1. WHY IS MY PATIENT BLEEDING?
Blood vessel damaged/severed
History
Bleeding confined to area of injury
Coag tests normal or nearly so
Potential intervention: sutures

2. Bleeding confined to an operative site is usually due to a severed vessel

3. WHY IS MY PATIENT BLEEDING?
Defective primary hemostasis (platelets/VWF)
Skin/mucosal bleeding may be prominent
Petechiae (mainly with thrombocytopenia)
Bleeding soon after injury
Lab results: abnormal platelet function screen, VWF activity, thromboelastography
Potential interventions: platelet transfusions, DDAVP, VWF concentrate

4. Platelet defects and vessel disorders: immediate bleeding from skin and mucosal surfaces, petechiae

5. WHY IS MY PATIENT BLEEDING?
Defective fibrin formation (clotting factor deficiency or circulating anticoagulant)
Bleeding into tissues
Bleeding may be delayed after injury
Lab results: Long PT/INR and/or PTT, low fibrinogen, abnormal TEG
Potential interventions: FFP, cryoprecipitate, specific factor concentrate, prothrombin complex concentrate, vit K, rVIIa

6. Coagulation factor deficiency: delayed bleeding into soft tissues

7. WHY IS MY PATIENT BLEEDING?
Hyperfibrinolysis
Generalized bleeding/oozing
Risk factors: liver disease, prostate cancer, leukemia, acute illness with DIC
Bleeding may be out of proportion to coag test abnormalities
Lab results: low antiplasmin, abnormal TEG
Potential intervention: antifibrinolytic drug

8. WHY IS MY PATIENT BLEEDING?
Defective fibrin crosslinking (factor XIII deficiency)
Rare
Most cases hereditary & diagnosed in early childhood
Not detected by usual screening tests
Lab result: low factor XIII
Potential intervention: factor XIII concentrate

9. WHY IS MY PATIENT BLEEDING?
Abnormal blood vessels
Examples: amyloidosis, Ehlers-Danlos syndrome, hereditary hemorrhagic telangiectasia
Coag tests usually normal
Exam findings often helpful

10. Hereditary hemorrhagic telangiectasia
Researchgate.net

11. Ehlers-Danlos Syndrome
Lifewitheds.com
Morphopedics.wikdot.com

12. Amyloidosis

13. EVALUATION OF THE BLEEDING PATIENT
HISTORY (inherited or acquired bleeding tendency?)
Prior invasive procedures, dental extractions
Family history
Medications, alcohol
PHYSICAL EXAM (platelet/VWD defect vs clotting factor deficiency vs vessel injury or defect?)
Mucosal/skin vs soft tissue bleeding?
Bleeding from one or multiple sites?
Mucosal hemangiomas, skin/joint laxity, etc

14. Laboratory tests to evaluate bleeding Initial screening
Platelet count
PT/INR
aPTT
Fibrinogen
Platelet function screen
Thromboelastography?
Normal results → Major defect in primary hemostasis or clotting factor deficiency unlikely

15. Prothrombin time/INR Long PT/INR
Liver disease
Vitamin K deficiency
Warfarin or warfarin analogs (rat poison)
DOAC or high level of heparin
DIC
Inherited conditions rare
Won’t detect hemophilia, factor VIII inhibitor, heparin at therapeutic concentrations
Magnitude of test abnormality usually proportional to clinical severity

16. aPTT Long aPTT with normal INR
Heparin (therapeutic or contaminant) or DOAC
Hemophilia A or B
von Willebrand disease (low VIII – but PTT may be normal)
Factor XI deficiency
Factor VIII inhibitor
Factor XII deficiency (does not cause bleeding)
Lupus anticoagulant (rarely causes bleeding)
Magnitude of test abnormality not necessarily proportional to clinical severity

17. Platelet function screen
Replaces the bleeding time
Advantages
Ex vivo test (no skin incision)
Better standardized
Better sensitivity and specificity
PFA-100
A patient with von Willebrand disease (VWF activity < 20%)

18. Platelet function screen
Sensitive to:
Defective platelet adhesion in von Willebrand disease
Platelet dysfunction due to drugs (variable sensitivity)
Inherited platelet disorders
Not useful in patients with moderate or severe Thrombocytopenia

19. Conditions that may cause bleeding with normal or near-normal screening tests
Mild hemophilia (factor level 20-30% of normal)
Von Willebrand disease
Dysfibrinogenemia
Factor XIII deficiency (rare)
Fibrinolytic disorders
Vascular disorders (Ehlers-Danlos, amyloid, etc)

20. Laboratory tests to evaluate bleeding Second round
Thrombin time (dysfibrinogenemia, heparin-like anticoagulant)
Von Willebrand activity
Alpha-2 antiplasmin (hyperfibrinolysis)
Factor XIII level
Platelet aggregation (if platelet function disorder strongly suspected)
Thromboelastography
Mixing study (if circulating inhibitor suspected)

21. IMMUNE THROMBOCYTOPENIA
ITP
Drug-induced purpura
Heparin-induced thrombocytopenia
Post-transfusion purpura

22. ITP Autoimmune platelet destruction Mild to severe thrombocytopenia
Other blood counts, coag tests typically normal
A diagnosis of exclusion
Bleeding risk low to moderate in most cases
Hospitalization not always needed
High risk: “wet purpura”, active bleeding, elderly, history of major bleeding
Rarely begins in hospital
Few symptoms other than bruising & petechiae

23. ITP: initial treatment
Corticosteroids: prednisone 1 mg/kg or pulse high dose dexamethasone
IVIG (high dose)
Platelet transfusion sometimes effective
Splenectomy rarely necessary as initial treatment

24. Drug-induced thrombocytopenia
Thrombocytopenia may be severe (<5K)
Often begins in hospital, precipitous drop in platelet count
Bleeding risk moderate to high
Typically occurs within days of starting a drug

25. DRUGS MOST LIKELY TO CAUSE THROMBOCYTOPENIA*
Hematology 2009;153

27. Drug-induced thrombocytopenia management
Stop any potentially offending drug
Resolution may take days to weeks
Steroids less effective than in ITP
IVIG in selected cases

28. Heparin-induced thrombocytopenia
Mild to moderate thrombocytopenia with onset 4-7 days after initial heparin exposure (UFH > LMWH)
Recent surgery, infection, inflammation increase risk
Bleeding risk low, thrombosis risk high
Heparin Ab test very sensitive – HIT can be ruled out if negative
Serotonin release assay predicts thrombotic risk
Rx: Stop heparin (any form), consider alternative anticoagulant (not warfarin or LMWH)

29. Post-transfusion purpura
Severe, precipitous drop in platelet count, usually a few days after blood product exposure (FFP, RBC most common)
Most patients are multigravid women
Prior exposure to platelet antigen during pregnancy, recall reaction after transfusion
Most affected patients lack the common platelet alloantigen HPA-1 (~ 2% of population)
Antibodies are directed against HPA-1 on transfused “passenger” platelets, patient’s own platelets are destroyed as “innocent bystanders”
Platelet transfusion may exacerbate the problem

30. Post-transfusion purpura
If suspected notify blood bank to arrange for appropriate testing and transfusion therapy
Test for HPA-1 antibodies in patient serum
Do NOT give platelet transfusion
If RBC transfusion needed give washed RBC
High dose IVIG
Steroids generally not helpful

32. DISSEMINATED INTRAVASCULAR COAGULATION
Rapid formation & lysis of intravascular fibrin
Consumption of clotting factors, platelets, inhibitors
Life-threatening underlying disease
Bleeding due to uncontrolled fibrinolysis, thrombocytopenia, clotting factor consumption and tissue injury from underlying disease
Tissue injury/necrosis due to microvascular occlusion, hypotension, cytokine-mediated endothelial damage
Most deaths due to underlying disease

33. Pneumococcal sepsis in splenectomized patient
PUPURA FULMINANS
Pneumococcal sepsis in splenectomized patient
NEJM 2001;344:1593

34. DIAGNOSIS OF DIC Underlying disease capable of causing DIC?
Evidence of accelerated clotting factor and platelet consumption, and increased fibrinolysis?
If both present DIC is likely

35. SCREENING FOR DIC D-dimer (most sensitive) PT/INR (PTT less helpful)
Fibrinogen
CBC/platelet count
Fibrin monomer (most specific)

36. TREATMENT OF DIC TREAT UNDERLYING DISEASE!
Clotting factor & inhibitor replacement if there is significant bleeding:
Fresh frozen plasma (goal INR ≤ 1.8)
Cryoprecipitate (goal fibrinogen ≥ 100)
Platelets (goal platelet count 50-75K)
Pharmacologic inhibitors (selected pts with major bleeding unresponsive to replacement)
Heparin (low dose – eg, 500 U/hr)
Antifibrinolytics (Amicar, tranexamic acid)

37. TTP Microangiopathic hemolytic anemia Thrombocytopenia
Organ dysfunction (CNS, renal, other) due to small vessel occlusion
Untreated mortality rate >90%
With treatment mortality < 20%
1-2 UWHC

38. TTP
Caused by autoimmune destruction of ADAMTS-13 protease that modulates von Willebrand factor multimer size
Very large multimers clump platelets
Microthrombi damage RBC and block vessels

39. TTP Thrombocytopenia (may be severe)
Intravascular hemolysis (high LDH, low haptoglobin, schistocytes in blood smear)
INR, PTT, fibrinogen usually normal
Organ dysfunction
Neurologic symptoms
Renal dysfunction (hematuria, proteinuria)
Cardiac (arrhythmia)
ADAMTS-13 activity low (usually <10%)

40. TTP - DDX Occult cancer Pregnancy complications (HELLP, etc)
Hemolytic-uremic syndrome (kidney main target organ)
Shiga toxin, GI prodrome
“Atypical” HUS: genetic component, complement-mediated, no GI prodrome
Vasculitis (SLE, scleroderma)
HIV infection
DIC
Drugs (calcineurin inhibitors, mitomycin C, interferon, clopidogrel, ticlopidine)

41. TTP Urgent plasma exchange Immunosuppression
Plasma infusion if PE not immediately available
Immunosuppression
Corticosteroids
Rituximab for patients with resistant, refractory or relapsed disease (or upfront?)
Do not transfuse platelets unless there is lifethreatening bleeding

42. HEMOPHILIA
Inherited deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B)
Sex-linked inheritance; almost all patients male
Most bleeding into joints, muscles; mucosal and CNS bleeding uncommon
Severity inversely proportional to factor level:
< 1%: severe, bleeding after minimal injury
1-5%: moderate, bleeding after mild injury
> 5%: mild, bleeding after significant trauma or surgery (may not be diagnosed until adulthood)

43. HEMOPHILIA Treatment of bleeding episodes
Unexplained pain in a hemophilia should be considered due to bleeding unless proven otherwise
External signs of bleeding may be absent
Treatment: factor replacement, pain control
Most adult patients self-administer factor
Test for inhibitor (antibody vs factor) if unexpectedly low response to factor replacement
Most inhibitors occur in children

44. TREATMENT OF BLEEDS IN HEMOPHILIA
Administer appropriate clotting factor concentrate
20-40 U/kg for minor bleeds, repeat daily for 2-3 days
40-50 U/kg for major bleeds, repeat daily for 4-7 days
50 U/kg q 12 hours for life-threatening bleeds
1 U/kg should increase plasma level of factor by about 2%
Initial dose higher with factor IX concentrate (greater volume of distribution, but longer half-life)

45. TREATMENT OF HEMOPHILIACS WITH INHIBITORS
Call a hematologist
Recombinant factor VIIa
High dose factor VIII (if low titer inhibitor)
Induce tolerance with daily factor infusion ± immunosuppression

46. ACQUIRED FACTOR VIII DEFICIENCY
Autoantibody to factor VIII
Most patients elderly
Extensive soft tissue or mucosal bleeding (different bleeding pattern than inherited hemophilia)
Laboratory: prolonged aPTT with normal INR, platelets
aPTT not corrected by mixing with normal plasma
Factor VIII activity typically < 10%
Bleeding risk not proportional to factor level
Treatment: rVIIa, immunosuppression

47. VON WILLEBRAND DISEASE
Quantitative or qualitative deficiency of von Willebrand factor
Defective platelet adhesion
Low factor VIII (not usually clinically significant)
Dominant inheritance (often positive family hx)
Mucosal bleeding, bruising – usually mild to moderate, rarely emergent except after surgery or trauma
Severe disease may have hemophilia-like symptoms due to low factor VIII

48. VON WILLEBRAND DISEASE
Diagnosis: von Willebrand factor activity most sensitive test
Most patients have abnormal platelet function screen
PTT may be long if factor VIII low enough
Levels <30% cause pathologic bleeding
Treatment:
DDAVP appropriate for most patients but need to demonstrate efficacy
If DDAVP known to be ineffective or patient has not had trial dose, use VWF-containing concentrate (Humate-P or equivalent)

49. TREATMENT OF BLEEDING DISORDERS

51. BLOOD COMPONENT TRANSFUSION TO TREAT OR PREVENT BLEEDING
Platelets:
Active bleeding: if platelet count < 50K
Prophylaxis: when platelets <10-20K
Patient having surgery: if platelets < K
FFP (active bleeding):
When INR ≥ 1.8
Cryoprecipitate (active bleeding):
Goal fibrinogen level 100

52. DDAVP (Desmopressin)
Vasopressin analogue, stimulates VWF/factor VIII release from endothelium
Intravenous or intranasal administration
Increases plasma VWF/factor VIII levels for 18-24h, enhances platelet adhesion
Effective in
Type I VWD (usually not in type 2, never in type 3)
Mild hemophilia A
Platelet dysfunction (variably effective)
HA, flushing, hyponatremia, tachyphylaxis with repeated dosing
Do not give for more than 3 consecutive days

53. Antifibrinolytic drugs
Amicar (IV or PO, requires frequent dosing)
Tranexamic acid (longer half-life)
Uses
Bleeding with evidence of hyperfibrinolysis or low antiplasmin (eg, DIC, liver disease)
Bleeding after thrombolytic drug administration
Prophylaxis in severe thrombocytopenia
GI tract bleeding
Menorrhagia
Prophylaxis after dental extraction in hemophilia
Decrease bleeding after major trauma

54. Recombinant Factor VIIa (rFVIIa)
Augments tissue factor-induced coagulation
FDA approved for treatment of Factor VIII inhibitor w/bleeding
Off-label use is common, efficacy uncertain:
Other coagulation inhibitors (including drugs) w/bleeding
Reversal of coagulopathy (eg, warfarin) in patients with lifethreatening bleeding (not recommended in UWHC guidelines)
Potent procoagulant → risk of thrombosis
Very expensive!

56. Prothrombin complex concentrate (PCC)
Mixture of vitamin K dependent procoagulant factors: II, IX, X ,VII
Used to rapidly correct warfarin effect (or severe vitamin K deficiency) in acutely bleeding patient or prior to urgent surgical procedure
Advantages vs FFP:
Less volume, no TACO risk
No TRALI risk, low risk of allergic rxn

57. VITAMIN K Indications: Oral or IV administration (unreliable
Correction of vitamin K deficiency
Treatment of warfarin or superwarfarin overdose
Prophylaxis in patients at risk for vitamin K deficiency
Oral or IV administration (unreliable
absorption with subcutaneous injection)

58. ANTICOAGULANT-RELATED BLEEDING

59. BLEEDING RISK VS INR Lancet 1996; 348:423 <2 2.0-2.9 3-4.4 4.5-6.9
>7
INR 50
100
150
200
Bleeding events/100 patient-yr
Lancet 1996; 348:423

60. Treatment of warfarin-induced coagulopathy in the absence of major bleeding
INR : Omit 1-2 doses of warfarin, repeat INR
INR > 9.9: Omit 1-2 doses of warfarin, give vit K (phytonadione) 1 – 2.5 mg orally (preferred) or IV

61. Treatment of warfarin-induced coagulopathy with major bleeding
Stop warfarin until bleeding controlled
Give vit K (phytonadione) 5-10 mg IV along with prothrombin complex concentrate

62. Reversal of heparin
Protamine sulfate: 1 mg/100U heparin (base dose on amount of heparin given in past 2 hours)
Neutralizes 80% of heparin
FFP, PCC, vit K won’t help

63. Reversal of LMWH Protamine (neutralizes 40% of LMWH)
If LMWH given in last 8 hours give 1 mg protamine per 100 (max 50 mg) anti-Xa units LMWH
If LMWH given 8-12 hours ago give 0.5 mg protamine per 100 anti-Xa units (max 50 mg)
Longer time frame if renal function impaired
FFP, PCC, vit K won’t help

64. Direct oral anticoagulant drugs: Dabigatran, rivaroxaban, apixaban, edoxaban
Specific antidote (idarucizumab) now available for dabigatran
Andexanet (antidote for Xa inhibitors) awaiting FDA approval
Activated charcoal if drug taken recently
PCC ~ 50 U/kg (rivaroxaban, apixaban, edoxaban)
FFP likely to be ineffective, risk of volume overload, TRALI