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
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
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:
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
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)
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
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
Crush injury Haptoglobin: due to intravascular hemolysis.
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
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.
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:
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.
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.
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
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
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
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
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.
Primary: Ab directed toward phospholipid.
Thromboses in 25-60% of pts. Recurrent fetal
Secondary: 5-10% SLE. Drugs. Autoimmune. HIV.
Inhibits Xa/II from binding phospholipids.
Prolonged PTT not corrected with 1:1 mix.
Dilute Russell Viper Venom Test: Prolonged in presence
of APL Ab. Confirm by correction with platelets.
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
After splenectomy Exercise
Post-Op state Drug epinephrine
Adrenal Hyperplasia Osteoporosis
After thrombocytopenia: Pernicious anemia, acute
thrombocytopenic purpura, EtOH-induced
thrombocytopenia, drug-induced thrombocytopenia.
Hodgkin’s Dz Carcinoma
Osteogenic sarcoma Retinoblastoma
Mesothelioma Fe deficiency
Splenic Atrophy Chronic hemolytic