Are You Confident of the Diagnosis?
What you should be alert for in the history
Skin findings are usually the trigger for a dermatologic consultation in a patient with suspected disseminated intravascular coagulation (DIC), consumptive coagulopathy, or purpura fulminans. but may precede the clinical recognition of the underlying coagulopathy. The dermatologist should be aware of the settings in which certain forms of purpura may either suggest or support the presence of an underlying coagulopathy.
DIC most often develops as a consequence of sepsis, severe trauma, or other insults leading to extensive tissue injury.
Consumptive coagulopathy is sometimes used to describe the status of a patient with DIC who is no longer able to achieve adequate hemostasis, and is bleeding inappropriately from minimal injury sites, such as venipuncture.
Purpura fulminans is a term with many meanings but is best restricted to one of three settings of widespread cutaneous microvascular occlusion: neonatal severe protein C or protein S deficiency, sepsis-associated DIC, or post-varicella or streptococcal infection with severe protein S dysfunction in children (original use of the term purpura fulminans).
Characteristic findings on physical examination
The cutaneous findings of DIC can include focal vasculitic lesions from septic vasculitis, but lesions resulting from the DIC coagulopathy are either those of simple hemorrhage or of microvascular occlusion. Simple ecchymoses (macular, non-blanching, non-retiform) or oozing are a sign of failure of hemostasis, while digital necrosis, non-inflammatory necrotic lesions, or retiform (branching, stellate) purpura signal microvascular occlusion in the skin (Figure 1, Figure 2).
Expected results of diagnostic studies
DIC is essentially a laboratory diagnosis, with evidence of both clot activation and clot lysis.
Clot activation is most commonly manifested by prolongation of the prothrombin time (PT) and the partial thromboplastin time (PTT), as prothrombotic factors are consumed faster than they can be replaced. Clot lysis is inferred by the presence of elevated fibrin degradation products (FDP, fibrin split products-FSP, or D-dimers). The presence of both pathologic clot activation and clot lysis may result in no clinically evident skin lesions, simple eccymoses or oozing, or retiform purpura from occlusion.
Patients may transition from cutaneous vascular occlusion to simple hemorrhage as clotting factors are consumed, and may transition back if clotting factors are replaced. Therefore, the type of newly developing cutaneous lesion provides an indication of the minute-to-minute coagulation status of the patient.
Biopsy of septic vasculitis should show leukocytoclastic vasculitis with prominent fibrin deposition, and occasionally may show organisms on special stains. Simple ecchymoses correlate with minimal inflammation with perivascular hemorrhage. Retiform purpura correlates with non-inflammatory fibrin vascular occlusion. However, the time needed for processing and interpretation of tissue, especially after hours and on weekends, even if attempted as frozen sections, greatly impairs the usefulness of biopsy in adjusting therapy. This is why the ability to relate the skin morphology to the histologic correlate of purpura is so critical in a time-sensitive clinical setting.
There are multiple diagnoses that must be considered in the setting of a seriously ill patient with newly developing purpuric lesions, including catastrophic antiphospholipid antibody syndrome, severe systemic vasculitis, thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS), Rocky Mountain spotted fever in North America, and various hemorrhagic fevers in other parts of the world and in travelers.
Antiphospholipid antibody syndrome can present in catastrophic form, often triggered by infection. In this syndrome, while the PTT may be prolonged due to lupus anticoagulant activity, the PT is typically normal and there is little laboratory evidence for fibrinolysis, especially at onset. Lesions are usually non-inflammatory retiform purpura morphology.
Systemic vasculitis seldom results in DIC laboratory parameters, unless the patient has developed severe multiorgan dysfunction with widespread tissue injury. Immune complex disease purpura is predominantly classical in morphology (round, 5 to 10mm pupuric papules) and distributed in a dependent fashion, sometimes with interspersed retiform lesions. The PTT may be elevated in lupus patients due to a concommitant lupus anticoagulant, but the PT and fibrin degradation products are normal. More problematic is the occasional patient with Wegener’s granulomatosis or microscopic polyangiitis, who may develop scattered retiform purpura in association with fever and severe multiorgan disease mimicking sepsis. However, the PT, PTT and FDP are typically not elevated, and both syndromes are usually positive for anti-neutrophil cytoplasmic antibodies (ANCA).
Platelet aggregation syndromes occur primarily in one of four settings: myeloproliferative disease with platelet counts near or above a million, heparin necrosis, thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS) syndromes, or HELLP (hemolysis, elevated liver function tests, low platelets syndrome). The first two may cause retiform purpura or digital necrosis, the last two may cause petechial hemorrhage or no skin changes.
In TTP/HUS, the PT and PTT is usually normal, the platelet count is usually 40K or above, there should be a microangiopathic hemolytic anemia (red cell fragmentation), renal disease, and fever, sometimes with central nervous system disease. HELLP syndrome is a pregnancy-associated syndrome usually occurring in the setting of preeclampsia with hypertension, and should be considered in the differential diagnosis of TTP/HUS in pregnant women.
Rocky Mountain spotted fever in early stages may develop erythematous papules or more characteristically widespread petechial hemorrhage, sometimes linear or comma-shaped due to focal rickettsial endotheliitis. If the syndrome is more advanced, extensive endothelial involvement may result in a DIC-like syndrome with retiform purpura and shock. Hemorrhagic fevers seem more likely to induce severe widespread ecchymoses or bleeding, rather than occlusive cutaneous disease.
Purpura fulminans as a term should, in my view, be used for only three clinical settings and confined to patients who develop scattered to widespread lesions or retiform purpura/microvascular occlusion: neonates with severe protein C or protein S deficiency (usually <10% of normal level), septic patients with DIC and severe acquired protein C deficiency or dysfunction (<23% normal at time of purpura development), and children who are post-varicella or post-streptococcal with severe acquired protein S dsyfunction due to antibody inhibitor. This last subset was the group for which the term purpura fulminans was coined over a century ago, and lesions typically develop as the patient is recovering, around 2 weeks after the onset of the triggering infection.
Who is at Risk for Developing this Disease?
DIC can occur at any age, in association with a number of triggering conditions, including sepsis, severe trauma, malignancy, obstetrical complications, severe pancreatitis, Kassabach-Merrit syndrome, aortic aneurysm, acute hepatic failure, snakebite envenomation, recreational drugs, severe tranfusion reactions, and transplant rejection. The clinical scenarios for purpura fulminans are listed in the previous section.
What is the Cause of the Disease?
Etiology–The etiologies are listed previously
Infection and inflammation are closely linked, and infection appears to both upregulate procoagulant pathways and downregulate natural anticoagulant pathways, particularly the thrombomodulin-protein C and S pathway. Clotting activation is multiplied by tissue death and endothelial injury.
Other pathophysiologic pathways depend on the type of injury but may relate to factors released by malignant cells and by tissue-factor release and activation due to extensive tissue injury from the other listed triggers.
Systemic Implications and Complications
These have been outlined in previous sections and vary somewhat with the particular syndrome. Infarctive injury may occur in essentially all potential organs. There are multiple diagnoses that must be considered in the setting of a seriously ill patient with newly developing purpuric lesions, including catastrophic antiphospholipid antibody syndrome, severe systemic vasculitis, TTP/HUS, Rocky Mountain spotted fever in North America, and various hemorrhagic fevers in other parts of the world and in travelers.
The therapeutic choices for all of these disorders, given the severity of illness, will largely be decided and directed by the primary hospital physician caring for the patient. No universally accepted therapy for DIC exists, though factor replacement and use of heparin are often considered. Protein C is believed to have some protective effect from mortality in sepsis, independent of its anticoagulant properties, and is available for use. The main role for the dermatologist is to correctly interpret the significance of cutaneous hemorrhage in these patients, correlating the morphology and distribution of purpura with the most likely histologic correlate.
Optimal Therapeutic Approach for this Disease
As above, the therapeutic approach is directed at correcting or stabilizing the underlying illness leading to the coagulopathy. In the setting of infection with DIC, the development of retiform purpura should be considered as a sign of either catastrophic antiphospholipid antibody syndrome, sepsis-related acquired severe protein C deficiency, or post-infectious acquired severe protein S dysfunction. Antiphospholipid antibodies and beta-2 glycoprotein I antibodies can help in the recognition of the first condition, and isolated elevated PTT with normal PT would favor lupus anticoagulant over DIC.
Sepsis-related DIC with purpura fulminans can be evaluated with a protein C function level drawn while lesions are still developing. A level of 23% or below supports this diagnosis. Post-infectious purpura fulminans with protein S dysfunction may be antiphospholipid antibody positive, but the timing of its onset, and the presence of severe protein S dysfunction/antibody inhibition supports this diagnosis.
Treatment of severe protein C deficiency by infusion of protein C replacement has been shown in neonatal protein C deficiency and should be considered in sepsis-related purpura fulminans, despite the relative contraindication for its use in patients with DIC.
Recognition of the transition from retiform purpura to petechial or ecchymotic hemorrhage is important in suggesting a change in the balance between coagulation and fibrinolysis and should be considered a sign of loss of either platelet activity or critical coagulation factors (especially fibrinogen) to levels below that capable of supporting effective clotting.
Treatment of post-infectious purpura fulminans is difficult, because it depends in part on overcoming the inhibitory action of an anti-protein S antibody, which makes simple replacement therapy difficult because of the amount of protein S needed and the lack of a good protein S concentrate option. Treatments include the use of corticosteroids, intravenous immunoglobulin (to bind pathogenic anti-protein S antibodies), and fresh-frozen plasma, as the best available supplement for free protein S, though these have not been proven.
This will be the responsibility of the primary physician and depend upon the cause of DIC, the therapy chosen, patient response to therapy, and duration and complications of the chosen treatment.
Unusual Clinical Scenarios to Consider in Patient Management
The unconventional component mentioned here is the consideration of protein C replacement in sepsis-related DIC with purpura fulminans (retiform purpura) as an antithrombotic agent rather than a sepsis-mortality protective agent. This is supported by an early abstract and a recent study in neonatal sepsis, but certainly has not been proven in a conventional double-blind placebo-controlled trial.
What is the Evidence?
Levi, M, Seligsohn, U, Kaushansky, K, Lichtman, MA, Beutler, E, Kipps, TJ, Seligsohn, U, Prchal, JT. “Disseminated intravascular coagulation”. Williams hematology. 2010. pp. 2101-20. (Overview of pathophysiology and assessment of DIC.)
Piette, W, Bolognia, JL, Jorizzo, JL, Rapini, RP. “Cutaneous manifestations of microvascular occlusion syndromes”. Dermatology. 2008. pp. 331-45. (Summary of many causes of cutaneous microvascular occlusion syndromes, with morphologic examples.)
Toh, CH, Downey, C. “Back to the future: Testing in disseminated intravascular coagulation”. Blood Coagul Fibrinolysis. vol. 16. 2005. pp. 535-42. (Discussion of best tests for evaluating DIC.)
Gando, S. “Microvascular thrombosis and multiple organ dysfunction syndrome”. Crit Care Med. vol. 38. 2010. pp. S35-S42. (Discussion of physiologic derangements with extensive microvascular thrombosis.)
Silver, RM, Major, H. “Maternal coagulation disorders and postpartum hemorrhage”. Clin Obstet Gynecol. vol. 53. 2010. pp. 252-64. (Review of pregnancy complications that might mimic DIC, including HELLP syndrome.)
Martini, WZ. “Coagulopathy by hypothermia and acidosis: Mechanisms of thrombin generation and fibrinogen availability”. J Trauma Injury, Infection, & Crit Care. vol. 67. 2009. pp. 202-9. (Discussion of some of the many derangements that may contribute to or cause DIC.)
Piette, W, Shasby, DM, Kealey, P, Olson, J. “Retiform purpura is a sign of severe protein C deficiency and risk of progression to purpura fulminans in sepsis and disseminated intravascular coagulation”. Clin Res. vol. 41. 1993. pp. 253A(Evidence for acquired protein C correlation with retiform purpura and microvascular thrombosis.)
Decembrin, L, D’Angelo, A, Manzato, F, Solinas, A, Tumminelli, F, De Silvestri, A. “Protein C concentrate as adjuvant treatment in neonates with sepsis-induced coagulopathy: a pilot study”. Shock. vol. 34. 2010. pp. 341-5. (Recent study suggesting benefit in neonatal septic DIC setting for protein C concentrate.)
Fluri, S, Kaczala, GW, Leibundgut, K, Alberio, L. “Chicken pox is not always benign: postvaricella purpura fulminans requires prompt and aggressive treatment”. Pediatr Emerg Care. vol. 26. 2010. pp. 932-4. (Reviews challenges of treating the inhibitor-related phenomenon.)
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