Disorders of Hemostasis

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Disorders of Hemostasis

• Dr. Batizy
• 11/2/06

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Primary Hemostasis

• The platelet contains lysosomes, granules, and
  trilaminar plasma membrane, microtubules.
• Granules are key in primary hemostasis and
  contain ADP, Thromboxane, platelet factor 4,
  adhesive and aggregation glycoproteins,
  coagulation factors, and fibrinolytic inhibitors

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Primary Hemostasis

• Dependent on Platelets and Von Willebrand Factor
  (vWF)
• Platelets gather and attach to vWF
• Platelets degranulate after attachment and
  release ADP and Thromboxane which attracts more
  platelets
• Forms a platelet plug
• Requires endothelial damage to adhere

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Secondary Hemostasis

• Platelet aggregation initiates secondary
  hemostasis through the coagulation cascade
• Coagulation cascade is initiated by the intrinsic
  or extrinsic pathway
• The final cascade results in fibrin deposition
  cross-linking platelets and clot formation

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The Coagulation Cascade
Common Pathway
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A word on clotting factors

• Vitamin K Dependent Factors
• Intrinsic Pathway IX, X
• Common Pathway II
• Extrinsic Pathway VII
• All clotting Factors are produced in liver except
  vWF/VIII
• VIII produced by the vascular endothelium
• Sites of heparin activity
• IIa, IXa, Xa ( major site), XIa, Platelet factor 3

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A word on clotting factors

• Factor VIII A factor by any other name?
• Same factor 3 different activities
• VIIIC antihemophilic or coagulation activity
• vWF supports platelet adhesion and carries VIII
  in the blood
• VIIIAg reacts with rabbit antibodies, relates
  to measured plasma level rather than activity

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Fibrinolysis

• The Ying to the Yang of clot formation
• Tissue Plasminogen activator (tPA)
• Released from endothelial cells
• Converts plasminogen to plasmin which degrades
  fibrinogen and fibrin into fibrin degradation
  products
• Cross linked fibrin is cleaved into D-Dimers

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Testing the hemostatic system

• CBC
• H/H drops often lag behind actual RBC loss due to
  slow equilibration
• Blood smear
• Schistocytes and fragemented RBC- DIC
• Teardrop-shaped or nucleated RBC Myelophthisic
  disease
• Characteristic WBC morphologies seen in
  thrombocytopenia in infectious mononucleosus,
  folate, B12 deficiency, or leukemia

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Testing the hemostatic system

• Platelet count
• Thrombocytopenia Less that 100,000/mL
• Spontaneous bleeding possible Less than
  20,000/mL
• Count does not have anything to do with
  functionality of platelet

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Testing the hemostatic system

• Bleeding time
• Tests vascular integrity and platelet function
• Incision on volar aspect of the forearm 1mm deep
  and 1 cm long
• BP cuff inflated to 40 mmHg
• Normal lt 8 minutes
• Borderline 8-10 minutes
• Abnormal 10 minutes
• Affected by ASA (permanent) and NSAIDs

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Testing the hemostatic system

• Bleeding time
• Prolonged with platelet counts below 100,000
• When prolonged with platelet count over 100,000
  suggests platelet dysfunction

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Testing the hemostatic system

• Prothrombin Time
• Test of extrinsic and common pathways
• International Normalized Ratio used to compensate
  for differences in thromboplastin reagents
• Used for coumadin
• Elevated in patients with liver disease and
  abnormalities in vitamin K sensitive factors

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Testing the hemostatic system

• Partial Thromboplastin Time (PTT)
• Tests intrinsic and common pathway
• Average normal 25-29
• Factor levels usually less than 40 to be
  affected
• Affected by heparin
• Can be effected by coumadin at supra-therapeutic
  levels due to effects on the common pathway

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History and Physical

• Platelet Disorders
• More common in Women
• Petechiae, Purpura, mucosal bleeding
• More commonly acquired

• Coagulation Disorder
• More common in Men
• Delayed deep muscle bleeding, hemarthrosis,
  hematuria
• More commonly congenital

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Thrombocytopenia

• Usually mucosal bleeding
• Epistaxis, menorrhagia, and GI bleeding is common
• Trauma does not usually cause bleeding

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Thrombocytopenia

• Three mechanisms of Thrombocytopenia
• Decreased production
• Usually chemotherapy, myelophthisic disease, or
  BM effects of alcohol or thiazides
• Splenic Sequesteration
• Rare
• Results from malignancy, portal hypertension, or
  increased Splenic RBC destruction ( hereditary
  spherocytosis, autoimmune hemolytic anemia)
• Increased Destruction

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Thrombocytopenia

• Immune thrombocytopenia
• Multiple causes including drugs, lymphoma,
  leukemia, collagen vascular disease
• Drugs Include
• Digitoxin, sulfonamindes, phenytoin, heparin,
  ASA, cocaine, Quinine, quinidine, glycoprotein
  IIb-IIa antagonists
• After stopping drugs platelet counts usually
  improve over 3 to 7 days
• Prednisone (1mg/kg) with rapid taper can shorten
  course

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Thrombocytopenia

• HIT
• Important Immunologic Thrombocytopenia
• Usually within 5-7 days of Initiation of Heparin
  Therapy but late onset cases are 14-40 days
• Occurrence 1-5 with unfractionated heparin and
  less than 1 with low molecular-weight heparin
• Thrombotic complications in up to 50 of HIT with
  loss of limb in 20 and mortality up to 30

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ITP

• Diagnosis of exclusion
• Associated with IgG anti-platelet antibody
• Platelet count falls to less that 20,000

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ITP

• Acute Form
• Most common in children 2 to 6 years
• Viral Prodrome common in the 3 weeks prior
• Self Limited and gt 90 remission rate
• Supportive Treatment
• Steroids are not helpful

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ITP

• Chronic Form
• Adult disease primarily
• Women more often than men
• Insidious onset with no prodrome
• Symptoms include easy bruising, prolonged
  menses, mucosal bleeding
• Bleeding complications are unpredictable
• Mortality is 1
• Spontaneous remission is rare

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ITP

• Chronic Form
• Hospitalization common because of a complex
  differential diagnosis
• Multiple treatments
• Platelet transfusions are used only for life
  threatening bleeding
• Life threatening bleeding is treated with IV
  Immune globulin (1g/kg)

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TTP??HUS

• Exist on a continuum and are likely the same
  disease
• Diagnosed by a common pentad
• Microangiopathic Hemolytic Anemia Schistocytes
  membranes are sheared passing through
  microthrombi
• Thrombocytopenia More sever in TTP
• Fever
• Renal Abnormalities More prominent in HUS
  include Renal insufficiency, azotemia,
  proteinuria, hematuria, and renal failure
• Neurologic Abnormalities hallmark of TTP 1/3 of
  HUS Sx of HA, confusion, CN palsies,
  seizure,coma

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TTP??HUS

• Labs
• PT, PTT, and fibrinogen are within reference
  range
• Helmet Cells (Shistocytes) are common

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TTP??HUS

• HUS
• Most common in infants and children 6mo - 4 years
• Often associated with a prodromal diarrhea
• Strongest association to E. coli O157H7 but also
  associated with SSYC as well as multiple virus
• Prognosis
• Mortality 5-15
• Younger patients do better

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TTP??HUS

• HUS
• Treatment
• Mostly supportive
• Plasma exchange reserved for sever cases
• Treat hyperkalemia
• Avoid antibiotics with Ecoli
• May actually increase verotoxin production with
  TMP-SMX
• May be helpful with cases of Shigella dysenteriae

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TTP??HUS

• TTP
• More common in adults
• Untreated mortality rate of 80 1 to 3 months
  after diagnosis
• Aggressive plasma exchange has dropped the
  mortality to 17
• Splenectomy, immune globulin, vincristine all
  play a role in therapy

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TTP??HUS

• AVOID PLATELET TRANSFUSION
• May lead to additional microthrombi in
  circulation
• Transfuse only with life threatening bleeding

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Dilutional Thrombocytopenia

• PRBC are platelet poor
• Monitor platelet count with every 10 u PRBC
• Transfuse when count below 50,000
• Get them upstairs before you transfuse 10 units
  PRBC

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DIC

• A few harmless snowflakes working together can
  create an avalanche of Destruction.

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DIC

• Early recognition important secondary to
  potentially devastating sequelae and effective
  therapy
• DIC Sequence ? Platelets and coagulation factors
  consumed ? Thrombin directly activates fibrinogen
  ?Fibrin deposition ? Fibrinolysis ? Inhibition of
  platelets and fibrin polymerization ? Decrease in
  inhibition levels
• Entire process leads to a massive consumption of
  coagulation factors

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DIC

• Life threatening combination of bleeding
  diathesis with small vessel ischemia
• There are varying levels of acuity
• Recommended testing
• Peripheral Smear Low platelets, schistocytes
• Platelet count Low (lt100,000)
• Pt, PTT, Thrombin Time Prolonged
• Fibrinogen Low
• Fibrin degredation products zero to large

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DIC

• Treatment
• Dependent on whether bleeding or ischemia
  predominate
• If bleeding
• Platelets, FFP or Cryoprecipitate, and blood
  recommended
• With Ischemia
• Heparin has a place in treatment
• Examples include Retained fetus, purpura
  fulminans, giant hemangioma, and acute
  promyelocytic leukemia

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DIC

• Treatment
• Goal in ER is suspicion, aggressive pursuit of
  diagnosis, understanding complications, and
  rarely initiation of therapy

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Coagulation Pathway Defects

• Hemophilia A
• Von Willebrands Disease
• Hemophilia B ( Christmas Disease)

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Hemophilia A
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Hemophilia A

• Variant form of Factor VIII
• 60 to 80 persons per million
• 70 Sex linked recessive
• Severity linked to level of VIIIC activity
• 1 Severe
• 1-5 Moderate
• 5-10 mild ( little risk of spontaneous bleeding)

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Hemophilia A

• Bleeding can occur anywhere
• Deep muscles
• Joints
• Urinary Tract
• Intracranial
• Recurrent Hemarthrosis and progressive join
  destruction are major cause of morbidity
• Intracranial bleed is major cause of death in all
  hemophiliacs

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Hemophilia A

• Mucosal bleeding is rare unless associated with
  von Willebrands or Platelet inhibition
• Unlike platelet defects Trauma initiates bleeding
• Bleeding can occur usually by 8 hours but as late
  as 1 to 3 days after trauma

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Hemophilia A

• Management
• Home therapy is increasingly common and most
  report to ER only with complicated problems or
  Trauma
• Hospitals should have files of known hemophiliacs
  in the area
• Accepted therapy is with Factor VIII replacement
  or VIIIC
• Newer preparation carry lower risk for Hep B and
  Hep C transmission

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Hemophilia A

• Management
• Multiple guidelines for therapy institution
• Most important physician should believe a patient
  saying they are bleeding and institute early
  therapy

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Hemophilia A

• Prophylaxis
• May require admission for anticipation of delayed
  bleeding
• Candidates
• Deep lacerations
• Soft tissue injury where hematoma could be
  destructive ie eye, mouth, neck, back, and
  spinal column

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Hemophilia A

• Treatment of haemophilic synovitis
• COX-2 important in Hemophiliacs because of
  antiinflammatory,and analgesic properties but
  they do not affect the platelet fuction
• With withdrawl of rofecoxib from the market
  celecoxib had become popular
• Study has shown that Celecoxib gives good relief
  of synovitis without serious adverse effects

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Von Willebrands Disease

• Most common inherited bleeding disorder
• Without vWF the ability of platelets to adhere is
  diminished
• VIIIC has diminished activity
• Bleeding sites are primarily mucosal
• Hemarthrosis is rare
• Menorrhagia and GI bleed are common

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Von Willebrands Disease

• Factor VIII replacement is treatment of choice
• FFP may be given in extreme circumstances
• Desmopressin is only useful for specific types of
  vWD and should only be give with advice from
  hematologist

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Hemophilia B (Christmas Disease)
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Hemophilia B (Christmas Disease)

• Clinically indistinguishable from hemophilia A
• Deficiency of factor IX
• Factor IX preparation used in treatment
• FFP and plasma prothrombin complex are also
  useful
• Gene manipulation in animals shows promising
  results for the future

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Take home message

• All Bleeding stops. Eventually

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References

• Rosens
• Emedicine
• Celecoxib in the treatment of haemophilic
  synovitis, target joints, and pain in adults and
  children with haemophilia, Haemophilia (2006),
  12, 514-517