothrombin Time: Extrinsic and common pathways.             Ristocetin.
Most sensitive for factor VII.
More sensitive to multiple deficiencies of Vit-K
    dependent liver factors.
INR: standardized method of expressing prolongation.
PT 1 to 1.5  than control  factor  below 20% of
                                                                     Production Disorders
    normal.                                                Inherited:
Other causes of prolongation: large amounts of heparin     Fanconi’s anemia
    &  fibrinogen. May be  if blood is stored too long   TAR syndrome
    prior to testing                                       Rubella
                                                           May-Hegglin anomaly: bizarre giant Plts and basophilic
Tests of Fibrinogen                                            inclusions in WBC
Thrombin Time:                                             Wiskott-Alsrich syndrome.
Measures conversion of fibrinogen to fibrin.
Prolonged TT:  or Abnl fibrinogen and  levels of         Acquired:
    fibrin degradation products.                           Drugs: thiazide diuretics, estrogens
     DIC and liver dz: sensitive indicator                EtOH
     Heparin: Very small amounts of heparin can           Viral Infections
       dramatically  TT by inhibiting the added           Any cause of pancytopenia
       thrombin.                                           Infiltrative dz of BM: Carcinoma, leukemia, lymphoma,
                                                                myelofibrosis, Osteopetrosis, and military Tb.
Radiation Tx and myelosuppresive therapy                    1) Effective management of underlying dz.
Megaloblastic anemia                                        2) FFP: Replacement of coagulation factors.
                                                            3) Cryoprecipitate: Replacement of fibrinogen.
Treatment: Plt transfusions. HLA matched. Must be
                                                            Isolated Platelet Consumption
   tailored to meet pts needs. Each unit of pheresed
   Plts should  plt count by 50,000. Need to beware        Pts w/vascular disorders such as vasculitis, HUS, and
   of alloimmunization.                                         TTP.
                                                            Symptoms and signs of organ damage
       Disorders of Distribution                            Renal failure from glomerular thrombosis
Splenomegaly: Spleen as storage organ for Plts. Can         Skin infarction
     splenic trapping of Plts. Plt survival is Nl &       Multifocal brain infarction
    little risk of thrombocytopenia related bleeding.       RBC hemolysis is common and is most marked in pts
    Splenomegaly should not  plt to < 40,000.                  with HUS. Bleeding is not a major component
    Myeloproliferative dz or 1* thrombocythemia.                unless plt count < 20,000.
Treatment: Not normally related to abnormal bleeding.       Treatment:
    Plt transfusions not normally needed. Only if plt       1) Prednisone, Methylprednisone and Plasmapheresis
    count   20,000 or 30,000. w/myelofibrosis can             w/FFP exchange.
    be difficult to predict whether splenectomy will        2) Should not receive Plt transfusions or Antiplatelet
    help or hurt. After splenectomy plts may  > 1              agent unless CT evidence of large intracranial
    million.                                                    bleed. Infusion can  accelerated organ damage.
                                                            Thrombotic Thrombocytopenic Purpura
         Destruction Disorders                              (TTP)
DIC                             Infection
ITP                             HUS                         Non-immune consumption of platelets, Plt thrombus
Post-transfusion purpura        Kasabach-Merrit                 formation, & organ damage. Can occur after chemo
    Syndrome                                                    or BMT or post-partum. Can be idiopathic.
Drug  Ristocetin               Malaria                     Cause: Etiology not clear.
Drug sensitivity: quinine, quinidine                           ?Viral illness
Autoimmune Thrombocytopenia                                    ?Endothelial damage  release of vWF
Acute hemolytic reaction: erythroblastosis                     ?Ab to protease that clips vWF. Left w/too large
                                                                vWF   plt clumping.
DIC:                                                        Clinical: Pentad.
Abnl bleeding w/thrombocytopenia and                        Fever: present at admit in ~ 50%.
   hypofibrinogenemia. May demonstrate gross                Thrombocytopenic purpura or other bleeding: Non-
   hemorrhage or thrombosis, or both.                           immune consumption of plts. Hyaline-platelet
1) Consumption of coagulation factors exceeds                   complexes form in small vessels, trapping platelets.
   production capacity.                                     Neurologic: CN palsies, dysphasia or aphasia, paresis,
2) Fibrin deposits in microcirculation                          confusion, stupor, coma, and seizures.
                                                            Renal: proteinuria, hematuria, & mild renal
 Dx: right clinical settings & lab evidence of aggressive       insufficiency.
     coagulation and fibrinolysis.                          Microangiopathic anemia w/fragmentation: Essential for
Clinical:                                                       diagnosis
Severe, systemic illnesses: esp. true if pt exhibits any    Other: SOB, jaundice, abdominal pain.
     signs of unexplained organ failure or an abnormal
     bleeding tendency.                                     Labs:
Sepsis: Esp. pts with meningococcemia.                      PT, PTT, fibrinogen, and fibrin degradation products: Nl
Shock                                                       LDH: 
Crush injury                                                Haptoglobin:  due to intravascular hemolysis.
Surgical trauma
Widespread malignancy                                       Treatment: Required. W/out will die from severe
Hemorrhagic pancreatitis                                        anemia or stroke.
Obstetric complication                                      1) Plasma Exchange w/plasma pheresis: Daily until
Intrauterine fetal death                                        respond. Exchange at least one plasma volume per
Amniotic fluid embolism                                         day
Abrupto placentae.
                                                            2) Steroid:  Ab production. Unproven benefit.
                                                            3) Platelet inhibitor: ASA or dipyridamole. Unproven
  Schistocytes: Fragmented RBC. RBC rubbing                4) Chemotherapy: Vincristine, cyclophosphamide, and
   across fibrin monomer. Lack does not rule out DIC            azathioprine. Second line therapy or for pts who
  No Plts. Toxic granules and Dohle bodies.                    refuse exchange.
                                                            Prognosis: Remission often permanent.
Lab Tests:
PT/PTT: Prolonged. Due to consumption of coagulation Hemolytic Uremic Syndrome (HUS)
     factors.                                        Cause: Associated with hemorrhagic colitis, 2* to esp.
Plts:  50,000 to 100,000                                E-Coli. No CNS abnormalities, marked
Thrombin Time:                                          thrombocytopenia, or fragmentation. Bacterial
Fibrinogen: Reduced.                                     infection —>release toxins —> damage to
D-Dimer: None to  depending on degree of 2* lysis       endothelial cells —>plt clumping.
PPP: (+) Pt is forming clots.                        Clinical: Children mainly. Pure HUS seen in children
VWF: normal. Not consumed.                               and young adults. Acute renal failure.
                                                     Smear: Fragmented RBC, and low # of plts.
Severity of DIC:                                     Treatment:
Antithrombin III:                                   1) Supportive therapy
-2 antiplasmin:  40 to 50% normal  severe ongoing 2) May require dialysis. Recovery should be complete
     DIC.                                            3) Iv Ig or steroids may be needed.
                                                            Thrombocytopenic purpura in adults
1) Exposure to blood products:                                   surrounding individual deformed corkscrew-shaped
2) Drugs: Quinine, quinidine, and sedormid. Heparin              hairs. Easy bruisability and formation of
   induced IgG antibodies can form and bind to                   ecchymoses over lower extremities is also seen.
   heparin. Treatment: Withdrawal of drug. If heparin            Bleeding gums and deep intramuscular and
   needed—> stop all heparin. Danapraoid as alt to               subperiosteal hemorrhages may also be present.
   heparin.                                                  3. Congenital Defects of vessel wall such as hereditary
3) Infections: HIV. Treatment: Can be treated with               telangiectasia.
   AZT. 60% will show response and 50% will have             Vasculitis:
   long lasting improvement. Splenectomy for those           1. Septic or aseptic vasculitis: Sudden appearance of
   that do not respond, but needs to be done early in dz         palpable purpura, preceded by urticarial rash
   process. Corticosteroids, IV Ig and IV anti-D. May        2. Henoch-Schonlein purpura: rash with fever,
   only respond to platelet transfusion. Also                    malaise, polyarthralgia, and colicky abdominal pain.
   plasmapheresis.                                               Most common in childhood and young adolescence.
4) Malignancies: Lymphomas. HL, NHL, and CLL                 Dysproteinemias: Therapy and Clinical Course: No Tx
   are associated with  production of autoantibodies            for pts without definable coagulation defect. Vit C
   with platelet specificity.                                    deficiency and aseptic vasculitis respond to therapy
5) Autoimmune dz: SLE. Look for arthralgia,
   arthritis, skin dz, unexplained pleurisy, hepatitis, or                 Loss of Platelets
   IBD. Treatment: Best controlled by controlling the        Hemorrhage and multiple blood transfusions
   systemic disease. Corticosteroids may be used             Extracorporeal circulation
   occasionally on a short-term basis.
Idiopathic Thrombocytopenic Purpura                                 Von Willebrand Dz:
(ITP):                                                       Most common congenital bleeding disorder.
Cause: Antibody formation vs. plt surface membrane           Role of vWF: Helps with platelet activation and
    Ag. Ab coat is read as abnormal  short plt                  adhesion. Also is carrier for factor 8. Not used up
    survival time. Need to exclude medications as                in acute reactions.
    cause.                                                   Type 1 vs. Type 2: Look at multimeric structure to help
Clinical: Can be acute. Usually starts as chronic.               distinguish from type I and type II.
    Presents because of abnormal bleeding.                   Ristocetin-induced platelet agglutination:
Smear: normal  plts.                                        Decreased Agglutination:
BM: Increase in Megakaryocytes.                              vWD: I, IIa, IIc, and III
Treatment:                                                   ITP                             Storage pool dz
1) If plt count ~50,000 watch. No treatment.                 Bernard-Soulier Synd            AML
2) Steroids: High dose.                                      ASA ingestion                   Infectious Mono
3) Plt transfusions: If evidence of intracranial             Cirrhosis                       Af-Am population
    hemorrhage.                                              Increased Agglutination:
4) Ig: if plt Transfusion or steroids do not work. May       vWD IIb            Psuedo vWD
    require repeat therapy.                                  Plasma Multimeric Structure:
5) If > 3 or 4 mo, splenectomy should be considered.         Platelet Multimeric Structure:
    75 to 80% will achieve permanent remission.
                                                             vWD: Type 1:
    Should work.
6) Serious refractory cases  platelet transfusion.          Quantitative defect in plasma vWF levels. Autosomal
Autoimmune Thrombocytopenia                                  Cause: Defect in vWF release from Weibel-Palade
Neonatal thrombocytopenia                                        bodies of the endothelial cells. Plts & endothelial
Clinical: Result of alloimmune sensitization during              stores of vWF are Nl. Have release of vWF with
    pregnancy or as a result of maternal autoimmune              administration of DDAVP.
    thrombocytopenia.                                        Clinical:
Treatment: When mild does not require therapy. Severe        Epistaxis
     Ig therapy. Binds antibody. Washed platelet            Menhorragia. ♀ more common. Clinical severity
    transfusion good.                                            variable. In symptomatic pts, vWF:Ag and vWF
                                                                 activity are reduced to below 50% of normal.
Postviral thrombocytopenia in children. Usually self             Blood type O show normal low levels so should not
    limited lasting less than 1 to 2 weeks.                      be confused with pts w/vWD.
Treatment: If plt count is above 30,000 and no               Lab Tests:
    mucocutaneous bleeding —>watch and wait. If              Bleeding time: Prolonged.
    below 10,000 should be hospitalized and given IV         PT: normal
    immune globulin. Also high dose glucocorticoid.          PTT: Prolonged. Lack of factor VIII
    Splenectomy reserved for only children                   VIII:Ag: Absolute 
    experiencing life threatening bleeding. 70%              VIII:C: Absolute 
    remission.                                               Ristocetin-induced Plt agglutination:  or Nl.
Vascular Purpura                                             Crossed Immunoelectrophoresis: Normal.
                                                             Response to DDAVP: Restore hemostasis to normal.
Clinical Features: Clinical pattern of bleeding,
    relationship to minor trauma and drug ingestion,
    dietary habits, and symptoms or signs of systemic
                                                             1) DDAVP: Show good response with administration.
    dz. PE: Skin atrophy and multiple bluish-colored
                                                             2) vWF replacement: Cryoprecipitate. 1 bag per 10 kg
    ecchymoses on forearms and backs of hands.
                                                                of body weight twice a week.
    Hyperpigmentation. Amyloidosis—plaques of
                                                             3) Avoidance of ASA containing compounds.
    papules of waxy skin.
Lab Studies: Normal coagulation studies. Platelet            Type IIa vWD:
    count, PT, PTT.                                          Qualitative defect in plasma vWF. Autosomal dominant
Differential:                                                Inability of form or stabilize large multimers.
Structural Abnormalities:
1. Senile/Steroid Purpura: atrophy of skin and               Clinical:
    subcutaneous tissue due to collagen breakdown.           Bleeding time: Prolonged
2. Scurvy: Vit-C deficiency. Needed for collagen             Crossed Immunoelectrophoresis: Abnormal.
    biosynthesis. Perifollicular hemorrhages                 Ristocetin cofactor activity: No response.
Response to DDAVP: No response. Factor VIII R:Ag         1:1 mix: Evaluate factor deficiency vs. inhibitor.
    , but multimeric abnormality is not corrected.          Immunologic measurement of level of factor
                                                             antigen and assay of coagulant activity
Treatment: DDAVP contraindicated. Give vWF               Treatment
     replacement.                                        1. Rapid and effective factor replacement. Factor
                                                             should be given regardless of location. Prophylaxis
Type IIb vWd                                                 should be reserved for anticipated bleeding (surgery
Autosomal dominant. Intrinsic abnormality of von             or high-risk physical activities).
     Willebrand factor  tissue binding.                 2. W/recombinant factors can give regular doses of
Abnormal vWF with increased affinity for the platelet        factor.
     GPIb/IX receptor. This leads to a lower plasma      3. Self infusion as soon as bleeding episode is
     level of these larger dimers. The vWF are clumped       suspected.
     onto the platelet  greater platelet aggregation in 4. CNS bleed get factor to 100% then take history.
     circulation, aggregate removal, thrombocytopenia    5. Immunologic measurement factor antigen & assay
     and suffer from bleeding tendency.                      of coagulant activity.
                                                         6. DDAVP: release of vWF   circulating VIII 
Clinical:                                                    coagulation.
Bleeding Time: Prolonged
Ristocetin-induced Plt agglutination: Hypersensitive     Hemophilia B (Christmas Factor) IX
     response.                                           Cause: Factor IX levels less than 1%  severe
Ristocetin cofactor activity:                               bleeding. Results from a number of genetic
Response to DDAVP: Transient correction of                   mutations. Most are mutations  nonfunctional
     multimeric abnormality. Bleeding time may be            protein. Normal levels of protein.
     corrected.                                          Clinical: Similar spectrum of dz as Hemo A. Bleeding
                                                             into the large joints of the upper and lower
Treatment:                                                   extremities. Begin once the affected child reaches
1) DDAVP can worsen condition by  vWF release               toddler and then increases as the child becomes
     and worsening the thrombocytopenia.                     more active. Chronic synovitis, destruction of
2) vWF replacement.                                          cartilage and bone, and a progressive flexion
                                                             contracture. Bleeding into muscles. Hematuria,
                                                             intracranial hemorrhage, mucous membrane
Liver dz & the coagulation                                   bleeding, and bleeding following minor trauma or
          system:                                            surgery.
                                                         Lab Studies: ↑ PTT/↑ BT/Normal PT. Then mixing 
All clotting proteins made in liver except factor VIII       factor deficiency vs. inhibitor. Immunologic
     which is made in the endothelium. W/dz will get no      measurement of level of factor antigen and assay of
     production of fibrinogen and other factors (except      coagulant activity.
     8) increased bleeding.                             Treatment: FFP, purified factor IX, recombinant IX.
Vit K deficiency:                                          Inhibitor of factor VIII (or IX) identified
Role: Vit K dependent—                                   1:1 mix of pt plasma and normal plasma to determine if
   Procoagulant: 7, 9, and 10.                              prolonged PTT can be corrected. Hemo A:
   Anticoagulant: Proteins C and S.                         deficiency of factor VIII will show partial or
Lab: ↑ PT/ ↑ PTT Then mixing to look for inhibitor. If       complete correction when normal plasma is added.
    no correction in PTT then determine if Vit-K lack        Pt with factor VIII inhibitor or lupus anticoagulant
    or liver dz. Pick factor made in liver and not Vit-K     will not correct the defect.
    dependent: 5. If liver dz then ↓ 5 . If Vit-K then 5 Low Responder: Factor 8 concentrates up to high levels.
    will be normal.                                          If poor response then have a …
Causes: Poor Diet. Malabsorption. Vit A or E             High Responder: Wait for minor bleeding episodes.
    administration. Drugs: Antibiotics,
    Cholestyramine, Mineral Oil. Liver Dz. Depletion
    can occur over as short as 1 week.                                NATURAL
Treatment: Administration of Vit-K. Will take 1 day to
    become effective.                                             ANTICOAGULANTS
                                                           Protein C
Non-Vit-K : 11, 12. Co-factors: 8 and 5. Fibrinogen.
                                                           Serine protease that is Vit K dependent Made in the
tPA                                                        Thrombin + intact endothelium  activated Protein C
Degraded in liver. When have  function in liver               cleaves Va and VIIIa
                                                           2-5% w/thrombosis
              HEMOPHILIA                                   15% of young adults w/thrombosis.
                                                           Coumadin induced skin necrosis during loading.
Hemophilia A VIII                                          Treatment: Long-term PO anticoagulants.
Inversion of factor VIII gene. X Chromosome. Variety
    of mutations lead to variety of levels of disease.    Protein S
    low levels of factor VIII antigen and activity.        Vit K dependent cofactor. Not a protease.
Clinical:                                                  Helps bind APC to phospholipid.
1) Severe hemophilia  have factor VIII activities < 1     Possible arterial thrombosis.
    % of normal. Dx  frequent, spontaneous                Antithrombin III
    hemorrhages into joints, muscles and vital organs.
2) Factor activity level of 1 to 5% of normal is enough    Serine Protease Inhibitor made in liver
    to reduce the severity of the disease. They are at     Autosomal dominant: 1/2000
    risk of bleeding with surgery or trauma. Women         Thrombin:Antithrombin complex  inhibits 75% of
    may also be at risk during surgery.                        thrombin.
Lab Studies:                                               Heparin enhances reaction 2000x  DVT
PTT: prolonged                                             Treatment: FFP or antithrombin III concentrates for
BT: prolonged                                                  short-term replacement therapy. Long-term oral
PT: normal.                                                    anticoagulants.
Factor V Leiden
Base pair substitution
Resists APC degradation.
6% of normal
40% of DVT pts.
Thrombosis at any time.

          LUPUS LIKE
Primary: Ab directed toward phospholipid.
    Thromboses in 25-60% of pts. Recurrent fetal
Secondary: 5-10% SLE. Drugs. Autoimmune. HIV.
    Virus. Malignancy.
Inhibits Xa/II from binding phospholipids.
Lab Tests:
Prolonged PTT not corrected with 1:1 mix.
Dilute Russell Viper Venom Test: Prolonged in presence
    of APL Ab. Confirm by correction with platelets.
    Most sensitive.
Clinical evidence:
Lab evidence: 2(+) Ab tests separated by 6 weeks.
Treatment and prognosis
No good long term studies on pts w/lupus Ab to look at
    what is their incidence of venous or arterial
Have looked at pregnant women. Steroid have helped.
Pre-operative: Make sure no underlying factor VIII or II
    antibody that can cause very severe problems.
    Having the antiphospholipid ab does not  risk

Secondary or Reactive:
Acute blood loss              Postpartum
Infection                     Post-traumatic
After splenectomy             Exercise
Post-Op state                 Drug  epinephrine
Ovulation                     Sarcoidosis
Adrenal Hyperplasia           Osteoporosis
Hemophilia A
After thrombocytopenia: Pernicious anemia, acute
    thrombocytopenic purpura, EtOH-induced
    thrombocytopenia, drug-induced thrombocytopenia.
IBD                            RA
Hodgkin’s Dz                   Carcinoma
Osteogenic sarcoma             Retinoblastoma
Mesothelioma                   Fe deficiency
Splenic Atrophy                Chronic hemolytic
                                   anemia sp

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