20 - Introduction to Coagulation Disorders & Acquired Disorders

Question 1

Coagulation Pathway

Answer 1

Question 2

Coagulation Pathway

Answer 2

Question 3

Coagulation Pathway

Answer 3

Question 4

Coagulation Pathway

Answer 4

Question 5

Coagulation Pathway

Answer 5

Question 6

Evaluation of the bleeding patient

Answer 6

• Type of bleeding:
• Local versus diffuse
• Spontaneous or secondary to trauma
• Excessive or minimal
• Mucosal or deep tissues /joints
• Bruising/petechial
• Early or late
• History:
• Personal history of bleeding
• Family history of bleeding
• Medical conditions or recent trauma (surgery is a form of trauma)
• Medications: prescribed and OTC, vitamins and herbs
• Nutritional status

Question 7

Types of bleeding:

Answer 7

Localized or diffuse

Question 8

Evaluation of the bleeding patient
Labs

Answer 8

• Platelet count
• PT INR
• PTT
• Liver function studies
• Renal function studies
• Fibrinogen
• Thrombin Time
• Platelet function
• Peripheral smear

Question 9

Evaluation of the bleeding patient
Labs: PT INR and aPTT

Answer 9

PT INR
(prothrombin time)

• measures how long it takes for a
  clot to form in a blood sample.
• An INR (international normalized
  ratio) is a type of calculation
  based on PT test results.
• in order to activate the extrinsic
  pathway, tissue factor (factor III)
  is added and the time the sample
  takes to clot is measured
  optically.
• A normal PT requires factors I
  (fibrinogen), II (prothrombin), V
  (proaccelerin), VII (proconvertin),
  and X (Stuart-Prower factor).

aPTT
(activated partial thromboplastin time)
* measures how long it takes for a
clot to form in a blood sample.
* In order to activate the intrinsic
pathway an activator (such as
silica, celite, laolin, or ellagic acid)
is added, and the time the sample
takes to clot is measured optically.
* A normal PTT requires factors I, II,
V, VIII, IX, X, XI and XII. Notably,
deficiencies in factors VII or XIII will
not be detected with the PTT test.

Question 10

Coagulation pathways

Answer 10

Question 11

Common Acquired Bleeding Disorders

Answer 11

Question 12

Case 1:
* A 27-year-old pediatric resident comes to your ER feeling terrible. He has had a “cold” with high fever for the past few days. His only significant past medical history was that he received radiation for Hodgkin’s disease at the age of 16. He has been well without evidence
of recurrence since then.

• His physical exam was remarkable for: a temperature of 104F, P 175, R 28, BP 70/50. He had rales in his left anterior chest, a well healed midline abdominal scar, and diffuse petechiae and ecchymoses covering a large portion of his body (which his wife said were not
  present earlier in the day).

LABS:
▪ WBC 3,500/ul
▪ ANC 700/ul !
▪ ALC 2,800/ul
▪ Hemoglobin 14.0 gm/dl
▪ Hematocrit 42%
▪ Platelets 6,000/ul !
▪ PT 16 sec, INR 2 !
▪ aPTT 58 sec !

Answer 12

Disseminated Intravascular Coagulation

▪ Increased activation of the clotting cascade
▪ Decreased natural anticoagulants
▪ Impaired fibrinolysis

Question 13

Conditions associated with DIC

Answer 13

Question 14

Clinical manifestations of DIC: Thrombotic

Answer 14

• Brain - Altered mental status, Stroke
• Renal - Acute renal failure
• GI - Mucosal ulceration, bleeding
• Skin - Digital ischemia, Purpura fulminans
• Lungs - ARDS
• Adrenals:
  Waterhouse-Friderichsen syndrome
  Acute adrenal infarction or hemorrhage
  Adrenal insufficiency

Question 15

Clinical Manifestation of DIC: Hemorrhagic

Answer 15

• Global bleeding
• Consumptive
  thrombocytopenia
• Consumption of coagulation
  factors
• Fibrinogen, FVIII, etc.
• FDPs inhibit fibrin
  polymerization and thus
  hinders platelet aggregation

Question 16

Clinical Manifestations of DIC: Thrombotic

Answer 16

Question 17

Diagnosis of DIC

Answer 17

▪ Prolonged PT INR
▪ Prolonged pTT
▪ Thrombocytopenia
▪ Decreased fibrinogen (sometimes NML; acute
phase reactant)
▪ Schistocytes on peripheral smear
▪ Decreased ATIII, protein C, protein S
▪ Increased FDP/FSP (fibrin split products), D-Dimer

Question 18

Treatment of DIC

Answer 18

▪ Treat the underlying disease or cause!!
▪ Replenish hemostatic factors/supportive measures
▪ Platelet transfusion (keep above 10K if bleeding or 20K if instrumented
▪ Fresh frozen plasma (FFP):
More volume to support the blood pressure
Provides all soluble plasma proteins and factors

▪ Cryoprecipitate
Fibrinogen, FVIII, FXIII, vWF
Less volume if fluid overload is a problem

▪ Not much evidence for anticoagulation prophylaxis for thrombosis, unless significant burden

Question 19

Case 2: An 18-year-old man is admitted to the Trauma Unit for abdominal gunshot wounds. He requires
multiple surgeries for bowel resection and draining
abscesses. He is NPO and has been getting broad
spectrum antibiotics for the past 3 weeks. Hematology
is consulted for a prolonged PT and PTT.

Answer 19

Vitamin K deficiency

Question 20

VITAMIN K

Answer 20

• Fat soluble
• Requirement: 50 mg/d
• Sources:
  green leafy vegetables 200 mg/d
  gut flora 200 mg/d
  Stores: Last 1-2 weeks
• Coagulation factors

II, VII, IX, X (VII has the shortest 1⁄2 life of 3-6 hours)

• Natural anticoagulants

Protein C (1⁄2 life 8 hours)
Protein S (1⁄2 life 30 hours)

Question 21

Vitamin K Function

Answer 21

• Factors II, VII, IX, X have 10 - 13
  glutamic acid residues
• Vitamin K necessary cofactor for
  g-carboxylation of glutamic acids
  [g-carboxyglutamic acid (gCGA)]
• Factor activity is proportional to
  the number of carboxylated
  glutamic acids on the molecule
• Ca2+ acts as a bridge between g-
  carboxyglutamic acid and

negatively charged platelet
phospholipids

Question 22

Vitamin K deficiency treatment

Answer 22

Treatment:
▪ Phytonadione (vitamin k1)
▪ PO: 5-10mg; should see INR change in 24-72 hours
▪ If gut is working
▪ IV: 10mg; should seen change in INR within 6 hours:
Slow infusion
Hypotension, anaphylactoid reaction (rarely seen)

▪ SQ: has erratic absorption in edema and CHF

Question 23

coagulation pathway

Answer 23

Question 24

Case 3

A 54-year-old man with cirrhosis is awaiting a liver
transplant. He presents to the emergency room with a
painful, swollen left calf. His labs show:

platelets 66,000
PT 28.2
PTT 43.2
Thrombin time 29.8
Fibrinogen 117
US shows a LLE deep vein thrombosis.

Answer 24

End stage liver disease: bleeding

Thrombocytopenia
▪ Hypersplenism
▪ Decreased TPO production by liver
▪ Marrow suppression if ETOH
▪ Immune destruction if hepatitis C

Platelet dysfunction
▪ Increased prostacyclin
Decreased factor production
▪ Vitamin K deficiency (II, VII, IX, X)
▪ Impaired synthesis (albumin <2.5) vWF, tPA, PAI-1

Dysfibrinogen
▪ Decreased fibrinogen activity compared to antigen

Increased consumption
▪ Like DIC
▪ Hyperfibrinolysis

Question 25

End stage liver disease: thrombosis

Answer 25

* Increased vWF/FVIII * Decreased ATIII * Decreased protein C and protein S * Decreased plasminogen * Decreased ADAMTS13

Question 26

End stage liver disease: treatment

Answer 26

▪ Treat the underlying coagulation problem ▪ Platelet transfusion if the degree of thrombocytopenia meets the guidelines for platelet transfusion (<10K if not bleeding, <20K if not bleeding but instrumented, and >20K if platelet type bleeding present) ▪ If fibrinogen <100, give cryoprecipitate ▪ FFP in life threatening bleed, especially if you also need intravascular volume

Question 27

Differentiating between Vitamin K deficiency, Liver disease, and DIC

Answer 27

Question 28

Case 4

Answer 28

A 65-year-old man has progressive bruising after hitting a wall moving furniture. Hecomes to the ER for a painful, swollen left leg. He has no bleeding history. Labs: Platelets 355,000 PT 10.6 PTT >100 TT 18.2 Fibrinogen 347 PTT mixing study Control 32 s Mix at 2 hours, 98 s Factor VIII <1% Factor IX 70% Factor XI 105% Factor XII 108%

Question 29

Acquired Factor Inhibitors

Answer 29

**▪ Lupus anticoagulant (inhibitor)** **▪ Acquired VIII inhibitor** ▪ Acquired XIII inhibitor (INH) ▪ Heparin or Heparin-like ▪ Fibrin degradation products **▪ Factor V, II (very rare except after exposure to fibrin glue)**

Question 30

Acquired Factor Inhibitors: Clinical

Answer 30

The most common is a factor VIII inhibitor (acquired hemophilia A) with an incidence which increases with age. The majority are IgG antibodies Presentation: ▪ Spontaneous and usually severe ▪ Typically seen in the elderly ▪ Mucocutaneous bleeding ▪ Subcutaneous/soft tissue hemorrhage ▪ Internal organ bleeding (GI, retroperitoneal) ▪ Less commonly hemarthrosis Underlying cause: ▪ Idiopathic (~50% of cases) ▪ Pregnancy (2-3 months postpartum; usually in 1st pregnancy; 20% of cases) ▪ Drugs (antibiotics, fludarabine, etc.) ▪ Malignancy (10% of cases) ▪ Autoimmune process (RA, SLE; 20% of cases) ▪ Cardio-pulmonary bypass - FXIII deficiency ▪ Topical bovine thrombin - FV inhibitor

Question 31

Acquired Factor Inhibitors: Diagnosis and treatment

Answer 31

**Diagnosis:** ▪ Elevated PT INR: FVII ▪ Elevated pTT: FVIII, FIX, FXI, FXII ▪ Elevated PT INR: FII, FV, FX and fibrinogen ▪ Mixing studies ▪ Almost normalizes or normalizes in 1:1 mixing study, but then after 1-2 hours of incubation, it rises again ▪ Low factor activity (%) along with correspondent inhibitor (Bethesda Unit) **Treatment:** ▪ Treat active bleeding ▪ Inhibitor elimination

Question 32

Medications for coagulation disorders

Answer 32

▪ Coagulation factor inhibition: apixaban, dabigatran, enoxaparin, heparin, rivaroxaban, warfarin ▪ Collagen degradation: corticosteroids ▪ Platelet function inhibition: aspirin, non-steroidal anti- inflammatories (ibuprofen), clopidogrel, selective serotonin reuptake inhibitors (paroxetine) ▪ Thrombocytopenia: alcohol, antibiotics (cephalosporins, linezolid, nitrofurantoin, penicillin, rifampin, sulfonamides,vancomycin), carbamazepine, quinine, thiazide diuretics, valproic acid.

Question 33

non-prescription medications for coagulation disorders

Answer 33

▪ Arnica – when used with other anticoagulants ▪ Chondroitin - when used with other anticoagulants ▪ Fish oil – use of >3 gms/day may potentiate bleeding and at smaller doses when used with other anticoagulants ▪ Garlic – may cause bleeding independently or when used with other anticoagulants ▪ Ginkgo - when used with other anticoagulants ▪ Green tea extracts – conflicting reports but quantity may matter ▪ Vitamin E – “high dose” may increase risk of bleeding or when used with other anticoagulants

Question 34

End Stage Renal Disease

Answer 34

▪ The primary effect is on decreasing platelet function. Platelet dysfunction occurs both as a result of intrinsic platelet abnormalities and impaired platelet-vessel wall interaction. ▪ If a patient with ESRD has platelet type bleeding, no matter what the platelet count, a platelet transfusion can be considered. ▪ DDAVP (vasopressin) as a single dose can be considered as it will cause immediate activation of V2 vasopressin receptors on endothelial cells and intracellular cyclic adenosine monophosphate (cAMP)–dependent signaling leading to exocytosis of von Willebrand factor (VWF) and tissue plasminogen activator from Weibel-Palade bodies as well enhancing intracellular Na+ and Ca2+ fluxes. This all serves to activate the platelets.

Question 35

Massive Transfusion

Answer 35

▪ Whole blood is the best replacement if available ▪ 1:1:1 is the next best RBC:FFP:platelets ▪ You will hear various other suggestions of 5:1:1 or 10:2:2. Follow the labs.