Heparin


Heparin is a highly acidic, anionic, sulfated mucopolysaccharide obtained from beef lung or beef and porcine intestinal mucosa and is highly antigenic. Heparin is widely used in surgery (cardiopulmonary bypass) and in medicine to treat deep venous thrombosis and pulmonary embolism.
 
Incidence
Heparin associated thrombocytopenia: 1 to 5% of patients receiving unfractioned heparin for at last 5 days.
 
Skin-necrosis: uncommon.
 
Type I manifestations: exceptional.
 
Risk Factors
Female gender and obesity (delayed allergic skin reactions).
 
Clinical manifestations
I Heparin associated thrombocytopenia (HAT).
  • Type I: moderate and transient decline in platelet count, occurring to 2 to 4 days after heparin administration (platelet sequestration?).
     
  • Type II: severe (often < 50000 platelets/ mm3), developing 6 to 12 days after start of heparin therapy and often complicated by venous and arterial thromboembolic events (immunological mechanism).

II Immediate hypersensitivity reactions.

  • Anaphylactic shock
     
  • Bronchospasm
     
  • Urticaria
     
  • Rhinitis, conjunctivitis

III Skin-necrosis.

With or without thrombocytopenia. 5 to 9 days after beginning of the treatment; indurated erythema occurring at the injection sites with subsequent skin-necrosis.
 
IV Delayed allergic skin-reactions.
  • 57 cases described (1996) with unfractioned heparins
     
  • 10 cases described (1996) with low weight molecular heparins
     
  • Infiltrative plaque after deep injection, eczematous lesion after superficial injection; occurring 10 days after initiation of therapy.
Diagnostic methods

I Thrombocytopenia.
 
Heparin-induced platelet activation test (HIPA)
 
Stagnation point flow adhesioaggregometry (SPAA)

These techniques must be performed to confirm the responsibility of heparin in thrombocytopenia (IgG antibodies) and also with the substitutes: low molecular weight heparins or heparinoid before using them.

II Cutaneous reactions.
 
Prick-tests and intradermal skin-tests are sometimes positive in immediate cutaneous reactions (urticaria).
 
Patch-tests are often negative in delayed allergic skin-reactions.
Subcutaneous injection of 0.1 ml, or pure heparin is often the better test. It must be read at 30 minutes, 2 days, 4 days.
 
Skin-biopsies show type III histologic lesions in skin-necrosis and type IV histologic lesions in delayed allergic skin-lesions.
 
Mechanisms
Platelets of patients with peripheral arterial disease are hypersensitive to heparin in vitro and in vivo.
 
Low molecular weight heparins show in vitro and in vivo cross-reactivity with unfractioned heparin, and must only be used after immunological exclusion of cross-reactivity.
 
Sensitization to heparin may occur with other polysulfated glycosaminoglycans.
 
Type I: immediate reactions (urticaria).
 
Type II: thrombocytopenia.
 
Type III: skin-necrosis.
 
Type IV: delayed skin reactions.
 
Reactions to preservatives (chlorocresol, chlorbutanol) were reported in the Seventies.
 
Management
Thrombocytopenia.
 
Immediate discontinuation of heparin.
 
Substitution with low molecular weight heparin or heparinoid (danaparoid sodium), if in vitro aggregation test is negative.
 
Use warfarin or coumadin therapy.
 
Vena cava filters are sometimes useful (pulmonary embolism).
 
Heparin allergy.
 
In a patient with history indicating possible heparin allergy, numerous alternatives exist:
  • use bovine lung heparin, if there is a reaction to porcine gut heparin (one case)
     
  • use low molecular weight heparin or heparinoids (beware of cross-reactivity)
     
  • use thrombin inhibitors: ancrod (thrombin-like enzyme extracted from the venom of Malayan pit viper), argatro ban, hirudin.
     
  • use iloprost in cardiopulmonary by-pass or dialysed patients
     
  • DESENSITIZATION is possible (2 cases reported), and if no other possibilities.
I Intravenous desensitization:
 
D1: 100 IU/1000 ml saline/24 hours.
 
D2: 1000 IU/1000 ml saline/24 hours.
 
D3: 5000 IU /1000 ml saline/24 hours.
 
Then 5000 IU subcutaneously twice daily until surgery.
 
II Subcutaneous and intravenous desensitization:
 
D1: 50 IU S.C
 
After 40 minutes: 250 IU S.C
 
After 40 minutes: 500 IU S.C
 
D2: 500 IU S.C
 
After 40 minutes: 1500 IU S.C
 
After 40 minutes: 3000 IU S.C
 
D3: 500 IU I.V
 
After 40 minutes: 1500 IU I.V
 
After 40 minutes: 3000 IU I.V
 
D4 5000 IU I.V

References

  1. Tholl U, Greinacher A, Overdick K, Anlauf M, "Life-threatening anaphylactic reaction following parathyroidectomy in a dialysis patient with heparin-induced thrombocytopenia", Nephrol. Dial. Transplant., 1997; 12 (12): 2750-5
  2. Smith R.E, Townsend G.E, Berry B.R, Bowen T, "Enoxaparin for unstable angina and ancrod for cardiac surgery following heparin allergy", Ann. Pharmacother., 1996; 30 (5): 476-80
  3. Reininger C.B, Greinacher A, Graf J, Lasser R, Steckmeier B, Schweiberer L, "Platelets of patients with peripheral arterial disease are hypersensitive to heparin", Thromb. Res., 1996; 81 (6): 641-9
  4. Bircher A.J, Itin P.H, Tsakiris D.A, Surber C, "Delayed hypersensitivity to one low-molecular-weight heparin with tolerance of other low-molecular-weight heparins", Br. J. Dermatol., 1995; 132 (3): 461-3
  5. al-Eryani A.Y, al-Momen A.K, Fayed D.F, Allam A.K, "Successful heparin desensitization after heparin-induced anaphylactic shock", Thromb. Res., 1995; 79 (5.6): 523-6
  6. Patriarca G, Rossi M, Schiavino D, Schinco G, Fais G, Varano C, Schiavello R, "Rush desensitization in heparin hypersensitivity: a case report", Allergy., 1994; 49 (4): 292-4

As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.